Joshua A. Gentges
Jaundice, a yellowish discoloration of the skin, sclerae, and mucous membranes, is a symptom that results from hyperbilirubinemia (breakdown of hemoglobin) and thus the deposition of bile pigments.
Hyperbilirubinemia can be divided into two types. The unconjugated form results from increased bilirubin production (eg, hemolysis) or a liver defect in its uptake or conjugation. The conjugated form occurs in the setting of intra- or extrahepatic cholestasis, resulting in decreased excretion of conjugated bilirubin via the intestinal tract.
The total serum bilirubin should be elevated in a jaundiced patient. The clinical assessment of jaundice can be unreliable, with only 70% sensitivity and specificity.
Sudden onset of jaundice in a previously healthy young person, together with a prodrome of fever, malaise, myalgias, and a tender enlarged liver, points to hepatitis (probably viral) as a likely cause.
Heavy ethanol use suggests alcoholic hepatitis. In the setting of alcoholic liver disease and cirrhosis, jaundice usually develops gradually (discussed later).
A family history of jaundice or a history of recurrent mild jaundice that spontaneously resolves usually accompanies inherited causes of jaundice such as Gilbert’s syndrome.
Cholecystitis in itself may not cause jaundice unless there is acute biliary obstruction present such as with a retained common bile duct gallstone.
Painless jaundice in an older patient classically suggests pancreatic or hepatobiliary malignancy.
Patients with a known prior malignancy and a hard, nodular liver accompanied by jaundice may be found to have liver metastases.
Biliary tract scarring or strictures must always be suspected as a cause of jaundice in patients with a prior history of biliary tract surgery, pancreatitis, cholangitis, or inflammatory bowel disease.
Hepatomegaly with jaundice, accompanied by pedal edema, jugular venous distention, and a gallop rhythm, suggests chronic heart failure.
DIAGNOSIS AND DIFFERENTIAL
Initial laboratory tests that should be obtained in the work-up of a jaundiced patient include total and direct serum bilirubin level, serum aminotransferases and alkaline phosphatase (AP) levels, urinalysis to check for bilirubin and urobilinogen, and a complete blood count (CBC).
Additional laboratory tests may be indicated based on the clinical setting (serum amylase and lipase levels, prothrombin time [PT], electrolytes and glucose levels, blood urea nitrogen [BUN] and creatinine levels, viral hepatitis panels, drug levels, and pregnancy test).
PT is the most sensitive measure of hepatic synthetic function and, if elevated, suggests significant hepatocellular dysfunction or necrosis.
With normal liver enzyme levels, the jaundice is more likely to be caused by sepsis or systemic infection, inborn errors of metabolism, or pregnancy, rather than by primary hepatic disease.
With abnormally elevated liver enzymes, the pattern of abnormalities may suggest the etiology. Aminotransferase elevation, if predominant, suggests hepatocellular diseases such as viral or toxic hepatitis or cirrhosis, whereas markedly elevated AP levels (two to three times normal) and GGT (γ-glutamyl transferase) point to intra- or extrahepatic obstruction (gallstones, stricture, or malignancy).
A Coombs’ test and hemoglobin electrophoresis may be useful if anemia is present, along with normal liver aminotransferase levels (to look for hemolysis and hemoglobinopathy).
If clinical features and initial laboratory results reveal conjugated hyperbilirubinemia, ultrasound studies of the biliary tract, liver, and pancreas should be performed to rule out gallstones, dilated extrahepatic biliary ducts, or mass/tumor in the liver, pancreas, and portal region.
A computed tomography (CT) scan may also be considered, but is more costly and is not as sensitive as ultrasound for detection of gallstones in the gallbladder.
EMERGENCY DEPARTMENT CARE AND DISPOSITION
Hemodynamically stable patients with new-onset jaundice may be appropriate for discharge and outpatient follow-up if there is no evidence of liver failure or acute biliary obstruction, if appropriate laboratory studies have been ordered, if the patient has timely follow-up readily available, and is reliable and has adequate social support.
If extrahepatic biliary obstruction is suspected, surgical consultation should be obtained in the emergency department (ED).
In the USA, 33% of the population has acquired immunity to hepatitis A (HAV). New hepatitis B (HBV) and hepatitis C (HCV) infections total approximately 50,000 and 20,000, respectively.
The incidence of HAV and HBV has fallen dramatically due to effective vaccination programs.
Acetaminophen is the most common cause of acute liver failure in the USA.
Hepatitis is liver inflammation from toxic, metabolic, or infectious insult. It follows a spectrum from asymptomatic infection to fulminant liver disease and chronic cirrhosis.
Hepatocellular death leads to disruption of liver metabolic and synthetic function, leading to toxin accumulation, coagulopathy, and nutritional deficiencies. Ongoing disease can cause scarring and disruption of liver anatomy. This leads to ascites, esophageal varices, and portal hypertension.
There is a continuum of disease from acute hepatitis to chronic hepatitis, cirrhosis, and liver failure (Table 50-1).
TABLE 50-1 Clinical Features of Hepatitis
Consider acute hepatitis in patients with right upper quadrant or epigastric abdominal pain, nausea, vomiting, diarrhea, jaundice, or pruritis. Patients may report anorexia, fatigue, or malaise.
A few days of generalized pruritus, clay-colored stools, and dark urine may precede the onset of gastrointestinal (GI) symptoms and jaundice. Malaise usually persists while the other prodromal symptoms resolve.
Rarely, fulminant hepatic failure develops with a clinical picture of encephalopathy, coagulopathy, and rapidly worsening jaundice.
HAV is transmitted predominantly by the fecal-oral route and is commonly seen in Americans. Children and adolescents are more commonly affected, but often subclinically, whereas most adults are symptomatic with a longer, more severe course. Symptom onset is often more abrupt than with other viruses. Epidemic outbreaks have been seen in children at day care centers, institutionalized patients, and in patients exposed to a common source case via contaminated food or water.
HBV is acquired primarily via a percutaneous exposure to infected blood or body fluids. Most cases are subclinical without jaundice. Often symptom onset is insidious and, in 5% to 10% of cases, is preceded by a serum sickness–like syndrome with polyarthritis, proteinuria, and angioneurotic edema. Symptomatic patients usually have a more severe and protracted course than those with HAV.
HCV is the most common of all blood-borne infections in the United States, and may be contracted via parenteral, sexual, and perinatal contact. Most patients remain asymptomatic or have milder symptoms than those with HBV or HAV.
Between 6% and 10% of HBV and over 50% of HCV patients progress to chronic liver disease and cirrhosis, and these patients are at increased risk of hepatocellular carcinoma.
Patients with alcoholic liver disease can present with acute hepatitis. Common findings are tender hepatomegaly, jaundice, nausea, fever, anorexia, and generalized weakness. Alcoholic liver disease follows a continuum from asymptomatic fatty liver, to hepatitis, to cirrhosis, and to end-stage liver disease.
Many medications cause liver disease, including hepatocellular necrosis (acetaminophen, phenytoin), cholestasis (oral contraceptives, anabolic steroids), steatohepatitis (valproic acid, amiodarone), and chronic disease (nitrofurantoin, minocycline).
Acetaminophen accounts for over 40% of the liver failure cases in the United States and is the most common fatal toxic ingestion. Toxic mushrooms are an uncommon but important cause of hepatitis and acute liver failure. See Chapters 108 and 130.
DIAGNOSIS AND DIFFERENTIAL
Initial laboratory tests for suspected liver disease include a serum bilirubin level (total and direct fractions; indirect fraction can be deduced by simple subtraction), aspartate aminotransferase, alanine ami-notransferase, and γ-glutamyl transpeptidase (AST/ALT/GGT), AP levels, and a CBC.
AST/ALT values in the hundreds of units per liter are consistent with mild viral inflammation, but elevations into the thousands suggest extensive acute hepatocellular necrosis and more fulminant disease.
In acute and chronic viral hepatitis, the ratio of AST to ALT is usually <1. A ratio >2 is more suggestive of alcoholic hepatitis.
Mild to moderate elevations of AP are seen in virtually all hepatobiliary disease. Suspect cholestasis if levels are elevated greater than four times normal. A concurrently elevated GGT supports this.
Isolated significant elevation of AP without marked hyperbilirubinemia (AP:bilirubin ratio of 1000:1) suggests an infiltrative or granulomatous disease such as lymphoma, tuberculosis, sarcoidosis, or fungal infection.
Total serum bilirubin along with its direct fraction may also be useful since a conjugated (direct) fraction of 30% or higher is consistent with viral hepatitis.
A persistent total bilirubin level >20 mg/dL or a PT prolonged by more than a few seconds indicates significant disruption of liver function.
Serum electrolytes, BUN, and creatinine should be checked if there is clinical suspicion of volume depletion or electrolyte abnormalities.
Abnormal mental status should prompt an immediate determination of serum glucose level, which may be low due to poor oral intake or hepatic failure. Other causes of abnormal mental status such as hypoxia, sepsis, intoxication, structural intracranial process, or encephalopathy must also be considered.
A CBC may be useful, as an early transient neutro-penia followed by a relative lymphocytosis with atypical forms is often seen with viral hepatitis. Anemia, if present, may be more suggestive of alcoholic hepatitis, decompensated cirrhosis, GI bleeding, or a hemolytic process.
Viral hepatitis panels are useful for definitive diagnosis but generally not immediately available in the ED.
Important differential diagnoses include alcohol- or toxin-induced hepatitis, infectious mononucleosis, cholecystitis, ascending cholangitis, sarcoidosis, lymphoma, liver metastases, and pancreatic or biliary tumors.
EMERGENCY DEPARTMENT CARE AND DISPOSITION
Most patients can be successfully managed as outpatients with emphasis on rest, adequate oral intake, strict personal hygiene, and avoidance of hepatotoxins (ethanol and drugs). Close follow-up arrangements should be made.
Admission is warranted in high-risk populations, including the elderly or pregnant patient, or patients with serum bilirubin greater than 20 milligrams/dL, elevated PT, hypoglycemia, hypoalbuminemia, encephalopathy, GI bleeding, or suspected toxic ingestion, especially acetaminophen.
Patients with mild alcohol-induced hepatitis may be managed as outpatients with emphasis on nutritional supplementation, including thiamine, folate, magnesium, and potassium supplements; adequate oral intake; and strict avoidance of alcohol and other hepa-totoxins. Patients should be instructed to return for worsening symptoms, in particular vomiting, fever, jaundice, or abdominal pain. Follow-up arrangements should be made.
Patients who require admission for alcoholic hepatitis should receive thiamine 100 milligrams PO or IV and also be given prophylactic treatment for alcohol withdrawal.
Volume depletion and electrolyte imbalances should be corrected with intravenous crystalloid. Hypoglycemia should be initially treated with 1 amp of 50% dextrose in water intravenously followed by the addition of dextrose to intravenous fluids and careful monitoring.
Fulminant hepatic failure should warrant admission to the intensive care unit, with aggressive support of circulation and respiration, monitoring and treatment of increased intracranial pressure if present, correction of hypoglycemia and coagulopathy, and administration of lactulose (20 grams PO or 300 mL of lactulose solution diluted with 700 mL of water or saline rectally as a 30-minute retention enema) for hepatic encephalopathy. Patients requiring ventila-tory support with hepatic failure generally require intubation, as they are obtunded and not candidates for bilevel positive pressure ventilation. Consultations with a hepatologist and liver transplant service are indicated.
CIRRHOSIS AND CHRONIC HEPATITIS
Longstanding hepatocellular injury leads eventually to the widespread fibrosis and isolation of functional hepatocytes into parenchymal nodules of chronic liver failure.
The metabolic and mechanical functions of the liver are compromised, leading to metabolic derangement and the manifestations of portal hypertension, including ascites, esophageal varices, and portal-systemic shunting.
Patients with cirrhosis may present with abdominal pain and distention, nausea and vomiting, peripheral edema, upper or lower GI bleeding, or jaundice. They may complain of altered mental status, weakness, and malaise.
Hepatomegaly is usually absent. Jaundice, pedal edema, ascites, palmar erythema, caput medusa, gynecomastia, splenomegaly, and spider angiomata are also common.
Hepatic encephalopathy, characterized by a progression from altered mental status to hyperreflexia, spasticity, seizures, and coma, may also be present. Asterixis (“liver flap”) is characteristic, but not specific for encephalopathy due to liver failure.
Spontaneous bacterial peritonitis, comorbid infections such as pneumonia or urinary tract infection, and renal dysfunction are all serious findings that complicate the management of these patients. Acute gastroesophageal bleeding from varices is a catastrophic complication of chronic liver disease discussed in Chap. 41.
DIAGNOSIS AND DIFFERENTIAL
Laboratory studies for cirrhosis include levels of serum transaminases (GGT, ALT, AST), serum AP, total bilirubin (and its fractions), serum albumin, serum glucose and electrolytes, BUN, creatinine, CBC, and PT. Obtain a serum ammonia if there is suspicion for hepatic encephalopathy.
Serum transaminases and bilirubin may be mildly elevated or normal in cirrhosis.
Elevated ammonia level suggests but does not diagnose hepatic encephalopathy, which is a diagnosis of exclusion. A thorough search for other causes of altered mental status (sepsis, meningitis, cerebral hemorrhage, metabolic and toxic derangement) is necessary.
Spontaneous bacterial peritonitis (SBP) has a yearly incidence of 30% in ascitic patients. SBP should be suspected in any cirrhotic patient with fever, abdominal pain or tenderness, worsening or new ascites, suba-cute functional decline, or encephalopathy.
SBP may be confirmed through sampling of ascitic fluid by paracentesis, ideally under ultrasound guidance. Ascitic fluid should be tested for total protein and glucose levels, lactic (acid) dehydrogenase (LDH), Gram’s stain, and white blood cell (WBC) count with differential. A total WBC count >1000 per cubic millimeter or neutrophil (PMN) count >250 per cubic millimeter is diagnostic for SBP. Low glucose or high protein values suggest infection.
Gram’s stain and culture results from ascitic fluid are often negative (30–40%), but placing 10 mL of ascitic fluid in a blood culture bottle may improve yield. Gram-negative Enterobacteriaceae (Escherichia coli, Klebsiella, etc.) account for 63% of SBP, followed by the pneumococcus (15%) and the enterococcus (6–10%). Empirical therapy with antimicrobial agents to cover typical enteric flora should be instituted as soon as SBP is suspected from ascitic fluid analysis.
Ultrasonography can identify ascites, infectious or mass lesions, cholecystitis, and hepatic and portal vein thrombosis (Fig. 50-1).
FIG. 50-1. Sonographic image of ascitic fluid showing bowel loops and an edematous gallbladder wall, a common finding in patients with ascites. (Courtesy of and used with permission of MedStar Health and Michael S. Antonis, DO, RDMS, Sonologist.)
Abdominal CT may help elucidate structural problems. Consider head CT in patients with mental status changes.
Hepatorenal syndrome is a form of acute renal failure that occurs in cirrhotic patients. It has a poor prognosis and the cause is unknown.
Gastroesophageal varices form as a result of intra-hepatic fibrosis and scarring, leading to portal vein resistance and hypertension, with resulting collateral flow through veins at the gastroesophageal junction. Bleeding may take the form of frank hematemesis, “coffee ground” emesis, with melena, or with massive hemorrhage, hematochezia. Symptoms may be more insidious with light-headedness, generalized weakness, fatigue, or increased confusion being the presenting features.
Cirrhosis is often caused by ethanol or chronic viral hepatitis; uncommon causes include drugs or toxins, hemochromatosis, Wilson’s disease, and primary (idiopathic) biliary cirrhosis.
EMERGENCY DEPARTMENT CARE AND DISPOSITION
Patients with chronic liver disease can sometimes be managed on an outpatient basis with management and medication changes by the patient’s gastroenterolo-gist or primary physician. Abstinence from alcohol and other hepatotoxins is essential for outpatient management.
Recommended diuretics for management of ascites include spironolactone, 50 to 200 milligrams daily, and amiloride, 5 to 10 milligrams daily. A protein-restricted diet helps prevent the complication of hepatic encephalopathy.
Patients with abdominal pain, fever, acidosis, leu-kocytosis, significant hypo- or hypervolemia, new onset or worsening encephalopathy, coagulopathy with bleeding, or significant electrolyte abnormalities should be admitted to the hospital. Hepatorenal syndrome warrants nephrology consultation.
Paracentesis is warranted for symptomatic relief of ascites or to diagnose SBP. Paracentesis can be performed in the ED, ideally under ultrasound guidance. Administer albumin, 1.5 grams/kg IV before paracentesis. Removal of more than 1 L of ascitic fluid can lead to hypotension, so careful monitoring is required. If performing diagnostic paracentesis, obtain at least 50 mL of ascitic fluid for cell count, Gram’s stain, and culture.
Treatment of SBP involves empiric antibiotic coverage. Cefotaxime 2 grams IV every 8 hours (4 grams every 8 hours if life threatening) or piperacil-lin-tazobactam 3.375 grams IV every 6 hours or ampicillin-sulbactam 3 grams IV every 6 hours or ticarcillin-clavulanate 3.1 grams IV every 6 hours or ceftriaxone 2 grams IV every 24 hours are acceptable empiric antimicrobial choices. Give albumin 1.5 grams/kg IV if it was not given at the time of paracentesis, as it may reduce the incidence of renal failure and hospital mortality in these patients.
The mainstay of therapy for hepatic encephalopathy is lactulose, 20 grams PO or 300 mL of the syrup diluted with 700 mL of water or normal saline as a 30-minute retention enema. Flumazenil, 1 to 4 milligrams IV can cause short-term improvement in symptoms but has no proven long-term effect. Patients should be placed on a protein-restricted diet.
Suspect gastroesophageal variceal bleeding in any chronic liver patient with hematemesis, melena, or hematochezia. Variceal bleeding is discussed in Chapter 41.
Elevated PT with signs of bleeding should be treated with vitamin K, 10 milligrams PO or IV. Massive or life-threatening bleeding may require fresh frozen plasma transfusion. Decreased or malfunctioning platelets should be repleted with pooled donor platelets.
Aggressive treatment of comorbidities, including alcohol-related syndromes (withdrawal, ketoacidosis, Wernicke-Korsakoff syndrome), sepsis, ventilatory and circulatory dysfunction, electrolyte abnormalities, and hypoglycemia, is very important to satisfactory patient outcomes.
Acute liver failure from any cause (with prolonged PT, hypoglycemia, coagulopathy, encephalopathy, marked jaundice, etc.) should warrant admission to the intensive care unit, aggressive treatment, and consultation with a hepatologist and transplant team, if available.
For further reading in Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7th ed., see Chapter 83, “Hepatic Disorders, Jaundice, and Hepatic Failure,” by Susan R. O’Mara and Kulleni Gebreyes.