16

Liver, Biliary Tract, & Pancreas Disorders

Lawrence S. Friedman, MD

JAUNDICE & EVALUATION OF ABNORMAL LIVER BIOCHEMICAL TESTS

 General Considerations

Jaundice (icterus) results from the accumulation of bilirubin—a product of heme metabolism—in body tissues. Hyperbilirubinemia may be due to abnormalities in the formation, transport, metabolism, or excretion of bilirubin. Total serum bilirubin is normally 0.2–1.2 mg/dL (3.42–20.52 mcmol/L) (mean levels are higher in men than women and higher in whites and Hispanics than blacks and correlate with an increased risk of symptomatic gallstone disease and inversely with the risk of stroke, respiratory disease, cardiovascular disease, and mortality, presumably because of an antioxidant effect). Jaundice may not be recognizable until serum bilirubin levels are about 3 mg/dL (51.3 mcmol/L).

Jaundice is caused by predominantly unconjugated or conjugated bilirubin in the serum (Table 16–1). Unconjugated hyperbilirubinemia may result from overproduction of bilirubin because of hemolysis; impaired hepatic uptake of bilirubin due to certain drugs; or impaired conjugation of bilirubin by glucuronide, as in Gilbert syndrome, due to mild decreases in uridine diphosphate (UDP) glucuronyl transferase, or Crigler–Najjar syndrome, caused by moderate decreases or absence of UDP glucuronyl transferase. Hemolysis alone rarely elevates the serum bilirubin level to more than 7 mg/dL (119.7 mcmol/L). Predominantly conjugated hyperbilirubinemia may result from impaired excretion of bilirubin from the liver due to hepatocellular disease, drugs, sepsis, or hereditary hepatocanalicular transport defects (such as Dubin–Johnson syndrome, progressive familial intrahepatic cholestasis syndromes, and some cases of intrahepatic cholestasis of pregnancy) or from extrahepatic biliary obstruction. Features of some hyperbilirubinemic syndromes are summarized in Table 16–2. The term “cholestasis” denotes retention of bile in the liver, and the term “cholestatic jaundice” is often used when conjugated hyperbilirubinemia results from impaired bile flow.

 Clinical Findings

A. Unconjugated Hyperbilirubinemia

Stool and urine color are normal, and there is mild jaundice and indirect (unconjugated) hyperbilirubinemia with no bilirubin in the urine. Splenomegaly occurs in hemolytic disorders except in sickle cell disease.

B. Conjugated Hyperbilirubinemia

1. Hereditary cholestatic syndromes or intrahepatic cholestasis—The patient may be asymptomatic; cholestasis is often accompanied by pruritus, light-colored stools, and jaundice.

2. Hepatocellular disease—Malaise, anorexia, low-grade fever, and right upper quadrant discomfort are frequent. Dark urine, jaundice, and, in women, amenorrhea occur. An enlarged tender liver, vascular spiders, palmar erythema, ascites, gynecomastia, sparse body hair, fetor hepaticus, and asterixis may be present, depending on the cause, severity, and chronicity of liver dysfunction.

C. Biliary Obstruction

There may be right upper quadrant pain, weight loss (suggesting carcinoma), jaundice, dark urine, and light-colored stools. Symptoms and signs may be intermittent if caused by a stone, carcinoma of the ampulla, or cholangiocarcinoma. Pain may be absent early in pancreatic cancer. Occult blood in the stools suggests cancer of the ampulla. Hepatomegaly and a palpable gallbladder (Courvoisier sign) are characteristic, but neither specific nor sensitive, of a pancreatic head tumor. Fever and chills are more common in benign obstruction with associated cholangitis.

 Diagnostic Studies (Tables 16–3, 16–4)

A. Laboratory Findings

Serum alanine and aspartate aminotransferase (ALT and AST) levels decrease with age and correlate with body mass index and mortality from liver disease and inversely with caffeine consumption and possibly serum vitamin D levels. There is controversy about whether an elevated ALT level is associated with mortality from coronary artery disease, cancer, diabetes mellitus, and all causes. Normal reference values for ALT and AST are lower than generally reported when persons with risk factors for fatty liver are excluded. Truncal fat and early-onset paternal obesity are risk factors for increased ALT levels. Levels are mildly elevated in > 25% of persons with untreated celiac disease and in type 1 diabetic patients with so-called glycogenic hepatopathy and often rise transiently in healthy persons who begin taking 4 g of acetaminophen per day or experience rapid weight gain on a fast-food diet. Levels may rise strikingly but transiently in patients with acute biliary obstruction from choledocholithiasis. Nonalcoholic fatty liver disease is by far the most common cause of mildly to moderately elevated aminotransferase levels. Elevated ALT and AST levels, often > 1000 units/L (> 20 mckat/L), are the hallmark of hepatocellular necrosis or inflammation. Elevated alkaline phosphatase levels are seen in cholestasis or infiltrative liver disease (such as tumor, granulomas, or amyloidosis). Isolated alkaline phosphatase elevations of hepatic rather than bone, intestinal, or placental origin are confirmed by concomitant elevation of gamma-glutamyl transpeptidase or 5′-nucleotidase levels. Serum gamma-glutamyl transpeptidase levels appear to correlate with the risk of mortality and disability in the general population. The differential diagnosis of any liver test elevation includes toxicity caused by drugs, herbal remedies, and toxins.

B. Imaging

Demonstration of dilated bile ducts by ultrasonography or CT indicates biliary obstruction (90–95% sensitivity). Ultrasonography, CT, and MRI may also demonstrate hepatomegaly, intrahepatic tumors, and portal hypertension. Use of color Doppler ultrasonography or contrast agents that produce microbubbles increases the sensitivity of transcutaneous ultrasonography for detecting small neoplasms. MRI is the most accurate technique for identifying isolated liver lesions such as hemangiomas, focal nodular hyperplasia, or focal fatty infiltration and for detecting hepatic iron overload. The most sensitive techniques for detection of individual small hepatic metastases in patients eligible for resection are multiphasic helical or multislice CT; CT arterial portography, in which imaging follows intravenous contrast infusion via a catheter placed in the superior mesenteric artery; MRI with use of gadolinium or ferumoxides as contrast agents; and intraoperative ultrasonography. Dynamic gadolinium-enhanced MRI and MRI following administration of superparamagnetic iron oxide show promise in visualizing hepatic fibrosis. Because of its much lower cost, ultrasonography is preferable to CT (~six times more expensive) or MRI (~seven times more expensive) as a screening test. Positron emission tomography (PET) can be used to detect small pancreatic tumors and metastases. Ultrasonography can detect gallstones with a sensitivity of 95%.

Magnetic resonance cholangiopancreatography (MRCP) is a sensitive, noninvasive method of detecting bile duct stones, strictures, and dilatation; however, it is less reliable than endoscopic retrograde cholangiopancreatography (ERCP) for distinguishing malignant from benign strictures. ERCP requires a skilled endoscopist and may be used to demonstrate pancreatic or ampullary causes of jaundice, carry out papillotomy and stone extraction, insert a stent through an obstructing lesion, or facilitate direct cholangiopancreatoscopy. Complications of ERCP include pancreatitis (≤ 5%) and, less commonly, cholangitis, bleeding, or duodenal perforation after papillotomy. Risk factors for post-ERCP pancreatitis include female sex, prior post-ERCP pancreatitis, suspected sphincter of Oddi dysfunction, and a difficult or failed cannulation. Percutaneous transhepatic cholangiography (PTC) is an alternative approach to evaluating the anatomy of the biliary tree. Serious complications of PTC occur in 3% and include fever, bacteremia, bile peritonitis, and intraperitoneal hemorrhage. Endoscopic ultrasonography is the most sensitive test for detecting small lesions of the ampulla or pancreatic head and for detecting portal vein invasion by pancreatic cancer. It is also accurate in detecting or excluding bile duct stones.

C. Liver Biopsy

Percutaneous liver biopsy is the definitive study for determining the cause and histologic severity of hepatocellular dysfunction or infiltrative liver disease. In patients with suspected metastatic disease or a hepatic mass, it is performed under ultrasound or CT guidance. A transjugular route can be used in patients with coagulopathy or ascites. The risk of bleeding after a percutaneous liver biopsy is approximately 0.5% and is increased in persons with a platelet count ≤ 60,000/mcL (60 × 10⁹/mcL). Panels of blood tests (eg, FibroSure) and ultrasound or magnetic resonance elastography to measure liver stiffness are emerging approaches for estimating the stage of liver fibrosis and degree of portal hypertension without the need for liver biopsy.

 When to Refer

Patients with jaundice should be referred for diagnostic procedures.

 When to Admit

Patients with liver failure should be hospitalized.

DISEASES OF THE LIVER

See Chapter 39 for Hepatocellular Carcinoma.

ACUTE HEPATITIS A

 General Considerations

Hepatitis can be caused by viruses, including the five hepatotropic viruses—A, B, C, D, and E—and many drugs and toxic agents; the clinical manifestations may be similar regardless of cause. Hepatitis A virus (HAV) is a 27-nm RNA hepatovirus (in the picornavirus family) that causes epidemics or sporadic cases of hepatitis. The virus is transmitted by the fecal–oral route, and its spread is favored by crowding and poor sanitation. Since introduction of the HAV vaccine in the United States in 1995, the incidence rate of HAV infection has declined from 14 to 1.3 per 100,000 population, with a corresponding decline of 32% in the mortality rate, and international travel has emerged as the leading risk factor, accounting for over 40% of cases, with another 18% of cases attributable to exposure to an international traveler. Common source outbreaks may still result from contaminated water or food, including inadequately cooked shellfish. Outbreaks among people who inject drugs and cases among international adoptees and their contacts also have been reported.

The incubation period averages 30 days. HAV is excreted in feces for up to 2 weeks before clinical illness but rarely after the first week of illness. The mortality rate for hepatitis A is low, and fulminant hepatitis A is uncommon except for rare instances in which it occurs in a patient with concomitant chronic hepatitis C. There is no chronic carrier state. In the United States, about 30% of the population have serologic evidence of previous HAV infection.

 Clinical Findings

A. Symptoms and Signs

Figure 16–1 shows the typical course of acute hepatitis A. Clinical illness is more severe in adults than in children, in whom it is usually asymptomatic. The onset may be abrupt or insidious, with malaise, myalgia, arthralgia, easy fatigability, upper respiratory symptoms, and anorexia. A distaste for smoking, paralleling anorexia, may occur early. Nausea and vomiting are frequent, and diarrhea or constipation may occur. Fever is generally present but is low-grade except in occasional cases in which systemic toxicity may occur. Defervescence and a fall in pulse rate often coincide with the onset of jaundice.

 Figure 16–1. The typical course of acute type A hepatitis. (HAV, hepatitis A virus; anti-HAV, antibody to hepatitis A virus; ALT, alanine aminotransferase.) (Reprinted, with permission, from Koff RS. Acute viral hepatitis. In: Friedman LS, Keeffe EB [editors]. Handbook of Liver Disease, 3rd ed. Philadelphia: Saunders Elsevier, 2012.)

Abdominal pain is usually mild and constant in the right upper quadrant or epigastrium, often aggravated by jarring or exertion, and rarely may be severe enough to simulate cholecystitis.

Jaundice occurs after 5–10 days but may appear at the same time as the initial symptoms. In many patients, jaundice never develops. With the onset of jaundice, prodromal symptoms often worsen, followed by progressive clinical improvement. Stools may be acholic during this phase.

The acute illness usually subsides over 2–3 weeks with complete clinical and laboratory recovery by 9 weeks. In some cases, clinical, biochemical, and serologic recovery may be followed by one or two relapses, but recovery is the rule. A protracted course has been reported to be associated with HLA DRB1*1301. Acute cholecystitis occasionally complicates the course of acute hepatitis A.

Hepatomegaly—rarely marked—is present in over half of cases. Liver tenderness is usually present. Splenomegaly is reported in 15% of patients, and soft, enlarged lymph nodes—especially in the cervical or epitrochlear areas—may occur.

B. Laboratory Findings

The white blood cell count is normal to low, especially in the preicteric phase. Large atypical lymphocytes may occasionally be seen. Mild proteinuria is common, and bilirubinuria often precedes the appearance of jaundice. Strikingly elevated ALT or AST levels occur early, followed by elevations of bilirubin and alkaline phosphatase; in a minority of patients, the latter persist after aminotransferase levels have normalized. Cholestasis is occasionally marked. Antibody to hepatitis A (anti-HAV) appears early in the course of the illness (Figure 16–1). Both IgM and IgG anti-HAV are detectable in serum soon after the onset. Peak titers of IgM anti-HAV occur during the first week of clinical disease and disappear within 3–6 months. Detection of IgM anti-HAV is an excellent test for diagnosing acute hepatitis A but is not recommended for the evaluation of asymptomatic persons with persistently elevated serum aminotransferase levels because false-positive results occur. False-negative results have been described in a patient receiving rituximab for rheumatoid arthritis. Titers of IgG anti-HAV rise after 1 month of the disease and may persist for years. IgG anti-HAV (in the absence of IgM anti-HAV) indicates previous exposure to HAV, noninfectivity, and immunity.

 Differential Diagnosis

The differential diagnosis includes other viruses that cause hepatitis, particularly hepatitis B and C, and diseases such as infectious mononucleosis, cytomegalovirus infection, and herpes simplex virus infection; spirochetal diseases such as leptospirosis and secondary syphilis; brucellosis; rickettsial diseases such as Q fever; drug-induced liver disease; and ischemic hepatitis (shock liver). Occasionally, autoimmune hepatitis (see below) may have an acute onset mimicking acute viral hepatitis. Rarely, metastatic cancer of the liver, lymphoma, or leukemia may present as a hepatitis-like picture.

The prodromal phase of viral hepatitis must be distinguished from other infectious disease such as influenza, upper respiratory infections, and the prodromal stages of the exanthematous diseases. Cholestasis may mimic obstructive jaundice.

 Prevention

Strict isolation of patients is not necessary, but hand washing after bowel movements is required. Unvaccinated persons who are exposed to HAV are advised to receive postexposure prophylaxis with a single dose of HAV vaccine or immune globulin (0.02 mL/kg) as soon as possible. The vaccine is preferred in healthy persons ages 1 year to 40 years, whereas immune globulin is preferred in those who are younger than 1 year or older than 40 years or who are immunocompromised or who have chronic liver disease.

Two effective inactivated hepatitis A vaccines are available in the United States and recommended for persons living in or traveling to endemic areas (including military personnel), patients with chronic liver disease upon diagnosis after prescreening for immunity (although the cost-effectiveness of vaccinating all patients with concomitant chronic hepatitis C has been questioned), persons with clotting-factor disorders who are treated with concentrates, men who have sex with men, animal handlers, illicit drug users, sewage workers, food handlers, close personal contacts of international adoptees, and children and caregivers in day-care centers and institutions. For healthy travelers, a single dose of vaccine at any time before departure can provide adequate protection. Routine vaccination is advised for all children in states with an incidence of hepatitis A at least twice the national average and has been approved by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (CDC) for use in all children between ages 1 and 2 in the United States. HAV vaccine is also effective in the prevention of secondary spread to household contacts of primary cases. The recommended dose for adults is 1 mL (1440 ELISA units) of Havrix (GlaxoSmithKline) or 1 mL (50 units) of Vaqta (Merck) intramuscularly, followed by a booster dose at 6–18 months. A combined hepatitis A and B vaccine (Twinrix, GlaxoSmithKline) is available. HIV infection impairs the response to the HAV vaccine, especially in persons with a CD4 count <200/mcL.

 Treatment

Bed rest is recommended only if symptoms are marked. If nausea and vomiting are pronounced or if oral intake is substantially decreased, intravenous 10% glucose is indicated.

Dietary management consists of palatable meals as tolerated, without overfeeding; breakfast is usually tolerated best. Strenuous physical exertion, alcohol, and hepatotoxic agents should be avoided. Small doses of oxazepam are safe because metabolism is not hepatic; morphine sulfate should be avoided.

Corticosteroids have no benefit in patients with viral hepatitis, including those with fulminant disease.

 Prognosis

In most patients, clinical recovery is generally complete within 3 months. Laboratory evidence of liver dysfunction may persist for a longer period, but most patients recover completely. Hepatitis A does not cause chronic liver disease, although it may persist for up to 1 year, and clinical and biochemical relapses may occur before full recovery. The mortality rate is < 0.6%.

 When to Admit

• Encephalopathy is present.

• INR > 1.6.

• The patient is unable to maintain hydration.

ACUTE HEPATITIS B

 General Considerations

Hepatitis B virus (HBV) is a 42-nm hepadnavirus with a partially double-stranded DNA genome, inner core protein (hepatitis B core antigen, HBcAg), and outer surface coat (hepatitis B surface antigen, HBsAg). There are eight different genotypes (A–H), which may influence the course of infection and responsiveness to antiviral therapy. HBV is usually transmitted by inoculation of infected blood or blood products or by sexual contact and is present in saliva, semen, and vaginal secretions. HBsAg-positive mothers may transmit HBV at delivery; the risk of chronic infection in the infant is as high as 90%.

Since 1990, the incidence of HBV infection in the United States has decreased from 8.5 to 1.5 cases per 100,000 population. The prevalence is 0.27% in persons aged 6 or over. Because of universal vaccination since 1992, exposure to HBV is now very low among persons aged 18 or younger. HBV is prevalent in men who have sex with men and in people who inject drugs (about 7% of HIV-infected persons are coinfected with HBV), but the greatest number of cases result from heterosexual transmission. Other groups at risk include patients and staff at hemodialysis centers, physicians, dentists, nurses, and personnel working in clinical and pathology laboratories and blood banks. Half of all patients with acute hepatitis B in the United States have previously been incarcerated or treated for a sexually transmitted disease. The risk of HBV infection from a blood transfusion in the United States is about 1 in 350,000 units transfused or less.

The incubation period of hepatitis B is 6 weeks to 6 months (average 12–14 weeks). The onset of hepatitis B is more insidious and the aminotransferase levels are higher on average than in HAV infection. Fulminant hepatitis occurs in <1%, with a mortality rate of up to 60%. Following acute hepatitis B, HBV infection persists in 1–2% of immunocompetent adults but in a higher percentage of children and immunocompromised adults. There are as many as 2.2 million persons (including an estimated 1.32 million foreign-born persons from endemic areas) with chronic hepatitis B in the United States. Persons with chronic hepatitis B, particularly when HBV infection is acquired early in life and viral replication persists, are at substantial risk for cirrhosis and hepatocellular carcinoma (up to 25–40%); men are at greater risk than women.

 Clinical Findings

A. Symptoms and Signs

The clinical picture of viral hepatitis is extremely variable, ranging from asymptomatic infection without jaundice to a fulminating disease and death in a few days. Figure 16–2 shows the typical course of HBV infection. The onset may be abrupt or insidious, and the clinical features are similar to those for acute hepatitis A (see earlier). Serum sickness may be seen early in acute hepatitis B. Fever is generally present and is low-grade. Defervescence and a fall in pulse rate often coincide with the onset of jaundice. Infection caused by HBV may be associated with glomerulonephritis and polyarteritis nodosa.

 Figure 16–2. The typical course of acute type B hepatitis. (anti-HBs, antibody to HBsAg; HBeAg, hepatitis Be antigen; anti-HBe, antibody to HBeAg; anti-HBc, antibody to hepatitis B core antigen; ALT, alanine aminotransferase.) (Reprinted, with permission, from Koff RS. Acute viral hepatitis. In: Friedman LS, Keeffe EB [editors]. Handbook of Liver Disease, 3rd ed. Philadelphia: Saunders Elsevier, 2012.)

The acute illness usually subsides over 2–3 weeks with complete clinical and laboratory recovery by 16 weeks. In 5–10% of cases, the course may be more protracted, but < 1% will have a fulminant course. Hepatitis B may become chronic (see below).

B. Laboratory Findings

The laboratory features are similar to those for acute hepatitis A (see earlier), although serum aminotransferase levels are higher on average in acute hepatitis B, and marked cholestasis is not a feature. Marked prolongation of the prothrombin time in severe hepatitis correlates with increased mortality.

There are several antigens and antibodies as well as HBV DNA that relate to HBV infection and that are useful in diagnosis. Interpretation of common serologic patterns is shown in Table 16–5.

1. HBsAg—The appearance of HBsAg in serum is the first evidence of infection, appearing before biochemical evidence of liver disease, and persisting throughout the clinical illness. Persistence of HBsAg more than 6 months after the acute illness signifies chronic hepatitis B.

2. Anti-HBs—Specific antibody to HBsAg (anti-HBs) appears in most individuals after clearance of HBsAg and after successful vaccination against hepatitis B. Disappearance of HBsAg and the appearance of anti-HBs signal recovery from HBV infection, noninfectivity, and immunity.

3. Anti-HBc—IgM anti-HBc appears shortly after HBsAg is detected. (HBcAg alone does not appear in serum.) In the setting of acute hepatitis, IgM anti-HBc indicates a diagnosis of acute hepatitis B, and it fills the serologic gap in rare patients who have cleared HBsAg but do not yet have detectable anti-HBs. IgM anti-HBc can persist for 3–6 months, and sometimes longer. IgM anti-HBc may also reappear during flares of previously inactive chronic hepatitis B (see later). IgG anti-HBc also appears during acute hepatitis B but persists indefinitely, whether the patient recovers (with the appearance of anti-HBs in serum) or chronic hepatitis B develops (with persistence of HBsAg). In asymptomatic blood donors, an isolated anti-HBc with no other positive HBV serologic results may represent a falsely positive result or latent infection in which HBV DNA is detectable in serum only by polymerase chain reaction (PCR) testing.

4. HBeAg—HBeAg is a secretory form of HBcAg that appears in serum during the incubation period shortly after the detection of HBsAg. HBeAg indicates viral replication and infectivity. Persistence of HBeAg beyond 3 months indicates an increased likelihood of chronic hepatitis B. Its disappearance is often followed by the appearance of anti-HBe, generally signifying diminished viral replication and decreased infectivity.

5. HBV DNA—The presence of HBV DNA in serum generally parallels the presence of HBeAg, although HBV DNA is a more sensitive and precise marker of viral replication and infectivity. Very low levels of HBV DNA, detectable only by PCR testing, may persist in serum and liver long after a patient has recovered from acute hepatitis B, but the HBV DNA in serum is bound to IgG and is rarely infectious. In some patients with chronic hepatitis B, HBV DNA is present at high levels without HBeAg in serum because of development of a mutation in the core promoter or precore region of the gene that codes HBcAg; these mutations prevent synthesis of HBeAg in infected hepatocytes. When additional mutations in the core gene are present, the pre-core mutant enhances the severity of HBV infection and increases the risk of cirrhosis (see later).

 Differential Diagnosis

The differential diagnosis includes hepatitis A and the same disorders listed for the differential diagnosis of acute hepatitis A (see earlier). In addition, coinfection with HDV must be considered (see later).

 Prevention

Strict isolation of patients is not necessary. Thorough hand washing by medical staff who may contact contaminated utensils, bedding, or clothing is essential. Medical staff should handle disposable needles carefully and not recap them. Screening of donated blood for HBsAg, anti-HBc, and anti-HCV has reduced the risk of transfusion-associated hepatitis markedly. All pregnant women should undergo testing for HBsAg. HBV-infected persons should practice safer sex. Cesarean section, in combination with immunoprophylaxis of the neonate (see below), reduces the risk of perinatal transmission of HBV infection when the mother’s serum HBV DNA level is ≥ 200,000 international units/mL, although initiation of antiviral therapy of the mother in the third trimester is an alternative approach (see Chronic Hepatitis B & Chronic Hepatitis D). HBV-infected health care workers are not precluded from practicing medicine or dentistry if they follow CDC guidelines.

Hepatitis B immune globulin (HBIG) may be protective—or may attenuate the severity of illness—if given within 7 days after exposure (adult dose is 0.06 mL/kg body weight) followed by initiation of the HBV vaccine series (see below). This approach is currently recommended for persons exposed to HBsAg-contaminated material via mucous membranes or through breaks in the skin and for individuals who have had sexual contact with a person with HBV infection (irrespective of the presence or absence of HBeAg in the source). HBIG is also indicated for newborn infants of HBsAg-positive mothers followed by initiation of the vaccine series (see below).

The CDC recommends HBV vaccination of all infants and children in the United States and all adults who are at risk for hepatitis B (including persons under age 60 with diabetes mellitus) or who request vaccination. Over 90% of recipients of the vaccine mount protective antibody to hepatitis B; immunocompromised persons, including patients receiving dialysis (especially those with diabetes mellitus), respond poorly (see Table 30–7). Reduced response to the vaccine may have a genetic basis in some cases and has also been associated with age over 40 years and celiac disease. The standard regimen for adults is 10–20 mcg (depending on the formulation) repeated again at 1 and 6 months, but alternative schedules have been approved, including accelerated schedules of 0, 1, 2, and 12 months and of 0, 7, and 21 days plus 12 months. For greatest reliability of absorption, the deltoid muscle is the preferred site of innoculation. Vaccine formulations free of the mercury-containing preservative thimerosal are given to infants < 6 months of age. When documentation of seroconversion is considered desirable, postimmunization anti-HBs titers may be checked. Protection appears to be excellent even if the titer wanes—at least for 20 years—and booster reimmunization is not routinely recommended but is advised for immunocompromised persons in whom anti-HBs titers fall below 10 milli-international units/mL. For vaccine nonresponders, three additional vaccine doses may elicit seroprotective anti-HBs levels in 30–50% of persons. Doubling of the standard dose may also be effective. Universal vaccination of neonates in countries endemic for HBV has reduced the incidence of hepatocellular carcinoma.

 Treatment

Treatment of acute hepatitis B is the same as that for acute hepatitis A (see earlier). Encephalopathy or severe coagulopathy indicates acute liver failure, and hospitalization at a liver transplant center is mandatory (see below). Antiviral therapy is generally unnecessary in patients with acute hepatitis B but is usually prescribed in cases of fulminant hepatitis B as well as in spontaneous reactivation of chronic hepatitis B presenting as acute-on-chronic liver failure.

 Prognosis

In most patients, clinical recovery is complete in 3–6 months. Laboratory evidence of liver dysfunction may persist for a longer period, but most patients recover completely. The mortality rate for acute hepatitis B is 0.1–1% but is higher with superimposed hepatitis D (see later).

Chronic hepatitis, characterized by elevated aminotransferase levels for > 6 months, develops in 1–2% of immunocompetent adults with acute hepatitis B but in as many as 90% of infected neonates and infants and a substantial proportion of immunocompromised adults. Ultimately, cirrhosis develops in up to 40% of those with chronic hepatitis B; the risk of cirrhosis is even higher in HBV-infected patients coinfected with hepatitis C or HIV. Patients with cirrhosis are at risk for hepatocellular carcinoma at a rate of 3–5% per year. Even in the absence of cirrhosis, patients with chronic hepatitis B—particularly those with active viral replication—are at increased risk for hepatocellular carcinoma.

 When to Refer

Refer patients with acute hepatitis who require liver biopsy for diagnosis.

 When to Admit

• Encephalopathy is present.

• INR > 1.6.

• The patient is unable to maintain hydration.

ACUTE HEPATITIS C & OTHER CAUSES OF ACUTE VIRAL HEPATITIS

Viruses other than HAV and HBV that can cause hepatitis are hepatitis C virus (HCV), hepatitis D virus (HDV) (delta agent), and hepatitis E virus (HEV) (an enterically transmitted hepatitis seen in epidemic form in Asia, the Middle East, and North Africa). Hepatitis G virus (HGV) rarely, if ever, causes frank hepatitis. A DNA virus designated the TT virus (TTV) has been identified in up to 7.5% of blood donors and found to be transmitted readily by blood transfusions, but an association between this virus and liver disease has not been established. A related virus known as SEN-V has been found in 2% of US blood donors, is transmitted by transfusion, and may account for some cases of transfusion-associated non-ABCDE hepatitis. In immunocompromised and rare immunocompetent persons, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus should be considered in the differential diagnosis of hepatitis. Severe acute respiratory syndrome (SARS) and influenza may be associated with marked serum aminotransferase elevations. Unidentified pathogens account for a small percentage of cases of acute viral hepatitis.

1. Hepatitis C

HCV is a single-stranded RNA virus (hepacivirus) with properties similar to those of flaviviruses. Six major genotypes of HCV have been identified. In the past, HCV was responsible for over 90% of cases of posttransfusion hepatitis, yet only 4% of cases of hepatitis C were attributable to blood transfusions. Over 50% of cases are transmitted by injection drug use, and both reinfection and superinfection of HCV are common in people who actively inject drugs. Body piercing, tattoos, and hemodialysis are risk factors. The risk of sexual and maternal–neonatal transmission is low and may be greatest in a subset of patients with high circulating levels of HCV RNA. Having multiple sexual partners may increase the risk of HCV infection, and HIV coinfection, unprotected receptive anal intercourse with ejaculation, and sex while high on methamphetamine increase the risk of HCV transmission in men who have sex with men. Transmission via breastfeeding has not been documented. An outbreak of hepatitis C in patients with immune deficiencies has occurred in some recipients of intravenous immune globulin. Hospital- and outpatient facility-acquired transmission has occurred via multidose vials of saline used to flush Portacaths; through reuse of disposable syringes (including drug “diversion” by an infected health care worker); through contamination of shared saline, radiopharmaceutical, and sclerosant vials; via inadequately disinfected endoscopy equipment; and between hospitalized patients on a liver unit. In the developing world, unsafe medical practices lead to a substantial number of cases of HCV infection. Covert transmission during bloody fisticuffs has even been reported, and incarceration in prison is a risk factor, with a frequency of 26% in the United States. In many patients, the source of infection is unknown. Coinfection with HCV is found in at least 30% of HIV-infected persons. HIV infection leads to an increased risk of acute liver failure and more rapid progression of chronic hepatitis C to cirrhosis; in addition, HCV increases the hepatotoxicity of highly active antiretroviral therapy. There are about 3.2 million HCV carriers in the United States (and 184 million worldwide) and another 1.3 million previously exposed persons who have cleared the virus. The incidence of new cases of acute, symptomatic hepatitis C declined from 1992 to 2005, but an increase was observed in persons aged 15 to 24 from 2002 to 2006, as a result of injection drug use.

 Clinical Findings

A. Symptoms and Signs

Figure 16–3 shows the typical course of HCV infection. The incubation period for hepatitis C averages 6–7 weeks, and clinical illness is often mild, usually asymptomatic, and characterized by waxing and waning aminotransferase elevations and a high rate (> 80%) of chronic hepatitis. Spontaneous clearance of HCV following acute infection is more common (64%) in persons with the CC genotype of theIL28B gene (which encodes interferon lambda-3 on chromosome 19) than in those with the CT or TT genotype (24% and 6%, respectively). In persons with the CC genotype, jaundice is more likely to develop during the course of acute hepatitis C. Patients with the CC genotype and chronic hepatitis C are more likely to respond to therapy with pegylated interferon (see Chronic Viral Hepatitis, below). Polymorphisms of genes encoding the killer cell immunoglobulin-like receptors (KIR) and their HLA class I ligands (HLA-C1) and near genes for HLA class II are also associated with spontaneous resolution of viremia following HCV exposure. In pregnant patients with chronic hepatitis C, serum aminotransferase levels frequently normalize despite persistence of viremia, only to increase again after delivery.

 Figure 16–3. The typical course of acute and chronic hepatitis C. (ALT, alanine aminotransferase; Anti-HCV, antibody to hepatitis C virus by enzyme immunoassay; HCV RNA [PCR], hepatitis C viral RNA by polymerase chain reaction.)

B. Laboratory Findings

Diagnosis of hepatitis C is based on an enzyme immunoassay (EIA) that detects antibodies to HCV. Anti-HCV is not protective, and in patients with acute or chronic hepatitis, its presence in serum generally signifies that HCV is the cause. Limitations of the EIA include moderate sensitivity (false-negatives) for the diagnosis of acute hepatitis C early in the course and low specificity (false-positives) in some persons with elevated gamma-globulin levels. In these situations, a diagnosis of hepatitis C may be confirmed by using an assay for HCV RNA. Occasional persons are found to have anti-HCV in serum, without HCV RNA in serum, suggesting recovery from HCV infection in the past.

 Complications

HCV is a pathogenetic factor in mixed cryoglobulinemia and membranoproliferative glomerulonephritis and may be related to lichen planus, autoimmune thyroiditis, lymphocytic sialadenitis, idiopathic pulmonary fibrosis, sporadic porphyria cutanea tarda, and monoclonal gammopathies. HCV infection confers a 20–30% increased risk of non-Hodgkin lymphoma. Hepatitis C may induce insulin resistance (which in turn increases the risk of hepatic fibrosis), and the risk of type 2 diabetes mellitus is increased in persons with chronic hepatitis C. Hepatic steatosis is a particular feature of infection with HCV genotype 3 and may also occur in patients infected with other HCV genotypes who have risk factors for fatty liver (see below). On the other hand, chronic HCV infection is associated with a decrease in serum cholesterol and low-density lipoprotein levels.

 Prevention

Testing donated blood for HCV has helped reduce the risk of transfusion-associated hepatitis C from 10% in 1990 to about 1 case per 2 million units in 2011. Birth cohort screening of persons born between 1945 and 1965 (“baby boomers”) for HCV infection has been recommended by the CDC and the US Preventive Services Task Force. HCV-infected persons should practice safe sex, but there is little evidence that HCV is spread easily by sexual contact or perinatally, and no specific preventive measures are recommended for persons in a monogamous relationship or for pregnant women. Vaccination against HAV (after prescreening for prior immunity) and HBV is recommended for patients with chronic hepatitis C, and vaccination against HAV is also recommended for patients with chronic hepatitis B, although the cost-effectiveness of vaccination has been questioned.

 Treatment

Treatment of patients with acute hepatitis C with peginterferon (see later) for 6–24 weeks appreciably decreases the risk of chronic hepatitis. In general, patients infected with HCV genotype 1 require a 24-week course of treatment, but a 12-week course is adequate if HCV RNA is undetectable in serum by 4 weeks. Those infected with genotypes 2, 3, or 4 generally require 8–12 weeks of therapy. Because 20% of patients with acute hepatitis C, particularly those who are symptomatic, clear the virus without such treatment, reserving treatment for patients in whom serum HCV RNA levels fail to clear after 3 months may be advisable. Ribavirin may be added if HCV RNA fails to clear after 3 months of peginterferon, but some authorities recommend using ribavirin with peginterferon from the start of therapy.

 Prognosis

In most patients, clinical recovery is complete in 3–6 months. Laboratory evidence of liver dysfunction may persist for a longer period. The overall mortality rate is < 1%, but the rate is reportedly higher in older people. Fulminant hepatitis C is rare in the United States.

Chronic hepatitis, which progresses very slowly in many cases, develops in as many as 85% of all persons with acute hepatitis C. Ultimately, cirrhosis develops in up to 30% of those with chronic hepatitis C; the risk of cirrhosis is higher in patients coinfected with both HCV and HBV or HIV. Patients with cirrhosis are at risk for hepatocellular carcinoma at a rate of 3–5% per year.

2. Hepatitis D (Delta Agent)

HDV is a defective RNA virus that causes hepatitis only in association with HBV infection and specifically only in the presence of HBsAg; it is cleared when the latter is cleared. Eight major genotypes (I-VIII) have been identified.

HDV may coinfect with HBV or may superinfect a person with chronic hepatitis B, usually by percutaneous exposure. When acute hepatitis D is coincident with acute HBV infection, the infection is generally similar in severity to acute hepatitis B alone. In chronic hepatitis B, superinfection by HDV appears to carry a worse short-term prognosis, often resulting in fulminant hepatitis or severe chronic hepatitis that progresses rapidly to cirrhosis.

In the 1970s and early 1980s, HDV was endemic in some areas, such as the Mediterranean countries (and later in Central and Eastern Europe), where up to 80% of HBV carriers were superinfected with HDV. In the United States, HDV occurred primarily among people who inject drugs. However, new cases of hepatitis D are now infrequent in the United States primarily because of the control of HBV infection, and cases seen today are usually from cohorts infected years ago who survived the initial impact of hepatitis D and now have cirrhosis. These patients are at risk for decompensation and have a threefold increased risk of hepatocellular carcinoma. New cases are primarily seen in immigrants from endemic areas, including Africa, central Asia, Eastern Europe, and the Amazon region of Brazil. More than 15 million people are infected worldwide. The diagnosis of hepatitis D is made by detection of antibody to hepatitis D antigen (anti-HDV) and, where available, hepatitis D antigen (HDAg) or HDV RNA in serum.

3. Hepatitis E

HEV is a 29- to 32-nm RNA hepevirus (in the Hepeviridae family) that is a major cause of acute hepatitis throughout Central and Southeast Asia, the Middle East, and North Africa, where it is responsible for waterborne hepatitis outbreaks. It is uncommon in the United States but should be considered in patients with acute hepatitis after a trip to an endemic area. In rare cases, hepatitis E can be mistaken for drug-induced liver injury. In industrialized countries, it may be spread by swine, and having a pet in the home and consuming organ meats are risk factors. Illness generally is self-limited (no carrier state), but instances of chronic hepatitis with rapid progression to cirrhosis attributed to HEV have been reported in transplant recipients (particularly when tacrolimus rather than cyclosporine is used as the main immunosuppressant) and, rarely, in persons with HIV infection, with preexisting liver disease, or receiving cancer chemotherapy. Preliminary observations suggest that treatment with oral ribavirin may induce sustained clearance of HEV RNA from the serum of such patients. The diagnosis of acute hepatitis E is made most readily by testing for IgM anti-HEV in serum, although available tests may not be reliable. Reported extrahepatic manifestations include arthritis, pancreatitis, and a variety of neurologic complications. In endemic regions, the mortality rate is high (10–20%) in pregnant women and correlates with high levels of HEV RNA in serum and gene mutations that lead to reduced expression of progesterone receptors, and the risk of hepatic decompensation is increased in patients with underlying chronic liver disease. Improved public hygiene reduces the risk of HEV infection in endemic areas. Recombinant vaccines against HEV have shown promise in clinical trials.

ACUTE LIVER FAILURE

 General Considerations

Acute liver failure may be fulminant or subfulminant. Fulminant hepatic failure is characterized by the development of hepatic encephalopathy within 8 weeks after the onset of acute liver disease. Coagulopathy (international normalized ratio [INR] ≥1.5) is invariably present. Subfulminant hepatic failure occurs when these findings appear between 8 weeks and 6 months after the onset of acute liver disease and carries an equally poor prognosis.

An estimated 1600 cases of acute liver failure occur each year in the United States. Acetaminophen toxicity is the most common cause, accounting for at least 45% of cases. Suicide attempts account for 44% of cases of acetaminophen-induced hepatic failure, and unintentional overdoses (“therapeutic misadventures”), which are often a result of a decrease in the threshold toxic dose because of chronic alcohol use or fasting, account for at least 48%. Other causes include idiosyncratic drug reactions (now the second most common cause, with antituberculosis drugs, antiepileptics, and antibiotics implicated most commonly), viral hepatitis, poisonous mushrooms (Amanita phalloides), shock, hyperthermia or hypothermia, Budd–Chiari syndrome, malignancy (most commonly lymphomas), Wilson disease, Reye syndrome, fatty liver of pregnancy and other disorders of fatty acid oxidation, autoimmune hepatitis, parvovirus B19 infection and, rarely, grand mal seizures. The risk of acute liver failure is increased in patients with diabetes mellitus, and outcome is worsened by obesity. Herbal and dietary supplements are thought to be contributory to acute liver failure in a substantial portion of cases, regardless of cause.

Viral hepatitis now accounts for only 12% of all cases of acute liver failure. The decline of viral hepatitis as the principal cause of acute liver failure is due to universal vaccination of infants and children against hepatitis B and the availability of the hepatitis A vaccine. In endemic areas, hepatitis E is an important cause of acute liver failure. Hepatitis C is a rare cause of acute liver failure in the United States, but acute hepatitis A or B superimposed on chronic hepatitis C may cause fulminant hepatitis.

 Clinical Findings

Gastrointestinal symptoms, systemic inflammatory response, renal dysfunction, and hemorrhagic phenomena are common. Adrenal insufficiency and subclinical myocardial injury manifesting as an elevated serum troponin I level often complicate acute liver failure. Jaundice may be absent or minimal early, but laboratory tests show severe hepatocellular damage. In acetaminophen toxicity, serum aminotransferase elevations are often towering (> 5000 units/L), and biomarkers of early detection are under study, including the detection of acetaminophen-protein adducts in serum. In acute liver failure due to microvesicular steatosis (eg, fatty liver of pregnancy), serum aminotransferase elevations may be modest (< 300 units/L). Over 10% of patients have an elevated serum amylase level at least three times the upper limit of normal, often as a result of renal dysfunction. The blood ammonia level is typically elevated and correlates (along with the Model for End-Stage Liver Disease [MELD] score) with the development of encephalopathy and intracranial hypertension. Intracranial hypertension rarely develops when the blood ammonia level is < 75 mcmol/L and is invariable when the level is > 200 mcmol/L. The severity of extrahepatic organ dysfunction (as assessed by the Sequential Organ Failure Assessment, or SOFA) also correlates with the likelihood of intracranial hypertension.

 Treatment

The treatment of acute liver failure is directed toward correcting metabolic abnormalities. These include coagulation defects, electrolyte and acid-base disturbances, advanced chronic kidney disease, hypoglycemia, and encephalopathy. Cerebral edema and sepsis are the leading causes of death. Prophylactic antibiotic therapy decreases the risk of infection, observed in up to 90%, but has no effect on survival and is not routinely recommended. For suspected sepsis, broad coverage is indicated. Despite a high rate of adrenal insufficiency, corticosteroids are of uncertain value. Stress gastropathy prophylaxis with an H₂-receptor blocker or proton pump inhibitor is recommended. Administration of acetylcysteine (140 mg/kg orally followed by 70 mg/kg orally every 4 hours for an additional 17 doses or 150 mg/kg in 5% dextrose intravenously over 15 minutes followed by 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours) is indicated for acetaminophen toxicity up to 72 hours after ingestion. For massive acetaminophen overdoses, treatment with intravenous acetylcysteine may need to be extended in duration until the serum aminotransferase levels are declining and serum acetaminophen levels are undetectable. Treatment with acetylcysteine improves cerebral blood flow and oxygenation as well as transplant-free survival in patients with stage 1 or 2 encephalopathy due to fulminant hepatic failure of any cause. (Acetylcysteine treatment can prolong the prothrombin time, leading to the erroneous assumption that liver failure is worsening; it can also cause nausea, vomiting, and an anaphylactoid reaction [especially in persons with a history of asthma]. It may be detrimental in children with nonacetaminophen acute liver failure.) Penicillin G (300,000 to 1 million units/kg/d) or silibinin (silymarin or milk thistle), which is not licensed in the United States, is administered to patients with mushroom poisoning. Nucleoside analogs are recommended for patients with fulminant hepatitis B (see Chronic Viral Hepatitis), and intravenous acyclovir has shown benefit in those with herpes simplex virus hepatitis. Plasmapheresis combined with D-penicillamine has been used in fulminant Wilson disease. Subclinical seizure activity is common in patients with acute liver failure, but the value of prophylactic phenytoin is uncertain.

Early transfer to a liver transplantation center is essential. The head of the patient’s bed should be elevated to 30 degrees, and patients with stage 3 or 4 encephalopathy should be intubated. Extradural sensors may be placed to monitor intracranial pressure for impending cerebral edema with the goal of maintaining the intracranial pressure below 20 mm Hg and the cerebral perfusion pressure above 70 mm Hg. Recombinant activated factor VII may be administered to reduce the risk of bleeding associated with intracranial pressure monitoring. Lactulose is administered for encephalopathy (see Cirrhosis). Mannitol, 0.5 g/kg, or 100–200 mL of a 20% solution by intravenous infusion over 10 minutes, may decrease cerebral edema but should be used with caution in patients with advanced chronic kidney disease. Intravenously administered hypertonic saline to induce hypernatremia (serum sodium concentration of 145–155 mEq/L [145–155 mmol/L]) also may reduce intracranial hypertension. Hypothermia to a temperature of 32–34°C may reduce intracranial pressure when other measures have failed and may improve survival long enough to permit liver transplantation. The value of hyperventilation and intravenous prostaglandin E₁ is uncertain. A short-acting barbiturate, propofol, or intravenous boluses of indomethacin, 25 mg, is considered for refractory intracranial hypertension. Nonbiologic liver support (eg, molecular adsorbent recirculating system [MARS], an albumin dialysis system), hepatic-assist devices using living hepatocytes, extracorporeal systems, hepatocyte transplantation, and liver xenografts have shown promise experimentally but have not been shown conclusively to reduce mortality in patients with acute liver failure. They may serve as a “bridge” to liver transplantation.

 Prognosis

With earlier recognition of acute liver failure, the frequency of cerebral edema has declined, and overall survival has improved steadily since the 1970s and is now as high as 75%. The mortality rate of fulminant hepatic failure with severe encephalopathy is as high as 80%, except for acetaminophen hepatotoxicity, in which the transplant-free survival is 65% and no more than 8% of patients undergo liver transplantation. For patients with fulminant hepatic failure of other causes, the outlook is poor in patients younger than 10 and older than 40 years of age and in those with an idiosyncratic drug reaction but appears to be improved when acetylcysteine is administered to patients with stage 1 or 2 encephalopathy. Spontaneous recovery is less likely for hepatitis B than for hepatitis A. Polymorphisms of the genes that encode keratins 8 and 18 appear to affect outcomes. Other adverse prognostic factors are a serum bilirubin level > 18 mg/dL (307.8 mcmol/L), INR > 6.5, onset of encephalopathy more than 7 days after the onset of jaundice, and a low factor V level (<20% of normal). For acetaminophen-induced fulminant hepatic failure, indicators of a poor outcome are acidosis (pH < 7.3), INR > 6.5, and azotemia (serum creatinine ≥ 3.4 mg/dL [283.22 mcmol/L]), whereas a rising serum alpha-fetoprotein level predicts a favorable outcome. An elevated blood lactate level (> 3.5 mEq/L or > 3.5 mmol/L), elevated blood ammonia level (> 211 mcg/dL or > 124 mcmol/L), and possibly hyperphosphatemia (> 3.7 mg/dL or 1.2 mmol/L) also predict poor survival. One study has shown that patients with persistent elevation of the arterial ammonia level (≥ 211 mcg/dL or ≥ 122 mcmol/L) for 3 days have greater rates of complications and mortality than those with decreasing ammonia levels. A number of prognostic indices have been proposed: the “BiLE” score, based on the serum bilirubin, serum lactate, and etiology; the Acute Liver Failure Early Dynamic (ALFED) model, based on the arterial ammonia level, serum bilirubin, INR, and hepatic encephalopathy; and the Acute Liver Failure Study Group (ALFSG) index, based on coma grade, INR, serum bilirubin and phosphatase levels, and serum levels of M30, a cleavage product of cytokeratin-18 caspase. Emergency liver transplantation is considered for patients with stage 2 to stage 3 encephalopathy (see Cirrhosis) and is associated with a 70% survival rate at 5 years. For mushroom poisoning, liver transplantation should be considered when the interval between ingestion and the onset of diarrhea is < 8 hours or the INR is ≥ 6.0, even in the absence of encephalopathy. Acute liver failure superimposed on chronic liver disease (acute-on-chronic liver failure) has a poor prognosis when associated with renal dysfunction.

 When to Admit

All patients with acute liver failure should be hospitalized.

CHRONIC VIRAL HEPATITIS

 General Considerations

Chronic hepatitis is defined as chronic necroinflammation of the liver of more than 3–6 months’ duration, demonstrated by persistently elevated serum aminotransferase levels or characteristic histologic findings. In many cases, the diagnosis of chronic hepatitis may be made on initial presentation. The causes of chronic hepatitis include HBV, HCV, and HDV as well as autoimmune hepatitis; alcoholic and nonalcoholic steatohepatitis; certain medications, such as isoniazid and nitrofurantoin; Wilson disease; alpha-1-antiprotease deficiency; and, rarely, celiac disease. Mortality from chronic HBV and HCV infection has been rising in the United States, and HCV has surpassed HIV as a cause of death. Chronic hepatitis is categorized on the basis of etiology; the grade of portal, periportal, and lobular inflammation (minimal, mild, moderate, or severe); and the stage of fibrosis (none, mild, moderate, severe, cirrhosis). In the absence of advanced cirrhosis, patients are often asymptomatic or have mild nonspecific symptoms.

1. Chronic Hepatitis B & Chronic Hepatitis D

 Clinical Findings & Diagnosis

Chronic hepatitis B afflicts 400 million people worldwide (2 billion overall have been infected; endemic areas include Asia and sub-Saharan Africa) and up to 2.2 million (predominantly males) in the United States. It may be noted as a continuum of acute hepatitis B or diagnosed because of repeated detection of HBsAg in serum, often with elevated aminotransferase levels.

Four phases of HBV infection are recognized: immune tolerant phase, immune clearance phase, inactive HBsAg carrier state, and reactivated chronic hepatitis B phase. In the immune tolerant phase,HBeAg and HBV DNA are present in serum, which is indicative of active viral replication, and serum aminotransferase levels are normal, with little necroinflammation in the liver. This phase is common in infants and young children whose immature immune system fails to mount an immune response to HBV. Persons in the immune tolerant phase and those who acquire HBV infection later in life may enter an immune clearance phase, in which aminotransferase levels are elevated and necroinflammation is present in the liver, with a risk of progression to cirrhosis (at a rate of 2–5.5% per year) and of hepatocellular carcinoma (at a rate of > 2% per year in those with cirrhosis); low-level IgM anti-HBc is present in serum in about 70%.

Patients enter the inactive HBsAg carrier state when biochemical improvement follows immune clearance. This improvement coincides with disappearance of HBeAg and reduced HBV DNA levels (< 10⁵ copies/mL, or < 20,000 international units/mL) in serum, appearance of anti-HBe, and integration of the HBV genome into the host genome in infected hepatocytes. Patients in this phase are at a low risk for cirrhosis (if it has not already developed) and hepatocellular carcinoma, and those with persistently normal serum aminotransferase levels infrequently have histologically significant liver disease, especially if the HBsAg level is low.

The reactivated chronic hepatitis B phase may result from infection by a pre-core mutant of HBV or spontaneous mutation of the pre-core or core promoter region of the HBV genome during the course of chronic hepatitis caused by wild-type HBV. So-called HBeAg-negative chronic hepatitis B accounts for < 10% of cases of chronic hepatitis B in the United States, up to 50% in southeast Asia, and up to 90% in Mediterranean countries, reflecting in part differences in the frequencies of HBV genotypes. In reactivated chronic hepatitis B, there is a rise in serum HBV DNA levels and possible progression to cirrhosis (at a rate of 8–10% per year), particularly when additional mutations in the core gene of HBV are present. Risk factors for reactivation include male sex and HBV genotype C. In patients with either HBeAg-positive or HBeAg-negative chronic hepatitis B, the risk of cirrhosis and of hepatocellular carcinoma correlates with the serum HBV DNA level. Other risk factors include advanced age, male sex, alcohol use, cigarette smoking, HBV genotype C, and coinfection with HCV or HDV. HIV coinfection is also associated with an increased frequency of cirrhosis when the CD4 count is low.

Acute hepatitis D infection superimposed on chronic HBV infection may result in severe chronic hepatitis, which may progress rapidly to cirrhosis and may be fatal. Patients with long-standing chronic hepatitis D and B often have inactive cirrhosis and are at risk for decompensation and hepatocellular carcinoma. The diagnosis is confirmed by detection of anti-HDV or HDAg (or HDV RNA) in serum.

 Treatment

Patients with active viral replication (HBeAg and HBV DNA [≥ 10⁵ copies/mL, or ≥ 20,000 international units/mL] in serum and elevated aminotransferase levels) may be treated with a nucleoside or nucleotide analog or with pegylated interferon. Nucleoside and nucleotide analogs are preferred because they are better tolerated and can be taken orally. For patients who are HBeAg-negative, the threshold for treatment is a serum HBV DNA level ≥ 10⁴ copies/mL, or ≥ 2000 international units/mL. If the threshold HBV DNA level for treatment is met but the serum ALT level is normal, treatment may still be considered in patients over age 35–40 if liver biopsy demonstrates a fibrosis stage of 2 of 4 (moderate) or higher. Therapy is aimed at reducing and maintaining the serum HBV DNA level to the lowest possible levels, thereby leading to normalization of the ALT level and histologic improvement. An additional goal in HBeAg-positive patients is seroconversion to anti-HBe, and some responders eventually clear HBsAg. Although nucleoside and nucleotide analogs generally have been discontinued 6–12 months after HBeAg-to-anti-HBe seroconversion, some patients serorevert to HBeAg after discontinuation, have a rise in HBV DNA levels and recurrence of hepatitis activity, and require long-term therapy, which also is required when seroconversion does not occur. All HBeAg-negative patients with chronic hepatitis B also require long-term therapy (see below).

The available nucleoside and nucleotide analogs—entecavir, tenofovir, lamivudine, adefovir, and telbivudine—differ in efficacy and rates of resistance; however, in HBeAg-positive patients, they all achieve an HBeAg-to-anti-HBe seroconversion rate of about 20% at 1 year, with higher rates after more prolonged therapy. The preferred first-line oral agents are entecavir and tenofovir. Entecavir is rarely associated with resistance unless a patient is already resistant to lamivudine. The daily dose is 0.5 mg orally for patients not resistant to lamivudine and 1 mg for patients who previously became resistant to lamivudine. Histologic improvement is observed in 70% of treated patients and suppression of HBV DNA in serum in nearly all patients. Entecavir has been reported to cause lactic acidosis when used in patients with decompensated cirrhosis. Tenofovir is equally effective and is used as a first-line agent or when resistance to a nucleoside analog has developed. Like entecavir, tenofovir has a low rate of resistance when used as initial therapy. Long-term use may lead to an elevated serum creatinine level and reduced serum phosphate level (Fanconi-like syndrome) that is reversible with discontinuation of the drug.

The first available nucleoside analog was lamivudine, 100 mg orally daily. By the end of 1 year of therapy with lamivudine, however, 15–30% of responders experience a relapse (and occasionally frank decompensation) as a result of a mutation in the polymerase gene (the YMDD motif) of HBV DNA that confers resistance to lamivudine. The rate of resistance reaches 70% by 5 years of therapy, and the drug is no longer considered first-line therapy in the United States but may be used in countries in which cost is a deciding factor. Adefovir dipivoxil has activity against wild-type and lamivudine-resistant HBV but is the least potent of the oral antiviral agents for HBV. The standard dose is 10 mg orally once a day for at least 1 year. As with lamivudine, only a small number of patients achieve sustained suppression of HBV replication with adefovir, and long-term suppressive therapy is often required. Resistance to adefovir is less frequent than with lamivudine but is seen in up to 29% of patients treated for 5 years. Patients with underlying kidney dysfunction are at risk for nephrotoxicity from adefovir. Telbivudine, given in a daily dose of 600 mg orally, is more potent than either lamivudine or adefovir. Resistance to this drug may develop, however, particularly in patients who are resistant to lamivudine, and elevated creatine kinase levels are common in patients treated with telbivudine. Other antiviral agents are under study, and strategies using multiple drugs are being investigated.

Nucleoside and nucleotide analogs are well tolerated even in patients with decompensated cirrhosis (for whom the treatment threshold may be an HBV DNA level < 10⁴ copies/mL) and may be effective in patients with rapidly progressive hepatitis B (“fibrosing cholestatic hepatitis”) following organ transplantation. Although therapy with these agents leads to biochemical, virologic, and histologic improvement in patients with HBeAg-negative chronic hepatitis B and baseline HBV DNA levels ≥ 10⁴ copies/mL (≥ 2000 international units/mL), relapse is frequent when therapy is stopped, and long-term treatment is often required. Resistance is most likely to develop to lamivudine and may develop to adefovir and telbivudine, but these drugs are no longer used as first-line agents in the United States. The development of resistance occasionally results in hepatic decompensation. Sequential addition of a second antiviral agent is usually effective after resistance to the first agent has developed. Combined use of peginterferon and a nucleoside or nucleotide analog has not been shown convincingly to have a substantial advantage over the use of either type of drug alone.

Nucleoside analogs are also recommended for inactive HBV carriers prior to the initiation of immunosuppressive therapy (including anti-tumor necrosis factor antibody therapy) or cancer chemotherapy to prevent reactivation. In patients infected with both HBV and HIV, antiretroviral therapy, including two drugs active against both viruses (eg, tenofovir plus lamivudine or emtricitabine), has been recommended when treatment of HIV infection is indicated. Telbivudine and tenofovir are classified as pregnancy category B drugs, and lamivudine, a category C drug, has been shown to be safe in pregnant women with HIV infection. Antiviral therapy, beginning in the third trimester, has been recommended when the mother’s serum HBV DNA level is ≥ 200,000 international units/mL to reduce levels at the time of delivery.

Peginterferon alfa-2a is still an alternative to the oral agents in selected cases. A dose of 180 mcg subcutaneously once weekly for 48 weeks leads to sustained normalization of aminotransferase levels, disappearance of HBeAg and HBV DNA from serum, appearance of anti-HBe, and improved survival in up to 40% of treated patients. A response is most likely in patients with a low baseline HBV DNA level and high aminotransferase levels and is more likely in those who are infected with HBV genotype A than with other genotypes (especially genotype D) and who have certain favorable polymorphisms of the IL28B gene. Moreover, most complete responders eventually clear HBsAg and develop anti-HBs in serum, and are thus cured. Relapses are uncommon in complete responders who seroconvert from HBeAg to anti-HBe. Peginterferon may be considered in order to avoid long-term therapy with an oral agent, as in young women who may want to become pregnant in the future. Patients with HBeAg-negative chronic hepatitis B have a response rate of 60% after 48 weeks of therapy with peginterferon, but the response may not be durable once peginterferon is stopped. A rapid decline in serum HBsAg titers predicts a sustained response and ultimate clearance of HBsAg. The response to peginterferon is poor in patients with HIV coinfection.

Peginterferon alfa-2b (1.5 mcg/kg/wk for 48 weeks) may lead to normalization of serum aminotransferase levels, histologic improvement, and elimination of HDV RNA from serum in 20–50% of patients with chronic hepatitis D, but patients may relapse and tolerance is poor. Nucleoside and nucleotide analogs are not effective in treating chronic hepatitis D.

 Prognosis

The course of chronic hepatitis B is variable. The sequelae of chronic hepatitis secondary to hepatitis B include cirrhosis, liver failure, and hepatocellular carcinoma. The 5-year mortality rate is 0–2% in those without cirrhosis, 14–20% in those with compensated cirrhosis, and 70–86% following decompensation. The risk of cirrhosis and hepatocellular carcinoma correlates with serum HBV DNA levels, and a focus of therapy is to suppress HBV DNA levels below 300 copies/mL (60 international units/mL). HBV genotype C is associated with a higher risk of cirrhosis and hepatocellular carcinoma than other genotypes. Antiviral treatment improves the prognosis in responders, prevents (or leads to regression of) cirrhosis, and decreases the frequency of liver-related complications.

2. Chronic Hepatitis C

 Clinical Findings & Diagnosis

Chronic hepatitis C develops in up to 85% of patients with acute hepatitis C. It is clinically indistinguishable from chronic hepatitis due to other causes and may be the most common. Worldwide, 170 million people are infected with HCV, with 1.8% of the US population infected. Peak prevalence in the United States (about 4%) is in persons born between 1945 and 1964. In approximately 40% of cases, serum aminotransferase levels are persistently normal. The diagnosis is confirmed by detection of anti-HCV by EIA. In rare cases of suspected chronic hepatitis C but a negative EIA, HCV RNA is detected by PCR testing. Progression to cirrhosis occurs in 20% of affected patients after 20 years, with an increased risk in men, those who drink more than 50 g of alcohol daily, and those who acquire HCV infection after age 40 years. The rate of fibrosis progression accelerates after age 50. African Americans have a higher rate of chronic hepatitis C but lower rates of fibrosis progression and response to therapy than whites (see below). Immunosuppressed persons—including patients with hypogammaglobulinemia or HIV infection with a low CD4 count or those receiving immunosuppressants—appear to progress more rapidly to cirrhosis than immunocompetent persons with chronic hepatitis C. Tobacco and cannibis smoking and hepatic steatosis also appear to promote progression of fibrosis, but coffee consumption appears to slow progression. Persons with chronic hepatitis C and persistently normal serum aminotransferase levels usually have mild chronic hepatitis with slow or absent progression to cirrhosis; however, cirrhosis is present in 10% of these patients.

 Treatment

Treatment of chronic hepatitis C is generally considered in patients under age 70 when there is moderate to severe fibrosis on liver biopsy. A liver biopsy may be avoided in persons infected with HCV genotype 1 if the results of a serum FibroSure test suggest absence of fibrosis or, alternatively, presence of cirrhosis. Liver biopsy is often deferred in those infected with HCV genotype 2 or 3, in whom cure rates are invariably high. The introduction of direct-acting and host-targeting antiviral agents is rapidly expanding the therapeutic armamentarium against HCV.

Standard therapy for HCV infection since the late 1990s has been a combination of peginterferon plus ribavirin. Sustained virologic response rates (negative HCV RNA in serum at 24 weeks after completion of therapy) to peginterferon plus ribavirin are 45% in patients with HCV genotype 1 infection and 70–80% in those with genotype 2 or 3 infection. Rates are lower in patients with advanced fibrosis, high levels of viremia, alcohol consumption, HIV coinfection, obesity, insulin resistance, severe steatosis, and vitamin A or D deficiency. Response rates are also lower in in women with early menopause and in Latinos and blacks compared to whites, in part because of a higher rate of HCV genotype 1 among infected black patients and in part because of intrinsic resistance to therapy. Response of genotype 1 infection to peginterferon plus ribavirin is associated most strongly with the CC genotype of the IL28B gene, with sustained response rates as high as 80%, compared to 40% for the CT genotype and 30% for the TT genotype. Caffeinated coffee consumption of more than three cups per day has also been reported to improve virologic response to peginterferon plus ribavirin.

In the past, patients infected with HCV genotype 1 were generally treated for 48 weeks with peginterferon plus ribavirin. If the serum HCV RNA level decreased to ≤ 50 international units/mL by 4 weeks (rapid virologic response), treatment for at least 24 weeks resulted in a sustained virologic response rate of 90%. For those who did not achieve a rapid virologic response but had a serum HCV RNA level ≤ 50 international units/mL by 12 weeks (complete early virologic response), treatment was continued for the full 48 weeks. If serum HCV RNA levels declined by at least 2 logs by 12 weeks (partial early virologic response) and became undetectable by 24 weeks (slow response), treatment might be extended to 72 weeks. If none of the aforementioned targets was reached, particularly a minimum of a partial early virologic response, treatment was discontinued.

Higher rates of response are achieved in persons infected with HCV genotype 1 when one of two first-generation direct-acting antiviral agents—telaprevir and boceprevir, which are NS3/4A serine protease inhibitors approved by the FDA in 2011—is added to peginterferon plus ribavirin. Sustained response rates are as high as 75% for HCV genotype 1 with a standard three-drug regimen. With the addition of one of these two protease inhibitors, the treatment duration for HCV genotype 1 infection can be shortened to as little as 24 weeks, depending on the rapidity of clearance of HCV RNA from serum—so-called response-guided therapy. The definition of clearance of HCV RNA requires use of a sensitive real-time reverse transcriptase-PCR assay to monitor HCV RNA during treatment (the lower limit of quantification should be ≤ 25 international units/mL, and the limit of detection should be 10–15 international units/mL). Detailed stopping rules for both treatments have been developed. Low levels of HCV RNA may persist in the liver, lymphocytes, and macrophages of successfully treated (“cured”) patients, but the significance of this finding is uncertain.

Patients infected with HCV genotype 2 or 3 (without cirrhosis and with low levels of viremia) may be treated for 24 weeks with peginterferon plus ribavirin and require a ribavirin total daily dose of only 800 mg. For the patients who clear the virus within 4 weeks (rapid virologic response), a total treatment duration of only 16 weeks may be sufficient, if the baseline HCV RNA level is ≤ 400,000 international units/mL; however, such a short course is not routinely recommended. For patients with cirrhosis or a high viral level (> 400,000 international units/mL), 48 weeks of treatment and ribavirin dosing based on the patient’s weight (as for HCV genotype 1) may be preferred.

Peginterferon-based therapy may be beneficial in the treatment of cryoglobulinemia associated with chronic hepatitis C; an acute flare of cryoglobulinemia may first require treatment with rituximab, cyclophosphamide plus methylprednisolone, or plasma exchange. “Chronic HCV carriers” with normal serum aminotransferase levels respond just as well to treatment as do patients with elevated aminotransferase levels. Patients with both HCV and HIV infections may benefit from treatment of HCV. Moreover, in persons coinfected with HCV and HIV, long-term liver disease–related mortality increases as HIV infection–related mortality is reduced by highly active antiretroviral therapy.

Treatment with peginterferon-based therapy is costly (up to $86,000 for 48 weeks of therapy with three drugs), and side effects are common and sometimes distressing. Discontinuation rates are as high as 15–30%, and higher in persons over 60 years of age than in younger patients. Sustained response rates decline if < 60% of the cumulative dose is taken. A complete blood count is recommended at week 1 or 2 and week 4 after therapy is started and then monthly thereafter. Peginterferon alfa is contraindicated in pregnant or breast-feeding women and those with decompensated cirrhosis, profound cytopenias, severe psychiatric disorders, autoimmune diseases, or an inability to self-administer or comply with treatment. HCV treatment can be successful in carefully selected people who continue to inject illicit drugs if they are managed by a multidisciplinary team.

Men and women taking ribavirin must practice strict contraception until 6 months after the conclusion of therapy because of teratogenic effects in animals. Ribavirin should be used with caution in persons over 65 years of age and in others in whom hemolysis could pose a risk of angina or stroke.

In patients with severe chronic kidney disease, the doses of peginterferon and ribavirin must be reduced. The dose of ribavirin may be reduced if severe therapy-induced anemia develops, and the dose reduction does not appear to affect the efficacy of three-drug therapy that includes a protease inhibitor. If necessary, erythropoietin (epoetin alfa) and granulocyte colony-stimulating factor (filgrastim) may be used to treat therapy-induced anemia and leukopenia, respectively. Eltrombopag may be considered in patients with a platelet count < 90,000/mcL (< 90 × 10⁹/L) before therapy. Treated patients exhibit a low genetic resistance to both first-generation protease inhibitors, boceprevir and telaprevir; however, both agents are inhibitors of cytochrome P450 3A and the drug transporter P-glycoprotein and thus they interact with many other drugs.

Numerous other antiviral agents with various, often novel, mechanisms of action are under study, and some are becoming commercially available. Emerging agents include other NS3/4A protease inhibitors (eg, asunaprevir, danoprevir, faldaprevir, simeprevir, vaniprevir); NS5A inhibitors (eg, daclatasvir, ledipasvir); polymerase inhibitors (eg, mericitabine, sofosbuvir); virus entry, assembly, and secretion inhibitors; microRNA-122 antisense oligonucleotides (eg, miravirsen); cyclophilin A inhibitors (eg, alisporivir); interferon lambda-3; and therapeutic vaccines. Some new regimens do not require peginterferon. For example, in patients infected with HCV genotype 2 or 3, a non-interferon–based regimen of ribavirin combined with the NS5B polymerase inhibitor, sofosbuvir (approved by the FDA in 2013), has yielded high sustained virologic response rates (redefined as undetectable HCV RNA in serum 12 weeks after completion of therapy). Such rates were at least 93% for patients with genotype 2 after 12 weeks of treatment and nearly 80% for genotype 3 after 24 weeks of treatment. Moreover, in previously untreated HCV genotype 1-infected patients, the combination of peginterferon, ribavirin, and sofosbuvir has resulted in a sustained virologic response rate of 89% when treatment is given for only 12 weeks.

The combination of sofosbuvir and ledipasvir shows particular promise. In addition, two other NS3/4A protease inhibitors–simeprevir (approved by the FDA in 2013) and faldaprevir–have each led to sustained virologic response rates of up to 85% when used once daily in combination with peginterferon plus ribavirin for HCV genotype 1 infection for as little as 12 weeks. However, simeprevir is less effective and not recommended in patients infected with HCV genotype 1a with the Q80K polymorphism of NS3/4A. It is anticipated that combinations of oral direct antiviral agents will ultimately obviate the need for peginterferon, shorten the duration of treatment, lead to higher cure rates, and result in fewer side effects. The most challenging groups of patients to treat with all-oral regimens include those infected with HCV genotype 3, those with nonresponse to prior treatment, and those with cirrhosis.

 Prognosis

Chronic hepatitis C is an indolent, often subclinical disease that may lead to cirrhosis and hepatocellular carcinoma after decades. The overall mortality rate in patients with transfusion-associated hepatitis C may be no different from that of an age-matched control population. Nevertheless, mortality or transplantation rates clearly rise to 5% per year once cirrhosis develops, and mortality from cirrhosis and hepatocellular carcinoma due to hepatitis C is rising. There is some evidence that HCV genotype 1b is associated with a higher risk of hepatocellular carcinoma than other genotypes. Antiviral therapy has a beneficial effect on mortality and quality of life, is cost-effective, appears to retard and even reverse fibrosis, and reduces the risk of decompensated cirrhosis and hepatocellular carcinoma in responders. Even patients who achieve a sustained virologic response remain at an increased risk for mortality compared with the general population. The risk of mortality from drug addiction is higher than that for liver disease in patients with chronic hepatitis C.

 When to Refer

• For liver biopsy.

• For antiviral therapy.

 When to Admit

• For complications of decompensated cirrhosis.

AUTOIMMUNE HEPATITIS

 General Considerations

Although autoimmune hepatitis is usually seen in young women, it can occur in either sex at any age. The incidence and prevalence are estimated to be 8.5 and 107 per million population, respectively. Affected younger persons are often positive for HLA-B8 and HLA-DR3; older patients are often positive for HLA-DR4. The principal susceptibility allele among white Americans and northern Europeans is HLA DRB1*0301; HLA DRB1*0401 is a secondary but independent risk factor.

 Clinical Findings

A. Symptoms and Signs

The onset is usually insidious, but up to 40% of cases present with acute (occasionally fulminant) hepatitis and some cases follow a viral illness (such as hepatitis A, Epstein-Barr infection, or measles) or exposure to a drug or toxin (such as nitrofurantoin, minocycline, or infliximab). Exacerbations may occur postpartum. Amenorrhea may be a presenting feature. Thirty-four percent of patients are asymptomatic. Typically, examination reveals a healthy-appearing young woman with multiple spider angiomas, cutaneous striae, acne, hirsutism, and hepatomegaly. Extrahepatic features include arthritis, Sjögren syndrome, thyroiditis, nephritis, ulcerative colitis, and Coombs-positive hemolytic anemia. Patients with autoimmune hepatitis are at increased risk for cirrhosis, which, in turn, increases the risk of hepatocellular carcinoma (at a rate of about 1% per year).

B. Laboratory Findings

Serum aminotransferase levels may be > 1000 units/L, and the total bilirubin is usually increased. In type I (classic) autoimmune hepatitis, ANA or smooth muscle antibodies (either or both) are usually detected in serum. Serum gamma-globulin levels are typically elevated (up to 5–6 g/dL [0.05–0.06 g/L]); in such patients, the EIA for antibody to HCV may be falsely positive. Other antibodies, including atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) and antibodies to histones and F-actin, may be found. Antibodies to soluble liver antigen (anti-SLA) characterize a variant of type I that is marked by severe disease, a high relapse rate after treatment, and absence of the usual antibodies (ANA and smooth muscle antibodies). Anti-SLA is directed against a transfer RNA complex responsible for incorporating selenocysteine into peptide chains—Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase, or SEPSECS. Type II, seen more often in girls under age 14 in Europe, is characterized by circulating antibodies to liver-kidney microsome type 1 (anti-LKM1)—directed against cytochrome P450 2D6—without anti-smooth muscle antibodies or ANA. In some cases, anti-liver cytosol type 1, directed against formimino-transferase cyclodeaminase, is detected. This type of autoimmune hepatitis can be seen in patients with autoimmune polyglandular syndrome type 1. Concurrent primary biliary cirrhosis or primary sclerosing cholangitis (“overlap syndrome”) has been recognized in 7–13% and 6–11% of patients with autoimmune hepatitis, respectively. Liver biopsy is indicated to help establish the diagnosis (interface hepatitis is the hallmark), evaluate disease severity, and determine the need for treatment.

Simplified diagnostic criteria based on the detection of autoantibodies (1 or 2 points depending on titers, ≥ 1:40 or ≥ 1:80), elevated IgG levels (1 or 2 points depending on levels, ≥ upper limit of normal or ≥ 1.1 upper limit of normal), and characteristic histologic features (1 or 2 points depending on how typical the features are) and exclusion of viral hepatitis (2 points) can be useful for diagnosis; a score of 6 indicates probable and a score of 7 indicates definite autoimmune hepatitis with a high degree of specificity but moderate sensitivity. Diagnostic criteria for an overlap of autoimmune hepatitis and primary biliary cirrhosis (“Paris criteria”) have been proposed.

 Treatment

Prednisone with or without azathioprine improves symptoms; decreases the serum bilirubin, aminotransferase, and gamma-globulin levels; and reduces hepatic inflammation. Symptomatic patients with aminotransferase levels elevated tenfold (or fivefold if the serum globulins are elevated at least twofold) are optimal candidates for therapy, and asymptomatic patients with modest enzyme elevations may be considered for therapy depending on the clinical circumstances and histologic severity; however, asymptomatic patients usually remain asymptomatic, have either mild hepatitis or inactive cirrhosis on liver biopsy specimens, and have a good long-term prognosis without therapy.

Prednisone is given initially in a dose of 30 mg orally daily with azathioprine, 50 mg orally daily, which is generally well tolerated and permits the use of lower corticosteroid doses than a regimen beginning with prednisone 60 mg orally daily alone. Prednisone, 60 mg orally daily, is recommended for patients with acute severe autoimmune hepatitis. Budesonide, 6–9 mg orally daily, may be at least as effective as prednisone in noncirrhotic autoimmune hepatitis and associated with fewer side effects. Whether patients should undergo testing for the genotype or level of thiopurine methyltransferase prior to treatment with azathioprine to predict toxicity is debated. Blood counts are monitored weekly for the first 2 months of therapy and monthly thereafter because of the small risk of bone marrow suppression. The dose of prednisone is lowered from 30 mg/d after 1 week to 20 mg/d and again after 2 or 3 weeks to 15 mg/d. Ultimately, a maintenance dose of 10 mg/d is achieved. While symptomatic improvement is often prompt, biochemical improvement is more gradual, with normalization of serum aminotransferase levels after several months in many cases. Histologic resolution of inflammation lags biochemical remission by 3–8 months, and repeat liver biopsy is recommended after 18 months of treatment. Failure of aminotransferase levels to normalize invariably predicts lack of histologic resolution.

The response rate to therapy with prednisone and azathioprine is 80%. Older patients and those with HLA genotype DRB1*04 are more likely to respond than younger patients and those with HLADRB1*03 hyperbilirubinemia or a high MELD score (≥ 12, see Cirrhosis). Fibrosis may reverse with therapy and rarely progresses after apparent biochemical and histologic remission. Once complete remission is achieved, therapy may be withdrawn, but the subsequent relapse rate is 50–80%. Relapses may again be treated in the same manner as the initial episode, with the same remission rate. After successful treatment of a relapse, the patient may continue taking azathioprine (up to 2 mg/kg) or the lowest dose of prednisone needed to maintain aminotransferase levels as close to normal as possible; another attempt at withdrawing therapy may be considered in patients remaining in remission long term (eg, ≥ 4 years). Prednisone can be used to treat rare flares during pregnancy, and maintenance azathioprine does not have to be discontinued.

Nonresponders to corticosteroids and azathioprine (failure of serum aminotransferase levels to decrease by 50% after 6 months) may be considered for a trial of cyclosporine, tacrolimus, sirolimus, everolimus, methotrexate, rituximab, or infliximab. Mycophenolate mofetil, 1 g twice daily, is an effective alternative to azathioprine in patients who cannot tolerate it but is less effective in nonresponders to azathioprine. Bone density should be monitored—particularly in patients receiving maintenance corticosteroid therapy—and measures undertaken to prevent or treat osteoporosis (see Chapter 26). Liver transplantation may be required for treatment failures and patients with a fulminant presentation, but the outcome may be worse than that for primary biliary cirrhosis because of an increased rate of infectious complications, and the disease has been recognized to recur in up to 40% of transplanted livers (and rarely to develop de novo) as immunosuppression is reduced; sirolimus can be effective in such cases. Overall long-term mortality of patients with autoimmune hepatitis appears to be greater than that of the general population despite response to immunosuppressive therapy. Factors that predict the need for liver transplantation or that predict liver-related death include the following: (1) age ≤ 20 years or > 60 years at presentation, (2) low serum albumin level at diagnosis, and (3) incomplete normalization of the serum ALT level after 6 months of treatment. Histologic severity is not a predictor.

 When to Refer

• For liver biopsy.

• For immunosuppressive therapy.

 When to Admit

• Hepatic encephalopathy.

• INR >1.6.

ALCOHOLIC LIVER DISEASE

 General Considerations

Excessive alcohol intake can lead to fatty liver, hepatitis, and cirrhosis. Alcoholic hepatitis is characterized by acute or chronic inflammation and parenchymal necrosis of the liver induced by alcohol. Alcoholic hepatitis is often a reversible disease but the most common precursor of cirrhosis in the United States. It is associated with four to five times the number of hospitalizations and deaths as hepatitis C, which is the second most common cause of cirrhosis.

The frequency of alcoholic cirrhosis is estimated to be 10–15% among persons who consume over 50 g of alcohol (4 oz of 100-proof whiskey, 15 oz of wine, or four 12-oz cans of beer) daily for over 10 years (although the risk of cirrhosis may be lower for wine than for a comparable intake of beer or spirits). The risk of cirrhosis is lower (5%) in the absence of other cofactors such as chronic viral hepatitis and obesity. Genetic factors, including polymorphisms of the genes encoding palatin-like phospholipase domain-containing protein 3 (PNPLA3), tumor necrosis factor, cytochrome P450 2E1, and glutathione S-transferase may also account for differences in susceptibility to and severity of liver disease. Women appear to be more susceptible than men, in part because of lower gastric mucosal alcohol dehydrogenase levels.

 Clinical Findings

A. Symptoms and Signs

The clinical presentation of alcoholic liver disease can vary from asymptomatic hepatomegaly to a rapidly fatal acute illness or end-stage cirrhosis. A recent period of heavy drinking, complaints of anorexia and nausea, and the demonstration of hepatomegaly and jaundice strongly suggest the diagnosis. Abdominal pain and tenderness, splenomegaly, ascites, fever, and encephalopathy may be present. Infection is common in patients with severe alcoholic hepatitis.

B. Laboratory Findings

In patients with steatosis, mild liver enzyme elevations may be the only laboratory abnormality. Anemia (usually macrocytic) may be present. Leukocytosis with a shift to the left is common in patients with severe alcoholic hepatitis. Leukopenia is occasionally seen and resolves after cessation of drinking. About 10% of patients have thrombocytopenia related to a direct toxic effect of alcohol on megakaryocyte production or to hypersplenism.

AST is usually elevated but infrequently above 300 units/L (6 mckat/L). AST is greater than ALT, usually by a factor of 2 or more. Serum alkaline phosphatase is generally elevated, but seldom more than three times the normal value. Serum bilirubin is increased in 60–90% of patients with alcoholic hepatitis.

Serum bilirubin levels >10 mg/dL (171 mcmol/L) and marked prolongation of the prothrombin time (≥ 6 seconds above control) indicate severe alcoholic hepatitis with a mortality rate as high as 50%. The serum albumin is depressed, and the gamma-globulin level is elevated in 50–75% of individuals, even in the absence of cirrhosis. Increased transferrin saturation, hepatic iron stores, and sideroblastic anemia are found in many alcoholic patients. Folic acid deficiency may coexist.

C. Imaging

Imaging studies can detect moderate to severe hepatic steatosis reliably but not inflammation or fibrosis. Ultrasonography helps exclude biliary obstruction and identifies subclinical ascites. CT with intravenous contrast or MRI may be indicated in selected cases to evaluate patients for collateral vessels, space-occupying lesions of the liver, or concomitant disease of the pancreas.

D. Liver Biopsy

Liver biopsy, if done, demonstrates macrovesicular fat and, in patients with alcoholic hepatitis, polymorphonuclear infiltration with hepatic necrosis, Mallory (or Mallory-Denk) bodies (alcoholic hyaline), and perivenular and perisinusoidal fibrosis. Micronodular cirrhosis may be present as well. The findings are identical to those of nonalcoholic steatohepatitis.

 Differential Diagnosis

Alcoholic hepatitis may be closely mimicked by cholecystitis and cholelithiasis and by drug toxicity. Other causes of hepatitis or chronic liver disease may be excluded by serologic or biochemical testing, imaging studies, or liver biopsy. A formula based on the AST/ALT ratio, body mass index, mean corpuscular volume, and gender has been reported to reliably distinguish alcoholic liver disease from nonalcoholic fatty liver disease (NAFLD).

 Treatment

A. General Measures

Abstinence from alcohol is essential. Naltrexone, acamprosate, or baclofen may be considered in combination with counseling to reduce the likelihood of recidivism. Fatty liver is quickly reversible with abstinence. Every effort should be made to provide sufficient amounts of carbohydrates and calories in anorectic patients to reduce endogenous protein catabolism, promote gluconeogenesis, and prevent hypoglycemia. Nutritional support (40 kcal/kg with 1.5–2 g/kg as protein) improves liver disease, but not necessarily survival, in patients with malnutrition. Use of liquid formulas rich in branched-chain amino acids does not improve survival beyond that achieved with less expensive caloric supplementation. The administration of micronutrients, particularly folic acid, thiamine, and zinc, is indicated, especially when deficiencies are noted; glucose administration increases the thiamine requirement and can precipitate Wernicke–Korsakoff syndrome if thiamine is not coadministered.

B. Pharmacologic Measures

Methylprednisolone, 32 mg/d orally, or the equivalent, for 1 month, may reduce short-term mortality in patients with alcoholic hepatitis and either encephalopathy or a Maddrey discriminant function index (defined by the patient’s prothrombin time minus the control prothrombin time times 4.6 plus the total bilirubin in mg/dL) of ≥ 32. No benefit has been demonstrated in patients with concomitant gastrointestinal bleeding, but infection should not preclude treatment with corticosteroids if otherwise indicated.

Pentoxifylline, 400 mg orally three times daily for 4 weeks, may reduce 1-month mortality rates in patients with severe alcoholic hepatitis, primarily by decreasing the risk of hepatorenal syndrome. It is often used when corticosteroids are contraindicated. The addition of pentoxifylline to prednisolone, however, has been shown in one study not to improve survival or reduce the frequency of hepatorenal syndrome compared with prednisolone alone. The combination of corticosteroids and N-acetylcysteine has been reported to improve 1-month but not 6-month survival and reduce the risk of hepatorenal syndrome and infections.

 Prognosis

A. Short-Term

The overall mortality rate is 34% (20% within 1 month) without corticosteroid therapy. Individuals in whom the prothrombin time prohibits liver biopsy have a 42% mortality rate at 1 year. Other unfavorable prognostic factors are older age, a serum bilirubin >10 mg/dL (171 mcmol/L), hepatic encephalopathy, coagulopathy, azotemia, leukocytosis, sepsis and other infections, lack of response to corticosteroid therapy, and possibly a paucity of steatosis on a liver biopsy specimen and reversal of portal blood flow by Doppler ultrasonography. Failure of the serum bilirubin level to decline after 7 days of treatment with corticosteroids predicts nonresponse and poor long-term survival, as does the Lille model (which includes age, serum creatinine, serum albumin, prothrombin time [or INR], serum bilirubin on admission, and serum bilirubin on day 7). The MELD score used for cirrhosis (see Cirrhosis) and the Glasgow alcoholic hepatitis score (based on age, white blood cell count, blood urea nitrogen, prothrombin time ratio, and bilirubin level) also correlate with mortality from alcoholic hepatitis and have higher specificities than the discriminant function and Lille score. A scoring system based on age, serum bilirubin, INR, and serum creatinine (ABIC) has been proposed, and one study has shown that the development of acute kidney injury is the most accurate predictor of 90-day mortality.

B. Long-Term

Overall mortality from alcoholic liver disease has declined slightly in the United States since 1980. Nevertheless, the 3-year mortality rate of persons who recover from acute alcoholic hepatitis is ten times greater than that of control individuals of comparable age; the 5-year mortality rate is as high as 85%. Histologically, severe disease is associated with continued excessive mortality rates after 3 years, whereas the death rate is not increased after the same period in those whose liver biopsies show only mild alcoholic hepatitis. Complications of portal hypertension (ascites, variceal bleeding, hepatorenal syndrome), coagulopathy, and severe jaundice following recovery from acute alcoholic hepatitis also suggest a poor long-term prognosis. Alcoholic cirrhosis is a risk factor for hepatocellular carcinoma, and the risk is highest in carriers of the C282Y mutation for hemochromatosis or those with increased hepatic iron.

The most important prognostic consideration is continued excessive drinking. A 6-month period of abstinence is generally required before liver transplantation is considered, although this requirement has been questioned and early liver transplantation has been performed in selected patients with alcoholic hepatitis, with good outcomes. Optimal candidates have adequate social support, do not smoke, have no psychosis or personality disorder, are adherent to therapy, and have regular appointments with a psychiatrist or psychologist who specializes in addiction treatment. Patients with alcoholic liver disease are at higher risk for posttransplant malignancy than those with other types of liver disease because of alcohol and tobacco use.

 When to Refer

Refer patients with alcoholic hepatitis who require liver biopsy for diagnosis.

 When to Admit

• Hepatic encephalopathy.

• INR > 1.6.

• Total bilirubin ≥10 mg/dL.

• Inability to maintain hydration.

DRUG- & TOXIN-INDUCED LIVER DISEASE

 General Considerations

Many therapeutic agents may cause drug-induced liver injury. The medications most commonly implicated are nonsteroidal anti-inflammatory drugs and antibiotics because of their widespread use. In any patient with liver disease, the clinician must inquire carefully about the use of potentially hepatotoxic drugs or exposure to hepatotoxins, including over-the-counter “natural” and herbal products. In some cases, coadministration of a second agent may increase the toxicity of the first (eg, isoniazid and rifampin, acetaminophen and alcohol). A relationship between increased serum ALT levels in premarketing clinical trials and postmarketing reports of hepatotoxicity has been identified. Except for drugs used to treat tuberculosis and HIV infection, the risk of hepatotoxicity is not increased in patients with preexisting cirrhosis. Drug toxicity may be categorized on the basis of pathogenesis or predominant histologic appearance. Drug-induced liver injury can mimic viral hepatitis, biliary tract obstruction, or other types of liver disease. A useful resource is the website, www.livertox.nih.gov/.

 Categorization by Pathogenesis

A. Direct Hepatotoxicity

Liver toxicity caused by this group of drugs is characterized by: (1) dose-related severity, (2) a latent period following exposure, and (3) susceptibility in all individuals. Examples include acetaminophen (toxicity is enhanced by fasting and chronic alcohol use because of depletion of glutathione and induction of cytochrome P450 2E1 and possibly reduced by statins, fibrates, and nonsteroidal anti-inflammatory drugs), alcohol, carbon tetrachloride, chloroform, heavy metals, mercaptopurine, niacin, plant alkaloids, phosphorus, pyrazinamide, tetracyclines, tipranavir, valproic acid, and vitamin A. Statins, like all cholesterol-lowering agents, may cause serum aminotransferase elevations but rarely cause true hepatitis, and even more rarely cause acute liver failure, and are no longer considered contraindicated in patients with liver disease.

B. Idiosyncratic Reactions

Except for acetaminophen, most severe hepatotoxicity is idiosyncratic. Reactions of this type are (1) sporadic, (2) not related to dose above a general threshold of 100 mg/d, and (3) occasionally associated with features suggesting an allergic reaction, such as fever and eosinophilia, which may be associated with a favorable outcome. In many instances, the drug is lipophilic, and toxicity results directly from a metabolite that is produced only in certain individuals on a genetic basis. Drug-induced liver injury may be observed only during post-marketing surveillance and not during preclinical trials. Examples include abacavir, amiodarone, aspirin, carbamazepine, chloramphenicol, diclofenac, disulfiram, duloxetine, ezetimibe, flavocoxid (a “medical food”), fluoroquinolones (moxifloxacin and levofloxacin, in particular), flutamide, halothane, isoniazid, ketoconazole, lamotrigine, methyldopa, natalizumab, nevirapine, oxacillin, phenytoin, pyrazinamide, quinidine, streptomycin, thiazolidinediones, tolvaptan, and perhaps tacrine.

 Categorization by Histopathology

A. Cholestasis

1. Noninflammatory—Drug-induced cholestasis results from inhibition or genetic deficiency of various hepatobiliary transporter systems. The following drugs cause cholestasis: anabolic steroids containing an alkyl or ethinyl group at carbon 17, azathioprine, cetirizine, cyclosporine, diclofenac, estrogens, indinavir (increased risk of indirect hyperbilirubinemia in patients with Gilbert syndrome), mercaptopurine, methyltestosterone, tamoxifen, temozolomide, and ticlopidine.

2. Inflammatory—The following drugs cause inflammation of portal areas with bile duct injury (cholangitis), often with allergic features such as eosinophilia: amoxicillin-clavulanic acid (among the most common causes of drug-induced liver injury), azathioprine, azithromycin, captopril, celecoxib, cephalosporins, chlorothiazide, chlorpromazine, chlorpropamide, erythromycin, mercaptopurine, penicillamine, prochlorperazine, semisynthetic penicillins (eg, cloxacillin), and sulfadiazine. Ketamine abuse may cause secondary biliary cirrhosis. Cholestatic and mixed cholestatic hepatocellular toxicity is more likely than pure hepatocellular toxicity to lead to chronic liver disease.

B. Acute or Chronic Hepatitis

Medications that may result in acute or chronic hepatitis that is histologically and in some cases clinically similar to autoimmune hepatitis include minocycline and nitrofurantoin, most commonly, as well as aspirin, isoniazid (increased risk in HBV and HCV carriers), methyldopa, nonsteroidal anti-inflammatory drugs, propylthiouracil, terbinafine, and tumor necrosis factor inhibitors. Histologic features that favor a drug cause include portal tract neutrophils and hepatocellular cholestasis. Hepatitis also can occur in patients taking cocaine, diclofenac, methylenedioxymethamphetamine (MDMA; Ecstasy), efavirenz, imatinib mesylate, ipilimumab, nafazodone (has a black box warning for a potential to cause liver failure), nevirapine (like other protease inhibitors, increased risk in HBV and HCV carriers), pioglitazone, ritonavir (greater rate than other protease inhibitors), rosiglitazone, saquinavir, sulfonamides, telithromycin, and zafirlukast, as well as a variety of alternative remedies (eg, chaparral, germander, green tea extracts, Herbalife products, hydroxycut, jin bu huan, kava, skullcap, and possibly black cohosh), as well as dietary supplements (eg, OxyELITE Pro). In patients with jaundice due to drug-induced hepatitis, the mortality rate without liver transplantation is at least 10%.

C. Other Reactions

1. Fatty liver

A. MACROVESICULAR—This type of liver injury may be produced by alcohol, amiodarone, corticosteroids, methotrexate, irinotecan, tamoxifen, vinyl chloride (in exposed workers), zalcitabine, and possibly oxaliplatin.

B. MICROVESICULAR—Often resulting from mitochondrial injury, this condition is associated with didanosine, stavudine, tetracyclines, valproic acid, and zidovudine.

2. Granulomas—Allopurinol, quinidine, quinine, phenylbutazone, phenytoin, and pyrazinamide can lead to granulomas.

3. Fibrosis and cirrhosis—Methotrexate and vitamin A are associated with fibrosis and cirrhosis.

4. Sinusoidal obstruction syndrome (veno-occlusive disease)—This disorder may result from treatment with antineoplastic agents (eg, pre-bone marrow transplant, oxaliplatin), and pyrrolizidine alkaloids (eg, Comfrey).

5. Peliosis hepatis (blood-filled cavities)—Peliosis hepatis may be caused by anabolic steroids and oral contraceptive steroids as well as azathioprine and mercaptopurine, which may also cause nodular regenerative hyperplasia.

6. Neoplasms—Neoplasms may result from therapy with oral contraceptive steroids, including estrogens (hepatic adenoma but not focal nodular hyperplasia), and vinyl chloride (angiosarcoma).

 When to Refer

Refer patients with drug- and toxin-induced hepatitis who require liver biopsy for diagnosis.

 When to Admit

Patients with liver failure should be hospitalized.

NONALCOHOLIC FATTY LIVER DISEASE

 General Considerations

Nonalcoholic fatty liver disease (NAFLD) is estimated to affect 20–45% of the US population. The principal causes of NAFLD are obesity (present in ≥ 40%), diabetes mellitus (in ≥ 20%), and hypertriglyceridemia (in ≥ 20%) in association with insulin resistance as part of the metabolic syndrome. The risk of NAFLD in persons with metabolic syndrome is 4 to 11 times higher than that of persons without insulin resistance. Other causes of fatty liver include corticosteroids, amiodarone, diltiazem, tamoxifen, irinotecan, oxaliplatin, highly active antiretroviral therapy, toxins (vinyl chloride, carbon tetrachloride, yellow phosphorus), endocrinopathies such as Cushing syndrome and hypopituitarism, polycystic ovary syndrome, hypothyroidism, hypobetalipoproteinemia and other metabolic disorders, obstructive sleep apnea (with chronic intermittent hypoxia), excessive dietary fructose consumption, starvation and refeeding syndrome, and total parenteral nutrition. Genetic factors are likely to play a role, and polymorphisms of the patatin-like phospholipase domain containing 3 (PNPLA3) gene modify the natural history of NAFLD and may account in part for an increased risk in Hispanics. The risk of NAFLD is increased in persons with psoriasis and appears to correlate with the activity of psoriasis. Soft drink consumption and cholecystectomy have been reported to be associated with NAFLD. Physical activity protects against the development of NAFLD. In addition to macrovesicular steatosis, histologic features may include focal infiltration by polymorphonuclear neutrophils and Mallory hyalin, a picture indistinguishable from that of alcoholic hepatitis and referred to as nonalcoholic steatohepatitis (NASH), which affects 3–5% of the US population. In patients with NAFLD, older age, obesity, and diabetes mellitus are risk factors for advanced hepatic fibrosis and cirrhosis, whereas coffee consumption appears to reduce the risk. Cirrhosis caused by NASH appears to be uncommon in African Americans.

Microvesicular steatosis is seen with Reye syndrome, didanosine or stavudine toxicity, valproic acid toxicity, high-dose tetracycline, or acute fatty liver of pregnancy and may result in fulminant hepatic failure. Women in whom fatty liver of pregnancy develops often have a defect in fatty acid oxidation due to reduced long-chain 3-hydroxyacyl-CoA dehydrogenase activity.

 Clinical Findings

A. Symptoms and Signs

Most patients with NAFLD are asymptomatic or have mild right upper quadrant discomfort. Hepatomegaly is present in up to 75% of patients, but stigmata of chronic liver disease are uncommon. Rare instances of subacute liver failure caused by previously unrecognized NASH have been described. Signs of portal hypertension generally signify advanced liver fibrosis or cirrhosis but occasionally occur in patients with mild and no fibrosis and severe steatosis.

B. Laboratory Findings

Laboratory studies may show mildly elevated aminotransferase and alkaline phosphatase levels; however, laboratory values may be normal in up to 80% of persons with hepatic steatosis. In contrast to alcoholic liver disease, the ratio of ALT to AST is almost always >1 in NAFLD, but it decreases to < 1 as advanced fibrosis and cirrhosis develop. Antinuclear or smooth muscle antibodies and an elevated serum ferritin level may each be detected in one-fourth of patients with NASH. Elevated serum ferritin levels may signify so-called dysmetabolic iron overload syndrome and mildly increased body iron stores, which may play a causal role in insulin resistance and oxidative stress in hepatocytes and correlate with advanced fibrosis; the frequency of mutations in the HFE gene for hemochromatosis is not increased in patients with NAFLD.

C. Imaging

Macrovascular steatosis may be demonstrated on ultrasonography, CT, or MRI. However, imaging does not distinguish steatosis from steatohepatitis or detect fibrosis.

D. Liver Biopsy

Percutaneous liver biopsy is diagnostic and is the standard approach to assessing the degree of inflammation and fibrosis. The risks of the procedure must be balanced against the impact of the added information on management decisions and assessment of prognosis. Liver biopsy is generally not recommended in asymptomatic persons with unsuspected hepatic steatosis detected on imaging but normal liver biochemistry test results. The histologic spectrum of NAFLD includes fatty liver, isolated portal fibrosis, steatohepatitis, and cirrhosis. A risk score for predicting advanced fibrosis, known as BARD, is based on body mass index >28, AST/ALT ratio ≥ 0.8, and diabetes mellitus; it has a 96% negative predictive value (ie, a low score reliably excludes advanced fibrosis). Another risk score for advanced fibrosis, the NAFLD Fibrosis Score (http://nafldscore.com) based on age, hyperglycemia, body mass index, platelet count, albumin, and AST/ALT ratio, has a positive predictive value of over 80% and identifies patients at increased risk of liver-related complications and death. A clinical scoring system to predict the likelihood of NASH in morbidly obese persons includes six predictive factors: hypertension, type 2 diabetes mellitus, sleep apnea, AST > 27 units/L (0.54 mckat/L), ALT > 27 units/L (0.54 mckat/L), and non-black race.

 Treatment

Treatment consists of lifestyle changes to remove or modify the offending factors. Weight loss, dietary fat restriction, and exercise (through reduction of abdominal obesity) often lead to improvement in liver biochemical tests and steatosis in obese patients with NAFLD. Loss of 3–5% of body weight appears necessary to improve steatosis, but loss of up to 10% may be needed to improve necroinflammation. Exercise may reduce liver fat with minimal or no weight loss and no reduction in ALT levels. Resistance training and aerobic exercise are equally effective in reducing hepatic fat content in patients with NAFLD and type 2 diabetes mellitus. Various drugs are under study. Thiazolidinediones reverse insulin resistance and, in most relevant studies, have improved both serum aminotransferase levels and histologic features of steatohepatitis but lead to weight gain. Vitamin E 800 international units/d (to reduce oxidative stress) also appears to be of benefit. Metformin, which reduces insulin resistance, improves abnormal liver chemistries but may not reliably improve liver histology. Pentoxifylline improves liver biochemical test levels but is associated with a high rate of side effects, particularly nausea. Ursodeoxycholic acid, 12–15 mg/kg/d, has not consistently resulted in biochemical and histologic improvement in patients with NASH but may be effective when given in combination with vitamin E. Hepatic steatosis due to total parenteral nutrition may be ameliorated—and perhaps prevented—with supplemental choline. Statins are not contraindicated in persons with NAFLD. Gastric bypass may be considered in patients with a body mass index > 35 and leads to improvement in hepatic steatosis. Liver transplantation is indicated in appropriate candidates with advanced cirrhosis caused by NASH, now the third most common indication for liver transplantation in the United States.

 Prognosis

Fatty liver often has a benign course and is readily reversible with discontinuation of alcohol (or no more than one glass of wine per day, which may actually reduce the frequency of NASH in persons with NAFLD), or treatment of other underlying conditions; if untreated, cirrhosis develops in 1–3% of patients. In patients with NAFLD, the likelihood of NASH is increased by the following factors: obesity, older age, non–African American ethnicity, female sex, diabetes mellitus, hypertension, higher ALT or AST level, higher AST/ALT ratio, low platelet count, elevated fasting C-peptide level, and an ultrasound steatosis score. NASH may be associated with hepatic fibrosis in 40% of cases; cirrhosis develops in 9–25%; and decompensated cirrhosis occurs in 30–50% of cirrhotic patients over 10 years. The course may be more aggressive in diabetic persons than in nondiabetic persons. Mortality is increased in patients with NAFLD and is more likely to be the result of malignancy and ischemic heart disease than liver disease. Risk factors for mortality are older age, male gender, white race, higher body mass index, hypertension, diabetes mellitus, and cirrhosis. Steatosis is a cofactor for the progression of fibrosis in patients with other causes of chronic liver disease, such as hepatitis C. Hepatocellular carcinoma is a complication of cirrhosis caused by NASH as it is for other causes of cirrhosis. NASH accounts for a substantial percentage of cases labeled as cryptogenic cirrhosis and can recur following liver transplantation. Central obesity is an independent risk factor for death from cirrhosis of any cause.

 When to Refer

Refer patients with non-alcoholic fatty liver disease who require liver biopsy for diagnosis.

CIRRHOSIS

 General Considerations

Cirrhosis, the twelfth leading cause of death in the United States, is the end result of hepatocellular injury that leads to both fibrosis and regenerative nodules throughout the liver. Hospitalization rates for cirrhosis and portal hypertension are rising in the United States. Causes include chronic viral hepatitis, alcohol, drug toxicity, autoimmune and metabolic liver diseases, and miscellaneous disorders. Many patients have more than one risk factor (eg, chronic hepatitis and alcohol use). Mexican Americans and African Americans have a higher frequency of cirrhosis than whites because of a higher rate of risk factors. In persons at increased risk for liver injury (eg, heavy alcohol use, obesity, iron overload), higher coffee and tea consumption has been reported to reduce the risk of cirrhosis. The risk of hospitalization or death due to cirrhosis has been reported to correlate with protein and cholesterol consumption and with hyperuricemia and inversely with carbohydrate consumption.

Clinically, cirrhosis is considered to progress through three stages: compensated, compensated with varices, and decompensated (ascites, variceal bleeding, encephalopathy, or jaundice) that correlate with the thickness of fibrous septa.

 Clinical Findings

A. Symptoms and Signs

The clinical features of cirrhosis result from hepatocyte dysfunction, portosystemic shunting, and portal hypertension. Patients may have no symptoms for long periods. The onset of symptoms may be insidious or, less often, abrupt. Fatigue, disturbed sleep, muscle cramps, and weight loss are common. In advanced cirrhosis, anorexia is usually present and may be extreme, with associated nausea and occasional vomiting, as well as reduced muscle strength and exercise capacity. Abdominal pain may be present and is related either to hepatic enlargement and stretching of Glisson capsule or to the presence of ascites. Menstrual abnormalities (usually amenorrhea), erectile dysfunction, loss of libido, sterility, and gynecomastia in men may occur. Hematemesis is the presenting symptom in 15–25%.

Skin manifestations consist of spider angiomas (invariably on the upper half of the body), palmar erythema (mottled redness of the thenar and hypothenar eminences), and Dupuytren contractures. Evidence of vitamin deficiencies (glossitis and cheilosis) is common. Weight loss, wasting (due to sarcopenia), and the appearance of chronic illness are present. Jaundice—usually not an initial sign—is mild at first, increasing in severity during the later stages of the disease. In 70% of cases, the liver is enlarged, palpable, and firm if not hard and has a sharp or nodular edge; the left lobe may predominate. Splenomegaly is present in 35–50% of cases and is associated with an increased risk of complications of portal hypertension. The superficial veins of the abdomen and thorax are dilated, reflecting the intrahepatic obstruction to portal blood flow, as do rectal varices. The abdominal wall veins fill from below when compressed. Ascites, pleural effusions, peripheral edema, and ecchymoses are late findings. Encephalopathy characterized by day–night reversal, asterixis, tremor, dysarthria, delirium, drowsiness, and ultimately coma also occurs late except when precipitated by an acute hepatocellular insult or an episode of gastrointestinal bleeding or infection. Fever may be a presenting symptom in up to 35% of patients and usually reflects associated alcoholic hepatitis, spontaneous bacterial peritonitis, or intercurrent infection.

B. Laboratory Findings

Laboratory abnormalities are either absent or minimal in early or compensated cirrhosis. Anemia, a frequent finding, is often macrocytic; causes include suppression of erythropoiesis by alcohol as well as folate deficiency, hemolysis, hypersplenism, and occult or overt blood loss from the gastrointestinal tract. The white blood cell count may be low, reflecting hypersplenism, or high, suggesting infection. Thrombocytopenia, the most common cytopenia in cirrhotic patients, is secondary to alcoholic marrow suppression, sepsis, folate deficiency, or splenic sequestration. Prolongation of the prothrombin time may result from reduced levels of clotting factors (except factor VIII). However, bleeding risk correlates poorly with the prothrombin time because of concomitant abnormalities of fibrinolysis, and among hospitalized patients under age 45, cirrhosis is associated with an increased risk of venous thromboembolism.

Blood chemistries reflect hepatocellular injury and dysfunction, manifested by modest elevations of AST and alkaline phosphatase and progressive elevation of the bilirubin. Serum albumin decreases as the disease progresses; gamma-globulin is increased and may be as high as in autoimmune hepatitis. The risk of diabetes mellitus is increased in patients with cirrhosis, particularly when associated with HCV infection, alcoholism, hemochromatosis, or NAFLD. Vitamin D deficiency has been reported in as many as 91% of patients with cirrhosis. Patients with alcoholic cirrhosis may have elevated serum cardiac troponin I and B-type natriuretic peptide (BNP) levels. Blunted cardiac inotropic and chronotropic responses to exercise, stress, and drugs, as well as systolic and diastolic ventricular dysfunction (“cirrhotic cardiomyopathy”) and prolongation of the QT interval in the setting of a hyperkinetic circulation, are common in cirrhosis of all causes, but overt heart failure is rare in the absence of alcoholism. Relative adrenal insufficiency appears to be common in patients with advanced cirrhosis, even in the absence of sepsis, and may relate in part to reduced synthesis of cholesterol and increased levels of proinflammatory cytokines.

C. Imaging

Ultrasonography is helpful for assessing liver size and detecting ascites or hepatic nodules, including small hepatocellular carcinomas. Together with a Doppler study, it may establish patency of the splenic, portal, and hepatic veins. Hepatic nodules are characterized further by contrast-enhanced CT or MRI. Nodules suspicious for malignancy may be biopsied under ultrasound or CT guidance.

D. Liver Biopsy

Liver biopsy may show inactive cirrhosis (fibrosis with regenerative nodules) with no specific features to suggest the underlying cause. Alternatively, there may be additional features of alcoholic liver disease, chronic hepatitis, NASH, or other specific causes of cirrhosis. Liver biopsy may be performed by laparoscopy or, in patients with coagulopathy and ascites, by a transjugular approach. Combinations of routine blood tests (eg, AST, platelet count), including the FibroSure test, and serum markers of hepatic fibrosis (eg, hyaluronic acid, amino-terminal propeptide of type III collagen, tissue inhibitor of matrix metalloproteinase 1) are potential alternatives to liver biopsy for the diagnosis or exclusion of cirrhosis. In persons with chronic hepatitis C, for example, a low FibroSure score reliably excludes advanced fibrosis, a high score reliably predicts advanced fibrosis, and intermediate scores are inconclusive.

E. Other Tests

Esophagogastroduodenoscopy confirms the presence of varices and detects specific causes of bleeding in the esophagus, stomach, and proximal duodenum. In selected cases, wedged hepatic vein pressure measurement may establish the presence and cause of portal hypertension. Ultrasound elastography and magnetic resonance elastography to measure liver stiffness are available in a limited number of centers as noninvasive tests for cirrhosis and portal hypertension.

 Differential Diagnosis

The most common causes of cirrhosis are alcohol, chronic hepatitis C infection, NAFLD, and hepatitis B infection, and the prevalence of NAFLD has been increasing steadily because of the rapidly increasing prevalence of obesity in the United States. Hemochromatosis is the most commonly identified genetic disorder that causes cirrhosis. Other metabolic diseases that may lead to cirrhosis include Wilson disease and alpha-1-antitrypsin (alpha-1-antiprotease) deficiency, and celiac disease has been associated with cirrhosis. Primary biliary cirrhosis occurs more frequently in women than men. Secondary biliary cirrhosis may result from chronic biliary obstruction due to a stone, stricture, or neoplasm. Heart failure and constrictive pericarditis may lead to hepatic fibrosis (“cardiac cirrhosis”) complicated by ascites and may be mistaken for other causes of cirrhosis. Hereditary hemorrhagic telangiectasia can lead to portal hypertension because of portosystemic shunting and nodular transformation of the liver as well as high-output heart failure. Many cases of cirrhosis are “cryptogenic,” in which unrecognized NAFLD may play a role.

 Complications

Upper gastrointestinal tract bleeding may occur from varices, portal hypertensive gastropathy, or gastroduodenal ulcer (see Chapter 15). Varices may also result from portal vein thrombosis, which may complicate cirrhosis. Liver failure may be precipitated by alcoholism, surgery, and infection. Hepatic Kupffer cell (reticuloendothelial) dysfunction and decreased opsonic activity lead to an increased risk of systemic infection (which may be increased further by the use of proton pump inhibitors), and which increase mortality fourfold. These infections include nosocomial infections, which may be classified as spontaneous bloodstream infections, urinary tract infections, pulmonary infections, spontaneous bacterial peritonitis, Clostridium difficile infection, and intervention-related infections. These nosocomial infections are increasingly caused by multidrug-resistant bacteria. Osteoporosis occurs in 12–55% of patients with cirrhosis. The risk of hepatocellular carcinoma is increased greatly in persons with cirrhosis (see Chapter 39).

 Treatment

A. General Measures

The most important principle of treatment is abstinence from alcohol. The diet should be palatable, with adequate calories (25–35 kcal/kg body weight per day in those with compensated cirrhosis and 35–45 kcal/kg/d in those with malnutrition) and protein (1–1.5 g/kg/d in those with compensated cirrhosis and 1.5 g/kg/d in those with malnutrition) and, if there is fluid retention, sodium restriction. In the presence of hepatic encephalopathy, protein intake should be reduced to no less than 60–80 g/d. Specialized supplements containing branched-chain amino acids to prevent or treat hepatic encephalopathy or delay progressive liver failure are generally unnecessary. Vitamin supplementation is desirable. Patients with cirrhosis should receive the HAV, HBV, and pneumococcal vaccines and a yearly influenza vaccine. Liver transplantation in appropriate candidates is curative, and pharmacologic treatments to halt progression of or even reverse cirrhosis are being developed.

B. Treatment of Complications

1. Ascites and edema—Diagnostic paracentesis is indicated for patients who have new ascites or who have been hospitalized for a complication of cirrhosis. Serious complications of paracentesis, including bleeding, infection, or bowel perforation, occur in 1.6% of procedures and are associated with therapeutic (vs diagnostic) paracentesis and possibly with Child-Turcotte-Pugh class C, a platelet count < 50,000/mcL (< 50 × 10⁹/L), and alcoholic cirrhosis. In patients with coagulopathy, however, pre-paracentesis prophylactic transfusions do not appear to be necessary. In addition to a cell count and culture, the ascitic albumin level should be determined: a serum-ascites albumin gradient (serum albumin minus ascitic albumin) ≥ 1.1 suggests portal hypertension. An elevated ascitic adenosine deaminase level is suggestive of tuberculous peritonitis, but the sensitivity of the test is reduced in patients with portal hypertension. Occasionally, cirrhotic ascites is chylous (rich in triglycerides); other causes of chylous ascites are malignancy, tuberculosis, and recent abdominal surgery or trauma.

Ascites in patients with cirrhosis results from portal hypertension (increased hydrostatic pressure); hypoalbuminemia (decreased oncotic pressure); peripheral vasodilation, perhaps mediated by endotoxin-induced release of nitric oxide from splanchnic and systemic vasculature, with resulting increases in renin and angiotensin levels and sodium retention by the kidneys; impaired liver inactivation of aldosterone; and increased aldosterone secretion secondary to increased renin production. In individuals with ascites, the urinary sodium concentration is often < 10 mEq/L (10 mmol/L). Free water excretion is also impaired in cirrhosis, and hyponatremia may develop.

In all patients with cirrhotic ascites, dietary sodium intake may initially be restricted to 2000 mg/d; the intake of sodium may be liberalized slightly after diuresis ensues. Nonsteroidal anti-inflammatory drugs are contraindicated, and angiotensin-converting enzyme inhibitors and angiotensin II antagonists should be avoided. In some patients, ascites diminishes promptly with bed rest and dietary sodium restriction alone. Fluid intake (800–1000 mL/d) is often restricted in patients with hyponatremia. Treatment of severe hyponatremia (serum sodium < 125 mEq/L [125 mmol/L]) with vasopressin receptor antagonists (eg, intravenous conivaptan, 20 mg daily) can be considered but such treatment is expensive, causes thirst, and does not improve survival; oral tolvaptan is contraindicated in patients with liver disease because of potential hepatotoxicity.

A. DIURETICS—Spironolactone, generally in combination with furosemide, should be used in patients who do not respond to salt restriction. An initial trial of furosemide 80 mg intravenously demonstrating a rise in urine sodium to 750 mmol in 8 hours may predict response to diuretic therapy. The dose of spironolactone is initially 100 mg orally daily and may be increased by 100 mg every 3–5 days (up to a maximal conventional daily dose of 400 mg/d, although higher doses have been used) until diuresis is achieved, typically preceded by a rise in the urinary sodium concentration. A “spot” urine sodium concentration that exceeds the potassium concentration correlates with a 24-hour sodium excretion > 78 mmol/d, which predicts diuresis in patients adherent to a salt-restricted diet. Monitoring for hyperkalemia is important. In patients who cannot tolerate spironolactone because of side effects, such as painful gynecomastia, amiloride (another potassium-sparing diuretic) may be used in a starting dose of 5–10 mg orally daily. Diuresis is augmented by the addition of a loop diuretic such as furosemide. This potent diuretic, however, will maintain its effect even with a falling glomerular filtration rate, with resulting prerenal azotemia. The dose of oral furosemide ranges from 40 mg/d to 160 mg/d, and the drug should be administered while blood pressure, urinary output, mental status, and serum electrolytes (especially potassium) are monitored. The goal of weight loss in the ascitic patient without associated peripheral edema should be no more than 1–1.5 lb/d (0.5–0.7 kg/d).

B. LARGE-VOLUME PARACENTESIS—In patients with massive ascites and respiratory compromise, ascites refractory to diuretics (“diuretic resistant”), or intolerable diuretic side effects (“diuretic intractable”), large-volume paracentesis (>5 L) is effective. Intravenous albumin concomitantly at a dosage of 6–8 g/L of ascites fluid removed protects the intravascular volume and may prevent postparacentesis circulatory dysfunction, although the usefulness of this practice is debated and the use of albumin is expensive. Large-volume paracentesis can be repeated daily until ascites is largely resolved and may decrease the need for hospitalization. If possible, diuretics should be continued in the hope of preventing recurrent ascites.

C. TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT (TIPS)—TIPS is an effective treatment of variceal bleeding refractory to standard therapy (eg, endoscopic band ligation or sclerotherapy) and has shown benefit in the treatment of severe refractory ascites. The technique involves insertion of an expandable metal stent between a branch of the hepatic vein and the portal vein over a catheter inserted via the internal jugular vein. Increased renal sodium excretion and control of ascites refractory to diuretics can be achieved in about 75% of selected cases. The success rate is lower in patients with underlying chronic kidney disease. TIPS appears to be the treatment of choice for refractory hepatic hydrothorax (translocation of ascites across the diaphragm to the pleural space); video-assisted thoracoscopy with pleurodesis using talc may be effective when TIPS is contraindicated. Complications of TIPS include hepatic encephalopathy in 20–30% of cases, infection, shunt stenosis in up to 60% of cases, and shunt occlusion in up to 30% of cases when bare stents are used; however, polytetrafluoroethylene-covered stents are associated with long-term patency rates of 80–90%. Long-term patency often requires periodic shunt revisions. In most cases, patency can be maintained by balloon dilation, local thrombolysis, or placement of an additional stent. TIPS is particularly useful in patients who require short-term control of variceal bleeding or ascites until liver transplantation can be performed. In patients with refractory ascites, TIPS results in lower rates of ascites recurrence and hepatorenal syndrome but a higher rate of hepatic encephalopathy than occur with repeated large-volume paracentesis; a benefit in survival has been demonstrated in one study and a meta-analysis. Chronic kidney disease, diastolic cardiac dysfunction, refractory encephalopathy, and hyperbilirubinemia (>5 mg/dL [85.5 mcmol/L]) are associated with mortality after TIPS.

2. Spontaneous bacterial peritonitis—Spontaneous bacterial peritonitis is heralded by abdominal pain, increasing ascites, fever, and progressive encephalopathy in a patient with cirrhotic ascites; symptoms are typically mild. (Analogously, spontaneous bacterial empyema may complicate hepatic hydrothorax and is managed similarly.) Risk factors in cirrhotic patients with ascites include gastroesophageal variceal bleeding and possibly use of a proton pump inhibitor. Paracentesis reveals an ascitic fluid with, most commonly, a total white cell count of up to 500 cells/mcL with a high percentage of polymorphonuclear cells (PMNs) (≥ 250/mcL) and a protein concentration of 1 g/dL (10 g/L) or less, corresponding to decreased ascitic opsonic activity. Rapid diagnosis of bacterial peritonitis can be made with a high degree of specificity with rapid reagent strips (“dipsticks”) that detect leukocyte esterase in ascitic fluid, but the sensitivity is too low for routine use. Cultures of ascites give the highest yield—80–90% positive—using specialized culture bottles inoculated at the bedside. Common isolates are Escherichia coli and pneumococci. Gram-positive cocci are the most common isolates in patients who have undergone an invasive procedure such as central venous line placement, and the frequency of enterococcal isolates is increasing. Anaerobes are uncommon. Pending culture results, if there are 250 or more PMNs/mcL or symptoms or signs of infection, intravenous antibiotic therapy should be initiated with cefotaxime, 2 g every 8–12 hours for at least 5 days. Ceftriaxone and amoxicillin-clavulanic acid are alternative choices. Oral ofloxacin, 400 mg twice daily for 7 days, or, in a patient not already taking a fluoroquinolone for prophylaxis against bacterial peritonitis, a 2-day course of intravenous ciprofloxacin, 200 mg twice daily, followed by oral ciprofloxacin, 500 mg twice daily for 5 days, may be effective alternative regimens in selected patients. A carbapenem has been recommended for patients with hospital-acquired spontaneous bacterial peritonitis. Supplemental administration of intravenous albumin prevents further renal impairment and reduces mortality, particularly in patients with a serum creatinine > 1 mg/dL (> 83.3 mcmol/L), blood urea nitrogen > 30 mg/dL (> 10.8 mmol/L), or total bilirubin > 4 mg/dL (> 68.4 mcmol/L). Response to therapy can be documented, if necessary, by a decrease in the PMN count of at least 50% on repeat paracentesis 48 hours after initiation of therapy. The overall mortality rate is high—up to 30% during hospitalization and up to 70% by 1 year. Mortality may be predicted by the 22/11 model: MELD score > 22 and peripheral white blood cell count > 11,000/mcL (> 11 × 10⁹/L). Patients with cirrhosis and septic shock have a high frequency of relative adrenal insufficiency, which if present requires administration of hydrocortisone. In survivors of bacterial peritonitis, the risk of recurrent peritonitis may be decreased by long-term norfloxacin, 400 mg orally daily; ciprofloxacin (eg, 500 mg orally once or twice a day), although with recurrence the causative organism is often resistant to fluoroquinolones; or trimethoprim-sulfamethoxazole (eg, one double-strength tablet five times a week). In high-risk cirrhotic patients without prior peritonitis (eg, those with an ascitic protein < 1.5 g/dL and serum bilirubin >3 mg/dL (> 51.3 mcmol/L), serum creatinine >1.2 mg/dL (> 99.96 mcmol/L), blood urea nitrogen ≥ 25 mg/dL (≥ 9 mmol/L), or sodium ≤ 130 mEq/L [≤ 130 mmol/L]), the risk of peritonitis, hepatorenal syndrome, and mortality for at least 1 year may be reduced by prophylactic norfloxacin, 400 mg orally once a day. Oral norfloxacin (400 mg orally twice a day) or intravenous ceftriaxone (1 g per day), which may be preferable, for 7 days reduces the risk of bacterial peritonitis in patients hospitalized for acute variceal bleeding.

3. Hepatorenal syndrome—Hepatorenal syndrome occurs in up to 10% of patients with advanced cirrhosis and ascites and is characterized by azotemia (serum creatinine >1.5 mg/dL [124.95 mcmol/L]) in the absence of parenchymal kidney disease or shock and by failure of kidney function to improve following 2 days of diuretic withdrawal and volume expansion with albumin, 1 g/kg up to a maximum of 100 g/d. Oliguria, hyponatremia, and a low urinary sodium concentration are typical features. Hepatorenal syndrome is diagnosed only when other causes of acute kidney injury (including prerenal azotemia and acute tubular necrosis) have been excluded. Urinary neutrophil gelatinase-associated lipocalin levels (normal, 20 ng/mL) may help distinguish hepatorenal syndrome (105 ng/mL) from chronic kidney disease (50 ng/mL) and acute kidney injury (325 ng/mL). Type I hepatorenal syndrome is characterized by doubling of the serum creatinine to a level >2.5 mg/dL (208.25 mcmol/L) or by halving of the creatinine clearance to < 20 mL/min (0.34 mL/s/1.73 m² BSA) in < 2 weeks. Type II hepatorenal syndrome is more slowly progressive and chronic. An acute decrease in cardiac output is often the precipitating event. In addition to discontinuation of diuretics, clinical improvement and an increase in short-term survival may follow intravenous infusion of albumin in combination with one of the following vasoconstrictor regimens for 7–14 days: oral midodrine plus octreotide, subcutaneously or intravenously; intravenous terlipressin (not yet available in the United States but may be the preferred agent where available); or intravenous norepinephrine. Oral midodrine, 7.5 mg three times daily, added to diuretics, to increase blood pressure has also been reported to convert refractory ascites to diuretic-sensitive ascites. Prolongation of survival has been associated with use of MARS, a modified dialysis method that selectively removes albumin-bound substances. Improvement and sometimes normalization of kidney function may also follow placement of a TIPS; survival after 1 year is reported to be predicted by the combination of a serum bilirubin level < 3 mg/dL (< 50 mcmol/L) and a platelet count > 75,000/mcL (> 75 × 10⁹/L). Continuous venovenous hemofiltration and hemodialysis are of uncertain value in hepatorenal syndrome. Liver transplantation is the treatment of choice, but many patients die before a donor liver can be obtained. Mortality correlates with the MELD score and presence of a systemic inflammatory response. The 3-month probability of survival in patients with hepatorenal syndrome (15%) is lower than that for renal failure associated with infections (31%), hypovolemia (46%), and parenchymal kidney disease (73%) in patients with cirrhosis.

4. Hepatic encephalopathy—Hepatic encephalopathy is a state of disordered central nervous system function resulting from failure of the liver to detoxify noxious agents of gut origin because of hepatocellular dysfunction and portosystemic shunting. The clinical spectrum ranges from day-night reversal and mild intellectual impairment to coma. Patients with covert (formerly minimal) hepatic encephalopathy have no recognizable clinical symptoms but demonstrate mild cognitive and psychomotor deficits and attention deficit on standardized psychometric tests and an increased rate of traffic accidents. The stages of overt encephalopathy are: (1) mild confusion, (2) drowsiness, (3) stupor, and (4) coma. A revised staging system known as SONIC (spectrum of neurocognitive impairment in cirrhosis) encompasses absent, covert, and stages 2 to 4 encephalopathy. Ammonia is the most readily identified and measurable toxin but is not solely responsible for the disturbed mental status. Bleeding into the intestinal tract may significantly increase the amount of protein in the bowel and precipitate encephalopathy. Other precipitants include constipation, alkalosis, and potassium deficiency induced by diuretics, opioids, hypnotics, and sedatives; medications containing ammonium or amino compounds; paracentesis with consequent hypovolemia; hepatic or systemic infection; and portosystemic shunts (including TIPS). The diagnosis is based primarily on detection of characteristic symptoms and signs, including asterixis. The role of neuroimaging studies (eg, cerebral PET, magnetic resonance spectroscopy) in the diagnosis of hepatic encephalopathy is evolving.

Dietary protein is withheld during acute episodes if the patient cannot eat. When the patient resumes oral intake, protein intake should be 60–80 g/d as tolerated; vegetable protein is better tolerated than meat protein. Gastrointestinal bleeding should be controlled and blood purged from the gastrointestinal tract. This can be accomplished with 120 mL of magnesium citrate by mouth or nasogastric tube every 3–4 hours until the stool is free of gross blood, or by administration of lactulose. The value of treating patients with covert hepatic encephalopathy is uncertain; probiotic agents may have some benefit.

Lactulose, a nonabsorbable synthetic disaccharide syrup, is digested by bacteria in the colon to short-chain fatty acids, resulting in acidification of colon contents. This acidification favors the formation of ammonium ion in the NH₄⁺  NH₃ + H⁺ equation; NH₄⁺ is not absorbable, whereas NH₃ is absorbable and thought to be neurotoxic. Lactulose also leads to a change in bowel flora so that fewer ammonia-forming organisms are present. When given orally, the initial dose of lactulose for acute hepatic encephalopathy is 30 mL three or four times daily. The dose should then be titrated so that two or three soft stools per day are produced. When rectal use is indicated because of the patient’s inability to take medicines orally, the dose is 300 mL of lactulose in 700 mL of saline or sorbitol as a retention enema for 30–60 minutes; it may be repeated every 4–6 hours. Continued use of lactulose after an episode of acute encephalopathy reduces the frequency of recurrences. Lactilol is a less sweet disaccharide alternative available as a powder in some countries.

The ammonia-producing intestinal flora may also be controlled with an oral antibiotic. The nonabsorbable agent rifaximin, 550 mg orally twice daily, is preferred and has been shown as well to maintain remission from and reduce the risk of rehospitalization for hepatic encephalopathy over a 6-month period in patients also taking lactulose. Metronidazole, 250 mg orally three times daily, has also shown benefit. In the past, neomycin sulfate, 0.5–1 g orally every 6 or 12 hours for 7 days, was used, but side effects (including diarrhea, malabsorption, superinfection, ototoxicity, and nephrotoxicity) were frequent, especially after prolonged use. Patients who do not respond to lactulose alone may improve with a course of an antibiotic added to treatment with lactulose.

Opioids and sedatives metabolized or excreted by the liver should be avoided. If agitation is marked, oxazepam, 10–30 mg, which is not metabolized by the liver, may be given cautiously by mouth or by nasogastric tube. Zinc deficiency should be corrected, if present, with oral zinc sulfate, 600 mg/d in divided doses. Sodium benzoate, 5 g orally twice daily, ornithine aspartate, 9 g orally three times daily, and L-acyl-carnitine (an essential factor in the mitochrondrial transport of long-chain fatty acids), 4 g orally daily, may lower blood ammonia levels, but there is less experience with these drugs than with lactulose. Flumazenil is effective in about 30% of patients with severe hepatic encephalopathy, but the drug is short-acting and intravenous administration is required. Use of special dietary supplements enriched with branched-chain amino acids is usually unnecessary except in occasional patients who are intolerant of standard protein supplements.

5. Coagulopathy—Hypoprothrombinemia caused by malnutrition and vitamin K deficiency may be treated with vitamin K (eg, phytonadione, 5 mg orally or intravenously daily); however, this treatment is ineffective when synthesis of coagulation factors is impaired because of hepatic disease. In such cases, correcting the prolonged prothrombin time requires large volumes of fresh frozen plasma (see Chapter 14). Because the effect is transient, plasma infusions are not indicated except for active bleeding or before an invasive procedure, and even then, the value of such treatment has been questioned because of concomitant alterations in anti-hemostatic factors and because bleeding risk does not correlate with the INR. Recombinant activated factor VIIa may be an alternative but is expensive and poses a 1–2% risk of thrombotic complications. Eltrombopag reduces the need for platelet transfusions in patients with cirrhosis and a platelet count < 50,000/mcL (< 50 × 10⁹/L) who undergo invasive procedures, but eltrombopag is associated with an increased risk of portal vein thrombosis.

6. Hemorrhage from esophageal varices—See Chapter 15.

7. Hepatopulmonary syndrome and portopulmonary hypertension—Shortness of breath in patients with cirrhosis may result from pulmonary restriction and atelectasis caused by massive ascites. The hepatopulmonary syndrome—the triad of chronic liver disease, an increased alveolar-arterial gradient while the patient is breathing room air, and intrapulmonary vascular dilatations or arteriovenous communications that result in a right-to-left intrapulmonary shunt—occurs in 5–32% of patients with cirrhosis. Patients often have greater dyspnea (platypnea) and arterial deoxygenation (orthodeoxia) in the upright than in the recumbent position. The diagnosis should be suspected in a cirrhotic patient with a pulse oximetry level ≤ 96%.

Contrast-enhanced echocardiography is a sensitive screening test for detecting pulmonary vascular dilatations, whereas macroaggregated albumin lung perfusion scanning is more specific and may be used to confirm the diagnosis. High-resolution CT may be useful for detecting dilated pulmonary vessels that may be amenable to embolization in patients with severe hypoxemia (P_o2 < 60 mm Hg [7.8 kPa]) who respond poorly to supplemental oxygen.

Medical therapy has been disappointing; experimentally, intravenous methylene blue, oral garlic powder, oral norfloxacin, and mycophenolate mofetil may improve oxygenation by inhibiting nitric oxide-induced vasodilatation and angiogenesis, and pentoxifylline may prevent hepatopulmonary syndrome by inhibiting production of tumor necrosis factor. Long-term oxygen therapy is recommended for severely hypoxemic patients. The syndrome may reverse with liver transplantation, although postoperative mortality is increased in patients with a preoperative arterial P_o2 < 50 mm Hg (6.5 kPa) or with substantial intrapulmonary shunting. TIPS may provide palliation in patients with hepatopulmonary syndrome awaiting transplantation.

Portopulmonary hypertension occurs in 0.7% of patients with cirrhosis. Female sex and autoimmune hepatitis have been reported to be risk factors, and large spontaneous portosystemic shunts are present in many affected patients and are associated with a lack of response to treatment. In cases confirmed by right-sided heart catheterization, treatment with the prostaglandin epoprostenol, the endothelin-receptor antagonists bosentan or ambrisentan, or the phosphodiesterase-5 inhibitors sildenafil or tadalafil may reduce pulmonary hypertension and thereby facilitate liver transplantation; beta-blockers worsen exercise capacity and are contraindicated, and calcium channel blockers should be used with caution because they may worsen portal hypertension. Liver transplantation is contraindicated in patients with moderate to severe pulmonary hypertension (mean pulmonary pressure > 35 mm Hg).

C. Liver Transplantation

Liver transplantation is indicated in selected cases of irreversible, progressive chronic liver disease, acute liver failure, and certain metabolic diseases in which the metabolic defect is in the liver. Absolute contraindications include malignancy (except relatively small hepatocellular carcinomas in a cirrhotic liver), advanced cardiopulmonary disease (except hepatopulmonary syndrome), and sepsis. Relative contraindications include age over 70 years, morbid obesity, portal and mesenteric vein thrombosis, active alcohol or drug abuse, severe malnutrition, and lack of patient understanding. With the emergence of effective antiretroviral therapy for HIV disease, a major cause of mortality in these patients has shifted to liver disease caused by HCV and HBV infection; experience to date suggests that the outcome of liver transplantation is comparable to that for non–HIV-infected liver transplant recipients. Patients with alcoholism should be abstinent for 6 months. Liver transplantation should be considered in patients with worsening functional status, rising bilirubin, decreasing albumin, worsening coagulopathy, refractory ascites, recurrent variceal bleeding, or worsening encephalopathy; prioritization is based on the MELD score. Combined liver-kidney transplantation is indicated in patients with associated kidney failure presumed to be irreversible. The major impediment to more widespread use of liver transplantation is a shortage of donor organs. Adult living donor liver transplantation is an option for some patients, and extended-criteria donors are being used. Five-year survival rates as high as 80% are now reported. Hepatocellular carcinoma, hepatitis B and C, and some cases of Budd-Chiari syndrome and autoimmune liver disease may recur in the transplanted liver. The incidence of recurrence of hepatitis B can be reduced by preoperative and postoperative treatment with a nucleoside or nucleotide analog and perioperative administration of HBIG. Immunosuppression is achieved with combinations of cyclosporine, tacrolimus or sirolimus, corticosteroids, azathioprine, and mycophenolate mofetil and may be complicated by infections, advanced chronic kidney disease, neurologic disorders, and drug toxicity as well as graft rejection, vascular occlusion, or bile leaks. Patients taking these drugs are at risk for obesity, diabetes mellitus, and hyperlipidemia.

 Prognosis

Prognostic scoring systems for cirrhosis include the Child-Turcotte-Pugh score (Table 16–6) and MELD score. The MELD score, which incorporates the serum bilirubin and creatinine levels and the INR, is also a measure of mortality risk in patients with end-stage liver disease and is particularly useful for predicting short- and intermediate-term survival and complications of cirrhosis (eg, bacterial peritonitis) as well as determining allocation priorities for donor livers. Additional (MELD-exception) points are given for patients with conditions such as hepatopulmonary syndrome and hepatocellular carcinoma that may benefit from liver transplantation. The consistency of the MELD score among different hospitals may be improved when the INR is calibrated based on prothrombin time control samples that include patients with liver disease rather than those taking oral anticoagulants, but this approach is not readily available. A MELD score of > 14 is required for liver transplant listing. In patients with a relatively low MELD score (< 21) and a low priority for liver transplantation, a low serum sodium concentration (< 130 mEq/L [130 mmol/L]), an elevated hepatic venous pressure gradient, persistent ascites, and a low health-related quality of life appear to be additional independent predictors of mortality, and modifications of the MELD score, including one that incorporates the serum sodium (MELDNa), are under consideration. Only 50% of patients with severe hepatic dysfunction (serum albumin < 3 g/dL [< 30 g/L]), bilirubin > 3 mg/dL [> 51.3 mcmol/L]), ascites, encephalopathy, cachexia, and upper gastrointestinal bleeding) survive 6 months without transplantation. The risk of death in this subgroup of patients with advanced cirrhosis is associated with muscle wasting, age ≥ 65 years, mean arterial pressure ≤ 82 mm Hg, renal failure, cognitive dysfunction, ventilatory insufficiency, and prothrombin time ≥ 16 seconds, delayed and suboptimal treatment of sepsis, and second infections. Renal failure increases mortality in patients with cirrhosis up to sevenfold. Obesity and diabetes mellitus appear to be risk factors for clinical deterioration and cirrhosis-related mortality, as is continued alcohol use in patients with alcoholic cirrhosis. The use of beta-blockers for portal hypertension is beneficial early in the course but is associated with poor survival in patients with refractory ascites because of their negative effect on cardiac compensatory reserve. Patients with cirrhosis are at risk for the development of hepatocellular carcinoma, with rates of 3–5% per year for alcoholic and viral hepatitis-related cirrhosis. Liver transplantation has markedly improved the outlook for patients with cirrhosis who are candidates and are referred for evaluation early. Patients with compensated cirrhosis are given additional priority for liver transplantation if they are found to have a lesion > 2 cm in diameter consistent with hepatocellular carcinoma. In-hospital mortality from variceal bleeding in patients with cirrhosis has declined from over 40% in 1980 to 15% in 2000. Medical treatments to reverse hepatic fibrosis are under investigation.

 When to Refer

• For liver biopsy.

• Before the MELD score is ≥ 14.

• For upper endoscopy to screen for gastroesophageal varices.

 When to Admit

• Gastrointestinal bleeding.

• Stage 3–4 hepatic encephalopathy.

• Worsening kidney function.

• Severe hyponatremia.

• Serious infection.

• Profound hypoxia.

PRIMARY BILIARY CIRRHOSIS

 General Considerations

Primary biliary cirrhosis is a chronic disease of the liver characterized by autoimmune destruction of small intrahepatic bile ducts and cholestasis. It is insidious in onset, occurs usually in women aged 40–60 years, and is often detected by the chance finding of elevated alkaline phosphatase levels. Estimated incidence and prevalence rates in the United States are 4.5 and 65.4 per 100,000, respectively, in women, and 0.7 and 12.1 per 100,000, respectively, in men. These rates may be increasing. The frequency of the disease among first-degree relatives of affected persons is 1.3–6%, and the concordance rate in identical twins is high. Primary biliary cirrhosis is associated with HLA DRB1*08 and DQB1. The disease may be associated with Sjögren syndrome, autoimmune thyroid disease, Raynaud syndrome, scleroderma, hypothyroidism, and celiac disease. Infection with Novosphingobium aromaticivorans or Chlamydophila pneumoniae may be triggering or causative in primary biliary cirrhosis. A history of urinary tract infections (caused by E coli or Lactobacillus delbrueckii) and smoking, and possibly use of hormone replacement therapy and hair dye, are risk factors, and clustering of cases in time and space argues for a causative role of environmental agents.

 Clinical Findings

A. Symptoms and Signs

Many patients are asymptomatic for years. The onset of clinical illness is insidious and is heralded by fatigue (excessive daytime somnolence) and pruritus. With progression, physical examination reveals hepatosplenomegaly. Xanthomatous lesions may occur in the skin and tendons and around the eyelids. Jaundice, steatorrhea, and signs of portal hypertension are late findings, although occasional patients have esophageal varices despite an early histologic stage (see below). Autonomic dysfunction, including orthostatic hypotension and associated with fatigue, and cognitive dysfunction appear to be common. The risk of low bone density, osteoporosis, and fractures is increased in patients with primary biliary cirrhosis (who tend to be older women) possibly due in part to polymorphisms of the vitamin D receptor.

B. Laboratory Findings

Blood counts are normal early in the disease. Liver biochemical tests reflect cholestasis with elevation of alkaline phosphatase, cholesterol (especially high-density lipoproteins), and, in later stages, bilirubin. Antimitochondrial antibodies are present in 95% of patients, and serum IgM levels are elevated.

 Diagnosis

The diagnosis of primary biliary cirrhosis is based on the detection of cholestatic liver chemistries (often initially an isolated elevation of the alkaline phosphatase) and antimitochondrial antibodies in serum. Liver biopsy is not essential for diagnosis but permits histologic staging: I, portal inflammation with granulomas; II, bile duct proliferation, periportal inflammation; III, interlobular fibrous septa; and IV, cirrhosis. Estimation of histologic stage by an “enhanced liver fibrosis assay” that incorporates serum levels of hyaluronic acid, tissue inhibitor of metalloproteinase-1, and procollagen III aminopeptide has shown promise.

 Differential Diagnosis

The disease must be differentiated from chronic biliary tract obstruction (stone or stricture), carcinoma of the bile ducts, primary sclerosing cholangitis, sarcoidosis, cholestatic drug toxicity (eg, chlorpromazine), and in some cases chronic hepatitis. Patients with a clinical and histologic picture of primary biliary cirrhosis but no antimitochondrial antibodies are said to have antimitochondrial antibody-negative primary biliary cirrhosis (“autoimmune cholangitis”), which has been associated with lower serum IgM levels and a greater frequency of smooth muscle antibodies and ANA. Many such patients are found to have antimitochondrial antibodies by immunoblot against recombinant proteins (rather than standard immunofluorescence). Some patients have overlapping features of primary biliary cirrhosis and autoimmune hepatitis.

 Treatment

Cholestyramine (4 g) in water or juice three times daily may be beneficial for pruritus; colestipol and colesevelam may be better tolerated but have not been shown to reduce pruritus. Rifampin, 150–300 mg orally twice daily, is inconsistently beneficial. Opioid antagonists (eg, naloxone, 0.2 mcg/kg/min by intravenous infusion, or naltrexone, starting at 12.5 mg/d by mouth) show promise in the treatment of pruritus but may cause opioid withdrawal symptoms. The 5-hydroxytryptamine (5-HT₃) serotonin receptor antagonist ondansetron, 4 mg orally three times a day as needed, and the selective serotonin uptake inhibitor sertraline, 75–100 mg/d orally, may also provide some benefit. For refractory pruritus, plasmapheresis or extracorporeal albumin dialysis may be needed. Modafinil, 100–200 mg/d orally, may improve daytime somnolence but is poorly tolerated. Deficiencies of vitamins A, D, and K may occur if steatorrhea is present and are aggravated when cholestyramine or colestipol is administered. SeeChapter 26 for discussion of prevention and treatment of osteoporosis and Chapter 20 for discussion of the treatment of Sjögren syndrome.

Because of its lack of toxicity, ursodeoxycholic acid (13–15 mg/kg/d in one or two doses) is the preferred medical treatment (and only treatment approved by the US FDA) for primary biliary cirrhosis. It has been shown to slow the progression of disease (particularly in early-stage disease), stabilize histology, improve long-term survival, reduce the risk of developing esophageal varices, and delay (and possibly prevent) the need for liver transplantation, although the benefit of the drug has been questioned. Complete normalization of liver biochemical tests occurs in 20% of treated patients within 2 years and 40% within 5 years, and survival is similar to that of healthy controls when the drug is given to patients with stage 1 or 2 primary biliary cirrhosis. Response rates have been reported to be lower in men than women (72% vs 80%) and higher in women diagnosed after age 70 than before age 30 (90% vs 50%). Ursodeoxycholic acid therapy has also been reported to reduce the risk of recurrent colorectal adenomas in patients with primary biliary cirrhosis. Side effects include weight gain and rarely loose stools. Colchicine (0.6 mg orally twice daily) and methotrexate (15 mg/wk orally) have had some reported benefit in improving symptoms and serum levels of alkaline phosphatase and bilirubin. Methotrexate may also improve liver histology in some patients, but overall response rates have been disappointing. Penicillamine, prednisone, and azathioprine have proved to be of no benefit. Budesonide may improve liver histology but worsens bone density. For patients with advanced disease, liver transplantation is the treatment of choice.

 Prognosis

Without liver transplantation, survival averages 7–10 years once symptoms develop but has improved for younger women since the introduction of ursodeoxycholic acid. Progression to liver failure and portal hypertension may be accelerated by smoking. Patients with early-stage disease in whom the alkaline phosphatase and AST are less than 1.5 times normal and bilirubin is ≤ 1 mg/dL (17.1 mcmol/L) after 1 year of therapy with ursodeoxycholic acid (Paris II criteria) are at low long-term risk for cirrhosis and have a life expectancy similar to that of the healthy population. In advanced disease, an adverse prognosis is indicated by a high Mayo risk score that includes older age, high serum bilirubin, edema, low serum albumin, and prolonged prothrombin time as well as by variceal hemorrhage. A prediction tool for varices based on the serum albumin, serum alkaline phosphatase, platelet count, and splenomegaly has been proposed. Fatigue is associated with an increased risk of cardiac mortality and may not be reversed by liver transplantation. Among asymptomatic patients, at least one-third will become symptomatic within 15 years. The risk of hepatocellular carcinoma appears to be increased in patients with primary biliary cirrhosis; risk factors include older age, male sex, prior blood transfusions, advanced histologic stage, and signs of cirrhosis or portal hypertension. Liver transplantation for advanced primary biliary cirrhosis is associated with a 1-year survival rate of 85–90%. The disease recurs in the graft in 20% of patients by 3 years, but this does not seem to affect survival.

 When to Refer

• For liver biopsy.

• For liver transplant evaluation.

 When to Admit

• Gastrointestinal bleeding.

• Stage 3–4 hepatic encephalopathy.

• Worsening kidney function.

• Severe hyponatremia.

• Profound hypoxia.

HEMOCHROMATOSIS

 General Considerations

Hemochromatosis is an autosomal recessive disease caused in most cases by a mutation in the HFE gene on chromosome 6. The HFE protein is thought to play an important role in the process by which duodenal crypt cells sense body iron stores, leading in turn to increased iron absorption from the duodenum. A decrease in the synthesis or expression of hepcidin, the principal iron regulatory hormone, is thought to be a key pathogenic factor in all forms of hemochromatosis. About 85% of persons with well-established hemochromatosis are homozygous for the C282Y mutation. The frequency of the gene mutation averages 7% in Northern European and North American white populations, resulting in a 0.5% frequency of homozygotes (of whom 38–50% will develop biochemical evidence of iron overload but only 28% of men and 1% of women will develop clinical symptoms). By contrast, the gene mutation and hemochromatosis are uncommon in blacks and Asian-American populations. A second genetic mutation (H63D) may contribute to the development of iron overload in a small percentage (1.5%) of persons who are compound heterozygotes for C282Y and H63D; iron overload-related disease develops in few patients (particularly those who have a comorbidity such as diabetes mellitus and fatty liver). Rare instances of hemochromatosis result from mutations in the genes that encode transferrin receptor 2 (TFR2) and ferroportin (FPN1). A juvenile-onset variant that is characterized by severe iron overload, cardiac dysfunction, hypogonadotropic hypogonadism, and a high mortality rate is usually linked to a mutation of a gene on chromosome 1q designated HJV that produces a protein called hemojuvelin or, rarely, to a mutation in the HAMP gene on chromosome 19 that encodes hepcidin, but not to the C282Ymutation.

Hemochromatosis is characterized by increased accumulation of iron as hemosiderin in the liver, pancreas, heart, adrenals, testes, pituitary, and kidneys. Cirrhosis is more likely to develop in affected persons who drink alcohol excessively or have obesity-related hepatic steatosis than in those who do not. Eventually, hepatic and pancreatic insufficiency, heart failure, and hypogonadism may develop; overall mortality is increased slightly. Heterozygotes do not develop cirrhosis in the absence of associated disorders such as viral hepatitis or NAFLD.

 Clinical Findings

A. Symptoms and Signs

The onset of clinical disease is usually after age 50 years—earlier in men than in women; however, because of widespread liver biochemical testing and iron screening, the diagnosis is usually made long before symptoms develop. Early symptoms are nonspecific (eg, fatigue, arthralgia). Later clinical manifestations include arthropathy (and ultimately the need for joint replacement surgery in some cases), hepatomegaly and evidence of hepatic dysfunction, skin pigmentation (combination of slate-gray due to iron and brown due to melanin, sometimes resulting in a bronze color), cardiac enlargement with or without heart failure or conduction defects, diabetes mellitus with its complications, and erectile dysfunction in men. Interestingly, population studies have shown an increased prevalence of liver disease but not of diabetes mellitus, arthritis, or heart disease in C282Y homozygotes. In patients in whom cirrhosis develops, bleeding from esophageal varices may occur, and there is a 15–20% frequency of hepatocellular carcinoma. Affected patients are at increased risk of infection with Vibrio vulnificus, Listeria monocytogenes, Yersinia enterocolitica, and other siderophilic organisms. The risk of porphyria cutanea tarda is increased in persons with the C282Y or H63D mutation, and C282Y homozygotes have twice the risk of colorectal and breast cancer than persons without the C282Y variant.

B. Laboratory Findings

Laboratory findings include mildly abnormal liver tests (AST, alkaline phosphatase), an elevated plasma iron with > 45% transferrin saturation, and an elevated serum ferritin (although a normal iron saturation or a normal ferritin does not exclude the diagnosis). Affected men are more likely than affected women to have an elevated ferritin level. Testing for HFE mutations is indicated in any patient with evidence of iron overload. Interestingly, in persons with an elevated serum ferritin, the likelihood of detecting C282Y homozygosity decreases with increasing ALT and AST levels, which are likely to reflect hepatic inflammation and secondary iron overload.

C. Imaging

MRI and CT may show changes consistent with iron overload of the liver, and MRI can quantitate hepatic iron stores. There is also an emerging role for MRI for assessment of the degree of hepatic fibrosis.

D. Liver Biopsy

In patients who are homozygous for C282Y, liver biopsy is often indicated to determine whether cirrhosis is present. Biopsy can be deferred, however, in patients in whom the serum ferritin level is < 1000 mcg/L, serum AST level is normal, and hepatomegaly is absent; the likelihood of cirrhosis is low in these persons. The combination of a serum ferritin level ≥ 1000 mcg/L and a serum hyaluronic acid level ≥ 46.5 mcg/L has been reported to identify all patients with cirrhosis, with a high specificity. Risk factors for advanced fibrosis include male sex, excess alcohol consumption, and diabetes mellitus. Liver biopsy is also indicated when iron overload is suspected even though the patient is not homozygous for C282Y or a C282Y/H63D compound heterozygote. In patients with hemochromatosis, the liver biopsy characteristically shows extensive iron deposition in hepatocytes and in bile ducts, and the hepatic iron index—hepatic iron content per gram of liver converted to micromoles and divided by the patient’s age—is generally > 1.9. Only 5% of patients with hereditary hemochromatosis identified by screening in a primary care setting have cirrhosis.

 Screening

Iron studies and HFE testing are recommended for all first-degree family members of a proband; children of an affected person (C282Y homozygote) need to be screened only if the patient’s spouse carries the C282Y or H63D mutation. Average-risk population screening for hemochromatosis is not recommended because the clinical penetrance of C282Y homozygosity and morbidity and mortality from hemochromatosis are low. Patients with otherwise unexplained chronic liver disease, chondrocalcinosis, erectile dysfunction, and type 1 diabetes mellitus (especially late-onset) should be screened for iron overload.

 Treatment

Affected patients should avoid foods rich in iron (such as red meat), alcohol, vitamin C, raw shellfish, and supplemental iron. Weekly phlebotomies of 1 or 2 units (250–500 mL) of blood (each containing about 250 mg of iron) is indicated in all symptomatic patients, those with a serum ferritin level of at least 1000 mcg/L, and those with an increased fasting iron saturation and should be continued for up to 2–3 years to achieve depletion of iron stores. The hematocrit and serum iron values should be monitored. When iron store depletion is achieved (iron saturation < 50% and serum ferritin level 50–100 mcg/L), phlebotomies (every 2–4 months) to maintain serum ferritin levels between 50 mcg/L and 100 mcg/L are continued, although compliance has been reported to decrease with time; administration of a proton pump inhibitor, which reduces intestinal iron absorption, appears to decrease the maintenance phlebotomy blood volume requirement. In C282Y homozygous women, a body mass index > 28 kg/m² is associated with a lower phlebotomy requirement, possibly because hepcidin levels are increased by overweight. Complications of hemochromatosis—arthropathy, diabetes mellitus, heart disease, portal hypertension, and hypopituitarism—also require treatment.

The chelating agent deferoxamine is indicated for patients with hemochromatosis and anemia or in those with secondary iron overload due to thalassemia who cannot tolerate phlebotomies. The drug is administered intravenously or subcutaneously in a dose of 20–40 mg/kg/d infused over 24 hours and can mobilize 30 mg of iron per day; however, treatment is painful and time-consuming. Two oral chelators, deferasirox, 20 mg/kg once daily, and deferiprone, 25 mg/kg three times daily, have been approved for treatment of iron overload due to blood transfusions and may be appropriate in persons with hemochromatosis who cannot tolerate phlebotomy; however, these agents have a number of side effects and drug-drug interactions.

The course of hemochromatosis is favorably altered by phlebotomy therapy. Hepatic fibrosis may regress, and in precirrhotic patients, cirrhosis may be prevented. Cardiac conduction defects and insulin requirements improve with treatment. In patients with cirrhosis, varices may reverse, and the risk of variceal bleeding declines, although the risk of hepatocellular carcinoma persists; in those with an initial serum ferritin level > 1000 mcg/L (> 2247 pmol/L), the risk of death is five fold greater than in those with a serum ferritin ≤ 1000 mcg/L (< 2247 pmol/L). In the past, liver transplantation for advanced cirrhosis associated with severe iron overload, including hemochromatosis, was reported to lead to survival rates that were lower than those for other types of liver disease because of cardiac complications and an increased risk of infections, but since 1997, posttransplant survival rates have been excellent.

 When to Refer

• For liver biopsy.

• For initiation of therapy.

WILSON DISEASE

 General Considerations

Wilson disease (hepatolenticular degeneration) is a rare autosomal recessive disorder that usually occurs in persons under age 40. The worldwide prevalence is about 30 per million population. The condition is characterized by excessive deposition of copper in the liver and brain. The genetic defect, localized to chromosome 13, has been shown to affect a copper-transporting adenosine triphosphatase (ATP7B) in the liver and leads to copper accumulation in the liver and oxidative damage of hepatic mitochondria. Most patients are compound heterozygotes (ie, carry two different mutations). Over 500 mutations in the Wilson disease gene have been identified. The H1069Q mutation accounts for 37–63% of disease alleles in populations of Northern European descent. The major physiologic aberration in Wilson disease is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver, resulting in increased tissue deposition, especially in the liver, brain, cornea, and kidney.

 Clinical Findings

Wilson disease tends to present as liver disease in adolescents and neuropsychiatric disease in young adults, but there is great variability, and onset of symptoms after age 40 is more common than previously thought. The diagnosis should always be considered in any child or young adult with hepatitis, splenomegaly with hypersplenism, Coombs-negative hemolytic anemia, portal hypertension, and neurologic or psychiatric abnormalities. Wilson disease should also be considered in persons under 40 years of age with chronic or fulminant hepatitis.

Hepatic involvement may range from elevated liver biochemical tests (although the alkaline phosphatase may be low) to cirrhosis and portal hypertension. In a patient with acute liver failure, the diagnosis of Wilson disease is suggested by an alkaline phosphatase (in units/L)-to-total bilirubin (in mg/dL) ratio < 4 and an AST-to-ALT ratio > 2.2. The neurologic manifestations of Wilson disease are related to basal ganglia dysfunction and include an akinetic-rigid syndrome similar to parkinsonism, pseudosclerosis with tremor, ataxia, and a dystonic syndrome. Dysarthria, dysphagia, incoordination, and spasticity are common. Migraines, insomnia, and seizures have been reported. Psychiatric features include behavioral and personality changes and emotional lability and may precede characteristic neurologic features. The pathognomonic sign of the condition is the brownish or gray-green Kayser-Fleischer ring, which represents fine pigmented granular deposits in Descemet membrane in the cornea (Figure 16–4). The ring is usually most marked at the superior and inferior poles of the cornea. It is sometimes seen with the naked eye and is readily detected by slit-lamp examination. It may be absent in patients with hepatic manifestations only but is usually present in those with neuropsychiatric disease. Renal calculi, aminoaciduria, renal tubular acidosis, hypoparathyroidism, infertility, and hemolytic anemia may occur in patients with Wilson disease.

 Figure 16–4. Brownish Kayser-Fleischer ring at the rim of the cornea in a patient with Wilson disease. (From Marc Solioz, University of Berne; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)

 Diagnosis

The diagnosis can be challenging, even with the use of scoring systems, and is generally based on demonstration of increased urinary copper excretion (> 40 mcg/24 h and usually > 100 mcg/24 h) or low serum ceruloplasmin levels (< 20 mg/dL [< 200 mg/L]; < 5 mg/dL [< 50 mg/L] is diagnostic), and elevated hepatic copper concentration (> 250 mcg/g of dry liver), as well as Kayser-Fleischer rings, neurologic symptoms, and Coombs-negative hemolytic anemia. However, increased urinary copper and a low serum ceruloplasmin level (by a standard immunologic assay) are neither completely sensitive nor specific for Wilson disease, although an enzymatic assay for ceruloplasmin appears to be more accurate. The ratio of exchangeable copper to total copper in serum has been reported to improve diagnostic accuracy. In equivocal cases (when the serum ceruloplasmin level is normal), the diagnosis may require demonstration of a rise in urinary copper after a penicillamine challenge, although the test has been validated only in children. Liver biopsy may show acute or chronic hepatitis or cirrhosis. MRI of the brain may show evidence of increased basal ganglia, brainstem, and cerebellar copper even early in the course of the disease. If available, molecular analysis of ATP7B mutations can be diagnostic.

 Treatment

Early treatment to remove excess copper before it can produce hepatic or neurologic damage is essential. Early in treatment, restriction of dietary copper (shellfish, organ foods, nuts, mushrooms, and chocolate) may be of value. Oral penicillamine (0.75–2 g/d in divided doses taken 1 h before or 2 h after food) is the drug of choice and enhances urinary excretion of chelated copper. Oral pyridoxine, 50 mg per week, is added because penicillamine is an antimetabolite of this vitamin. If penicillamine treatment cannot be tolerated because of gastrointestinal intolerance, hypersensitivity, autoimmune reactions, nephrotoxicity, or bone marrow toxicity, consider the use of trientine, 250–500 mg three times a day, a chelating agent as effective as penicillamine but with a lower rate of adverse effects. Oral zinc acetate or zinc gluconate, 50 mg three times a day, interferes with intestinal absorption of copper, promotes fecal copper excretion, and has been used as first-line therapy in presymptomatic or pregnant patients and those with neurologic disease and as maintenance therapy after decoppering with a chelating agent, but adverse gastrointestinal effects often lead to discontinuation and its long-term efficacy and safety (including a risk of hepatotoxicity) have been questioned. Ammonium tetrathiomolybdate, which complexes copper in the intestinal tract, has shown promise as initial therapy for neurologic Wilson disease.

Treatment should continue indefinitely. The doses of penicillamine and trientine should be reduced during pregnancy. Supplemental vitamin E, an antioxidant, has been recommended but not rigorously studied. Once the serum nonceruloplasmin copper level is within the normal range (50–150 mcg/L), the dose of chelating agent can be reduced to the minimum necessary for maintaining that level. The prognosis is good in patients who are effectively treated before liver or brain damage has occurred. Liver transplantation is indicated for fulminant hepatitis (often after plasma exchange or dialysis with MARS as a stabilizing measure), end-stage cirrhosis, and, in selected cases, intractable neurologic disease, although survival is lower when liver transplantation is undertaken for neurologic disease than for liver disease. Family members, especially siblings, require screening with serum ceruloplasmin, liver biochemical tests, and slit-lamp examination or, if the causative mutation is known, with mutation analysis.

 When to Refer

All patients with Wilson disease should be referred for diagnosis and treatment.

 When to Admit

• Acute liver failure.

• Gastrointestinal bleeding.

• Stage 3–4 hepatic encephalopathy.

• Worsening kidney function.

• Severe hyponatremia.

• Profound hypoxia.

HEPATIC VEIN OBSTRUCTION (Budd-Chiari Syndrome)

 General Considerations

Factors that predispose patients to hepatic vein obstruction, or Budd-Chiari syndrome, including hereditary and acquired hypercoagulable states, can be identified in 75% of affected patients; multiple disorders are found in up to 45%. Up to 50% of cases are associated with polycythemia vera or other myeloproliferative disease (which has a risk of Budd-Chiari syndrome of 1%). These cases (37% of patients with Budd-Chiari syndrome) are often associated with a specific mutation (V617F) in the gene that codes for JAK2 tyrosine kinase and may be subclinical. In some cases, other predispositions to thrombosis (eg, activated protein C resistance [factor V Leiden mutation] [25% of cases], protein C or S or antithrombin deficiency, hyperprothrombinemia [factor II G20210A mutation], the methylenetetrahydrofolate reductase TT677 mutation, antiphospholipid antibodies) can be identified. Hepatic vein obstruction may be associated with caval webs, right-sided heart failure or constrictive pericarditis, neoplasms that cause hepatic vein occlusion, paroxysmal nocturnal hemoglobinuria, Behçet syndrome, blunt abdominal trauma, use of oral contraceptives, and pregnancy. Some cytotoxic agents and pyrrolizidine alkaloids (Comfrey or “bush teas”) may cause sinusoidal obstruction syndrome (previously known as veno-occlusive disease because the terminal venules are often occluded), which mimics Budd-Chiari syndrome clinically. Sinusoidal obstruction syndrome is common in patients who have undergone hematopoietic stem cell transplantation, particularly those with pretransplant serum aminotransferase elevations or fever during cytoreductive therapy with cyclophosphamide, azathioprine, carmustine, busulfan, or etoposide or those receiving high-dose cytoreductive therapy or high-dose total body irradiation. In India, China, and South Africa, Budd-Chiari syndrome is associated with a poor standard of living and often the result of occlusion of the hepatic portion of the inferior vena cava, presumably due to prior thrombosis. The clinical presentation is mild but the course is frequently complicated by hepatocellular carcinoma.

 Clinical Findings

A. Symptoms and Signs

The presentation may be fulminant, acute, subacute, or chronic. An insidious (subacute) onset is most common. Clinical manifestations generally include tender, painful hepatic enlargement, jaundice, splenomegaly, and ascites. With chronic disease, bleeding varices and hepatic encephalopathy may be evident; hepatopulmonary syndrome may occur.

B. Imaging

Hepatic imaging studies may show a prominent caudate lobe, since its venous drainage may not be occluded. The screening test of choice is contrast-enhanced, color, or pulsed-Doppler ultrasonography, which has a sensitivity of 85% for detecting evidence of hepatic venous or inferior vena caval thrombosis. MRI with spin-echo and gradient-echo sequences and intravenous gadolinium injection allows visualization of the obstructed veins and collateral vessels. Direct venography can delineate caval webs and occluded hepatic veins (“spider-web” pattern) most precisely.

C. Liver Biopsy

Percutaneous or transjugular liver biopsy in Budd-Chiari syndrome may be considered when the results of noninvasive imaging are inconclusive and frequently shows characteristic centrilobular congestion and fibrosis and often multiple large regenerative nodules. Liver biopsy is often contraindicated in sinusoidal obstruction syndrome because of thrombocytopenia, and the diagnosis is based on clinical findings.

 Treatment

Ascites should be treated with fluid and salt restriction and diuretics. Treatable causes of Budd-Chiari syndrome should be sought. Prompt recognition and treatment of an underlying hematologic disorder may avoid the need for surgery; however, the optimal anticoagulation regimen is uncertain, and anticoagulation is associated with a high risk of bleeding, particularly in patients with portal hypertension and those undergoing invasive procedures. Low-molecular-weight heparins are preferred over unfractionated heparin because of a high rate of heparin-induced thrombocytopenia with the latter. Infusion of a thrombolytic agent into recently occluded veins has been attempted with success. Defibrotide, an adenosine receptor agonist that increases endogenous tissue plasminogen activator levels, has shown promise in the prevention and treatment of sinusoidal obstruction syndrome. TIPS placement may be attempted in patients with Budd-Chiari syndrome and persistent hepatic congestion or failed thrombolytic therapy and possibly in those with sinusoidal obstruction syndrome. Late TIPS dysfunction is less frequent with the use of polytetrafluoroethylene-covered stents than uncovered stents. TIPS is now preferred over surgical decompression (side-to-side portacaval, mesocaval, or mesoatrial shunt), which, in contrast to TIPS, has generally not been proven to improve long-term survival. Older age, a higher serum bilirubin level, and a greater INR predict a poor outcome with TIPS. Balloon angioplasty, in some cases with placement of an intravascular metallic stent, is preferred in patients with an inferior vena caval web and is being performed increasingly in patients with a short segment of thrombosis in the hepatic vein. Liver transplantation is considered in patients with fulminant hepatic failure, cirrhosis with hepatocellular dysfunction, and failure of a portosystemic shunt, and outcomes have improved with the advent of patient selection based on the MELD score. Patients with Budd-Chiari syndrome often require lifelong anticoagulation and treatment of the underlying myeloproliferative disease; antiplatelet therapy with aspirin and hydroxyurea has been suggested as an alternative to warfarin in patients with a myeloproliferative disorder. The overall 5-year survival rate is 50–90% with treatment (but <10% without intervention). Adverse prognostic factors in patients with Budd-Chiari syndrome are older age, high Child-Turcotte-Pugh score, ascites, encephalopathy, elevated total bilirubin, prolonged prothrombin time, elevated serum creatinine, concomitant portal vein thrombosis, and histologic features of acute liver disease superimposed on chronic liver injury; 3-month mortality may be predicted by the Rotterdam score, which is based on encephalopathy, ascites, prothrombin time, and bilirubin. A serum ALT level at least fivefold above the upper limit of normal on presentation indicates hepatic ischemia and also predicts a poor outcome, particularly when the ALT level decreases slowly.

 When to Admit

All patients with hepatic vein obstruction should be hospitalized.

THE LIVER IN HEART FAILURE

Ischemic hepatitis, also called ischemic hepatopathy, hypoxic hepatitis, shock liver, or acute cardiogenic liver injury may affect up to 10% of patients in an intensive care unit and results from an acute fall in cardiac output due to acute myocardial infarction, arrhythmia, or septic or hemorrhagic shock, usually in a patient with passive congestion of the liver. Clinical hypotension may be absent (or unwitnessed). In some cases, the precipitating event is arterial hypoxemia due to respiratory failure, sleep apnea, severe anemia, heat stroke, carbon monoxide poisoning, cocaine use, or bacterial endocarditis. More than one precipitant is common. The hallmark is a rapid and striking elevation of serum aminotransferase levels (often > 5000 units/L); an early rapid rise in the serum lactate dehydrogenase (LD) level (with an ALT-to-LD ratio < 1.5) is also typical. Elevations of serum alkaline phosphatase and bilirubin are usually mild, but jaundice is associated with worse outcomes. The prothrombin time may be prolonged, and encephalopathy or hepatopulmonary syndrome may develop. The mortality rate due to the underlying disease is high (particularly in patients receiving vasopressor therapy or with septic shock, acute kidney disease, or coagulopathy), but in patients who recover, the aminotransferase levels return to normal quickly, usually within 1 week—in contrast to viral hepatitis.

In patients with passive congestion of the liver (“nutmeg liver”) due to right-sided heart failure, the serum bilirubin level may be elevated, occasionally as high as 40 mg/dL (684 mcmol/L), due in part to hypoxia of perivenular hepatocytes, and the level is a predictor of mortality and morbidity. Serum alkaline phosphatase levels are normal or slightly elevated, and aminotransferase levels are only mildly elevated in the absence of superimposed ischemia. Hepatojugular reflux is present, and with tricuspid regurgitation the liver may be pulsatile. Ascites may be out of proportion to peripheral edema, with a high serum ascites-albumin gradient (≥ 1.1) and a protein content of more than 2.5 g/dL (25 g/L). A markedly elevated serum N-terminal-proBNP level has been reported to distinguish ascites due to heart failure from ascites due to cirrhosis. In severe cases, signs of encephalopathy may develop.

NONCIRRHOTIC PORTAL HYPERTENSION

 General Considerations

Causes of noncirrhotic portal hypertension include extrahepatic portal vein obstruction (portal vein thrombosis often with cavernous transformation [portal cavernoma]), splenic vein obstruction (presenting as gastric varices without esophageal varices), schistosomiasis, nodular regenerative hyperplasia, and arterial-portal vein fistula. Idiopathic noncirrhotic portal hypertension is common in India and has been attributed to chronic infections, exposure to medications or toxins, prothrombotic disorders, immunologic disorders, and genetic disorders that result in obliterative vascular lesions in the liver. It is rare in Western countries, where increased mortality is attributable to associated disorders and older age. Portal vein thrombosis may occur in 10–25% of patients with cirrhosis and may be associated with hepatocellular carcinoma. Other risk factors are oral contraceptive use, pregnancy, chronic inflammatory diseases (including pancreatitis), injury to the portal venous system (including surgery), other malignancies, and treatment of thrombocytopenia with eltrombopag. Splenic vein thrombosis may complicate pancreatitis or pancreatic cancer. Pylephlebitis (septic thrombophlebitis of the portal vein) may complicate intra-abdominal inflammatory disorders such as appendicitis or diverticulitis, particularly when anaerobic organisms (especially Bacteroides species) are involved. Nodular regenerative hyperplasia results from altered hepatic perfusion and can be associated with collagen vascular diseases; myeloproliferative disorders; and drugs, including azathioprine, 5-fluorouracil, and oxaliplatin. In patients infected with HIV, long-term use of didanosine and use of a combination of didanosine and stavudine have been reported to account for some cases of noncirrhotic portal hypertension often due to nodular regenerative hyperplasia, and genetic factors may play a role. The term obliterative portal venopathy is used to describe primary occlusion of intrahepatic portal veins in the absence of cirrhosis, inflammation, or hepatic neoplasia.

 Clinical Findings

A. Symptoms and Signs

Acute portal vein thrombosis usually causes abdominal pain. Aside from splenomegaly, the physical findings are not remarkable, although hepatic decompensation can follow severe gastrointestinal bleeding or a concurrent hepatic disorder, and intestinal infarction may occur when portal vein thrombosis is associated with mesenteric venous thrombosis. Ascites may occur in 25% of persons with noncirrhotic portal hypertension. Minimal hepatic encephalopathy is reported to be common in patients with noncirrhotic portal vein thrombosis.

B. Laboratory Findings

Liver biochemical test levels are usually normal, but there may be findings of hypersplenism. An underlying hypercoagulable state is found in many patients with portal vein thrombosis; this includes myeloproliferative disorders (often associated with a specific mutation [V617F] in the gene coding for JAK2 tyrosine kinase, which is found in 24% of cases of portal vein thrombosis), mutation G20210A of prothrombin, factor V Leiden mutation, protein C and S deficiency, antiphospholipid syndrome, mutation TT677 of methylenetetrahydrofolate reductase, elevated factor VIII levels, hyperhomocysteinemia, and a mutation in the gene that codes for thrombin-activatable fibrinolysis inhibitor. It is possible, however, that in many cases evidence of hypercoagulability is a secondary phenomenon due to portosystemic shunting and reduced hepatic blood flow.

C. Imaging

Color Doppler ultrasonography and contrast-enhanced CT are usually the initial diagnostic tests for portal vein thrombosis. Magnetic resonance angiography (MRA) of the portal system is generally confirmatory. Endoscopic ultrasonography may be helpful in some cases. In patients with jaundice, magnetic resonance cholangiography may demonstrate compression of the bile duct by a large portal cavernoma (portal biliopathy), a finding that may be more common in patients with an underlying hypercoagulable state than in those without one. In patients with pylephlebitis, CT may demonstrate an intra-abdominal source of infection, thrombosis or gas in the portal venous system, and a hepatic abscess.

D. Other Studies

Endoscopy shows esophageal or gastric varices. Needle biopsy of the liver may be indicated to diagnose schistosomiasis, nodular regenerative hyperplasia, and noncirrhotic portal fibrosis and may demonstrate sinusoidal dilatation.

 Treatment

If splenic vein thrombosis is the cause of variceal bleeding, splenectomy is curative. For other causes of noncirrhotic portal hypertension, band ligation (or sclerotherapy) followed by beta-blockers to reduce portal pressure is initiated for variceal bleeding, and portosystemic shunting (including TIPS) is reserved for failures of endoscopic therapy; rarely progressive liver dysfunction requires liver transplantation. Anticoagulation particularly with low-molecular-weight heparin or thrombolytic therapy may be indicated for isolated acute portal vein thrombosis (and leads to at least partial recanalization in up to 75% of cases) and possibly for acute splenic vein thrombosis; it is continued long-term if a hypercoagulable disorder is identified or if an acute portal vein thrombosis extends into the mesenteric veins. The use of enoxaparin to prevent portal vein thrombosis and hepatic decompensation in patients with cirrhosis has shown promise.

 When to Refer

All patients with noncirrhotic portal hypertension should be referred.

PYOGENIC HEPATIC ABSCESS

 General Considerations

The incidence of liver abscess is 3.6 per 100,000 population in the United States and has increased since the 1990s. The liver can be invaded by bacteria via (1) the bile duct (ascending cholangitis); (2) the portal vein (pylephlebitis); (3) the hepatic artery, secondary to bacteremia; (4) direct extension from an infectious process; and (5) traumatic implantation of bacteria through the abdominal wall. Risk factors for liver abscess include older age and male gender. Predisposing conditions include malignancy, diabetes mellitus, inflammatory bowel disease, cirrhosis, and liver transplantation.

Ascending cholangitis resulting from biliary obstruction due to a stone, stricture, or neoplasm is the most common identifiable cause of hepatic abscess in the United States. In 10% of cases, liver abscess is secondary to appendicitis or diverticulitis. At least 40% of abscesses have no demonstrable cause and are classified as cryptogenic; a dental source is identified in some cases. The most frequently encountered organisms are E coli, Klebsiella pneumoniae, Proteus vulgaris, Enterobacter aerogenes, and multiple microaerophilic and anaerobic species (eg, Streptococcus milleri). Liver abscess caused by virulent strains of K pneumoniae may be associated with thrombophlebitis of the portal or hepatic veins and hematogenously spread septic ocular or central nervous system complications. Staphylococcus aureus is usually the causative organism in patients with chronic granulomatous disease. Uncommon causative organisms include Salmonella, Haemophilus, Yersinia, and Listeria. Hepatic candidiasis, tuberculosis, and actinomycosis are seen in immunocompromised patients and those with hematologic malignancies. Rarely, hepatocellular carcinoma can present as a pyogenic abscess because of tumor necrosis, biliary obstruction, and superimposed bacterial infection (see Chapter 39). The possibility of an amebic liver abscess must always be considered (see Chapter 35).

 Clinical Findings

A. Symptoms and Signs

The presentation is often insidious. Fever is almost always present and may antedate other symptoms or signs. Pain may be a prominent complaint and is localized to the right upper quadrant or epigastric area. Jaundice, tenderness in the right upper abdomen, and either steady or spiking fever are the chief physical findings.

B. Laboratory Findings

Laboratory examination reveals leukocytosis with a shift to the left. Liver biochemical tests are nonspecifically abnormal. Blood cultures are positive in 50–100% of cases.

C. Imaging

Chest radiographs usually reveal elevation of the diaphragm if the abscess is in the right lobe of the liver. Ultrasonography, CT, or MRI may reveal the presence of intrahepatic lesions. On MRI, characteristic findings include high signal intensity on T2-weighted images and rim enhancement. The characteristic CT appearance of hepatic candidiasis, usually seen in the setting of systemic candidiasis, is that of multiple “bull’s-eyes,” but imaging studies may be negative in neutropenic patients.

 Treatment

Treatment should consist of antimicrobial agents (generally a third-generation cephalosporin such as cefoperazone 1–2 g intravenously every 12 hours and metronidazole 500 mg intravenously every 6 hours) that are effective against coliform organisms and anaerobes. Antibiotics are administered for 2–3 weeks, and sometimes up to 6 weeks. If the abscess is at least 5 cm in diameter or the response to antibiotic therapy is not rapid, intermittent needle aspiration, percutaneous or endoscopic ultrasound-guided catheter drainage or, if necessary, surgical (eg, laparoscopic) drainage should be done. Other suggested indications for abscess drainage are patient age of at least 55 years, symptom duration of at least 7 days, and involvement of two lobes of the liver. The underlying source (eg, biliary disease, dental infection) should be identified and treated. The mortality rate is still substantial (≥ 5% in most studies) and is highest in patients with underlying biliary malignancy or severe multiorgan dysfunction. Other risk factors for mortality include older age, cirrhosis, chronic kidney disease, and other cancers. Hepatic candidiasis often responds to intravenous amphotericin B (total dose of 2–9 g). Fungal abscesses are associated with mortality rates of up to 50% and are treated with intravenous amphotericin B and drainage.

 When to Admit

Nearly all patients with pyogenic hepatic abscess should be hospitalized.

BENIGN LIVER NEOPLASMS

Benign neoplasms of the liver must be distinguished from hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and metastases (see Chapter 39). The most common benign neoplasm of the liver is the cavernous hemangioma, often an incidental finding on ultrasonography or CT. This lesion may enlarge in women who take hormonal therapy and must be differentiated from other space-occupying intrahepatic lesions, usually by contrast-enhanced MRI, CT, or ultrasonography. Rarely, fine-needle biopsy is necessary to differentiate these lesions and does not appear to carry an increased risk of bleeding. Surgical resection of cavernous hemangiomas is rarely necessary but may be required for abdominal pain or rapid enlargement, to exclude malignancy, or to treat Kasabach-Merritt syndrome (consumptive coagulopathy complicating a hemangioma).

In addition to rare instances of sinusoidal dilatation and peliosis hepatis, two distinct benign lesions with characteristic clinical, radiologic, and histopathologic features have been described in women taking oral contraceptives—focal nodular hyperplasia and hepatocellular adenoma. Focal nodular hyperplasia occurs at all ages and in both sexes and is probably not caused by the oral contraceptives. It is often asymptomatic and appears as a hypervascular mass, often with a central hypodense “stellate” scar on CT or MRI. Microscopically, focal nodular hyperplasia consists of hyperplastic units of hepatocytes that stain positively for glutamine synthetase with a central stellate scar containing proliferating bile ducts. It is not a true neoplasm but a proliferation of hepatocytes in response to altered blood flow. Focal nodular hyperplasia is associated with an elevated angiopoietin 1/angiopoietin 2 mRNA ratio that is thought to promote angiogenesis and may also occur in patients with cirrhosis, with exposure to certain drugs such as azathioprine, and in antiphospholipid syndrome. The prevalence of hepatic hemangiomas is increased in patients with focal nodular hyperplasia.

Hepatocellular adenoma occurs most commonly in women in the third and fourth decades of life and is usually caused by oral contraceptives; acute abdominal pain may occur if the tumor undergoes necrosis or hemorrhage. The tumor may be associated with mutations in: (1) the gene coding for hepatocyte nuclear factor 1 alpha (HNF1alpha) in 30–40% of cases (characterized by steatosis and a low risk of malignant transformation, although in men concomitant metabolic syndrome appears to increase the risk of malignant transformation); (2) the gene coding for beta-catenin (characterized by a high rate of malignant transformation) in 10–15% of cases; or (3) neither gene with the designation inflammatory adenoma (previously termed “telangiectatic focal nodular hyperplasia”), which is associated with a high body mass index and serum biomarkers of inflammation (such as C-reactive protein) in 40–50% of cases. Unclassified adenomas account for 10% of tumors. Rare instances of multiple hepatocellular adenomas in association with maturity-onset diabetes of the young occur in families with a germline mutation in HNF1alpha. Hepatocellular adenomas also occur in patients with glycogen storage disease (inflammatory or unclassified adenomas) and familial adenomatous polyposis. The tumor is hypovascular. Grossly, the cut surface appears structureless. As seen microscopically, the hepatocellular adenoma consists of sheets of hepatocytes without portal tracts or central veins.

Cystic neoplasms of the liver, such as cystadenoma and cystadenocarcinoma, must be distinguished from simple and echinococcal cysts, von Meyenburg complexes (hamartomas), and polycystic liver disease.

 Clinical Findings

The only physical finding in focal nodular hyperplasia or hepatocellular adenoma is a palpable abdominal mass in a minority of cases. Liver function is usually normal. Arterial phase helical CT and MRI with contrast can distinguish an adenoma from focal nodular hyperplasia in 80–90% of cases and may suggest a specific subtype of adenoma (eg, homogeneous fat pattern in HNF1alpha-mutated adenomas and marked and persistent arterial enhancement in inflammatory adenomas).

 Treatment

Treatment of focal nodular hyperplasia is resection only in the symptomatic patient; rarely is liver transplantation necessary. The prognosis is excellent. Hepatocellular adenoma may undergo bleeding, necrosis, and rupture, often after hormone therapy, in the third trimester of pregnancy, or in men in whom the rate of malignant transformation is high. Resection is advised in all affected men and in women in whom the tumor causes symptoms or is > 5 cm in diameter, even in the absence of symptoms. If an adenoma is < 5 cm in size, resection is also recommended if a beta-catenin gene mutation is present in a biopsy sample. In selected cases, laparoscopic resection or percutaneous radiofrequency ablation may be feasible. Regression of benign hepatic tumors may follow cessation of oral contraceptives.

 When to Refer

• Diagnostic uncertainty.

• For surgery.

 When to Admit

• Severe pain.

• Rupture.

DISEASES OF THE BILIARY TRACT

See Chapter 39 for Carcinoma of the Biliary Tract.

CHOLELITHIASIS (Gallstones)

 General Considerations

Gallstones are more common in women than in men and increase in incidence in both sexes and all races with age. In the United States, the prevalence of gallstones is 8.6% in women and 5.5% in men, with the highest rates in persons over age 60 and higher rates in Mexican-Americans than in non-Hispanic whites and African Americans, and gallstone disease is associated with increased overall, cardiovascular, and cancer mortality. Although cholesterol gallstones are less common in black people, cholelithiasis attributable to hemolysis occurs in over a third of individuals with sickle cell disease. Native Americans of both the Northern and Southern Hemispheres have a high rate of cholesterol cholelithiasis, probably because of a predisposition resulting from “thrifty” (LITH) genes that promote efficient calorie utilization and fat storage. As many as 75% of Pima and other American Indian women over the age of 25 years have cholelithiasis. Other genetic mutations that predispose persons to gallstones have been identified. Obesity is a risk factor for gallstones, especially in women. Rapid weight loss, as occurs after bariatric surgery, also increases the risk of symptomatic gallstone formation. Diabetes mellitus, glucose intolerance, and insulin resistance are risk factors for gallstones, and a high intake of carbohydrate and high dietary glycemic load increase the risk of cholecystectomy in women. Hypertriglyceridemia may promote gallstone formation by impairing gallbladder motility. The prevalence of gallbladder disease is increased in men (but not women) with cirrhosis and hepatitis C virus infection. Moreover, cholecystectomy has been reported to be associated with an increased risk of NAFLD and cirrhosis, possibly because gallstones and liver disease have some risk factors in common. A low-carbohydrate diet, physical activity, and cardiorespiratory fitness may help prevent gallstones. Consumption of caffeinated coffee appears to protect against gallstones in women, and a high intake of magnesium and of polyunsaturated and monounsaturated fats reduces the risk of gallstones in men. A diet high in fiber, a diet rich in fruits and vegetables, and statin use reduce the risk of cholecystectomy, particularly in women. The incidence of gallstones is high in individuals with Crohn disease; approximately one-third of those with inflammatory involvement of the terminal ileum have gallstones due to disruption of bile salt resorption that results in decreased solubility of the bile. Drugs such as clofibrate, octreotide, and ceftriaxone can cause gallstones. In contrast, aspirin and other nonsteroidal anti-inflammatory drugs may protect against gallstones. Prolonged fasting (over 5–10 days) can lead to formation of biliary “sludge” (microlithiasis), which usually resolves with refeeding but can lead to gallstones or biliary symptoms. Pregnancy, particularly in obese women and those with insulin resistance, is associated with an increased risk of gallstones and of symptomatic gallbladder disease. Hormone replacement therapy appears to increase the risk of gallbladder disease and need for cholecystectomy; the risk is lower with transdermal than oral therapy.

Gallstones are classified according to their predominant chemical composition as cholesterol or calcium bilirubinate stones. The latter comprise < 20% of the stones found in Europe or the United States but 30–40% of stones found in Japan.

 Clinical Findings

Table 16–7 lists the clinical and laboratory features of several diseases of the biliary tract as well as their treatment. Cholelithiasis is frequently asymptomatic and is discovered in the course of routine radiographic study, operation, or autopsy. Symptoms (biliary [or “episodic gallbladder”] pain) develop in 10–25% of patients (1–4% annually), and acute cholecystitis develops in 20% of these symptomatic persons over time. Occasionally, small intestinal obstruction due to “gallstone ileus” (or Bouveret syndrome when the obstructing stone is in pylorus or duodenum) presents as the initial manifestation of cholelithiasis.

 Treatment

Nonsteroidal anti-inflammatory drugs (eg, diclofenac 50–75 mg intramuscularly) can be used to relieve biliary pain. Laparoscopic cholecystectomy is the treatment of choice for symptomatic gallbladder disease. Pain relief after cholecystectomy is most likely in patients with episodic pain (generally once a month or less), pain lasting 30 minutes to 24 hours, pain in the evening or at night, and the onset of symptoms 1 year or less before presentation. Patients may go home within 1 day of the procedure and return to work within days (instead of weeks for those undergoing open cholecystectomy). The procedure is often performed on an outpatient basis and is suitable for most patients, including those with acute cholecystitis. Conversion to a conventional open cholecystectomy may be necessary in 2–8% of cases (higher for acute cholecystitis than for uncomplicated cholelithiasis). Bile duct injuries occur in 0.1% of cases done by experienced surgeons. There is generally no need for prophylactic cholecystectomy in an asymptomatic person unless the gallbladder is calcified, gallstones are > 3 cm in diameter, or the patient is a Native American or a candidate for bariatric surgery or cardiac transplantation. Cholecystectomy may increase the risk of esophageal, proximal small intestinal, and colonic adenocarcinomas because of increased duodenogastric reflux and changes in intestinal exposure to bile. In pregnant patients a conservative approach to biliary pain is advised, but for patients with repeated attacks of biliary pain or acute cholecystitis, cholecystectomy can be performed—even by the laparoscopic route—preferably in the second trimester. Enterolithotomy alone is considered adequate treatment in most patients with gallstone ileus. Cholecystectomy via natural orifice translumenal endoscopic surgery (NOTES) has been performed and is under study.

Ursodeoxycholic acid is a bile salt that when given orally for up to 2 years dissolve some cholesterol stones and may be considered in occasional, selected patients who refuse cholecystectomy. The dose is 8–13 mg/kg in divided doses daily. It is most effective in patients with a functioning gallbladder, as determined by gallbladder visualization on oral cholecystography, and multiple small “floating” gallstones (representing not more than 15% of patients with gallstones). In half of patients, gallstones recur within 5 years after treatment is stopped. Ursodeoxycholic acid, 500–600 mg daily, reduces the risk of gallstone formation with rapid weight loss. Lithotripsy in combination with bile salt therapy for single radiolucent stones < 20 mm in diameter was an option in the past but is no longer generally used in the United States.

 When to Refer

Patients should be referred when they require surgery.

ACUTE CHOLECYSTITIS

 General Considerations

Cholecystitis is associated with gallstones in over 90% of cases. It occurs when a stone becomes impacted in the cystic duct and inflammation develops behind the obstruction. Acalculous cholecystitis should be considered when unexplained fever or right upper quadrant pain occurs within 2–4 weeks of major surgery or in a critically ill patient who has had no oral intake for a prolonged period; multiorgan failure is often present. Acute cholecystitis may be caused by infectious agents (eg, cytomegalovirus, cryptosporidiosis, or microsporidiosis) in patients with AIDS or by vasculitis (eg, polyarteritis nodosa, Henoch-Schönlein purpura).

 Clinical Findings

A. Symptoms and Signs

The acute attack is often precipitated by a large or fatty meal and is characterized by the sudden appearance of steady pain localized to the epigastrium or right hypochondrium, which may gradually subside over a period of 12–18 hours. Vomiting occurs in about 75% of patients and in half of instances affords variable relief. Fever is typical. Right upper quadrant abdominal tenderness (often with a Murphy sign, or inhibition of inspiration by pain on palpation of the right upper quadrant) is almost always present and is usually associated with muscle guarding and rebound tenderness (Table 16–7). A palpable gallbladder is present in about 15% of cases. Jaundice is present in about 25% of cases and, when persistent or severe, suggests the possibility of choledocholithiasis.

B. Laboratory Findings

The white blood cell count is usually high (12,000–15,000/mcL [12–15 × 10⁹/L]). Total serum bilirubin values of 1–4 mg/dL (17.1–68.4 mcmol/L) may be seen even in the absence of bile duct obstruction. Serum aminotransferase and alkaline phosphatase levels are often elevated—the former as high as 300 units/mL, and even higher when associated with ascending cholangitis. Serum amylase may also be moderately elevated.

C. Imaging

Plain films of the abdomen may show radiopaque gallstones in 15% of cases. ^99mTc hepatobiliary imaging (using iminodiacetic acid compounds), also known as the hepatic iminodiacetic acid (HIDA) scan, is useful in demonstrating an obstructed cystic duct, which is the cause of acute cholecystitis in most patients. This test is reliable if the bilirubin is under 5 mg/dL (85.5 mcmol/L) (98% sensitivity and 81% specificity for acute cholecystitis). False-positive results can occur with prolonged fasting, liver disease, and chronic cholecystitis, and the specificity can be improved by intravenous administration of morphine, which induces spasm of the sphincter of Oddi. Right upper quadrant abdominal ultrasonography, which is often performed first, may show gallstones but is not as sensitive for acute cholecystitis (67% sensitivity, 82% specificity); findings suggestive of acute cholecystitis are gallbladder wall thickening, pericholecystic fluid, and a sonographic Murphy sign. CT may show complications of acute cholecystitis, such as perforation or gangrene.

 Differential Diagnosis

The disorders most likely to be confused with acute cholecystitis are perforated peptic ulcer, acute pancreatitis, appendicitis in a high-lying appendix, perforated colonic carcinoma or diverticulum of the hepatic flexure, liver abscess, hepatitis, pneumonia with pleurisy on the right side, and even myocardial ischemia. Definite localization of pain and tenderness in the right upper quadrant, with radiation around to the infrascapular area, strongly favors the diagnosis of acute cholecystitis. True cholecystitis without stones suggests acalculous cholecystitis.

 Complications

A. Gangrene of the Gallbladder

Continuation or progression of right upper quadrant abdominal pain, tenderness, muscle guarding, fever, and leukocytosis after 24–48 hours suggests severe inflammation and possible gangrene of the gallbladder, resulting from ischemia due to splanchnic vasoconstriction and intravascular coagulation. Necrosis may occasionally develop without specific signs in the obese, diabetic, elderly, or immunosuppressed patient. Gangrene may lead to gallbladder perforation, usually with formation of a pericholecystic abscess, and rarely to generalized peritonitis. Other serious acute complications include emphysematous cholecystitis (secondary infection with a gas-forming organism) and empyema.

B. Chronic Cholecystitis and Other Complications

Chronic cholecystitis results from repeated episodes of acute cholecystitis or chronic irritation of the gallbladder wall by stones and is characterized pathologically by varying degrees of chronic inflammation of the gallbladder. Calculi are usually present. In about 4–5% of cases, the villi of the gallbladder undergo polypoid enlargement due to deposition of cholesterol that may be visible to the naked eye (“strawberry gallbladder,” cholesterolosis). In other instances, hyperplasia of all or part of the gallbladder wall may be so marked as to give the appearance of a myoma (adenomyomatosis). Hydrops of the gallbladder results when acute cholecystitis subsides but cystic duct obstruction persists, producing distention of the gallbladder with a clear mucoid fluid. Occasionally, a stone in the neck of the gallbladder may compress the common hepatic duct and cause jaundice (Mirizzi syndrome). Xanthogranulomatous cholecystitis is a rare variant of chronic cholecystitis characterized by grayish-yellow nodules or streaks, representing lipid-laden macrophages, in the wall of the gallbladder.

Cholelithiasis with chronic cholecystitis may be associated with acute exacerbations of gallbladder inflammation, bile duct stone, fistulization to the bowel, pancreatitis and, rarely, carcinoma of the gallbladder. Calcified (porcelain) gallbladder is associated with gallbladder carcinoma and is generally an indication for cholecystectomy; the risk of gallbladder cancer may be higher when calcification is mucosal rather than intramural.

 Treatment

Acute cholecystitis will usually subside on a conservative regimen (withholding of oral feedings, intravenous alimentation, analgesics, and intravenous antibiotics—generally a second- or third-generation cephalosporin such as cefoperazone, 1–2 g intravenously every 12 hours, with the addition of metronidazole, 500 mg intravenously every 6 hours; in severe cases, a fluoroquinolone such as ciprofloxacin, 250 mg intravenously every 12 hours, plus metronidazole may be given). Morphine or meperidine may be administered for pain. Because of the high risk of recurrent attacks (up to 10% by 1 month and over 30% by 1 year), cholecystectomy—generally laparoscopically—should generally be performed within 24 hours of admission to the hospital for acute cholecystitis. If nonsurgical treatment has been elected, the patient (especially if diabetic or elderly) should be watched carefully for recurrent symptoms, evidence of gangrene of the gallbladder, or cholangitis. In high-risk patients, ultrasound-guided aspiration of the gallbladder, if feasible, percutaneous cholecystostomy, or endoscopic insertion of a stent or nasobiliary drain into the gallbladder may postpone or even avoid the need for surgery. Immediate cholecystectomy is mandatory when there is evidence of gangrene or perforation.

Surgical treatment of chronic cholecystitis is the same as for acute cholecystitis. If indicated, cholangiography can be performed during laparoscopic cholecystectomy. Choledocholithiasis can also be excluded by either preoperative or postoperative ERCP or MRCP.

 Prognosis

The overall mortality rate of cholecystectomy is < 0.2%, but hepatobiliary tract surgery is a more formidable procedure in the elderly, in whom mortality rates are higher; mortality rates are also higher in persons with diabetes mellitus. A technically successful surgical procedure in an appropriately selected patient is generally followed by complete resolution of symptoms.

 When to Admit

All patients with acute cholecystitis should be hospitalized.

PRE- & POSTCHOLECYSTECTOMY SYNDROMES

1. Precholecystectomy

In a small group of patients (mostly women) with biliary pain, conventional radiographic studies of the upper gastrointestinal tract and gallbladder—including cholangiography—are unremarkable. Emptying of the gallbladder may be markedly reduced on gallbladder scintigraphy following injection of cholecystokinin; cholecystectomy may be curative in such cases. Histologic examination of the resected gallbladder may show chronic cholecystitis or microlithiasis. An additional diagnostic consideration is sphincter of Oddi dysfunction (see below).

2. Postcholecystectomy

Following cholecystectomy, some patients complain of continuing symptoms, ie, right upper quadrant pain, flatulence, and fatty food intolerance. The persistence of symptoms in this group of patients suggests the possibility of an incorrect diagnosis prior to cholecystectomy, eg, esophagitis, pancreatitis, radiculopathy, or functional bowel disease. Choledocholithiasis or bile duct stricture should be ruled out. Pain may also be associated with dilatation of the cystic duct remnant, neuroma formation in the ductal wall, foreign body granuloma, or traction on the bile duct by a long cystic duct.

The clinical presentation of right upper quadrant pain, chills, fever, or jaundice suggests biliary tract disease. Endoscopic ultrasonography or retrograde cholangiography may be necessary to demonstrate a stone or stricture. Biliary pain associated with elevated liver biochemical tests or a dilated bile duct in the absence of an obstructing lesion suggests sphincter of Oddi dysfunction. Biliary manometry may be useful for documenting elevated baseline sphincter of Oddi pressures typical of sphincter dysfunction when biliary pain is associated with elevated liver biochemical tests (twofold) or a dilated bile duct (> 12 mm) (type II sphincter of Oddi dysfunction) but is not necessary when both are present (type I sphincter of Oddi dysfunction) and is associated with a high risk of pancreatitis. In the absence of either elevated liver biochemical tests or a dilated bile duct (type III sphincter of Oddi dysfunction), a nonbiliary source of symptoms should be suspected. (Analogous criteria have been developed for pancreatic sphincter dysfunction.) Biliary scintigraphy after intravenous administration of morphine and MRCP following intravenous administration of secretin are under study as screening tests for sphincter dysfunction. Endoscopic sphincterotomy is most likely to relieve symptoms in patients with types I or II sphincter of Oddi dysfunction or an elevated sphincter of Oddi pressure, although many patients continue to have some pain. In some cases, treatment with a calcium channel blocker, long-acting nitrate, or phosphodiesterase inhibitor (eg, vardenafil) or possibly injection of the sphincter with botulinum toxin may be beneficial. In refractory cases, surgical sphincteroplasty or removal of the cystic duct remnant may be considered.

 When to Refer

Patients with sphincter of Oddi dysfunction should be referred for diagnostic procedures.

CHOLEDOCHOLITHIASIS & CHOLANGITIS

 General Considerations

About 15% of patients with gallstones have choledocholithiasis (bile duct stones). The percentage rises with age, and the frequency in elderly people with gallstones may be as high as 50%. Bile duct stones usually originate in the gallbladder but may also form spontaneously in the bile duct after cholecystectomy. The risk is increased twofold in persons with a juxtapapillary duodenal diverticulum. Symptoms result if there is obstruction.

 Clinical Findings

A. Symptoms and Signs

A history of biliary pain or jaundice may be obtained. Biliary pain results from rapid increases in bile duct pressure due to obstructed bile flow. The features that suggest the presence of a bile duct stone are: (1) frequently recurring attacks of right upper abdominal pain that is severe and persists for hours; (2) chills and fever associated with severe pain; and (3) a history of jaundice associated with episodes of abdominal pain (Table 16–7). The combination of pain, fever (and chills), and jaundice represents Charcot triad and denotes the classic picture of acute cholangitis. The addition of altered mental status and hypotension (Reynolds pentad) signifies acute suppurative cholangitis and is an endoscopic emergency. According to the Tokyo guidelines (2006), the diagnosis of acute cholangitis is established by the presence of (1) the Charcot triad; or (2) two elements of the Charcot triad plus laboratory evidence of an inflammatory response (eg, elevated white blood cell count, C-reactive protein), elevated liver biochemical test levels, and imaging evidence of biliary dilatation or a cause of obstruction.

Hepatomegaly may be present in calculous biliary obstruction, and tenderness is usually present in the right upper quadrant and epigastrium. Bile duct obstruction lasting > 30 days results in liver damage leading to cirrhosis. Hepatic failure with portal hypertension occurs in untreated cases.

B. Laboratory Findings

Acute obstruction of the bile duct typically produces a transient albeit striking increase in serum aminotransferase levels (often > 1000 units/L [20 mckat/L]). Bilirubinuria and elevation of the serum bilirubin are present if the bile duct remains obstructed; levels commonly fluctuate. Serum alkaline phosphatase levels rise more slowly. Not uncommonly, serum amylase elevations are present because of secondary pancreatitis. When extrahepatic obstruction persists for more than a few weeks, differentiation of obstruction from chronic cholestatic liver disease becomes more difficult. Leukocytosis is present in patients with acute cholangitis. Prolongation of the prothrombin time can result from the obstructed flow of bile to the intestine. In contrast to hepatocellular dysfunction, hypoprothrombinemia due to obstructive jaundice will respond to 10 mg of intravenous vitamin K or water-soluble oral vitamin K (phytonadione, 5 mg) within 24–36 hours.

C. Imaging

Ultrasonography and CT may demonstrate dilated bile ducts, and radionuclide imaging may show impaired bile flow. Endoscopic ultrasonography, helical CT, and magnetic resonance cholangiography are accurate in demonstrating bile duct stones and may be used in patients thought to be at intermediate risk for choledocholithiasis (age > 55 years, cholecystitis, bile duct diameter > 6 mm on ultrasonography, serum bilirubin 1.8–4 mg/dL [30.78–68.4 mcmol/L], elevated serum liver enzymes, pancreatitis). ERCP (occasionally with intraductal ultrasonography) or percutaneous transhepatic cholangiography provides the most direct and accurate means of determining the cause, location, and extent of obstruction. If the likelihood that obstruction is caused by a stone is high (bile duct diameter > 6 mm, bile duct stone seen on ultrasonography, serum bilirubin > 4 mg/dL [68.4 mcmol/L]) or acute cholangitis is present, ERCP is the procedure of choice because it permits sphincterotomy with stone extraction or stent placement. Meticulous technique is required to avoid causing acute cholangitis.

 Differential Diagnosis

The most common cause of obstructive jaundice is a bile duct stone. Next in frequency are neoplasms of the pancreas, ampulla of Vater, or bile duct or an obstructed stent placed previously for decompression of an obstructing tumor. Extrinsic compression of the bile duct may result from metastatic carcinoma (usually from the gastrointestinal tract or breast) involving porta hepatis lymph nodes or, rarely, from a large duodenal diverticulum. Gallbladder cancer extending into the bile duct often presents as obstructive jaundice. Chronic cholestatic liver diseases (primarily biliary cirrhosis, sclerosing cholangitis, drug-induced) must be considered. Hepatocellular jaundice can usually be differentiated by the history, clinical findings, and liver biochemical tests, but liver biopsy is necessary on occasion. Recurrent pyogenic cholangitis should be considered in persons from Asia (and occasionally elsewhere) with intrahepatic biliary stones (particularly in the left ductal system) and recurrent cholangitis.

 Treatment

In general, bile duct stones should be removed, even in an asymptomatic patient. A bile duct stone in a patient with cholelithiasis or cholecystitis is usually treated by endoscopic sphincterotomy and stone extraction followed by laparoscopic cholecystectomy within 72 hours in patients with cholecystitis and within 2 weeks in those without cholecystitis. An alternative approach, which may be associated with a shorter duration of hospitalization, is laparoscopic cholecystectomy and bile duct exploration. For the elderly (> 70 years) or poor-risk patient with cholelithiasis and choledocholithiasis, cholecystectomy may be deferred after endoscopic sphincterotomy because the risk of subsequent cholecystitis is low. ERCP with sphincterotomy should be performed before cholecystectomy in patients with gallstones and cholangitis, jaundice (serum total bilirubin > 4 mg/dL [68.4 mcmol/L]), a dilated bile duct (> 6 mm), or stones in the bile duct seen on ultrasonography or CT. (Stones may ultimately recur in up to 12% of patients, particularly in the elderly, when the bile duct diameter is ≥ 15 mm or when brown pigment stones are found at the time of the initial sphincterotomy.) Endoscopic balloon dilation of the sphincter of Oddi may be associated with a higher rate of pancreatitis than endoscopic sphincterotomy unless adequate dilation for > 1 min is carried out. This procedure is generally reserved for patients with coagulopathy because the risk of bleeding is lower with balloon dilation than with sphincterotomy. Endoscopic ultrasound-guided biliary drainage and PTC with drainage are second-line approaches if ERCP fails or is not possible. In patients with biliary pancreatitis that resolves rapidly, the stone usually passes into the intestine, and ERCP prior to cholecystectomy is not necessary if an intraoperative cholangiogram is planned.

Choledocholithiasis discovered at laparoscopic cholecystectomy may be managed via laparoscopic or, if necessary, open bile duct exploration or by postoperative endoscopic sphincterotomy. Operative findings of choledocholithiasis are palpable stones in the bile duct, dilatation or thickening of the wall of the bile duct, or stones in the gallbladder small enough to pass through the cystic duct. Laparoscopic intraoperative cholangiography (or intraoperative ultrasonography) should be done at the time of cholecystectomy in patients with liver enzyme elevations but a bile duct diameter of <5 mm; if a ductal stone is found, the duct should be explored. In the post-cholecystectomy patient with choledocholithiasis, endoscopic sphincterotomy with stone extraction is preferable to transabdominal surgery. Lithotripsy (endoscopic or external), direct choledoscopy (cholangioscopy), or biliary stenting may be a therapeutic consideration for large stones. For the patient with a T tube and bile duct stone, the stone may be extracted via the T tube.

Postoperative antibiotics are not administered routinely after biliary tract surgery. Cultures of the bile are always taken at operation. If biliary tract infection was present preoperatively or is apparent at operation, ampicillin (500 mg every 6 hours intravenously) with gentamicin (1.5 mg/kg intravenously every 8 hours) and metronidazole (500 mg intravenously every 6 hours) or ciprofloxacin (250 mg intravenously every 12 hours) or a third-generation cephalosporin (eg, cefoperazone, 1–2 g intravenous every 12 hours) is administered postoperatively until the results of sensitivity tests on culture specimens are available. A T-tube cholangiogram should be done before the tube is removed, usually about 3 weeks after surgery. A small amount of bile frequently leaks from the tube site for a few days.

Urgent ERCP with sphincterotomy and stone extraction is generally indicated for choledocholithiasis complicated by acute cholangitis and is preferred to surgery. Before ERCP, liver function should be evaluated thoroughly. The prothrombin time should be restored to normal by intravenous administration of vitamin K (see above). For mild-to-moderately severe community-acquired acute cholangitis, ciprofloxacin, 500 mg intravenously every 12 hours, penetrates well into bile and is effective treatment, with the possible addition of metronidazole, 500 mg every 6–8 hours. Alternative regimens include intravenous cefoxitin, 1–2 g every 6 hours, ampicillin, 2 g every 6 hours, plus gentamicin, 1.7 mg/kg every 8 hours, or ceftriaxone 1–2 g daily, among others. Regimens for severe or hospital-acquired acute cholangitis include intravenous piperacillin and tazobactam, 3.375 g every 6 hours; ticarcillin and clavulanate, 3.1 g every 6 hours; ceftriaxone, 1–2 g daily, plus metronidazole, 500 mg every 6–8 hours; or, in patients at high risk for harboring antibiotic-resistant pathogens, meropenem, 1 g every 8 hours. Aminoglycosides should not be given for more than a few days because the risk of aminoglycoside nephrotoxicity is increased in patients with cholestasis. Regimens that include drugs active against anaerobes are required when a biliary-enteric communication is present. Emergent decompression of the bile duct, generally by ERCP, is required for patients who are septic or fail to improve on antibiotics within 12–24 hours. Medical therapy alone is most likely to fail in patients with tachycardia, serum albumin < 3 g/dL (30 g/L), marked hyperbilirubinemia, high serum ALT level, high white blood cell count, and prothrombin time > 14 seconds on admission. If sphincterotomy cannot be performed, the bile duct can be decompressed by a biliary stent or nasobiliary catheter. Once decompression is achieved, antibiotics are generally continued for at least another 3 days. Elective cholecystectomy can be undertaken after resolution of cholangitis, unless the patient remains unfit for surgery. Mortality from acute cholangitis has been reported to correlate with a high total bilirubin level, prolonged partial thromboplastin time, and presence of a liver abscess.

 When to Refer

All symptomatic patients with choledocholithiasis should be referred.

 When to Admit

All patients with acute cholangitis should be hospitalized.

BILIARY STRICTURE

Benign biliary strictures are the result of surgical (including liver transplantation) anastomosis or injury in about 95% of cases. The remainder of cases are caused by blunt external injury to the abdomen, pancreatitis, erosion of the duct by a gallstone, or prior endoscopic sphincterotomy.

Signs of injury to the duct may or may not be recognized in the immediate postoperative period. If complete occlusion has occurred, jaundice will develop rapidly; more often, however, a tear has been made accidentally in the duct, and the earliest manifestation of injury may be excessive or prolonged loss of bile from the surgical drains. Bile leakage resulting in a bile collection (biloma) may predispose to localized infection, which in turn accentuates scar formation and the ultimate development of a fibrous stricture.

Cholangitis is the most common complication of stricture. Typically, the patient experiences episodes of pain, fever, chills, and jaundice within a few weeks to months after cholecystectomy. Physical findings may include jaundice during an acute attack of cholangitis and right upper quadrant abdominal tenderness. Serum alkaline phosphatase is usually elevated. Hyperbilirubinemia is variable, fluctuating during exacerbations and usually remaining in the range of 5–10 mg/dL (85.5–171 mcmol/L). Blood cultures may be positive during an acute episode of cholangitis. Secondary biliary cirrhosis will inevitably develop if a stricture is not treated.

MRCP can be valuable in demonstrating the stricture, whereas ERCP permits biopsy and cytologic specimens to exclude malignancy (in conjunction with endoscopic ultrasound-guided fine-needle aspiration, an even more sensitive test for distal bile duct malignancy), sphincterotomy to allow closure of a bile leak, and dilation (often repeated) and stent placement, thereby avoiding surgical repair in some cases; when ERCP is unsuccessful, dilation of a stricture may be accomplished by PTC. Placement of multiple plastic stents appears to be more effective than placement of a single stent. Metal stents, which often cannot be removed endoscopically, are generally avoided in benign strictures unless life expectancy is < 2 years. The use of covered metal stents, which are more easily removed endoscopically than uncovered metal stents, as well as bioabsorbable stents, is an alternative to use of plastic stents. Strictures related to chronic pancreatitis are more difficult than postsurgical strictures to treat endoscopically, and preliminary reports suggest that they may be best managed with a temporary covered metal stent. Following liver transplantation, endoscopic management is more successful for anastomotic than for nonanastomotic strictures, although results for nonanastomotic strictures may be improved with repeated dilation or the use of multiple plastic stents. Biliary strictures after live liver donor liver transplantation, particularly in patients with a late-onset (after 24 weeks) stricture or with intrahepatic biliary dilatation, are also challenging and require aggressive endoscopic therapy; in addition, the risk of post-ERCP pancreatitis appears to be increased. When malignancy cannot be excluded with certainty, additional endoscopic diagnostic approaches may be considered—if available—including endoscopic ultrasonography, intraductal ultrasonography, direct choledoscopy (cholangioscopy), and confocal laser endomicroscopy. Differentiation from cholangiocarcinoma may ultimately require surgical exploration. Operative treatment of a stricture frequently necessitates performance of an end-to-end ductal repair, choledochojejunostomy, or hepaticojejunostomy to reestablish bile flow into the intestine.

 When to Refer

All patients with biliary stricture should be referred.

 When to Admit

Patients with acute cholangitis should be hospitalized.

PRIMARY SCLEROSING CHOLANGITIS

 General Considerations

Primary sclerosing cholangitis is an uncommon disease thought to result from an increased immune response to intestinal endotoxins and characterized by diffuse inflammation of the biliary tract leading to fibrosis and strictures of the biliary system. The disease is most common in men aged 20–50 years, with an incidence of nearly 3.3 per 100,000 in Asian Americans, 2.8 per 100,000 in Hispanic Americans, and 2.1 per 100,000 in African Americans, and an intermediate incidence in whites (possibly increasing), and a prevalence of 21 per 100,000 men and 6 per 100,000 women in the United States. Primary sclerosing cholangitis is closely associated with inflammatory bowel disease (more commonly ulcerative colitis than Crohn colitis), which is present in approximately two-thirds of patients with primary sclerosing cholangitis; however, clinically significant sclerosing cholangitis develops in only 1–4% of patients with ulcerative colitis. As in ulcerative colitis, smoking is associated with a decreased risk of primary sclerosing cholangitis. Primary sclerosing cholangitis is associated with the histocompatible antigens HLA-B8 and -DR3 or -DR4, and first-degree relatives of patients with primary sclerosing cholangitis have a fourfold increased risk of primary sclerosing cholangitis and a threefold increased risk of ulcerative colitis. The diagnosis of primary sclerosing cholangitis may be difficult to make after biliary surgery.

 Clinical Findings

A. Symptoms and Signs

Primary sclerosing cholangitis presents as progressive obstructive jaundice, frequently associated with fatigue, pruritus, anorexia, and indigestion. Patients may be diagnosed in the presymptomatic phase because of an elevated alkaline phosphatase level. Complications of chronic cholestasis, such as osteoporosis and malabsorption of fat-soluble vitamins, may occur late in the course. Risk factors for osteoporosis include older age, lower body mass index, and longer duration of inflammatory bowel disease. Esophageal varices on initial endoscopy are most likely in patients with a higher Mayo risk score based on age, bilirubin, albumin, and AST and a higher AST/ALT ratio, and new varices are likely to develop in those with a lower platelet count and higher bilirubin at 2 years. In patients with primary sclerosing cholangitis, ulcerative colitis is frequently characterized by rectal sparing and backwash ileitis.

B. Diagnostic Findings

The diagnosis of primary sclerosing cholangitis is increasingly made by MRCP, the sensitivity of which approaches that of ERCP. Characteristic cholangiographic findings are segmental fibrosis of bile ducts with saccular dilatations between strictures. Biliary obstruction by a stone or tumor should be excluded. Liver biopsy is not necessary for diagnosis when cholangiographic findings are characteristic. The disease may be confined to small intrahepatic bile ducts in about 15% of cases, in which case MRCP and ERCP are normal and the diagnosis is suggested by liver biopsy findings. These patients have a longer survival than patients with involvement of the large ducts and do not appear to be at increased risk for cholangiocarcinoma unless large-duct sclerosing cholangitis develops (which occurs in about 20% over 7–10 years). Liver biopsy may show characteristic periductal fibrosis (“onion-skinning”) and allows staging, which is based on the degree of fibrosis. Perinuclear ANCA (directed against myeloid-specific tubulin-beta isotype 5) as well as antinuclear, anticardiolipin, antithyroperoxidase, and anti-Saccharomyces cerevisiae antibodies and rheumatoid factor are frequently detected in serum. Occasional patients have clinical and histologic features of both sclerosing cholangitis and autoimmune hepatitis. An association with autoimmune pancreatitis is also seen, and this entity (IgG₄-associated cholangitis) is often responsive to corticosteroids, although it may be difficult to distinguish from primary sclerosing cholangitis and even cholangiocarcinoma. Primary sclerosing cholangitis must be distinguished from idiopathic adulthood ductopenia (a rare disorder that affects young to middle-aged adults who manifest cholestasis resulting from loss of interlobular and septal bile ducts yet who have a normal cholangiogram and that is caused in some cases by a mutation in the canalicular phospholipid transporter gene ABCB4) and from other cholangiopathies (including primary biliary cirrhosis; cystic fibrosis; eosinophilic cholangitis; AIDS cholangiopathy; allograft rejection; graft-versus-host disease; ischemic cholangiopathy [often with biliary “casts,” a rapid progression to cirrhosis, and a poor outcome] caused by hepatic artery thrombosis, shock, respiratory failure, or drugs; intra-arterial chemotherapy; and sarcoidosis).

 Complications

Cholangiocarcinoma may complicate the course of primary sclerosing cholangitis in up to 20% of cases (1.2% per year) and may be difficult to diagnose by cytologic examination or biopsy because of false-negative results. A serum CA 19-9 level >100 units/mL is suggestive but not diagnostic of cholangiocarcinoma. Annual right-upper-quadrant ultrasonography or MRI with MRCP and serum CA 19-9 testing (a level of 20 is the threshold for further investigation) are recommended for surveillance, with ERCP and biliary cytology if the results are suggestive of malignancy. PET and choledochoscopy may play roles in the early detection of cholangiocarcinoma. Patients with ulcerative colitis and primary sclerosing cholangitis are at high risk (tenfold higher than ulcerative colitis patients without primary sclerosing cholangitis) for colorectal neoplasia. The risks of gallstones, cholecystitis, gallbladder polyps, and gallbladder carcinoma appear to be increased in patients with primary sclerosing cholangitis.

 Treatment

Episodes of acute bacterial cholangitis may be treated with ciprofloxacin (750 mg twice daily orally or intravenously). Ursodeoxycholic acid in standard doses (10–15 mg/kg/d orally) may improve liver biochemical test results but does not appear to alter the natural history. High-dose ursodeoxycholic acid (25–30 mg/kg/d) also has been shown not to reduce cholangiographic progression and liver fibrosis, nor to improve survival or prevent cholangiocarcinoma, and has been shown to increase the risk of death and need for liver transplantation in patients with a normal serum bilirubin level and an early histologic stage. Other drugs such as antibiotics (vancomycin, metronidazole, minocycline, azithromycin), obeticholic acid (a farsenoid-X receptor agonist), 24-norursodeoxycholic acid, budesonide, anti-tumor necrosis factor antibodies, cyclosporine, tacrolimus, and antifibrotic agents are under study. Careful endoscopic evaluation of the biliary tree may permit balloon dilation of localized strictures, and repeated dilation of a dominant stricture may improve survival, although such patients have reduced survival compared with patients who do not have a dominant stricture. Short-term (2–3 weeks) placement of a stent in a major stricture also may relieve symptoms and improve biochemical abnormalities, with sustained improvement after the stent is removed; however, long-term stenting may increase the rate of complications such as cholangitis and is not recommended. In patients without cirrhosis, surgical resection of a dominant bile duct stricture may lead to longer survival than endoscopic therapy by decreasing the subsequent risk of cholangiocarcinoma. When feasible, extensive surgical resection of cholangiocarcinoma complicating primary sclerosing cholangitis may result in 5-year survival rates of > 50%. In patients with ulcerative colitis, primary sclerosing cholangitis is an independent risk factor for the development of colorectal dysplasia and cancer (especially in the right colon), and strict adherence to a colonoscopic surveillance program (yearly for those with ulcerative colitis and every 5 years for those without ulcerative colitis) is recommended. Whether treatment with ursodeoxycholic acid reduces the risk of colorectal dysplasia and carcinoma in patients with ulcerative colitis and primary sclerosing cholangitis is still uncertain. For patients with cirrhosis and clinical decompensation, liver transplantation is the procedure of choice; primary sclerosing cholangitis recurs in the graft in 30% of cases, with a possible reduction in the risk of recurrence when colectomy has been performed for ulcerative colitis before transplantation.

 Prognosis

Survival of patients with primary sclerosing cholangitis averages 9–17 years, and up to 21 years in population-based studies. Adverse prognostic markers are older age, hepatosplenomegaly, higher serum bilirubin and AST levels, lower albumin levels, a history of variceal bleeding, a dominant bile duct stricture, and extrahepatic duct changes. Variceal bleeding is also a risk factor for cholangiocarcinoma. Patients in whom serum alkaline phosphatase levels decline by 40% or more (spontaneously or with ursodeoxycholic acid therapy) have longer transplant-free survival times than those in whom the alkaline phosphatase does not decline. Moreover, improvement in the serum alkaline phosphatase to < 1.5 times the upper limit of normal is associated with a reduced risk of cholangiocarcinoma. Reduced quality of life is associated with older age, large-duct disease, and systemic symptoms. Interestingly, patients with milder ulcerative colitis tend to have more severe primary cholangitis and a higher rate of liver transplantation. Actuarial survival rates with liver transplantation are as high as 85% at 3 years, but rates are much lower once cholangiocarcinoma has developed. Following transplantation, patients have an increased risk of nonanastomotic biliary strictures and—in those with ulcerative colitis—colon cancer. The retransplantation rate is higher than that for primary biliary cirrhosis. Those patients who are unable to undergo liver transplantation will ultimately require high-quality palliative care (see Chapter 5).

DISEASES OF THE PANCREAS

See Chapter 39 for Carcinoma of the Pancreas and Periampullary Area.

ACUTE PANCREATITIS

 General Considerations

Most cases of acute pancreatitis are related to biliary tract disease (a passed gallstone, usually < 5 mm in diameter) or heavy alcohol intake. The exact pathogenesis is not known but may include edema or obstruction of the ampulla of Vater, reflux of bile into pancreatic ducts, and direct injury of pancreatic acinar cells by prematurely activated pancreatic enzymes. Among the numerous other causes or associations are hypercalcemia, hyperlipidemias (chylomicronemia, hypertriglyceridemia, or both), abdominal trauma (including surgery), drugs (including azathioprine, mercaptopurine, asparaginase, pentamidine, didanosine, valproic acid, tetracyclines, dapsone, isoniazid, metronidazole, estrogen and tamoxifen [by raising serum triglycerides], sulfonamides, mesalamine, sulindac, leflunomide, thiazides, simvastatin, fenofibrate, enalapril, methyldopa, procainamide, sitagliptin, exenatide, possibly corticosteroids, and others), vasculitis, infections (eg, mumps, cytomegalovirus, M avium intracellularecomplex), peritoneal dialysis, cardiopulmonary bypass, and ERCP. Genetic mutations also predispose to chronic pancreatitis, particularly in persons < 30 years of age if no other cause is evident and a family history of pancreatic disease is present (see later). In patients with pancreas divisum, a congenital anomaly in which the dorsal and ventral pancreatic ducts fail to fuse, acute pancreatitis may result from stenosis of the minor papilla with obstruction to flow from the accessory pancreatic duct, although concomitant genetic mutations, particularly in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, have also been reported to account for acute pancreatitis in some patients with pancreas divisum. Acute pancreatitis may also result from anomalous union of the pancreaticobiliary duct. Rarely, acute pancreatitis may be the presenting manifestation of a pancreatic or ampullary neoplasm. Celiac disease appears to be associated with an increased risk of acute and chronic pancreatitis. Apparently “idiopathic” acute pancreatitis is often caused by occult biliary microlithiasis and may be caused by sphincter of Oddi dysfunction involving the pancreatic duct. Between 15% and 25% of cases are truly idiopathic. Smoking and abdominal adiposity increase the risk of pancreatitis, and older age and obesity increase the risk of a severe course; vegetable consumption may reduce the risk of non-gallstone pancreatitis. The incidence of pancreatitis has increased since 1990.

 Clinical Findings

A. Symptoms and Signs

Epigastric abdominal pain, generally abrupt in onset, is steady, boring, and severe and often made worse by walking and lying supine and better by sitting and leaning forward. The pain usually radiates into the back but may radiate to the right or left. Nausea and vomiting are usually present. Weakness, sweating, and anxiety are noted in severe attacks. There may be a history of alcohol intake or a heavy meal immediately preceding the attack or a history of milder similar episodes or biliary pain in the past.

The abdomen is tender mainly in the upper part, most often without guarding, rigidity, or rebound. The abdomen may be distended, and bowel sounds may be absent with associated ileus. Fever of 38.4–39°C, tachycardia, hypotension (even shock), pallor, and cool clammy skin are present in severe cases. Mild jaundice may be seen. Occasionally, an upper abdominal mass due to the inflamed pancreas or a pseudocyst may be palpated. Acute kidney injury (usually prerenal) may occur early in the course of acute pancreatitis.

B. Laboratory Findings

Serum amylase and lipase are elevated—usually more than three times the upper limit of normal—within 24 hours in 90% of cases; their return to normal is variable depending on the severity of disease. Lipase remains elevated longer than amylase and is slightly more accurate for the diagnosis of acute pancreatitis. Leukocytosis (10,000–30,000/mcL), proteinuria, granular casts, glycosuria (10–20% of cases), hyperglycemia, and elevated serum bilirubin may be present. Blood urea nitrogen and serum alkaline phosphatase may be elevated and coagulation tests abnormal. An elevated serum creatinine level (>1.8 mg/dL [149.94 mcmol/L]) at 48 hours is associated with the development of pancreatic necrosis. In patients with clear evidence of acute pancreatitis, a serum ALT level of more than 150 units/L (3 mkat/L) suggests biliary pancreatitis. A decrease in serum calcium may reflect saponification and correlates with severity of the disease. Levels lower than 7 mg/dL (1.75 mmol/L) (when serum albumin is normal) are associated with tetany and an unfavorable prognosis. Patients with acute pancreatitis caused by hypertriglyceridemia generally have fasting triglyceride levels above 1000 mg/dL (10 mmol/L); in some cases, the serum amylase is not elevated substantially because of an inhibitor in the serum of patients with marked hypertriglyceridemia that interferes with measurement of serum amylase. An early rise in the hematocrit value above 44% suggests hemoconcentration and predicts pancreatic necrosis. An elevated C-reactive protein concentration (> 150 mg/L [1500 mg/L]) at 48 hours suggests severe disease.

Other diagnostic tests that offer the possibility of simplicity, rapidity, ease of use, and low cost—including urinary trypsinogen-2, trypsinogen activation peptide, and carboxypeptidase B—are not widely available. In patients in whom ascites or a left pleural effusion develops, fluid amylase content is high. Electrocardiography may show ST–T wave changes.

C. Assessment of Severity

In addition to the individual laboratory parameters noted above, the severity of acute alcoholic pancreatitis can be assessed using several scoring systems, including the Ranson criteria (Table 16–8). TheSequential Organ Failure Assessment (SOFA) score or modified Marshall scoring system can be used to assess injury to other organs, and the Acute Physiology and Chronic Health Evaluation(APACHE II) score is another tool for assessing severity. A simple 5-point clinical scoring system (the Bedside Index for Severity in Acute Pancreatitis, or BISAP) based on blood urea nitrogen > 25 mg/dL (9 mmol/L), impaired mental status, systemic inflammatory response syndrome, age > 60 years, and pleural effusion during the first 24 hours (before the onset of organ failure) identifies patients at increased risk for mortality. More simply, the presence of a systemic inflammatory response alone and an elevated blood urea nitrogen level on admission as well as a rise in blood urea nitrogen within the first 24 hours of hospitalization are independently associated with increased mortality; the greater the rise in blood urea nitrogen after admission, the greater the mortality rate. An early rise in serum levels of neutrophil gelatinase-associated lipocalin has also been proposed as a marker of severe acute pancreatitis. The absence of rebound abdominal tenderness or guarding, a normal hematocrit value, and a normal serum creatinine level (the “harmless acute pancreatitis score,” or HAPS) predicts a nonsevere course with 98% accuracy. The revised Atlanta classification of the severity of acute pancreatitis uses the following three categories: (1) mild disease is the absence of organ failure and local ([peri] pancreatic necrosis or fluid collections) or systemic complications; (2) moderate disease is the presence of transient (< 48 hrs) organ failure or local or systemic complications, or both; and (3) severe disease is the presence of persistent (≥ 48 hrs) organ failure. A similar “determinant-based” classification includes a category of critical acute pancreatitis characterized by both persistent organ failure and infected peripancreatic necrosis.

D. Imaging

Plain radiographs of the abdomen may show gallstones (if calcified), a “sentinel loop” (a segment of air-filled small intestine most commonly in the left upper quadrant), the “colon cutoff sign”—a gas-filled segment of transverse colon abruptly ending at the area of pancreatic inflammation—or focal linear atelectasis of the lower lobe of the lungs with or without pleural effusion. Ultrasonography is often not helpful in diagnosing acute pancreatitis because of intervening bowel gas but may identify gallstones in the gallbladder. Unenhanced CT is useful for demonstrating an enlarged pancreas when the diagnosis of pancreatitis is uncertain, differentiating pancreatitis from other possible intra-abdominal catastrophes, and providing an initial assessment of prognosis but is often unnecessary early in the course (Table 16–9). Rapid-bolus intravenous contrast-enhanced CT following aggressive volume resuscitation is of particular value after the first 3 days of severe acute pancreatitis for identifying areas of necrotizing pancreatitis and assessing the degree of necrosis, although the use of intravenous contrast may increase the risk of complications of pancreatitis and of acute kidney injury and should be avoided when the serum creatinine level is > 1.5 mg/dL (124.95 mcmol/L). MRI appears to be a suitable alternative to CT. Perfusion CT on day 3 demonstrating areas of ischemia in the pancreas has been reported to predict the development of pancreatic necrosis. The presence of a fluid collection in the pancreas correlates with an increased mortality rate. CT-guided needle aspiration of areas of necrotizing pancreatitis after the third day may disclose infection, usually by enteric organisms, which typically requires debridement. The presence of gas bubbles on CT implies infection by gas-forming organisms. Endoscopic ultrasonography is useful in identifying occult biliary disease (eg, small stones, sludge, microlithiasis), which is present in a majority of patients with apparently idiopathic acute pancreatitis, and is indicated in persons over age 40 to exclude malignancy. ERCP is generally not indicated after a first attack of acute pancreatitis unless there is associated cholangitis or jaundice or a bile duct stone is known to be present, but endoscopic ultrasonography or MRCP should be considered, especially after repeated attacks of idiopathic acute pancreatitis. In selected cases, aspiration of bile for crystal analysis may confirm the suspicion of microlithiasis, and manometry of the pancreatic duct sphincter may detect sphincter of Oddi dysfunction as a cause of recurrent pancreatitis.

 Differential Diagnosis

Acute pancreatitis must be differentiated from an acutely perforated duodenal ulcer, acute cholecystitis, acute intestinal obstruction, leaking aortic aneurysm, renal colic, and acute mesenteric ischemia. Serum amylase may also be elevated in high intestinal obstruction, in gastroenteritis, in mumps not involving the pancreas (salivary amylase), in ectopic pregnancy, after administration of opioids, and after abdominal surgery. Serum lipase may also be elevated in many of these conditions.

 Complications

Intravascular volume depletion secondary to leakage of fluids in the pancreatic bed and ileus with fluid-filled loops of bowel may result in prerenal azotemia and even acute tubular necrosis without overt shock. This sequence usually occurs within 24 hours of the onset of acute pancreatitis and lasts 8–9 days. Some patients require renal replacement therapy.

According to the revised Atlanta classification, fluid collections and necrosis may be acute (within the first 4 weeks) or chronic (after 4 weeks) and sterile or infected. Chronic collections, including pseudocysts and walled-off necrosis, are characterized by encapsulation. Sterile or infected necrotizing pancreatitis may complicate the course of 5–10% of cases and accounts for most of the deaths. The risk of infection does not correlate with the extent of necrosis. Pancreatic necrosis is often associated with fever, leukocytosis, and, in some cases, shock and is associated with organ failure (eg, gastrointestinal bleeding, respiratory failure, acute kidney injury) in 50% of cases. Because infected pancreatic necrosis is often an indication for debridement, fine-needle aspiration of necrotic tissue under CT guidance should be performed (if necessary, repeatedly) for Gram stain and culture.

A serious complication of acute pancreatitis is acute respiratory distress syndrome (ARDS); cardiac dysfunction may be superimposed. It usually occurs 3–7 days after the onset of pancreatitis in patients who have required large volumes of fluid and colloid to maintain blood pressure and urinary output. Most patients with ARDS require intubation, mechanical ventilation, and supplemental oxygen.

Pancreatic abscess (also referred to as infected or suppurative pseudocyst) is a suppurative process characterized by rising fever, leukocytosis, and localized tenderness and an epigastric mass usually 6 or more weeks into the course of acute pancreatitis. The abscess may be associated with a left-sided pleural effusion or an enlarging spleen secondary to splenic vein thrombosis. In contrast to infected necrosis, the mortality rate is low following drainage.

Pseudocysts, encapsulated fluid collections with high amylase content, commonly appear in pancreatitis when CT is used to monitor the evolution of an acute attack. Pseudocysts that are smaller than 6 cm in diameter often resolve spontaneously. They most commonly are within or adjacent to the pancreas but can present almost anywhere (eg, mediastinal, retrorectal) by extension along anatomic planes. Multiple pseudocysts are seen in 14% of cases. Pseudocysts may become secondarily infected, necessitating drainage as for an abscess. Pancreatic ascites may present after recovery from acute pancreatitis as a gradual increase in abdominal girth and persistent elevation of the serum amylase level in the absence of frank abdominal pain. Marked elevations in ascitic protein (> 3 g/dL) and amylase (> 1000 units/L [20 mkat/L]) concentrations are typical. The condition results from disruption of the pancreatic duct or drainage of a pseudocyst into the peritoneal cavity.

Rare complications of acute pancreatitis include hemorrhage caused by erosion of a blood vessel to form a pseudoaneurysm and colonic necrosis. Chronic pancreatitis develops in about 10% of cases. Permanent diabetes mellitus and exocrine pancreatic insufficiency occur uncommonly after a single acute episode.

 Treatment

A. Treatment of Acute Disease

1. Mild disease—In most patients, acute pancreatitis is a mild disease (“nonsevere acute pancreatitis”) that subsides spontaneously within several days. The pancreas is “rested” by a regimen of withholding food and liquids by mouth, bed rest, and, in patients with moderately severe pain or ileus and abdominal distention or vomiting, nasogastric suction. Early fluid resuscitation (one-third of the total 72-hour fluid volume administered within 24 hours of presentation, 250–500 mL/h initially) may reduce the frequency of systemic inflammatory response syndrome and organ failure in this group of patients, and lactated Ringer solution may be preferable to normal saline; however, overly aggressive fluid resuscitation may lead to morbidity as well. Pain is controlled with meperidine, up to 100–150 mg intramuscularly every 3–4 hours as necessary. In those with severe liver or kidney dysfunction, the dose may need to be reduced. Morphine has been thought to cause sphincter of Oddi spasm but is now considered an acceptable alternative and, given the potential side effects of meperidine, may even be preferable. Oral intake of fluid and foods can be resumed when the patient is largely free of pain and has bowel sounds (even if the serum amylase is still elevated). Clear liquids are given first (this step may be skipped in patients with mild acute pancreatitis), followed by gradual advancement to a low-fat diet, guided by the patient’s tolerance and by the absence of pain. Pain may recur on refeeding in 20% of patients. Following recovery from acute biliary pancreatitis, laparoscopic cholecystectomy is generally performed, preferably during the same hospital admission, although in selected cases endoscopic sphincterotomy alone may be done. In patients with recurrent pancreatitis associated with pancreas divisum, insertion of a stent in the minor papilla (or minor papilla sphincterotomy) may reduce the frequency of subsequent attacks, although complications of such therapy are frequent. In patients with recurrent acute pancreatitis attributed to pancreatic sphincter of Oddi dysfunction, biliary sphincterotomy alone is as effective as combined biliary and pancreatic sphincterotomy in reducing the frequency of recurrent acute pancreatitis, but chronic pancreatitis may still develop in treated patients. Hypertriglyceridemia with acute pancreatitis has been treated with insulin, heparin, or apheresis, but the benefit of these approaches has not been proven.

2. Severe disease—In more severe pancreatitis—particularly necrotizing pancreatitis—there may be considerable leakage of fluids, necessitating large amounts of intravenous fluids (eg, 500–1000 mL/h for several hours, then 250–300 mL/h) to maintain intravascular volume. Hemodynamic monitoring in an intensive care unit is required, and the importance of aggressive intravenous hydration targeted to adequate urinary output, stabilization of blood pressure and heart rate, restoration of central venous pressure, and a modest decrease in hematocrit value cannot be overemphasized. Calcium gluconate must be given intravenously if there is evidence of hypocalcemia with tetany. Infusions of fresh frozen plasma or serum albumin may be necessary in patients with coagulopathy or hypoalbuminemia. With colloid solutions, there may be an increased risk of developing ARDS. If shock persists after adequate volume replacement (including packed red cells), pressors may be required. For the patient requiring a large volume of parenteral fluids, central venous pressure and blood gases should be monitored at regular intervals. Enteral nutrition via a nasojejunal or possibly nasogastric feeding tube is preferable to parenteral nutrition in patients who will otherwise be without oral nutrition for at least 7–10 days but may not be tolerated in some patients with an ileus. Parenteral nutrition (including lipids) should be considered in patients who have severe pancreatitis and ileus. The routine use of antibiotics to prevent conversion of sterile pancreatic necrosis to infected necrosis is still controversial and generally is not indicated in those with < 30% pancreatic necrosis. Imipenem (500 mg every 8 hours intravenously) and possibly cefuroxime (1.5 g intravenously three times daily, then 250 mg orally twice daily) administered for no more than 14 days to patients with sterile pancreatic necrosis has been reported in some studies to reduce the risk of pancreatic infection and mortality; meropenem and the combination of ciprofloxacin and metronidazole do not appear to reduce the frequency of infected necrosis, multiorgan failure, or mortality. When infected necrosis is confirmed, imipenem or meropenem should be continued. In occasional cases, a fungal infection is found, and appropriate antifungal therapy should be prescribed. The role of intravenous somatostatin in severe acute pancreatitis is uncertain, and octreotide is thought to have no benefit. To date, probiotic agents have not been shown to reduce infectious complications of severe pancreatitis and may increase mortality. Nonsteroidal anti-inflammatory drugs (eg, indomethacin administered rectally), allopurinol, and ulinastatin have been reported to reduce the frequency and severity of post-ERCP pancreatitis in persons at high risk. There is conflicting evidence about whether the risk of pancreatitis after ERCP can be reduced by the administration of somatostatin, octreotide, gabexate mesilate and other protease inhibitors, or nitroglycerin. Placement of a stent across the pancreatic duct or orifice has been shown to reduce the risk of post-ERCP pancreatitis and is also a common practice but has not been compared directly with rectal indomethacin.

B. Treatment of Complications and Follow-Up

A surgeon should be consulted in all cases of severe acute pancreatitis. If the diagnosis is in doubt and investigation indicates a strong possibility of a serious surgically correctable lesion (eg, perforated peptic ulcer), exploratory laparotomy is indicated. When acute pancreatitis is found unexpectedly, it is usually wise to close without intervention. If the pancreatitis appears mild and cholelithiasis or microlithiasis is present, cholecystectomy or cholecystostomy may be justified. When severe pancreatitis results from choledocholithiasis and jaundice (serum total bilirubin >5 mg/dL [85.5 mcmol/L]) or cholangitis is present, ERCP with endoscopic sphincterotomy and stone extraction is indicated. MRCP may be useful in selecting patients for therapeutic ERCP. Endoscopic sphincterotomy does not appear to improve the outcome of severe pancreatitis in the absence of cholangitis or jaundice.

Necrosectomy may improve survival in patients with necrotizing pancreatitis and clinical deterioration with multiorgan failure or lack of resolution by 4 weeks and is often indicated for infected necrosis, although a select group of relatively stable patients with infected pancreatic necrosis may be managed with antibiotics alone. The goal is to debride necrotic pancreas and surrounding tissue and establish adequate drainage. Outcomes are best if necrosectomy is delayed until the necrosis has organized, usually about 4 weeks after disease onset. A “step-up” approach in which nonsurgical drainage of walled-off pancreatic necrosis under radiologic guidance with subsequent open surgical necrosectomy if necessary has been shown to reduce mortality and resource utilization in selected patients with necrotizing pancreatitis and confirmed or suspected secondary infection. Endoscopic (transgastric or transduodenal) drainage combined with percutaneous drainage and, in some cases, laparoscopic guidance are additional options, depending on local expertise. Treatment is labor intensive, and multiple procedures are often required. Peritoneal lavage has not been shown to improve survival in severe acute pancreatitis, in part because the risk of late septic complications is not reduced.

The development of a pancreatic abscess is an indication for prompt percutaneous or surgical drainage. Chronic pseudocysts require endoscopic, percutaneous catheter, or surgical drainage when infected or associated with persisting pain, pancreatitis, or bile duct obstruction. For pancreatic infections, imipenem, 500 mg every 8 hours intravenously, is a good choice of antibiotic because it achieves bactericidal levels in pancreatic tissue for most causative organisms. Pancreatic duct leaks and fistulas may require endoscopic or surgical therapy.

 Prognosis

Mortality rates for acute pancreatitis have declined from at least 10% to around 5% since the 1980s, but the mortality rate for severe acute pancreatitis (more than three Ranson criteria; Table 16–8) remains at least 20%, with rates of 10% and 25% in those with sterile and infected necrosis, respectively. Severe acute pancreatitis is predicted by features of the systemic inflammatory response on admission; a persistent systemic inflammatory response is associated with a mortality rate of 25%, and a transient response, with a mortality rate of 8%. Half of the deaths occur within the first 2 weeks, usually from multiorgan failure. Multiorgan failure is associated with a mortality rate of at least 30%, and if it persists beyond the first 48 hours, the mortality rate is over 50%. Later deaths occur because of complications of infected necrosis. The risk of death doubles when both organ failure and infected necrosis are present. Moreover, hospital-acquired infections increase the mortality of acute pancreatitis, independent of severity. Readmission to the hospital for acute pancreatitis within 30 days may be predicted by a scoring system based on five factors during the index admission: eating less than a solid diet at discharge; nausea, vomiting, or diarrhea at discharge; pancreatic necrosis; use of antibiotics at discharge; and pain at discharge. Recurrences are common in alcoholic pancreatitis but can be reduced by repeated, regularly scheduled interventions to eliminate alcohol consumption after discharge from the hospital. The risk of chronic pancreatitis following an episode of acute alcoholic pancreatitis is 13% in 10 years and 16% in 20 years.

 When to Admit

Nearly all patients with acute pancreatitis should be hospitalized.

CHRONIC PANCREATITIS

 General Considerations

Chronic pancreatitis occurs most often in patients with alcoholism (45–80% of all cases). The risk of chronic pancreatitis increases with the duration and amount of alcohol consumed, but pancreatitis develops in only 5–10% of heavy drinkers. Tobacco smoking is a risk factor for idiopathic chronic pancreatitis and has been reported to accelerate progression of alcoholic chronic pancreatitis. About 2% of patients with hyperparathyroidism develop pancreatitis. In tropical Africa and Asia, tropical pancreatitis, related in part to malnutrition, is the most common cause of chronic pancreatitis. A stricture, stone, or tumor obstructing the pancreas can lead to obstructive chronic pancreatitis. Autoimmune pancreatitis is associated with hypergammaglobulinemia (IgG₄ in particular), and often with autoantibodies and other autoimmune diseases, and is responsive to corticosteroids. Affected persons are at increased risk for various cancers. Type 1 autoimmune pancreatitis is a multisystem disease characterized by lymphoplasmacytic sclerosing pancreatitis on biopsy, associated bile duct strictures, retroperitoneal fibrosis, renal and salivary gland lesions, and a high rate of relapse after treatment. Type 2 affects the pancreas alone and is characterized by idiopathic duct centric pancreatitis on biopsy, lack of systemic IgG₄ involvement, an association with inflammatory bowel disease, and a lower rate of relapse after treatment. Between 10% and 30% of cases of chronic pancreatitis are idiopathic, with either early onset (median age 23) or late onset (median age 62). Genetic factors may predispose to chronic pancreatitis in some of these cases and include mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the pancreatic secretory trypsin inhibitory gene (PSTI, serine protease inhibitor,SPINK1), and possibly the gene for uridine 5′-diphosphate glucuronosyltransferase. Mutation of the cationic trypsinogen gene on chromosome 7 (serine protease 1,PRSS1) is associated with hereditary pancreatitis, transmitted as an autosomal dominant trait with variable penetrance. In addition, a variant in an X-linked gene CLDN2, which encodes claudin-2 has been associated with chronic pancreatitis; its presence on the X chromosome may partly explain the male predominance of chronic pancreatitis. A useful mnemonic for the predisposing factors to chronic pancreatitis is TIGAR-O: toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute pancreatitis, or obstructive.

The pathogenesis of chronic pancreatitis may be explained by the SAPE (sentinel acute pancreatitis event) hypothesis by which the first (sentinel) acute pancreatitis event initiates an inflammatory process that results in injury and later fibrosis (“necrosis-fibrosis”). In many cases, chronic pancreatitis is a self-perpetuating disease characterized by chronic pain or recurrent episodes of acute pancreatitis and ultimately by pancreatic exocrine or endocrine insufficiency (sooner in alcoholic pancreatitis than in other types). After many years, chronic pain may resolve spontaneously or as a result of surgery tailored to the cause of pain. Over 80% of adults develop diabetes mellitus within 25 years after the clinical onset of chronic pancreatitis.

 Clinical Findings

A. Symptoms and Signs

Persistent or recurrent episodes of epigastric and left upper quadrant pain with referral to the left upper quadrant are typical. The pain results in part from impaired inhibitory pain modulation by the central nervous system. Anorexia, nausea, vomiting, constipation, flatulence, and weight loss are common. During attacks tenderness over the pancreas, mild muscle guarding, and ileus may be noted. Attacks may last only a few hours or as long as 2 weeks; pain may eventually be almost continuous. Steatorrhea (as indicated by bulky, foul, fatty stools) may occur late in the course.

B. Laboratory Findings

Serum amylase and lipase may be elevated during acute attacks; however, normal values do not exclude the diagnosis. Serum alkaline phosphatase and bilirubin may be elevated owing to compression of the bile duct. Glycosuria may be present. Excess fecal fat may be demonstrated on chemical analysis of the stool. Pancreatic insufficiency generally is confirmed by response to therapy with pancreatic enzyme supplements; the secretin stimulation test can be used if available (and has a high negative predictive factor for ruling out early acute chronic pancreatitis), as can detection of decreased fecal chymotrypsin or elastase levels, although the latter tests lack sensitivity and specificity. Vitamin B₁₂ malabsorption is detectable in about 40% of patients, but clinical deficiency of vitamin B₁₂ and fat-soluble vitamins is rare. Accurate diagnostic tests are available for the major trypsinogen gene mutations, but because of uncertainty about the mechanisms linking heterozygous CFTR and PSTI mutations with pancreatitis, genetic testing for mutations in these two genes is not currently recommended. Elevated IgG₄ levels, ANA, and antibodies to lactoferrin and carbonic anhydrase II are often found in patients with autoimmune pancreatitis (especially type 1). Pancreatic biopsy, if necessary, shows a lymphoplasmacytic inflammatory infiltrate with characteristic IgG₄ immunostaining, which is also found in biopsy specimens of the major papilla, bile duct, and salivary glands, in type 1 autoimmune pancreatitis.

C. Imaging

Plain films show calcifications due to pancreaticolithiasis in 30% of affected patients. CT may show calcifications not seen on plain films as well as ductal dilatation and heterogeneity or atrophy of the gland. Occasionally, the findings raise suspicion of pancreatic cancer (“tumefactive chronic pancreatitis”). ERCP is the most sensitive imaging study for chronic pancreatitis and may show dilated ducts, intraductal stones, strictures, or pseudocyst, but is infrequently used for diagnosis alone; moreover, the results may be normal in patients with so-called minimal change pancreatitis. MRCP (including secretin-enhanced MRCP) and endoscopic ultrasonography (with pancreatic tissue sampling) are less invasive alternatives to ERCP. Endoscopic ultrasonographic (“Rosemont”) criteria for the diagnosis of chronic pancreatitis include hyperechoic foci with shadowing indicative of calculi in the main pancreatic duct and lobularity with honeycombing of the pancreatic parenchyma. Characteristic imaging features of autoimmune pancreatitis include diffuse enlargement of the pancreas, a peripheral rim of hypoattenuation, and irregular narrowing of the main pancreatic duct. In the United States, the diagnosis of autoimmune pancreatitis is based on the HISORt criteria: histology, imaging, serology, other organ involvement, and response to corticosteroid therapy.

 Complications

Opioid addiction is common. Other frequent complications include often brittle diabetes mellitus, pancreatic pseudocyst or abscess, cholestatic liver enzymes with or without jaundice, bile duct stricture, steatorrhea, malnutrition, and peptic ulcer. Pancreatic cancer develops in 4% of patients after 20 years; the risk may relate to tobacco and alcohol use. In patients with hereditary pancreatitis, the risk of pancreatic cancer rises after age 50 years and reaches 19% by age 70 years (see Chapter 39).

 Treatment

Correctable coexistent biliary tract disease should be treated surgically.

A. Medical Measures

A low-fat diet should be prescribed. Alcohol is forbidden because it frequently precipitates attacks. Opioids should be avoided if possible. Preferred agents for pain are acetaminophen, nonsteroidal anti-inflammatory drugs, and tramadol, along with pain-modifying agents such as tricyclic antidepressants, selective serotonin uptake inhibitors, and gabapentin or pregabalin. Steatorrhea is treated with pancreatic supplements that are selected on the basis of their high lipase activity (Table 16–10). A total dose of at least 40,000 units of lipase in capsules is given with each meal (during and after the meal). Doses of 90,000 units or more of lipase per meal may be required in some cases. The tablets should be taken at the start of, during, and at the end of a meal. Concurrent administration of a H₂-receptor antagonist (eg, ranitidine, 150 mg orally twice daily), a proton pump inhibitor (eg, omeprazole, 20–60 mg orally daily), or sodium bicarbonate, 650 mg orally before and after meals, decreases the inactivation of lipase by acid and may thereby further decrease steatorrhea. In selected cases of alcoholic pancreatitis and in cystic fibrosis, enteric-coated microencapsulated preparations may offer an advantage. However, in patients with cystic fibrosis, high-dose pancreatic enzyme therapy has been associated with strictures of the ascending colon. Pain secondary to idiopathic chronic pancreatitis may be alleviated in some cases by the use of pancreatic enzymes (not enteric-coated) or octreotide, 200 mcg subcutaneously three times daily. Antioxidant therapy to inhibit electrophilic stress on key macromolecules in the pancreas by toxic metabolites has shown promise in some, but not all, studies. Associated diabetes mellitus should be treated (see Chapter 27). Autoimmune pancreatitis is treated with prednisone 40 mg/d orally for 1–2 months, followed by a taper of 5 mg every 2–4 weeks. Nonresponse or relapse occurs in 45% of cases (particularly in those with concomitant IgG₄-associated cholangitis); azathioprine appears to reduce the risk of relapse. Other immunomodulators and biologic agents, including rituximab, are under study.

B. Endoscopic and Surgical Treatment

Endoscopic therapy or surgery may be indicated in chronic pancreatitis to treat underlying biliary tract disease, ensure free flow of bile into the duodenum, drain persistent pseudocysts, treat other complications, eliminate obstruction of the pancreatic duct, attempt to relieve pain, or exclude pancreatic cancer. Liver fibrosis may regress after biliary drainage. Distal bile duct obstruction may be relieved by endoscopic placement of multiple bile duct stents. When obstruction of the duodenal end of the pancreatic duct can be demonstrated by ERCP, dilation of or placement of a stent in the duct and pancreatic duct stone lithotripsy or surgical resection of the tail of the pancreas with implantation of the distal end of the duct by pancreaticojejunostomy may be performed. Endoscopic therapy is successful in about 50% of cases. In patients who do not respond to endoscopic therapy, surgery is successful in about 50%. When the pancreatic duct is diffusely dilated, anastomosis between the duct after it is splitlongitudinally and a defunctionalized limb of jejunum (modified Puestow procedure), in some cases combined with resection of the head of the pancreas (Beger or Frey procedure), is associated with relief of pain in 80% of cases. In advanced cases, subtotal or total pancreatectomy may be considered as a last resort but has variable efficacy and causes pancreatic insufficiency and diabetes mellitus. Perioperative administration of somatostatin or octreotide may reduce the risk of postoperative pancreatic fistulas. Endoscopic or surgical (including laparoscopic) drainage is indicated for symptomatic pseudocysts and, in many cases, those over 6 cm in diameter. Endoscopic ultrasonography may facilitate selection of an optimal site for endoscopic drainage. Pancreatic ascites or pancreaticopleural fistulas due to a disrupted pancreatic duct can be managed by endoscopic placement of a stent across the disrupted duct. Pancreatic sphincterotomy or fragmentation of stones in the pancreatic duct by lithotripsy and endoscopic removal of stones from the duct may relieve pain in selected patients. For patients with chronic pain and nondilated ducts, a percutaneous celiac plexus nerve block may be considered under either CT or endoscopic ultrasound guidance, with pain relief (albeit often short-lived) in approximately 50% of patients. A single session of radiation therapy to the pancreas has been reported to relieve otherwise refractory pain.

 Prognosis

Chronic pancreatitis often leads to disability. The prognosis is best in patients with recurrent acute pancreatitis caused by a remediable condition, such as cholelithiasis, choledocholithiasis, stenosis of the sphincter of Oddi, or hyperparathyroidism, and in those with autoimmune pancreatitis. Medical management of hyperlipidemia, if present, may also prevent recurrent attacks of pancreatitis. In alcoholic pancreatitis, pain relief is most likely when a dilated pancreatic duct can be decompressed. In patients with disease not amenable to decompressive surgery, addiction to opioids is a frequent outcome of treatment. The quality of life is poorer in patients with constant pain than in those with intermittent pain.

 When to Refer

All patients with chronic pancreatitis should be referred for diagnostic and therapeutic procedures.

 When to Admit

• Severe pain.

• New jaundice.

• New fever.