College of American Pathologists
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2010 — February Case of the Month

Posted February 17, 2010


CAP Foundation February 2010 Online Case of the Month

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A 58-year-old woman, who had been treated for rheumatoid arthritis with leflunomide for 10 weeks, presented with abdominal pain and jaundice. She developed fulminant hepatic failure over the course of 2 months and died while being worked up for liver transplant. The liver was smaller than normal (weight 800 grams) with a wrinkled capsule; sectioning revealed a dark red appearance with variegated yellow and green nodules.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 3 and is a submassive hepatic necrosis.

Criteria for Diagnosis and Comments: The histologic features are those of submassive hepatic necrosis. There is reticulin collapse and extensive loss of hepatic parenchyma of the centrilobular zones throughout, resulting in broad bridging septa that connect central veins to central veins and to portal tracts. In some areas, the periportal parenchyma is extant, while in many areas, entire lobules have undergone necrosis (massive necrosis). At the interface of the portal areas and necrotic lobules, there is marked extraportal ductular proliferation. The portal areas have a mainly lymphocytic infiltrate, but neutrophils are prominent within and around the proliferating ductules. Normal bile ducts are identified which show no evidence of cholangitis. The necrotic lobules are replaced by collapsed reticulin, mononuclear cells and macrophages that contain bile pigment. Larger hepatic veins are identified by an elastin sheath, but coarse collagen and elastin fibers are largely absent from the collapsed lobules. The residual liver parenchyma shows mild histologic abnormalities with focal swelling, bile stasis, vacuolation, a mild mononuclear infiltrate and rare acidophil bodies.

The histological findings can be mistaken for active cirrhosis if the necrotic septa are misinterpreted as fibrous bands. This would be an unlikely finding in the present clinical setting of rapid onset of hepatic insufficiency without previous history of long-standing liver disease and is effectively excluded by the absence of coarse collagen bundles and elastin fibers in the septa, the latter best demonstrated by elastin stains such as the orcein stain. The septa also contain abundant histiocytes (Kupffer cells) and mononuclear inflammatory cells. Immunohistochemistry can identify numerous MSA (+) myofibroblasts within the septa; these are presumed to be of Ito cell histogenesis and to represent potential initiators of fibrous scarring in those survivors who go on to develop post-necrotic cirrhosis. The presence of proliferating ductules associated with a neutrophilic infiltrate, characteristic of this condition, can be misinterpreted as cholangitis associated with biliary obstruction; this extraportal proliferation is considered to represent a reparative response, perhaps originating in stem cells located along the canals of Hering. Further differential diagnoses to be considered include centrilobular necrosis with bridging due to ischemia and acute hepatic venous outflow obstruction (Budd-Chiari Syndrome). The latter may be associated with dissection of red blood cells into the space of Disse. Centrilobular and bridging fibrosis of sclerosing hyaline necrosis due to alcohol toxicity could, perhaps, also mimic this condition but in that entity the contiguous liver lobule shows pericellular fibrosis and Mallory’s hyaline, steatosis and other features of alcoholic hepatitis.

In the past, viral hepatitis accounted for 70% of cases of fulminant hepatic failure but currently in the US it is incriminated in as few as 12% of instances. In developing countries viral etiologies still predominate. The shift seen in the US has been attributed in large part to vaccination of infants and children for Hepatitis B. Hepatotropic viruses other than Hepatitis B that can cause fulminant hepatic failure include Hepatitis A, Delta agent and Hepatitis E in endemic areas. Hepatitis C virus is a rare cause of acute liver failure in the US but Hepatitis A or B superimposed on chronic hepatitis C presents a significant risk for this complication. Other viral agents that have the potential to cause massive hepatic necrosis include herpes virus, varicella-zoster, adenovirus, parvovirus B19, and in endemic areas, viruses of the enterohemorrhagic fevers, particularly yellow fever virus. The latter produces a distinctive pattern of mid-zonal necrosis. Herpes virus is associated with a geographic non-zonal micro-infarct-like pattern of necrosis and is also characterized by Cowdry A type nuclear inclusions and typical ground glass and multinucleated hepatocytes. A similar irregular pattern of necrosis may be seen with varicella-zoster and adenovirus, the latter apt to show distinguishing smudged dark nuclear inclusions.

The principal etiologic agent of submassive and massive hepatic necrosis in the US and other developed countries is drug induced injury, which now accounts for more than 50% of cases. Some drugs such as acetaminophen, currently by far the most frequent cause of acute hepatic failure (39% of cases in a recent survey), act in a dose dependent manner that is modulated by individual susceptibility and exposure to cytochrome P-450 enzyme inducers such as ethanol or phenobarbital. The liver in patients with acetaminophen toxicity typically shows centrizonal to mid-zonal coagulative necrosis with macro and micro-vesicular steatosis prominent in surviving hepatocytes. Other dose dependent drugs and toxins that may show a similar histological picture include various herbal and alternative medications including germander and chaparral leaf. The toxin of Amanita phalloides mushrooms is a notorious cause of fulminant hepatic failure on the European continent but cases are now also reported from Northern California and New York State, locations into which spores of this non-native mushroom were inadvertently introduced several decades ago.

Most drug reactions are mild and idiosyncratic occurring at therapeutic doses but only in a tiny fraction of exposed individuals (1/1000 – 1/100,000). These adverse reactions are more frequent in women than men and are apt to be associated with a more severe reaction on re-exposure. Severe hepatic drug reactions represent the most frequent reasons cited for the withdrawal from the market of an approved drug. Examples of drugs recently withdrawn because of such complications include Bromfenac [Duract], a non-steroidal anti-inflammatory agent, and troglitazone [Rezulin] for type 2 diabetes. The patient in the present case had been treated with Leflunomide, an orally administered inhibitor of pyrimidine synthesis that is an effective disease modifying agent (DMD) in rheumatoid arthritis. There have been reports of the rare occurrence of hepatic injury including acute liver failure in patients using this drug.

Findings such as those in the present case are most likely to present to the pathologist in a liver explant or at autopsy on a deceased patient who has been hospitalized with fulminant hepatic failure. Linking this anatomical finding causally to a specific drug reaction can be difficult. The exclusion of agents of injury other than drugs such as viral hepatitis is essential; a detailed drug history that includes use of non-prescription herbal or alternative medications should be ascertained and optimally a known potential agent identified; for a putative hypersensitivity drug reaction, a temporal relationship between 5 and 90 days from the initial exposure to the onset of the illness ideally should be established; the contributory role of other agents is often difficult to assess and ultimately in an individual case a causative association can only be tentatively proposed based on the evidence available.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
Which of the following is the most common cause of fulminant hepatic failure in the U.S.? A. Amanita phalloides toxin
B. Drug induced hepatotoxicity
C. Hepatic vein thrombosis
D. Herpes simplex hepatitis
E. Viral hepatitis
Which of the following supports a drug hypersensitivity response as a cause of acute hepatitis? A. A more severe illness on repeat exposure to the drug
B. A time frame of 5-90 days between initiation of exposure
    and onset of symptoms

C. Improvement within weeks of stopping the drug
D. Negative serology for viral hepatitis
E. All of the above
Which of the following associations is least likely? A. Acetaminophen toxicity and steatosis
B. Alcohol and central hyaline sclerosis
C.  Cytochrome P-450 enzyme induction and phenobarbital
D.  Hepatitis C and massive hepatic necrosis
E.  Yellow fever and mid-zonal necrosis


  1. Lee WM. Drug-Induced Hepatoxicity. N Engl J Med. 2003;349:474-85.
  2. Lamps LW, Washington K. Acute and Chronic Hepatitis. In: Odze RD, Goldblum JR, Crawford JM, eds. Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas. Philadelphia, Pa: WB Saunders; 2004:783-810.
  3. Olsen NJ, Stein CM. Drug Therapy: New Drugs for Rheumatoid Arthritis. N Engl J Med. 2004;350:2167-2179.
  4. Sass DA. Shakil AO. Fulminant hepatic failure. Liver Transpl. 2005;11(6):594-605.
  5. Williams R, Riordan SM. Acute Liver Failure: established and putative hepatitis viruses and therapeutic implications. J Gastroenterol Hepatol. 2000;15(suppl):G17-25.
  6. Zimmerman HJ, Ishak KG. Hepatic Injury due to Drugs and Toxins, In: MacSween RN, Anthony PP, Scheuer PJ, Burt AD, Portmann BC, eds. Pathology of the Liver, 3rd ed. Edinburgh, United Kingdom: Churchill Livingstone; 1994:563-635.

Shveta Arya, MD
Boston Medical Center
Boston, MA

Michael J O’Brien, MD
Surgical Pathology Committee
Boston Medical Center
Boston, MA