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An otherwise healthy 70-year-old man presented with abrupt onset of fever and abdominal pain. His medication history included aspirin and acetaminophen. Laboratory studies showed marked elevation of AST and ALT (>1000 U/L) and an abnormal coagulation profile. Serological studies for hepatitis A, B and C as well as autoantibodies were negative. Renal failure and encephalopathy developed, and the patient died. An autopsy showed an enlarged liver with extensive hemorrhagic necrosis.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 3, and is herpes simplex virus hepatitis.
Criteria for Diagnosis and Comments:
The liver shows extensive non-zonal coagulative necrosis accompanied by areas of hemorrhage. The inflammatory response is negligible and limited to a few lymphocytes in the portal tracts. The bile ducts are intact. At the periphery of the necrotic areas, many hepatocytes show ground-glass nuclei with margination of chromatin. Eosinophilic intranuclear inclusions (Cowdry type A) are present in some hepatocytes. Multinucleated cells can be identified in some sections. Immunohistochemistry confirmed the presence of herpes simplex virus (HSV).
Herpes simplex virus hepatitis generally occurs in the neonatal period, pregnancy or in immunocompromised individuals. However, fulminant infection can occur in healthy individuals. Both HSV types 1 and 2 can involve the liver. Symptoms are generally nonspecific but may include fever, headache, abdominal or muscle pain. Marked elevation of transaminases in the absence of jaundice and hepatomegaly is typical. Mucocutaneous manifestations are observed in half of the cases. Since the disease can follow a rapidly progressive course, early diagnosis and treatment with acyclovir are imperative.
Adenoviral hepatitis usually occurs in immunocompromised hosts, but may rarely involve healthy individuals. It is histologically similar to HSV hepatitis; immunohistochemistry or in situ hybridization is necessary for the distinction. Both Epstein-Barr virus (EBV) and cytomegalovirus (CMV) cause infectious mononucleosis-like syndrome. Liver involvement is mild but occurs frequently. Liver transaminases can be elevated, but jaundice is rare. The typical histological feature is a diffuse lymphocytic sinusoidal infiltrate. A few atypical lymphocytes and occasional non-necrotizing granulomas can be present. Focal apoptotic bodies can be seen, but cholestasis or prominent hepatocellular damage is not present. Extensive necrosis seen in HSV or adenoviral hepatitis is not present. Other less common viral infections that can cause acute hepatitis with widespread necrosis include yellow fever, dengue fever and Ebola fever. Parvovirus B19 can cause fulminant hepatitis in children. Mild nonspecific liver inflammation can also be seen with human herpes virus 6 (HHV-6), Coxsackie virus, rubella and measles.
Acetaminophen toxicity is the most common cause of drug-induced liver injury in the US. Accidental as well as suicidal overdose is on the rise. The minimum toxic dose in adults is 7.5 – 10 g (therapeutic dose 1 – 4 g per day), but severe liver damage occurs with ingestion of 15 – 25 g. Chronic alcohol consumption, obesity and drugs that induce the P-450 cytochrome system (like isoniazid, phenytoin, carbamazepine, cimetidine) can lower the toxic threshold of acetaminophen.
Typically, patients experience GI symptoms for 12 – 24 hours and a latent phase of 24 – 48 hours. The onset of acute hepatitis/acute liver failure occurs 72 – 96 hours after drug ingestion. The histological picture is dominated by necrosis, most prominent in zone 3, with little inflammatory response. Congestion and dilatation of sinusoids around the central vein can be seen. Cholestasis may be present. History of acetaminophen intake, elevated blood levels of the drug and absence of viral inclusions help in the distinction from HSV hepatitis. With early presentation and institution of therapy with acetyl-cysteine (within 12 hours), hepatotoxicity can be prevented. Other drugs like cocaine, herbal medications, mushroom poisoning and toxins like carbon tetrachloride, can also lead to hepatic necrosis with minimal inflammation.
Wilson disease should always be considered in the differential diagnosis of acute or fulminant hepatitis, especially in patients younger than 50 years. There are no pathognomonic histological features, and the diagnosis is based on demonstration of elevated hepatic copper and alterations in serum ceruloplasmin and urinary copper levels. Rubeanic acid or rhodanine can be used to demonstrate copper but are unreliable for diagnosis as negative or equivocal results do not rule out Wilson disease. Quantitative determination of copper by spectrophotometry using tissue from the paraffin block is a more reliable indicator of hepatic copper. Patients with untreated Wilson disease invariably have levels exceeding 250µg/g, and often exceeding 1000µg/g (15 – 55µg/g of dry liver tissue). Normal hepatic copper excludes the possibility of untreated Wilson disease. Ceruloplasmin is an acute phase reactant and may rise to normal levels in response to hepatic inflammation in acute hepatitis. Low ceruloplasmin levels can also occur in patients heterozygous for Wilson disease gene mutation; these patients do not develop symptomatic Wilson disease. High levels of 24-hour urinary copper exceeding 100µg/24 hours are common in fulminant Wilson disease.
Vascular etiologies like acute hepatic ischemia and venous outflow obstruction can lead to vascular congestion and hemorrhagic necrosis, predominantly around the central vein. Periportal ductular cholestasis as well as canalicular cholestasis can be seen in ischemic necrosis associated with circulatory failure or shock. The presence of sinusoidal dilatation and hepatocellular atrophy helps in the diagnosis of venous outflow obstruction due to right heart failure or Budd-Chiari syndrome. Viral inclusions in HSV hepatitis and the history in drug-related hepatitis help in differentiation from vascular etiologies.
Role of liver biopsy in acute liver failure: Liver biopsy may not be attempted due to coagulopathy, but can be helpful to determine the etiology. Based on the histological changes, ALF can be divided into 3 categories; some etiologies can manifest as more than one histological pattern.
- Necrosis with marked inflammatory activity: Idiosyncratic drug reactions, autoimmune hepatitis, viral hepatitis, Wilson disease.
- Necrosis with little or no inflammation: acetaminophen toxicity, herpes simplex hepatitis, Wilson disease, vascular diseases.
- Extensive microvesicular steatosis with little necrosis or inflammation: Reye syndrome, acute fatty liver of pregnancy, drugs like valproic acid and anti-retroviral drugs (nucleoside analogues).
|Acute liver failure: etiology
A, B, less commonly D, E
Wilson disease Pregnancy-related
Acute fatty liver of pregnancy