Current Diagnosis & Treatment in Infectious Diseases

Section II - Clinical Syndromes

21. Hepatobiliary Infections

Paul B. Eckburg MD

Jose G. Montoya MD

Essentials of Diagnosis

  • History of household or sexual contact with individuals with hepatitis, travel or residence in endemic areas, human immunodeficiency virus (HIV) risk factors or established acquired immunodeficiency syndrome (AIDS), blood transfusion, needle stick injury, hepatotoxic medication or alcohol use, intravenous (IV) drug use, biliary colic or known gallstones, recurrent cholangitis, or liver transplant.
  • Fever, nausea, vomiting, aversion to smoking, tender hepatomegaly, or right-upper-quadrant pain.
  • Hepatocellular damage (elevated aminotransferases) or cholestasis (elevated bilirubin and alkaline phosphatase) on hepatic biochemical testing.
  • Positive serologies for hepatitis viruses or Entamoeba histolytica, or positive blood culture for enteric bacteria.
  • Inflamed gallbladder, dilated intra- or extrahepatic ducts, or intrahepatic lesion on hepatobiliary imaging.
  • Liver biopsy histopathology with nonspecific hepatocellular necrosis or granulomas.

General Considerations

A large number of infectious organisms can cause liver or biliary tract abnormalities, either by direct invasion or by the effects of systemic infection and sepsis (Table 21-1). There is a wide range of clinical presentations in hepatobiliary infections, depending on the specific organism, the host response, and the immune status of the host. Clinical syndromes may feature abnormal hepatic biochemical tests, focal hepatic lesions, granulomatous disease, or obstructive jaundice. A thorough history, physical exam, and biochemical liver test panel are usually sufficient for making a diagnosis of the type of hepatobiliary disease in ≥ 80% of cases. However, symptoms, signs, and liver test abnormalities are often not specific enough to make an accurate diagnosis without the aid of cultures or serologies, hepatobiliary imaging, or liver biopsy.

  1. History and physical exam.The history should elicit a detailed sexual, occupational-exposure, IV drug use, and blood transfusion record (eg, assess HIV and hepatitis risk factors), as well as travel to endemic areas, alcohol use, current medications, diet (eg, risk of hepatitis A), and history of cholelithiasis. Symptoms are often nonspecific (eg, prodromal fatigue and malaise in acute hepatitis) and rarely helpful in establishing the cause of hepatobiliary disease. Some clinical syndromes may be asymptomatic (eg, chronic hepatitis B), whereas others may have a fulminant course (eg, acute hepatitis B).

The clinical exam is also nonspecific, with fever, hepatomegaly, and right-upper-quadrant abdominal pain and tenderness being common in a variety of hepatobiliary infections. The abdominal exam may be unremarkable, as in some cases of chronic hepatitis and granulomatous hepatitis. Clues to the diagnosis can be obtained by finding extrahepatic manifestations of disease. For example, urticaria may be seen in early hepatitis B, and porphyria cutanea tarda may be associated with hepatitis C. Autoimmune phenomena such as thyroiditis and inflammatory bowel disease (IBS) may be seen with autoimmune hepatitis or sclerosing cholangitis. Glomerulonephritis may be seen in either hepatitis B or C infection.

  1. Diagnostic methods for evaluation of hepatobiliary infection.
  2. Laboratory studies.Abnormal hepatic biochemical tests may be the first evidence of liver disease. Elevated serum aminotransferase levels are sensitive indicators of hepatocellular injury. Alanine aminotransferase is located in the hepatocyte cytosol and is more specific for liver disease. Aspartate aminotransferase is located in both the cytosol and mitochondria and is also found in other organs such as the brain, kidneys, blood cells, and skeletal muscle. The degree of aminotransferase elevation does not seem to correlate with the severity of liver injury and is of little prognostic value. However, the magnitude of the elevation may help in differentiating the cause of liver injury. For example, markedly elevated levels are seen in ischemic injury, damage from toxins (eg, acetaminophen), viral hepatitis, and occasionally acute common bile duct obstruction.

Elevated alkaline phosphatase level is helpful in diagnosing biliary tract disease in the context of other abnormal hepatic tests, but it is not helpful in differentiating the site of damage within the biliary system. For example, elevated alkaline phosphatase is common in obstruction or disease of the extrahepatic biliary tree (eg, acute cholangitis caused by choledocholithiasis), the main hepatic ducts (eg, in sclerosing cholangitis), interlobular ducts (eg, granulomatous hepatitis), and canalicular membranes (eg, with rifampin therapy). Serum γ-glutamyl transpeptidase can be used to confirm a hepatic origin of an elevated alkaline phosphatase, but it otherwise lacks specificity for hepatic dysfunction.

Table 21-1. Systemic infectious diseases with associated hepatobiliary abnormalities.

Bacterial
   Gram-negative sepsis
   Pneumococcal pneumonia
   Listeriosis
   Toxic shock syndrome
   Legionnaires' disease
   Brucellosis
   Fitz-Hugh-Curtis syndrome
   Salmonellosis
   Nocardiosis
   Syphilis
   Lyme disease
   Leptospirosis
   Psittacosis
   Tuberculosis
   Hansen's disease (Leprosy)
   Tularemia
Rickettsial
   Q fever
   Rocky Mountain spotted fever
Viral
   Cytomegalovirus
   Infectious mononucleosis
   Adenovirus
Fungal
   Histoplasmosis
   Coccidiodomycosis
   Candidiasis
   Invasive aspergillosis
Parasitic
   Schistosomiasis
   Toxoplasmosis
   Hydatid cyst disease
   Visceral larva migrans
   Fascioliasis

Hyperbilirubinemia is of little prognostic value in acute biliary obstruction, but its level can be correlated with mortality in chronic liver diseases. High levels of total bilirubin can be seen in acute cholangitis, sclerosing cholangitis, and certain systemic infections involving the liver, such as septic shock and leptospirosis. Most other hepatic infections are associated with only mild elevations in bilirubin (< 5 mg/dL). Almost all infections of the hepatobiliary system feature > 50% direct bilirubin as part of the total bilirubin level.

  1. Imaging.See Table 21-2.
  2. Ultrasonography.Ultrasonography is the preferred method for diagnostic imaging of the right upper quadrant when gallbladder disease is suspected. It is relatively inexpensive, noninvasive, and may be performed at the patient's bedside. Gallstones, gallbladder wall thickening, and localized tenderness over the gallbladder (sonographic Murphy's sign) correlate highly with the presence of acute cholecystitis. Cystic duct calculi may be more difficult to visualize, and the overlying duodenum may prevent visualization of choledocholithiasis (75% sensitivity vs 95% sensitivity in detecting cholelithiasis).

Table 21-2. Diagnostic imaging of choice in hepatobiliary infections.

Suspected Disease

Diagnostic Imaging of Choice1

Cholelithiasis and cholecystitis

Abdominal ultrasonography

Choledocholithiasis and cholangitis

Direct cholangiography (ERCP preferred over PTC)

Extrahepatic biliary obstruction of unclear etiology

Abdominal CT

Liver abscess

Abdominal CT

Acute hepatitis

No role for diagnostic imaging

1Abbreviations: ERCP, endoscopic retrograde cholangiopan creatography; PTC, percutaneous transhepatic cholangiography; CT, computed tomography

  1. Abdominal computed tomography (CT).Abdominal CT is less reliable than ultrasound in detecting gallbladder wall abnormalities or gallstones, and it has sensitivity similar to that of ultrasound in detecting choledocholithiasis (75%). However, CT is the preferred test in detecting other causes of posthepatic biliary obstruction, because it has better visualization of the retroperitoneum and lymph nodes and can simultaneously visualize the liver, biliary tree, and pancreas. CT is also the test of choice in evaluating for liver abscesses, and it can identify air and calcifications within intrahepatic lesions (eg, echinococcal cysts).
  2. Direct cholangiography.Direct cholangiography, with injection of contrast into the biliary tree, is used when there is strong suspicion of choledocholithiasis (eg, in acute cholangitis). This can be performed by either percutaneous transhepatic cholangiography (PTC) or by endoscopic retrograde cholangiopancreatography (ERCP). It is superior to both ultrasonography and CT in detecting common bile duct stones, and offers the potential for therapeutic intervention in removing the stones. ERCP has the advantage over PTC in being able to perform a papillotomy or placing a common bile duct stent if needed for stone extraction.
  3. Hepatobiliary scintigraphy.Hepatobiliary scintigraphy (eg, dimethyl iminodiacetic acid scan) uses a radiolabel such as 99mTc to visualize the path of biliary excretion. This test may be used to evaluate for cystic duct obstruction (eg, in acute cholecystitis) if ultrasonography is negative.
  4. Magnetic resonance cholangiography.Magnetic resonance cholangiography is emerging as an alternative to ERCP for imaging the biliary tree. The test is noninvasive and does not require contrast material. However, if choledocholithiasis is detected, the stone cannot be removed during the procedure as with ERCP.
  1. Liver biopsy.Percutaneous liver biopsy is indicated when imaging studies reveal a space-occupying lesion and an infectious or neoplastic etiology is suspected but not yet established. It is also useful in staging disease and determining the severity of hepatocellular damage in chronic viral hepatitis (often used to assess the need for and predict response to antiviral therapy). Liver biopsy can be used to diagnose infiltrative processes such as granulomatous hepatitis (eg, in patients with fever of unknown origin). In patients with a focal hepatic lesion, liver biopsy should be performed under ultrasound or CT guidance.

INFECTIONS OF THE LIVER

ACUTE VIRAL HEPATITIS

Essentials of Diagnosis

  • Prodrome of malaise, nausea, vomiting, and low-grade fever.
  • Possible tender hepatomegaly, jaundice, dark urine, and acholic stools.
  • Marked elevation in aminotransferase levels.
  • Presence of serum antigen or antibody to a specific hepatitis virus.

General Considerations

Acute viral hepatitis is caused by five agents, the hepatitis A, B, C, D, and E viruses. Acute viral hepatitis may also be part of other systemic viral illnesses, such as infectious mononucleosis and cytomegalovirus (CMV) infection. Several recently discovered viruses (hepatitis F, GB-C, and G viruses) are currently being further characterized. In the United States, ~ 40% of cases of acute viral hepatitis are caused by hepatitis B virus (HBV), 30% by hepatitis A virus (HAV), 20% by hepatitis C virus (HCV), 2% by hepatitis D virus (HDV), and 1% by hepatitis E virus (HEV) (the remaining cases are of unclear etiology). All five viruses can cause acute hepatitis, which is clinically similar to other causes of hepatitis, eg, drug-induced or ischemic hepatitis, and can only be distinguished by specific viral serologies. Only HBV, HCV, and HDV can cause chronic infection. Each of these viruses is discussed briefly; for details on the hepatitis viruses, see Chapter 39.

HAV is a single-stranded RNA-containing picornavirus that causes sporadic outbreaks and epidemics of acute hepatitis. It does not cause chronic hepatitis. Its major route of transmission is fecal-oral spread, which is enhanced by crowding and poor hygiene. Common-source outbreaks may involve contaminated water and food (eg, shellfish). Household contacts are at highest risk for infection (~ 25% of cases), followed by participants in daycare centers (15% of cases), travelers to endemic areas (5%), homosexual men (4%), and IV drug users (2%). Transfusion-associated HAV is extremely rare. Viremia occurs during the incubation period (2–6 weeks), and fecal excretion of HAV may occur for ≤ 2 weeks before clinical illness. Replication and shedding of the virus therefore may occur although the subject is asymptomatic, which suggests that this process is noncytopathic to the liver. Liver injury is mediated by the host immune response, primarily involving cytotoxic T cells and natural killer cells.

HBV is a hepadnavirus that has a partially double-stranded DNA genome, an inner core protein (hepatitis B core antigen), and outer surface antigen [hepatitis B surface antigen (HBsAg)]. It infects > 400 million people worldwide, although it is more prevalent in Southeast Asia, China, and Africa. In the United Sates, most HBV infection results from sexual exposure (≤ 60%), IV drug use (10–15%), and rarely occupational exposure; ≤ 30% have an unknown source of infection. In endemic countries, maternal-neonatal vertical transmission and horizontal spread among children is quite common. Like HAV, HBV does not kill hepatocytes. Liver injury occurs from the host's immune attack against the virus, including a specific cytotoxic T cell response against hepatitis B core antigen (presented on the surface of infected hepatocytes). The immature immune systems of neonates are unable to clear the virus, and > 90% of infected neonates become chronic asymptomatic carriers. Only 1–5% of immunocompetent adults remain chronically infected, however acute infection may feature severe hepatocellular injury and symptomatic illness. Fulminant hepatitis occurs in < 1% of cases.

HDV (or delta agent) is a blood-borne defective RNA virus that causes hepatitis only in association with HBV. Like HBV, prevalence rates vary from region to region, although it is endemic in the Mediterranean, Russia, Middle East, and the Amazon basin of South America. Percutaneous spread is the major route of transmission. The pathogenesis of HDV infection is not fully understood. Both acute HDV coinfection with HBV and HDV superinfection in HBsAg carriers have been well-described. In superinfection, acute disease is more severe, and chronic hepatitis with rapid progression to cirrhosis is more common.

HCV is a single-stranded RNA virus related to the flaviviruses. It is the most common cause of post-transfusion hepatitis worldwide. Six genotypes have been identified to date, each with varying disease severity and treatment response. The most common genotypes in the United States and Europe are 1a and 1b; the latter is associated with more advanced disease and suboptimal treatment response. Prevalences of HCV seropositivity are 1–2% in the United States and 4–6% in parts of Africa and the Middle East. HCV is primarily transmitted in contaminated blood and less effectively through other body fluids. Risk factors for infection include IV drug use (≤ 50% of cases), hemodialysis, tattooing, and blood and IV immunoglobulin (Ig) transfusion. Perinatal and sexual transmissions are relatively rare. The exact mechanism of hepatic injury remains undefined, but cytotoxic T cells directed against viral epitopes are likely involved. High rates of viral mutations into quasi-species allow the virus to evade immune surveillance, leading to chronic infection in > 80% of cases.

HEV is a caliciviruslike RNA virus involved in waterborne outbreaks of acute hepatitis. Like HAV, it causes a self-limited hepatitis spread via the fecal-oral route and does not result in a chronic carrier state. HEV causes epidemic and endemic disease in India, Southeast Asia, parts of Africa, and Mexico, and it should be suspected in travelers to these areas with acute hepatitis. Pathogenesis of liver damage by HEV is poorly understood, but may involve both direct viral and immune-mediated effects.

Clinical Findings

  1. Signs and symptoms.The clinical presentation is variable, from asymptomatic (eg, majority of acute hepatitis C) to fulminant (eg, acute hepatitis E in pregnancy). The five types of viral hepatitis cannot be distinguished based on clinical findings alone (Table 21-3). During the incubation period, patients may have malaise, myalgias, arthralgias, anorexia, nausea, vomiting, and aversion to smoking. Low-grade fevers and abdominal pain may be experienced during this prodrome phase. An icteric phase that features jaundice and transient worsening of prodromal symptoms may follow, with subsequent gradual improvement during convalescence. On examination, tender hepatomegaly may be present in over half of cases; however splenomegaly is uncommon. Immune complexes may develop in acute hepatitis B, leading to a preicteric serum sickness-like syndrome with glomerulonephritis, polyarthritis, urticaria, and systemic vasculitis in < 10% of cases. Extrahepatic syndromes have also been associated with acute hepatitis C, including cryoglobulinemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda, and Mooren corneal ulcers.

Table 21-3. Clinical characteristics of acute viral hepatitis.1

Characteristic

HAV

HBV

HCV

HDV

HEV

Incubation (mean days)

30

60–90

50

60–90

40

Severity

Mild

Moderate to severe

Moderate

Moderate to severe

Mild

Fulminant

<1% (higher if underlying chronic HBV or liver disease)

1%

<1%

10–15%

1% (10–20% in pregnancy)

Diagnostic serology

HAV Ab (IgM)

HBsAg and HBcAb (IgM)

HCV Ab and HCV RNA

HDV Ab and HBcAB (IgM in coinfection, IgG in superinfection)

HEV Ab (IgM)

Progression to chronicity

None

90% neonates, 1–5% adults

80%

Nearly 100% if superinfection of chronic HBV

None

1Abbreviations: HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; IgM, immunoglobulin M; HBsAg, hepatitis B surface antigen; HBcAg, hepatitis B core antigen antibody; Ab, antibody.

  1. Laboratory findings.Aminotransferase levels are typically > 300 U/L and often > 1000–2000 U/L. Elevated aminotransferases may be discovered on routine testing in asymptomatic patients. Moderately elevated bilirubin and alkaline phosphatase levels occur during the icteric phase and may persist after normalization of the aminotransferases. Leukocytosis is uncommon; however, a relative leukopenia may be seen. Urinalysis may reveal a mild proteinuria and bilirubinuria during the icteric phase.

Serology for the specific viral antibodies and antigens is key to making the correct diagnosis (see Chapter 39). In acute hepatitis A, HAV IgM is the most important diagnostic test. This antibody appears early in the disease, peaks within the first week of illness, and disappears in 3–6 months (HAV IgG may persist for years).

In hepatitis B, HBsAg is the first serum marker to appear. It is detectable before evidence of abnormal biochemical tests and persists throughout acute (and chronic) hepatitis. Hepatitis B surface antibody rises after the clearance of HBsAg, leaving a window of seronegativity to the surface protein (between the disappearance of HBsAg and the appearance of hepatitis B surface antibody). The appearance of hepatitis B surface antibody signals noninfectivity and protection from recurrence and is the only positive marker in those vaccinated for HBV. Hepatitis B core antibody may be used to diagnose HBV infection because IgM rises shortly after the appearance of HBsAg and will be present before hepatitis B surface antibody appears. Hepatitis B core IgG rises later and persists whether recovery or chronic hepatitis B develops; it is not a protective antibody. Of note, hepatitis B core antigen does not appear in the serum. HBeAg and HBV DNA are more specific markers for infectivity and ongoing replication, and they appear only in HBsAg-positive sera. HBV polymerase chain reaction is now available and has been used to assess the response of chronic hepatitis to antiviral therapy; however, its role has not been fully established. Coinfection with HDV is suggested by a positive HDV antibody or HDV RNA.

In hepatitis C, HCV antibody can be detected by enzyme-linked immunosorbent assay; however, this test has suboptimal sensitivity and 50% specificity. If a false-negative or -positive test is suspected, recombinant immunoblot assay for HCV antibody may be used to confirm the diagnosis. Serum HCV RNA can be detected by polymerase chain reaction; a positive result indicates infectivity. Polymerase chain reaction should be used only if recombinant immunoblot assay for antibodies is indeterminate or when assessing response to antiviral treatment. Similarly, HEV antibody and RNA are present in acute hepatitis E.

Differential Diagnosis

Acute hepatitis may be clinically similar in such systemic infections as infectious mononucleosis, CMV, herpes simplex virus, leptospirosis, secondary syphilis, brucellosis, and Q fever. Right-upper-quadrant pain, jaundice, and markedly elevated transaminases may also occur in drug-induced hepatotoxicity or ischemic liver damage (eg, “shock liver” in sepsis). Fever, jaundice, and abnormal hepatic biochemical tests may be seen in autoimmune hepatitis and cholangitis. The prodromal phase of acute viral hepatitis is nonspecific and may resemble influenza virus infection.

Treatment

Only supportive and symptomatic treatment is available. No specific antiviral agents have been shown to be useful in this syndrome, and there is no benefit of corticosteroid therapy. Patients should avoid hepatotoxic medications, alcohol, and narcotic agents. Those with fulminant hepatitis should be hospitalized for intensive monitoring and correction of coagulopathy. Limited studies in the treatment of acute hepatitis C with interferon-α (IFN-α) suggest a reduction in the risk of chronic hepatitis; however, this should be considered experimental at this time. This approach is impractical for HBV because > 95% of infected adults have self-limited hepatitis.

Prevention

Hand washing, needle precautions, and protected intercourse are important in preventing disease. Continued screening of blood donors and blood products may further reduce the frequency of blood-borne infections. Vaccines and immune globulin are available for the prevention and postexposure prophylaxis of HAV and HBV infection. HAV vaccination is recommended for those planning travel to endemic areas, and is available as Havrix (1.0 mL intramuscularly) or Vaqta (0.5 mL intramuscularly). HAV Ig is indicated for all close contacts (ie, household contacts) of known HAV-infected individuals, given as a 0.02 mL/kg intramuscular injection within the incubation period. HBV vaccine (Recombivax-HB or Engerix-B) is now universally recommended for all infants and high-risk adults, and is given in a series of three injections, at 0, 1, and 6 months. HDV is also best prevented by this vaccine. Postexposure prophylaxis with HBV Ig should be administered as early as possible after sexual, mucous membrane, or perinatal exposure (0.06 mL/kg intramuscularly), followed by the vaccination series. There is no effective vaccine for HCV.

Prognosis

Patients with acute viral hepatitis usually recover within 3–16 weeks of clinical illness. It is not uncommon for abnormal hepatic biochemical tests to persist longer. Overall mortality is < 1%. HAV and HEV do not have chronic carrier states, although HAV infection may persist up to 1 year with the potential for relapses before complete recovery. HEV infection during pregnancy is associated with a higher mortality. HBV infection is associated with a higher mortality if there is an associated HDV infection, and superinfection of HDV invariably leads to chronic infection. Chronic hepatitis B occurs in ≤ 90% of infected infants and 1–5% of adults. Chronic HCV infection occurs in 80% of all cases, with ≤ 30% progressing to cirrhosis.

CHRONIC VIRAL HEPATITIS

Essentials of Diagnosis

  • Possible malaise, fatigue, weakness, and elevated aminotransferase levels.
  • Persistent serum HBsAg or HCV antibodies for ≥ 6 months.
  • Liver biopsy histopathology with characteristic hepatocellular necrosis and fibrosis.

General Considerations

Chronic viral hepatitis is currently the leading indication for liver transplantation and is the main cause of cirrhosis and hepatocellular carcinoma in the world. It is defined as persistently elevated aminotransferase levels with characteristic histopathologic changes for ≥ 6 months duration. Of the hepatitis viruses, only HBV, HCV, and HDV can cause chronic hepatitis.

Chronic hepatitis B features persistent HBsAg for > 6 months. It affects > 400 million people worldwide. The disease is highly endemic in Southeast Asia, the Pacific islands, Africa, and the Middle East, and ≤ 15% of these populations are chronically infected. Of infected neonates, ≥ 90% later develop chronic hepatitis B, in contrast to 1–5% of adults. The pathogenesis underlying the rates of chronic infection in different age groups is largely unknown. However, in children it likely involves immune tolerance, in allowing viral replication to proceed without a destructive cytotoxic T-cell response. The natural history of disease is variable. Some patients spontaneously enter a phase of immune clearance, with a decrease of HBeAg and HBV DNA and appearance of HBeAb. The course may fluctuate with recurrent flares or sustained remission.

Unlike HBV, HCV infection does not involve integration into the host genome (there is no DNA intermediate in its life cycle). Persistence of the virus results from a high mutation rate during replication, with production of quasispecies and avoidance of the host immune response. Of acute HCV cases, 80% develop chronic disease.

Clinical Findings

  1. Signs and symptoms.The different forms of chronic hepatitis cannot be distinguished by clinical presentation. Patients may be asymptomatic with incidental abnormal hepatic serum tests, or they may present with end-stage liver disease with cirrhosis and portal hypertension. Malaise and weakness are common symptoms.
  2. Laboratory findings.Hepatic biochemical tests usually reveal mildly elevated aminotransferases (2- to 20-fold), hyperbilirubinemia, elevated prothrombin time, and hypoalbuminemia. Chronic hepatitis B is distinguished by persistent serum HBsAg, HBeAg, and HBV DNA levels (Table 21-4), in conjunction with characteristic histopathologic findings on liver biopsy. Remission or response to treatment may be suggested by loss of HBeAg and DNA levels despite persistent HBsAg. Chronic HCV is diagnosed by persistent HCV antibodies and positive serum HCV RNA with concurrent histopathologic changes on biopsy. Of note, false-positive HCV antibodies can occur in autoimmune hepatitis, which can clinically present like chronic hepatitis C.
  3. Biopsy.Liver biopsy is used to assess disease activity and is recommended before institution of treatment to determine disease severity and predict response to treatment. Histopathology of chronic hepatitis features nonspecific diffuse inflammation (T-cell infiltration) and hepatocyte necrosis. Chronic hepatitis C may be associated with periportal lymphoid aggregates, steatosis, and bile duct damage.

Table 21-4. Interpretation of serologic patterns in chronic viral hepatitis.1

HBsAg

HBcAb (IgG)

HBeAg

HBeAb

HBV DNA

HCV Ab (IgG)

HDV Ab

HCV RNA

Interpretation

+

+

+

-

+

-

-

-

Chronic HBV with high infectivity

+

+

-

+

+

-

-

-

Chronic HBV with low infectivity

-

+

-

+

-

-

-

-

Low-level HBV carrier (remote infection or response to treatment)

-

-

-

-

-

-

+

+

Chronic HCV

+

+

-

+

+

+

-

-

Superinfection of HDV on chronic HBV

-

+

-

-

-

-

+

+

Chronic HCV and distant acute HBV

-

-

-

-

-

-

+

-

False-positive HCV antibody or recovery after acute HCV

1Abbreviations: HBsAg, hepatitis B surface antigen; HBcAb, hepatitis B core antibody; HBeAg, hepatis Be antigen; HBeAb, hepatis Be antibody; HBV, hepatitis B virus; HDV Ab, hepatitis D virus antibody; HCV Ab, hepatitis C virus antibody; HCV, hepatitis C virus.

Treatment

Despite similarities in clinical and histopathologic characteristics, chronic viral hepatitis caused by HBV or HCV responds differently to therapy. IFN-α is the only effective treatment for both hepatitis C and B.

IFN-α induces the clearance of HBV by enhancing the host immune response. Of chronic hepatitis B cases, ~ 33% enter remission (negative HBeAg) after a 4- to 6-month course of IFN. This therapy is indicated only when the patient has persistent elevations in aminotransferases, HBeAg, and HBV DNA. Patients with normal aminotransferase levels respond poorly to IFN therapy (eg, Asian patients who acquired the disease in childhood). Liver biopsy is recommended before treatment to assess severity of fibrosis and cellular injury. IFN-α is administered over a 4- to 6-month course (Box 21-1). Patients with concomitant chronic HDV require higher and longer doses of IFN (9 million units thrice weekly for 12 months), which leads to a sustained response in only 15–25% of cases. In addition to IFN-α, long-term suppressive therapy with nucleoside analogs (eg, lamivudine) may prove to be beneficial in achieving sustained inhibition of HBV replication. Lamivudine is approved for treatment of chronic HBV with evidence of active replication (administered 100 mg orally daily for 1 year). However, long-term treatment may lead to the emergence of resistant mutant virus.

IFN-α is also recommended for patients with chronic HCV (Box 21-1). Therapy lasting 6 months may lead to remission of disease in 50% but a sustained response in only 10–25%. Long-term response is unlikely if HCV RNA is still detectable after 3 months of therapy. Ribavirin may prove to have long-term benefit when used initially in combination with IFN. Early studies showed that higher rates of remission are possible when ribavirin is used in combination with IFN-α. This has been confirmed in a recent double-blind, placebo-controlled trial from Sweden, showing that more patients have a sustained virologic response at 1 year after 24 weeks of therapy with combination IFN and ribavirin than IFN therapy alone. Combination of IFN and ribavirin is the therapy of choice for chronic HCV. A sustained virologic response rate of 40% is seen in patients treated with this combination for 48 weeks. This response rate is higher in patients with non-1 genotype or a low HCV viral load.

BOX 21-1 Use of Interferon-α in the Treatment of Chronic Hepatitis B and C1

 

Chronic Hepatitis B

Chronic Hepatitis C4

Adults

5 million U SC daily, OR 10 million U SC three times weekly OR
30–35 million U SC weekly, for 16 weeks2

3 million U SC or IM three times weekly for 12 mos (interferon-α2a) or 18–24 mos (interferon-α2b)2,3

Children

5–6 million units/m2/d IM or SC three weekly for 3–6 mos

3 million U/m2SC three times weekly times for 6 mos

1Abbreviations, SC, subcutaneously; IM, intramuscularly.

2A 50% dose reduction is recommended in patients who do not tolerate the initial dose.
3If there is no response after 12–16 weeks, discontinuation should be considered.
4In combination with ribavirin (600 mg orally twice a day if >75 kg weight, or 400 mg orally in the morning with 600 mg orally in the evening if ≤75 kg in weight).

Prognosis

The exact frequency of progression of chronic hepatitis B to cirrhosis is unknown, but likely occurs in 10–50% of cases. HBsAg carriers have a 200-fold–higher relative risk of developing hepatocellular carcinoma than noncarriers. Chronic hepatitis C progresses to cirrhosis in 20–30% of cases, and the risk of developing hepatocellular carcinoma is higher than in HBV infection, occurring a mean of 30 years after initial HCV infection. Chronic hepatitis C has a better long-term response to IFN if HCV genotype 2 or 3 is present. In contrast, < 10% of HCV genotype 1 cases (80% of cases in the United States) respond to IFN.

GRANULOMATOUS HEPATITIS

Essentials of Diagnosis

  • Fever and nonspecific liver test abnormalities.
  • Constitutional symptoms or asymptomatic.
  • Characteristic granulomas on liver biopsy histopathology.

General Considerations

Granulomas develop in the liver when the reticuloendothelial system is exposed to certain foreign antigens. They usually reflect a systemic disease process, whether being infectious or noninfectious in etiology. Granulomas are nodular infiltrates of epithelioid cells, which are transformed macrophages. The stimuli for such a transformation may include undegraded foreign matter (eg, mycobacterial products) or inflammatory mediators released by sensitized T cells. Triggered macrophages release interleukin-1 and other pyrogens that account for the fevers seen in this disease.

Infectious diseases are the most common cause of granulomatous hepatitis (Table 21-5), of which tuberculosis is the most common. The diagnosis of tuberculous granulomas is difficult, because Mycobacterium tuberculosis can cause either noncaseating or caseating hepatic granulomas, and the organism is demonstrated on staining or culture in < 50% of cases. Fungi are another common cause, with histoplasmosis being the most common fungal etiology of granulomatous hepatitis in the United States.

Clinical Findings

Fever is common, and granulomatous hepatitis may present as a fever of unknown origin. Clinical presentation varies from nonspecific hepatic biochemical abnormalities in asymptomatic individuals to vague abdominal pain, weight loss, and night sweats. Laboratory abnormalities are also nonspecific, however elevated alkaline phosphatase levels are common, and aminotransferase and erythrocyte sedimentation rate levels are variably elevated. Liver biopsy is essential for diagnosis to demonstrate the characteristic granulomas. This must be supplemented with specific stains (eg, acid-fast stains and silver staining), cultures (eg, for bacteria, fungi, and mycobacteria), and serum serologies (eg, for viral causes and Q fever) to diagnose the specific cause. Imaging is not helpful in the workup of granulomatous hepatitis.

Table 21-5. Systemic infections that can cause granulomatous hepatitis.

Bacterial
      Tuberculosis
      Atypical mycobacterial disease
      Lepromatous leprosy
      Brucellosis
      Listeriosis
      Bartonellosis
      Secondary or tertiary syphilis
      Tularemia
Rickettsial
      Q fever
Viral
      Cytomegalovirus infection
      Infectious mononucleosis
Fungal
      Histoplasmosis
      Coccidioidomycosis
      Candidiasis
      Cryptococcosis
Parasitic
      Schistosomiasis
      Visceral larva migrans
      Fascioliasis
      Toxoplasmosis

 

Differential Diagnosis

This syndrome may be indistinguishable from hepatic granulomas caused by noninfectious diseases. Sarcoidosis and hypersensitivity drug reactions (eg, allopurinol, sulfonamides, and quinidine) are the most common, followed by chronic granulomatous disease of childhood, Hodgkin's disease, and other lymphomas. Of note, the cause remains unknown in ≤ 50% of cases in some series.

Treatment

Treatment of infectious causes of granulomatous hepatitis is directed toward the specific cause. Granulomas seem to resolve as the systemic infection clears. Corticosteroids have been shown to be efficacious in some cases of idiopathic granulomatous hepatitis. However, some experts recommend an empiric trial of two-drug antituberculous therapy before steroid administration, given the frequency of false-negative cultures for tuberculosis and the potential for disseminated tuberculosis with steroid therapy. Treatment response should be monitored by clinical parameters and repeat biopsy at 6–12 months.

HEPATIC ABSCESS

  1. PYOGENIC LIVER ABSCESS

Essentials of Diagnosis

  • Right upper quadrant abdominal pain.
  • Fever, chills, and leukocytosis.
  • Tender hepatomegaly.
  • Intrahepatic lesion on hepatic imaging.
  • Possible indolent course, with malaise and poorly localized abdominal pain.

General Considerations

Despite frequent exposure of the liver to bacteria in both the portal and systemic circulatory systems, the development of pyogenic liver abscesses is rather rare. The extensive network of reticuloendothelial cells in the hepatic sinusoids is highly protective. Hepatic abscess formation can occur when this defense system is overwhelmed, by bacterial invasion from either the biliary tree (eg, acute cholangitis), the portal vein (pyelephlebitis), the hepatic artery, direct trauma, or adjacent bacterial infection. The incidence of pyogenic liver abscess is ~ 15 cases/100,000 hospital admissions, and over one-third of such cases are secondary to direct extension from a biliary tract infection. Bacteria less commonly invade the liver from the portal system (eg, with appendicitis or IBS), systemic circulation (eg, Staphylococcus aureus abscesses in children), or penetrating trauma (eg, complication of ventriculoperitoneal shunt placement). Over half of liver abscesses are polymicrobic (Box 21-2), but a single organism may be involved in abscesses from a systemic source (eg, Candida spp. in neutropenic hosts). Either hepatic lobe may be involved; however, the right lobe is more commonly involved given its size and propensity to receive most portal blood flow. Abscesses may be single or multiple, ranging from widely scattered microabscesses (eg, in S aureus sepsis) to single large polymicrobic abscesses. Of pyogenic liver abscesses, ~ 15% have no known cause and are classified as cryptogenic.

Clinical Findings

  1. Signs and symptoms.The patient may present with high fever, rigors, and severe right-sided abdominal pain. A more acute and severe clinical picture (with fever, jaundice, abdominal pain, and shock) may be seen with multiple abscesses, usually associated with acute cholangitis. However, up to half of cases may have chronic symptoms of malaise, fatigue, weight loss, and poorly localized pain that worsens with movement. If the abscess is adjacent to the liver capsule, referred right shoulder pain may occur, which may worsen with coughing. Breath sounds may be reduced over the right lung base secondary to an associated pleural effusion. Physical exam often reveals tender hepatomegaly, which is often accentuated by percussion over the surface of the liver.
  2. Laboratory findings.Hepatic biochemical abnormalities are nonspecific, including a slightly elevated total bilirubin, elevated aminotransferases (two- to threefold), and hypoalbuminemia. Alkaline phosphatase and γ-glutamyl transferase levels may be elevated up to fivefold of normal values, especially when associated with biliary tract obstruction. Leukocytosis with a left shift is common, and anemia is often noted. Blood cultures may be positive in ≤ 50% of cases.
  3. Imaging.Abdominal CT with contrast is the procedure of choice. It allows for the precise localization and visualization of small abscesses (< 1 cm); detects gas within abscesses in ≤ 30% of cases (which suggests that gas-producing bacteria are present); distinguishes tumors, cysts, and hematomas; defines other intraabdominal abnormalities; and allows for CT-guided aspiration of the abscess if indicated. Abscesses appear as well-defined hypodense lesions that enhance on CT with contrast; rim enhancement is relatively uncommon. Right-upper-quadrant ultrasonography is a rapid alternative and has 70–90% sensitivity for differentiating cystic vs solid intrahepatic lesions. As seen sonographically, an abscess may be a hypodense or hyperdense ill-defined lesion. Note that both imaging tests may be negative in identifying intrahepatic abscesses in the neutropenic host (eg, hepatic candidiasis).

BOX 21-2 Microbiology of Pyogenic Liver Abscess

 

Adults

Children

Most Common

Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa
Streptococcus species (e.g. S milleri)
Bacteroides fragilis
Fusobacterium necrophorum
Clostridium perfringens
Peptostreptococci and microaerophilic streptococci

Staphylococcus aureus
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Fusobacterium necrophorum
Bacteroides fragilis

Less Common

Salmonella typhi
Staphylococcal species
Yersinia enterocolitica
Burkholderia pseudomallei
Pasteurella multocida
Listeria monocytogenes
Candida species
Mycobacterium tuberculosis (eg, miliary)

Candida albicans
Salmonella typhi

Differential Diagnosis

The major diagnostic challenge is to distinguish pyogenic from amebic abscess, because treatment differs depending on the etiology. Amebic abscess may be suggested by a hepatic abscess in an immigrant or traveler from an endemic area, a young or previously healthy adult, or a positive enzyme-linked immunosorbent assay for E histolytica. Pyogenic abscess is suggested by a positive blood culture and the presence of associated biliary tract infection, underlying liver disease, or IBS. Tender hepatomegaly and liver lesions on imaging may also be seen with liver cysts, metastatic carcinoma, lymphoma, and infarction.

Treatment

Drainage of the abscess and IV administration of antibiotics are the mainstays of treatment. Drainage is often done via percutaneous catheter drainage or percutaneous needle aspiration, usually under CT or ultrasound guidance. Recently, percutaneous needle aspiration has been deemed as safe and effective as continuous catheter drainage; however, repeated aspirations may be necessary in ≤ 30%. Percutaneous drainage may not be necessary in cases with relatively small abscesses (< 5-cm diameter), and successful treatment may be achieved with antibiotics alone, depending on the clinical stability of the patient. Open abdominal surgery is reserved for cases that fail to respond to percutaneous drainage.

Initial antibiotic regimens should include metronidazole until amebic abscess is ruled out by serologies (Box 21-3). The antibiotics should cover the most common bacterial pathogens, including gram-negative bacilli and anaerobes. Ampicillin, an aminoglycoside, and metronidazole have been effective, although an increase in the incidence of ampicillin-resistant Enterobacteriaceae has been noted, and aminoglycoside nephrotoxicity is a serious limitation of this regimen. An alternative regimen is a third-generation cephalosporin plus metronidazole (or clindamycin if amebic abscess has been ruled out) or a B-lactam/β-lactamase inhibitor combination plus metronidazole. In patients with a history of recent exposure to third-generation cephalosporins and prolonged hospitalization, certain gram-negative bacilli (ie, Serratia spp., Pseudomonas spp., indole-positive Proteus spp., Citrobacter spp., Enterobacter spp., and Acinetobacter spp.) may have developed resistance to all cephalosporins and β-lactam/β-lactamase inhibitor combinations. Pending susceptibility studies, alternative regimens for these patients include a carbapenem, or a fourth-generation cephalosporin or ciprofloxacin plus clindamycin or metronidazole. (Fluoroquinolones are the antibiotics of choice in patients allergic to penicillin, and a combination of ciprofloxacin plus either clindamycin or metronidazole is a reliable alternative.) Antibiotics should be continued for a minimum of 6 weeks, usually to 12 weeks (2–3 weeks IV, followed by oral regimen). Some authors recommend treatment for ≤ 6 months if the abscess is streptococcal.

BOX 21-3 Empiric Therapy of Pyogenic Liver Abscess in Patients with Normal Renal Function

 

Children

Adults

First Choice

· Nafcillin (100-200 mg/kg/d in 4 equal doses per 6 h) and gentamicin (2-2.5 mg/kg every 8 h) and metronidazole (30–50 mg/kg/d IV in 3 equal doses, per 8 h)

· Metronidazole (30–50 mg/kg/d IV in 3 equal doses per 8 h) and third-generation cephalosporin (eg, ceftazidime), 25–50 mg/kg IV per 8 h)

· Ampicillin (2 g every 6 h) and gentamicin (2 mg/kg load, then 1.7 mg/kg IV every 8 h) and metronidazole (1 g IV load, then 500 mg IV every 8 h)

· Metronidazole (1 g IV load, then 500 mg IV every 8 h) and third-generation cephalosporin (eg, ceftazidime, 2 g IV every 8 h) OR ticarcillin/clavulanate (3.1 g IV every 6 h) OR pipercillin/tazobactam 3.375 g IV every 6 h) OR ampicillin/sulbactam (3 g IV every 6 h)

Alternative

· Imipenem (15-25 mg/kg IV every 6 h) and metronidazole

· Imipenem (500 mg IV every 6 h) and metronidazole

· Ciprofloxacin (400 mg IV every 12 h) and metronidamycin (600–900 mg IV every 8 h)

Prognosis

Despite aggressive treatment, the mortality ranges from 10–25%. An increase in mortality is noted in patients with multiple abscesses, increased age, and associated comorbid conditions. Morbidity and mortality may be caused by formation of portal or splenic thromboses, pleural or pericardial effusions, rupture into the pericardium, fistula formation, empyema, or sepsis.

  1. AMEBIC ABSCESS

Essentials of Diagnosis

  • Fever and right-upper-quadrant abdominal pain.
  • Cystic lesion on abdominal imaging.
  • Positive serology for antibody to Entamoeba histolytica.

General Considerations

E histolytica is endemic worldwide, with an estimated 10% of the world's population being infected. It is more prevalent in India, Africa, the Far East, and Central and South America, especially in areas with poor hygiene. Amebic liver abscess is the most common extraintestinal complication of amebiasis (occurring in 8.5% of cases). Hepatic infection occurs when trophozoites in the colon ascend in the portal system and invade the parenchyma. Subsequent ischemia and lysis of neutrophils with release of toxic products contribute to parenchymal destruction. Trophozoites advance away from the necrosis and are located in the outer edge of the abscess. The term abscess is actually a misnomer because the central necrosis contains proteinaceous material without neutrophils.

Clinical Findings

  1. Signs and symptoms.Amebic abscesses may be difficult to distinguish from pyogenic abscesses. Patients with an amebic abscess are usually more acutely ill, with fever and abdominal pain for < 10-days duration. An indolent course is uncommon. Patients are also younger, usually from high-prevalence areas, or are recent travelers. If the pericardium is involved, the patient may present with chest pain or congestive heart failure, and a pericardial friction rub may be present. Dyspnea, cough, and pleuritic chest pain may be present when rupture into the pleural space occurs. Diarrhea is relatively uncommon, occurring in < 30% (despite the colon being the organism's point of entry). Jaundice and tender hepatomegaly are uncommon.
  2. Laboratory findings.Aminotransferase levels are variable; however, alkaline phosphatase is usually elevated and albumin decreased. Leukocytosis without eosinophilia is common. The erythrocyte sedimentation rate may be elevated, and anemia may be present. Serum antibodies to amoebae via enzyme-linked immunosorbent assay or indirect hemagglutination assay are present in > 90% of cases. However, serology may be negative in acute disease (but positive on repeated testing in 7–10 days) and may be positive if the patient had amebiasis in the past (as the antibody levels may persist for years after acute infection).
  3. Imaging.Both CT and ultrasonography are sensitive imaging studies for diagnosis of amebic abscess, but it is difficult to distinguish amebic abscesses from pyogenic abscesses or complex cysts. On sonography, the abscess usually appears as a round hypoechoic lesion near the liver capsule, with a paucity of significant wall echoes. CT with contrast may demonstrate a well-defined low attenuation lesion with a thick enhancing wall and surrounding zone of edema. Either CT or ultrasonography allows for percutaneous aspiration if pyogenic abscess needs to be ruled out. Of note, viable trophozoites are seen only in the periphery of the abscess. Fluid from the center of the abscess yields no organisms and varies in appearance, from yellow to reddish-brown (“anchovy paste”).

Treatment

Because amebicidal therapy is highly effective, percutaneous aspiration is not necessary. Catheter drainage should be considered only when amebic serologies are negative, bacterial superinfection of an amebic abscess is suspected, or a left-hepatic-lobe abscess threatens rupture into the pericardium. Metronidazole is the drug of choice (Box 21-4). This must be followed by a luminal agent, as E histolytica is present in the colon previous to hepatic invasion. Luminal agents include diloxanide furoate, paromomycin, or diiodohydroxyquin. Symptoms usually respond in 3 days. If no improvement occurs after 3 days of treatment, consider percutaneous aspiration of the abscess to rule out a bacterial process.

BOX 21-4 Treatment of Amebic Liver Abscess

 

Children

Adults

Amebicidal Agent

Metronidazole, 35-50 mg/kg/d to max 2250 mg/d per mouth in three divided doses for 10 days

Metronidazole 750 mg by mouth three times daily OR 500 mg IV every 6 h for 10 days

Luminal Agent

Diloxanide furoate, 20 mg/kg/d in three divided doses for 10 days OR
Paromomycin, 25-35 mg/kg/d in three divided doses for 10 days, OR
Diiodohydroxyquin, 30–40 mg/kg/d to max 1950 mg in three divided doses for 20 days

Diloxanide furoate, 500 mg by mouth three times daily for 10 days, OR
Paromomycin, 30 mg/kg/d by mouth in three divided doses for 10 days OR
Diiodohydroxyquin, 650 mg by mouth three times daily for 20 days

Prognosis

Mortality caused by uncomplicated amebic abscess is < 1%. Mortality is higher if the abscess ruptures into the peritoneum, pleural space, or pericardium. Cure of the amebic abscess apparently results in immunity, because recurrence in patients with positive amebic antibodies is extremely rare.

LIVER INFECTIONS IN PATIENTS WITH HIV

General Considerations

The majority of patients with AIDS have abnormalities on hepatic biochemical tests at some point in their illness. Opportunistic infections and neoplasms affect the liver in ≤ 80% of patients with AIDS in autopsy studies. The types of hepatic disease in HIV infection vary (Table 21-6). Acute hepatocellular damage is usually caused by viruses (eg, the hepatitis viruses, CMV, Epstein-Barr virus, herpes simplex virus, and HIV itself) or hepatotoxic drugs (eg, azidothymidine, dideoxyinosine, isoniazid, rifampin, ritonavir, or trimethoprim-sulfamethoxazole). The most common viral cause of hepatitis in HIV is HBV, and 20% of persons who are HIV-positive become chronic carriers (in contrast to 5% of HIV-negative adults). Granulomatous hepatitis is one of the most common presentations of hepatic infection in HIV patients, usually secondary to mycobacterial disease (eg, Mycobacterium avium complex), fungi (eg, disseminated histoplasmosis), or protozoa (eg, Pneumocystis carinii infection in patients receiving aerosolized pentamidine prophylaxis). Mass lesions are most commonly neoplastic. Vascular lesions may be caused by peliosis hepatis (Bartonella henselae infection) or Kaposi's sarcoma.

Table 21-6. Opportunistic hepatic infections in AIDS.

Liver Pathology

Microorganisms

Granulomas

· Mycobacteria (eg, M avium complex and M tuberculosis)

· Fungi (Cryptococcus, Histoplasma, Pneumocystis carinii)

Pyogenic abscess

· Enteric gram-negative bacilli, staphylococci, streptococci, Listeria monocytogenes

Vascular lesions

· Human herpesvirus 8 (Kaposi's sarcoma)

· Bartonella henselae (peliosis hepatis)

Hepatitis

· Hepatitis viruses, cytomegalovirus, herpes simplex virus, HIV

Lymphomatous infiltrates

· Epstein Barr virus (associated B-cell lymphoma)

Clinical Findings

Liver disease in HIV patients has an extremely variable presentation depending on the cause. Patients may be asymptomatic or have a fever of unknown origin (eg, in granulomatous hepatitis). Fever and right-upper-quadrant abdominal pain are common in acute viral hepatitis from any cause. Liver infection may be heralded as weight loss and hepatomegaly (eg, in peliosis hepatis). Jaundice is relatively uncommon and, when present, is usually caused by drug-induced hepatotoxicity (eg, with isonicotinic acid hydrazide or trimethoprim-sulfamethoxazole). Extrahepatic findings on exam may give clues to the diagnosis, eg, the presence of concomitant cutaneous lesions (in Kaposi's sarcoma or bartonellosis) or pulmonary tuberculosis. Hepatic biochemical tests are almost always abnormal, however, in nonspecific patterns. CD4 cell counts may aid in the differential diagnosis. For example, tuberculosis, Kaposi's sarcoma, and acute viral hepatitis are possible at any time in the course of disease, even with a normal CD4 count. Patients with CD4 < 100/mm3 are more susceptible to such infections as M avium complex and CMV.

Diagnostic Approach

A detailed history and physical are imperative and should focus on previous opportunistic infections, hepatotoxic medications, alcohol use, and recent travel. Hepatic biochemical testing is usually not helpful in diagnosis. Evidence for hepatocellular damage warrants further serologic testing, such as hepatitis viral serologies, and a trial of cessation of potentially toxic medications. If workup remains negative, consider liver biopsy. If a cholestatic pattern predominates on biochemical testing, imaging can be used to search for focal lesions or dilated biliary ducts. Consider ERCP in patients who present with fevers, jaundice, and abdominal pain or who have dilated biliary ducts on imaging, for potential biliary drainage, cultures, and biopsy specimens for further testing. Patients with HIV usually have histopathologic abnormalities on liver biopsy. About one-third of biopsy specimens yield nonspecific findings, however liver biopsy remains the most specific diagnostic tool for effective diagnosis of liver infection in HIV.

INFECTIONS OF THE BILIARY TRACT

ACUTE CALCULOUS CHOLECYSTITIS

Essentials of Diagnosis

  • Severe abdominal pain and tenderness localized to the right upper quadrant.
  • Nausea and vomiting.
  • Fever and leukocytosis.

General Considerations

Acute calculous cholecystitis, associated with cholelithiasis, accounts for > 90% of cases of cholecystitis. This severe inflammation of the gallbladder wall results from stasis of bile secondary to an obstructed gallbladder infundibulum or cystic duct by a stone. Obstructed bile and the associated increase in pressure lead to damage of the gallbladder mucosa and the release of inflammatory mediators. Bacteria may be present in the inflamed gallbladder in up to half of cases, but they likely play a secondary role in the inflammatory process. Distention and edema of the gallbladder wall may lead to ischemia, with resulting gangrene, empyema, or perforation. Cholecystitis in children usually results from pigment stones that develop in hemolytic disease.

Clinical Findings

  1. Signs and symptoms.Patients may have had previous episodes of biliary colic associated with cholelithiasis, but acute cholecystitis is heralded by severe and sustained pain that is more localized to the right upper quadrant. Children may have periumbilical, back, or poorly localized abdominal pain. Nausea, emesis, and fever are common. On exam, right-upper-quadrant tenderness is invariably present and may be associated with guarding and rebound caused by peritoneal irritation. Murphy's sign may be present, characterized by sudden cessation of inspiration secondary to severe tenderness during right upper quadrant palpation. Approximately 20% of cases have jaundice, and 20% have a palpable mass in the right upper quadrant secondary to irritated omentum overlying the inflamed gallbladder.
  1. Laboratory findings.The leukocyte count is usually high, with an associated bandemia. The total bilirubin may be elevated; however, the level rarely rises above 4 mg/dL. Mild elevations in alkaline phosphatase and aminotransferase levels are also present.
  2. Imaging.Abdominal ultrasound is the test of choice. It has 88–94% sensitivity and 78–80% specificity for detecting acute cholecystitis, suggested by a thickened gallbladder wall (> 5 mm), positive sonographic Murphy's sign, and the presence of pericholic fluid. Hepatobiliary imaging with 99mTc (eg, dimethyl iminodiacetic acid scan) may be useful in detecting an obstructed cystic duct, which is often the precipitating event in acute cholecystitis. The test is reliable when the total bilirubin is < 5 mg/dL, and is 98% sensitive and 81% specific for acute cholecystitis. However, biliary scintigraphy is more time consuming, involves injection of radiopharmaceuticals, and does not allow for imaging of the gall bladder and surrounding structures. Plain films of the abdomen may show radiopaque gallstones (≤ 15% of cases); however, they are not helpful in the diagnosis of acute cholecystitis.

Differential Diagnosis

Fever, nausea, vomiting, and right-upper-quadrant abdominal pain may be present in a number of other disorders, such as acute hepatitis, liver abscess, acute pancreatitis, perforated peptic ulcer, right-lower-lobe pneumonia with associated pleurisy, and appendicitis (especially in pregnancy). Definite localization of tenderness over a palpable gallbladder with radiation of pain to the right scapular area strongly supports the diagnosis of acute cholecystitis.

Complications

Perforation of the gallbladder may occur, especially if gangrene develops from progressive ischemia and gas-forming bacteria, including Escherichia coli in diabetic patients and Clostridium perfringens in emphysematons cholecystitis. This syndrome is more common in males and diabetics, and ~ 30% of cases are associated with acalculous cholecystitis. Empyema may result from bacterial invasion of the gallbladder wall, usually involving enteric gram-negative bacilli and anaerobes. Treatment is essentially the same as for acute cholecystitis; however, urgent surgical treatment is usually indicated in patients with empyema. Repeated episodes of acute calculous cholecystitis or chronic irritation of the gall bladder wall by stones may lead to chronic cholecystitis. Cholangitis and pancreatitis are potential complications if gallstones migrate and obstruct the common bile duct or pancreatic duct.

Treatment

In most cases, acute calculous cholecystitis will subside with conservative therapy alone. Bowel rest should be instituted and IV fluids administered. Antibiotics are most likely required in such clinical settings as sepsis, empyema, emphysematous cholecystitis, and cholangitis. In these patients, antibiotic options include a β-lactam/β-lactamase inhibitor, a carbapenem, ciprofloxacin plus metronidazole or clindamycin, or trovafloxacin. Ampicillin should be used with caution, given recent emergence of ampicillin-resistant E coli in community-acquired infections with this organism. If urgent cholecystectomy is considered, prophylactic antibiotics may be administered perioperatively; regimens include a second-generation cephalosporin with moderate anaerobic activity, such as cefoxitin or cefotetan.

Laparoscopic cholecystectomy is now considered the procedure of choice for removal of the gallbladder. Cholecystectomy is mandatory if there is evidence of emphysematous cholecystitis or perforation.

ACUTE ACALCULOUS CHOLECYSTITIS

General Considerations

Acute acalculous cholecystitis is infection of the gallbladder in the absence of gallstones. It is less common than gallstone-associated disease (2–12% of cases of acute cholecystitis); however it is much more serious. Gangrene of the gallbladder is 30-fold more common than in calculous cholecystitis, and perforation is ~ 5-fold more common, which leads to a higher mortality (≥ 67% mortality, in contrast to 3%). Patients with this syndrome are usually elderly or seriously ill and include patients with severe burns and trauma, patients who are recuperating from major surgery, or those receiving intensive care and parenteral nutrition. Comorbid conditions with higher risk of developing acalculous cholecystitis include cardiovascular disease, diabetes mellitus, systemic arteritis (eg, polyarteritis nodosa), and immunocompromise (eg, AIDS). The pathophysiology is poorly understood, but may be associated with bile stasis and gallbladder dysfunction. Bile stasis and paucity of gallbladder contractions may occur in critically ill patients and patients who receive parenteral nutrition. The retained bile may lead to gallbladder wall inflammation and ischemia, with subsequent microbial invasion of the gallbladder mucosa. In immunocompetent patients, the most common offending microorganisms include gram-negative bacilli and anaerobes. In immunocompromised patients including patients with AIDS (particularly in those who have not yet received benefit from highly active antiretroviral therapy), organisms include CMV, Cryptosporidium spp., microsporidia, Isospora spp., Salmonella spp., and Campylobacter spp.

 

Clinical Findings

  1. Signs and symptoms.Acute acalculous cholecystitis is often clinically indistinguishable from calculous cholecystitis, with fever, right upper abdominal pain and tenderness, nausea, vomiting, and anorexia. This syndrome is extremely difficult to diagnose, because many patients are critically ill with vague, generalized complaints or are unable to provide a history given sedation or mechanical ventilation in an intensive care unit.
  2. Laboratory findings.Leukocytosis, hyperbilirubinemia, and mild elevations in aminotransferase levels are common.
  3. Imaging.As in acute calculous cholecystitis, abdominal ultrasound often reveals a thickened gallbladder wall, distention, subserosal edema, and pericholic fluid. The sensitivity and specificity of abdominal CT may approach 100% in detecting this disease.

Treatment

Removal of the infected gallbladder and administration of antibiotics are imperative. IV fluids and antibiotics should be started promptly. Antibiotics should cover gram-negative bacilli and anaerobes (see treatment of acute cholangitis).

ACUTE CHOLANGITIS

Essentials of Diagnosis

  • Fever, jaundice, and leukocytosis.
  • Severe right-upper-quadrant abdominal pain.
  • Nausea and vomiting.
  • Possible progression to hypothermia, hypotension, and altered mental status.

BOX 21-5 Microbiology of Cholangitis

 

Children

Adults

More Common

Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Enterococcus faecalis
Pseudomonas aeruginosa
Enterobacteriaceae
Bacteroides fragilis
Clostridium perfringens

Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Proteus mirabilis
Enterococcus faecalis
Viridans streptococci
Bacteroides fragilis
Clostridium perfringens

Less Common

Viridans streptococci
Serratia spp.
Haemophilus influenzae
Candida albicans
Cryptococcus neoformans
Clonorchis sinensis
Echinococcus granulosus

Enterobacteriaceae
Serratia spp.
Morganella morgani
Aeromonas spp.
Pseudomonas maltophila
Citrobacter freundii
Peptostreptococci
Fusobacterium spp.

General Considerations

First described by Charcot in 1877, acute cholangitis is acute biliary infection superimposed on an obstructed biliary tree. Bile is normally sterile, because of constant bile flow into the duodenum and the presence of secretory IgA in the biliary tract. However, in the presence of obstruction, bile under pressure may be infected by ascending bacteria in the common bile duct from the gut or from the portal or systemic circulation (Box 21-5). Obstruction of the common bile duct is primarily from stones (≤ 80% of cases), which usually arise from the gallbladder but may spontaneously form in the bile duct (eg, postcholecystectomy). Obstruction may also be secondary to carcinoma of the common bile duct or adjacent pancreas, biliary stricture, or sclerosing cholangitis. In children, acute cholangitis occurs in the presence of ductal abnormalities or immunocompromise. It is most often a complication of the Kasai procedure for biliary atresia, which establishes biliary drainage via a Roux-en-Y connection to the porta hepatis. Cholangitis results from the removal of the protective sphincter of Oddi during the procedure and ascension of bacteria from the jejunal limb.

This syndrome may range from an acute ascending cholangitis, associated with incomplete common bile duct obstruction and ascending bacteria from the duodenum, to acute obstructive suppurative cholangitis, which features complete bile duct obstruction, pus in the biliary tree, and potential for progression to sepsis and intrahepatic abscess formation.

Clinical Findings

  1. Signs and symptoms.A previous history of biliary colic with jaundice may be present. The classic triad of fever, jaundice, and right-upper-quadrant pain, known as Charcot's triad, is present in only 20–70% of cases. Patients with acute obstructive suppurative cholangitis may present with septic shock, including altered mental status and hypotension (which, along with the classic triad, make up Reynolds pentad). Children infrequently present in septic shock, and fever may be their only symptom. Hepatomegaly is variably palpable in association with biliary obstruction; however, right-upper-quadrant and epigastric pain is usually present on exam.
  2. Laboratory findings.Most patients have elevated leukocyte counts, hyperbilirubinemia, and elevated alkaline phosphatase levels. Serum aminotransferase levels are often elevated, although to a lesser degree (only severalfold). Up to one-third of cases have elevated serum amylase caused by concomitant obstruction of the pancreatic duct; 10% of cases have clinical evidence of gallstone pancreatitis.
  3. Imaging.Both abdominal ultrasonography and CT may demonstrate dilated biliary ducts, but CT scan is more effective in demonstrating both the cause (70% vs 38%) and the level (88% vs 60%) of the obstruction. Cholangiography via PTC or ERCP provides the most accurate means of determining the cause and location of the obstruction. If choledocholithiasis is suspected, ERCP is the procedure of choice because it allows for papillotomy or papillary dilation with stone extraction or stent placement.

Differential Diagnosis

Fever, jaundice, right-upper-quadrant pain, and abnormal liver tests can also be seen in acute viral hepatitis (often with higher aminotransferase levels and lower total bilirubin), acute common bile duct obstruction, sepsis-associated cholestasis, liver abscess (jaundice less common), and sclerosis cholangitis (fever is uncommon). Biliary tract imaging or liver biopsy may be required to distinguish between an obstructive process and hepatocellular damage.

Complications

Prolonged, untreated obstructive jaundice may lead to hepatocellular damage and possible cirrhosis. Hypoprothrombinemia may predispose the patient to excessive bleeding. In contrast to hypoprothrombinemia in hepatocellular disease, prolonged prothrombin times associated with obstructive jaundice may be corrected with daily intake of vitamin K.

Treatment

Antibiotics and biliary drainage are the mainstays of treatment, because acute cholangitis is invariably fatal without urgent decompression of the biliary tree. Before drainage, IV fluid resuscitation and IV vitamin K (if elevated prothrombin time) should be administered. The empiric antibiotic regimen of choice should have broad-spectrum coverage of enteric gram-negative bacilli, however it is controversial whether gram-positive cocci and anaerobes should be covered in the empiric regimen (Box 21-6). No studies have shown a particular antibiotic regimen superior over others. Combinations of antibiotics include a 7- to 10-day course of a β-lactam/β-lactamase inhibitor, an amino penicillin with an aminoglycoside and metronidazole, a second-generation cephalosporin with antianaerobic activity, a third-generation cephalosporin plus metronidazole or clindamycin, or a ureidopenicillin plus either metronidazole or clindamycin. Ciprofloxacin plus metronidazole, or clindamycin, or imipenem, appear to be promising alternatives. Aminoglycosides must be used with caution (especially after the fifth day of use), given their potential for nephrotoxicity. Ampicillin should be used with caution given the recent emergence of ampicillin-resistant E coli in community acquired infections caused by this organism. Prolonged therapy with ceftriaxone should be avoided given its propensity to form biliary sludge.

Of cases of acute cholangitis, ≤ 75% initially respond to IV fluids and antibiotics, allowing for a small delay in biliary drainage. However, biliary decompression with drainage of the obstructed biliary tree is crucial in the management of this syndrome in severely ill patients. Classically, common bile duct exploration and placement of a T-tube were the procedures of choice. Now drainage can be accomplished with either PTC or ERCP during the diagnostic workup of these patients. They are both associated with less morbidity (34% vs 66%) and mortality (10% vs 33%) than open abdominal surgery, although PTC is associated with significant bleeding in the context of liver dysfunction. ERCP is usually more appropriate, as it allows for stone extraction or placement of a biliary stent during the procedure. After decompression of the biliary tree, antibiotics should be continued until there is full resolution of symptoms or for 7–10 days of therapy. Longer courses are advocated for refractory or recurrent disease. In children with post-Kasai procedure cholangitis, many support the use of long-term prophylaxis with trimethoprim-sulfamethoxazole (20 mg/kg/d of trimethoprim).

Prognosis

With appropriate treatment, mortality from acute cholangitis is < 10%. Mortality rates are higher in those with acute obstructive suppurative cholangitis, sepsis, and severe underlying disease. Clinical factors associated with poorer prognosis include old age, female sex, evidence of acute renal failure, concomitant liver abscess or cirrhosis, and malignant biliary tract obstruction. Acidosis (pH < 7.4), hyperbilirubinemia (total bilirubin > 90 mmol/L), hypoalbuminemia (albumin < 30 g/L), and thrombocytopenia (platelet count < 150) also predicted poorer outcome.

BOX 21-6 Empiric Therapy of Acute Cholangitis in Patients with Normal Renal Function

 

Children

Adults

First Choice

· Ampicillin/sulbactam (300 mg/kg/d IV

divided every 6 h) or ticarcillin/clavulanate

(300 mg of ticarcillin/kg/d IV divided every 4 h)

· Ampicillin (50-100 mg/kg/d IV divided every 6 h), gentamicin (2-2.5 mg/kg IV every 8 h), and metronidazole (30–50 mg/kg/d IV divided every 8h)

· Pipercillin/tazobactam (3.375 g IV every 6 h)
OR
ampicillin/sulbactam (3 g IV every 6 h),
OR
ticarcillin/clavulanate (3.1 g IV every 6 h)

· Pipercillin or ticarcillin (4 g IV every 6 h) and metronidazole (1 g IV load, then 500 mg IV every 6 h)

· Ampicillin (2 g IV every 6 h), gentamicin (2 mg/kg, load then 1.7 mg/kg IV every 8 h) and metronidazole (1 g IV load, then 500 mg IV every 8 h)

Alternative

· Third-generation cephalosporin (eg, cefoperazone, 100-150 mg/kg/d IV divided per 12 h, OR ceftazidime, 25-50 mg/kg IV every 8 h) and metronidazole (30–50 mg/kg/d IV divided every 8 h)

· Imipenem (15-25 mg/kg IV every 6 h)

· Third-generation cephalosporin (eg, cefoperazone 2-4 g IV every 12 h OR ceftazidime, 2 g IV every 8 h) and metronidazole (1 g IV load, then 500 mg IV every 8 h)

· Imipenem (500 mg IV every 6 h)

Penicillin Allergic

· Aztreonam (30 mg/kg IV every 8 h) and metronidazole

· Aztreonam (2 g IV every 8 h) and metronidazole

· Clindamycin (400 mg IV every 12 h) and metronidazole (above doses) or clindamycin (600-900 mg IV every 8 h)

In children, the incidence of cholangitis after the Kasai procedure is highest in the first postoperative year (43–78%). This incidence is significantly lower if an intussusception valve is designed at the site of the jejunostomy. Each episode of postoperative cholangitis carries a 1% mortality rate in these patients.

RECURRENT PYOGENIC CHOLANGITIS

Also known as oriental cholangiohepatitis, recurrent pyogenic cholangitis is characterized by recurrent attacks of suppurative cholangitis. It is endemic in Southeast Asia and may be seen in Asian immigrants. The bile duct infections are caused by gram-negative bacilli and less commonly anaerobes (Box 21-5) via transient portal bacteremia, in the context of bile stasis and ductal epithelium damage. The recurrent infections lead to the formation of large, muddy-brown pigment stones within the ducts. The initial damage to bile duct epithelium may be secondary to parasitic infection (eg, Clonorchis sinensis, Opisthorchis spp., or Ascaris lumbricoides) or a low-protein diet (leading to pigment stone formation), both common in Southeast Asia. The biliary damage is usually localized to the left hepatic lobe.

This syndrome peaks in 30- to 40-year-olds. Patients may have a history of recurrent attacks of acute cholangitis. Clinically, recurrent pyogenic cholangitis is indistinguishable from acute cholangitis. Abdominal CT is the imaging test of choice, which identifies the characteristic dilated central intrahepatic ducts that taper peripherally, often localized to the left hepatic lobe. As in acute cholangitis, ERCP can be used to visualize the biliary tree and allow for drainage. Treatment includes prompt administration of broad-spectrum antibiotics and IV fluids. Drainage may be needed in the 15% of cases that fail antibiotic therapy. Removal of pigment stones and relieving biliary strictures may help prevent future attacks.

SCLEROSING CHOLANGITIS

Primary sclerosing cholangitis is a cholestatic disease of unknown etiology, featuring chronic inflammation and scarring of the intra- and extrahepatic bile ducts. Although the cause is unknown, recurrent damage of the bile ducts has been a proposed mechanism, possibly from chronic portal bacteremia (eg, in IBS), toxins from enteric flora, chronic viral infections, or ischemic damage. It is more common in men aged 20–40 years and often occurs in patients with IBS. Cholangiography reveals a characteristic beaded appearance to the biliary tree, secondary to focal areas of ductal dilatation proximal to strictures. There is no effective treatment to date. Survival is improved with liver transplantation.

In contrast, secondary sclerosing cholangitis occurs as a known complication of obstructive cholangitis (eg, choledocholithiasis), toxic damage to the biliary tract (eg, intraductal formaldehyde during echinococcal cyst extirpation), ischemia (eg, vasculitis), or a neoplastic process (eg, cholangiocarcinoma). Obstructive cholangitis may be seen with a number of different infections, including A lumbricoides, recurrent pyogenic cholangitis, or Cryptococcus neoformans. Clinical presentation is similar to that of primary sclerosing cholangitis, including jaundice, pruritus, and right-upper-quadrant abdominal pain. Fever and weight loss are less common. A history of recurrent bouts of ascending cholangitis may be elicited. Cholangiography often shows focal strictures and dilated ducts, in contrast to the more uniform involvement of the biliary tree in primary sclerosing cholangitis. Treatment of recurrent episodes of cholangitis is similar to that of acute cholangitis, namely IV fluids, antibiotics directed against the specific pathogen, and biliary drainage. Pruritus is treated symptomatically, usually with topical emollients, antihistamines, or cholestyramine. Focal biliary strictures can be treated with endoscopic dilation or stent placement.

AIDS-RELATED CHOLANGITIS

AIDS-related cholangitis is a form of secondary cholangitis caused by opportunistic infections in late-stage AIDS. It was first discovered to be caused by Cryptosporidium spp. and CMV in the mid 1980s, and later found to be also associated with microsporidia, Isospora spp., M avium complex, and human herpes virus 8. Portal tract invasion by these pathogens leads to bile duct injury and ischemia, with subsequent scarring of the biliary tract. Such organisms may also contribute to sphincter of Oddi dysfunction and development of papillary stenosis, which is seen in ≤ 70% of cases.

Clinically, patients present with right-upper-quadrant pain and fever; however, jaundice is distinctly less common than in acute cholangitis (10% of cases). Nausea, vomiting, weight loss, and diarrhea are common. Patients typically have elevated alkaline phosphatase, mildly elevated aminotransferases, and CD4 cell count < 100/mm3. Stool cultures may be positive for Cryptosporidium, and bile culture obtained during ERCP may grow microsporidia. Definitive diagnosis is via biopsy of the involved tissue. ERCP is the procedure of choice for cholangiography, biopsies, and possible sphincterotomy if papillary stenosis is present.

There is no effective treatment for this condition. The course of cholangitis is not significantly influenced by therapy directed at specific pathogens, including ganciclovir, foscarnet, paromomycin, or azithromycin. Pain management is imperative, and ursodeoxycholic acid may improve pain and cholestasis in some patients. Prognosis is poor with a median survival of 7 months after diagnosis. Death is usually secondary to another opportunistic process in late-stage AIDS.

REFERENCES

Infections Of The Liver

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Infections Of The Biliary Tract

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Lai FCS et al: Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med 1992;362:1582 (Eighty-two patients with acute cholangitis associated with choledocholithiasis were randomized to surgical or endoscopic biliary drainage. The latter was as effective and associated with lower mortality [10 vs 32%] than surgery.)

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