A 42-year-old woman with history of anorexia nervosa, depression, and alcohol abuse presents with a several-day history of progressive confusion and acute right quadrant abdominal pain. Her only medication is a “headache medicine” she has been taking over the last several weeks. Besides alcohol, no other toxic exposures are identified by history and review of her outpatient chart. Her initial laboratory tests show transaminases greater than 10 times the upper limit of normal (aspartate aminotransferase [AST] 1090 U/L and alanine aminotransferase [ALT] 1205 U/L) and a mildly elevated bilirubin at 2.8 mg/dL. Serologies for antinuclear antibody (ANA), smooth muscle antibody (SMA), and viral hepatitides are negative. Blood ethanol (EtOH) is negative. She rapidly develops progressive hepatic failure with hepatic encephalopathy and is listed status 1 for liver transplantation. A liver transplant is performed 48 hours after listing.

Master List of Diagnoses

  • Acetaminophen hepatotoxicity
  • Alcoholic steatohepatitis
  • Amoxicillin-clavulanic acid (Augmentin) hepatotoxicity
  • Autoimmune hepatitis
  • Herpes simplex hepatitis
  • Wilson disease
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 21, and is acetaminophen hepatoxicity of the liver.

Criteria for Diagnosis and Comments

The liver resection shows hepatocyte coagulative necrosis and congestion limited to zone 3 (centrilobular) without significant inflammation. This histomorphologic pattern in the context of the patient’s history is most consistent with acetaminophen hepatoxicity, which was confirmed with serum acetaminophen blood levels.

The most common classes of medications associated with drug induced liver disease (DILI) are antibacterials, antimycobacterials, and seizure medications and, with rapidly rising herbal usage, herbal-related injury is now also becoming more common. DILI can have a wide range of presentations, one of the most common being asymptomatic elevations in liver tests. Presentation with acute liver failure, such as in this case, is fortunately seen in only small minority of DILI cases. Histologically DILI can manifest as almost any pattern and can thus replicate most non-drug/toxin related liver diseases. However, certain patterns of injury are more common with DILI (eg, bland cholestasis and acute cholestatic hepatitis) and individual agents tend to consistently induce the same pattern or a narrow range of histologic patterns. An invaluable resource in evaluating a patient’s medication list for potential hepatotoxic agents is the National Library of Medicine’s “LiverTox” website, https://livertox.nlm.nih.gov/, which provides easy to search information on drug-induced liver disease.

Acetaminophen is a name derived from the International Union of Pure and Applied Chemistry (IUPAC) name for the drug N-Acetyl-Para-Amino-Phenol (APAP). APAP is sold as a non-prescription medication in the United States and is commonly used for its analgesic and antipyretic effects. APAP is also by far the leading cause of acute liver failure due to DILI, accounting for up to 75% of DILI related acute liver failure cases in the United States. The mechanism of toxicity is intrinsic (dose dependent) and indirect as it is due to the drug metabolite N-acetyl-p-benzoquinone imine (NAPQI), not the parent compound. Glutathione is used to detoxify the parent compound; it however is easily depleted which allows for the production of NAPQI by a reaction catalyzed by cytochrome P450 2E1 (CYP2E1). In this case, the patient’s alcohol abuse and possible malnutrition/fasting due to anorexia both worked to enhance the production of the toxic agent NAPQI by enhancing expression of CYP2E1 and depleting glutathione stores respectively and thus lower the threshold for a toxic dose of APAP.

In adults and adolescents, the APAP toxicity is most often the result of attempted suicide or accidental overdose, either of which may be the explanation in this case. In children, who are relatively more resistant to APAP toxicity, APAP DILI is most commonly due to chronic overdosing. Of those who overdose, only 10% develop acute liver failure. The development of liver failure not only depends on the dose but also the time of presentation as treatment with the anti-oxidant N-acetyl-cysteine during the first 12 - 15 hours prevents the progression to liver failure. Liver transplant is an effective therapy in those patients that do develop liver failure.

The typical histologic manifestation of APAP DILI starts with zone 3 (centrilobular) coagulative necrosis with no or only minimal neutrophilic inflammation. The zone 3 pattern relates to enhanced expression of CYP2E1 and the relatively lower level of glutathione in this zone. As the injury progresses, necrosis extends into zone 2 (submassive necrosis [ie, confluent but not complete necrosis of the acinar parenchyma]), and finally panacinar necrosis (massive necrosis) as the necrosis spreads to zone 1 (periportal hepatocytes). With this necrosis and subsequent parenchymal collapse, the liver macroscopically becomes shrunken and has a crumpled capsule. Like most drugs that cause DILI, APAP consistently reproduces the same pattern of injury; however, rarely cholestatic hepatitis and granulomas can be seen with APAP hepatotoxicity. If the patient clinically recovers, there is typically complete resolution to normal liver parenchyma. The differential diagnosis of APAP hepatotoxicity includes other causes of acute liver failure including drug/toxin, viral, autoimmune, and ischemia. The centrilobular necrosis pattern seen is a pattern that strongly favors drugs, toxins (eg, aflatoxin, carbon tetrachloride, and cocaine) or ischemia. In the case presented here, the clinical data shows no evidence of circulatory failure to suggest ischemia as a possibility and no toxin exposure is suspected.

Amoxicillin-clavulanic acid (AMC) is the most prescribed antibiotic in the world (used primarily for respiratory and sinusitis/otitis media infections) and is the second most common cause of DILI after APAP related hepatoxicity. While the medication history is limited in this patient AMC DILI can be excluded based on the histologic pattern, as AMC DILI consistently manifests as a bland cholestatic (bile plugs in dilated centrilobular canaliculi without hepatitis) or cholestatic hepatitis picture. In addition, AMC DILI only rarely leads to acute liver failure.

Autoimmune hepatitis (AIH) is characterized by variable but often intense panacinar hepatitis with varying degrees of fibrosis. The typical lymphoplasmacytic infiltrate of AIH has a proclivity to be most active in the portal-acinar interface (interface hepatitis) and in centrilobular region.

Since herpes simplex virus (HSV) hepatitis is also characterized by necrosis it is a consideration in a case like this, however, HSV related necrosis is non-zonal and thus easily distinguished from the strict zonal pattern present with APAP DILI.

While both Wilson disease and alcoholic hepatitis can present with acute hepatic failure, the absence of a steatohepatitic pattern essentially excludes these conditions.

  1. A 36-year-old man presents with asymptomatic mild elevation in transaminases. Drug induced liver disease (DILI) is suspected as he is taking an antibiotic that is noted on NLM LiverTox website to sometimes be associated with liver injury.
    Which of the following is true regarding this patient?

    1. DILI is unlikely as antibiotics are rarely associated with liver injury.
    2. If this is DILI, progression to acute liver failure is likely.
    3. If this patient were to have a liver biopsy, knowing the exact medication would be helpful, as each specific drug tends to consistently induce the same or narrow range of histologic patterns.
    4. Since DILI can manifest as almost any histologic pattern and can thus replicate almost any non-drug/toxin related liver disease, liver biopsy provides no useful information in the evaluation of DILI.
    5. This is an atypical presentation for DILI.
  2. A 29-year-old woman who suffers from alcoholism attempts suicide by taking a single large dose Acetaminophen (APAP).
    Which of the following is true about this case?

    1. Acute liver failure is the most likely outcome here, as 90% of patients with an APAP overdose develop acute liver failure.
    2. The administration of metabolite N-acetyl-p-benzoquinone imine (NAPQI) during the first 12 - 15 hours prevents the progression to liver failure in this patient.
    3. The mechanism of toxicity with APAP is intrinsic (dose dependent) and direct, as the liver injury is due to the APAP compound itself.
    4. The only predictive factor that will determine the course in this patient is the dose of APAP taken.
    5. The patient’s alcoholism increases her susceptibility to APAP injury by enhancing the expression of cytochrome P450 2E1 in liver cells.
  3. Which of the following is true regarding the histopathology of DILI?

    1. Amoxicillin-clavulanic acid (AMC) DILI consistently manifests as a steatohepatitis pattern of liver injury.
    2. AMC is the most prescribed antibiotic in the world and is also by far the leading cause of acute liver failure due to DILI.
    3. Most patients that recover from APAP hepatotoxicity, will not show complete resolution to normal liver histopathology.
    4. The typical histologic manifestation of APAP DILI is zone 3 (centrilobular) coagulative necrosis with no or only minimal neutrophilic inflammation.
    5. While both Wilson disease and EtOH hepatitis can present with acute hepatic failure, the characteristic panacinar hepatitis with varying degrees of fibrosis help distinguish them from other causes of liver disease.

References

  1. Chitturi S, Teoh NC, Farrell GC. Chapter 88 - hepatic drug metabolism and liver disease caused by drugs. In: Feldman M, Friedman L, Brandt L, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. Tenth ed. Philadelphia, PA: Elsevier; 2016:1442.
  2. Goodman ZD. Phenotypes and pathology of drug-induced liver disease. Clin Liver Dis. 2017;21(1):89-101.
  3. Kleiner DE. Chapter 24: Liver injury due to drugs and herbal agents. In: Saxena R, ed. Practical Hepatic Pathology: A Diagnostic Approach. First ed. London, England, UK: Churchill Livingstone; 2011:311.
  4. Le Bail B, Balabaud C, Bioulac-Sage P. Chapter 48: Toxin- and drug-induced disorders of the liver. In: Odze R, Goldblum JR, eds. Odze and Goldblum Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas. Third ed. Philadelphia, PA: Elsevier; 2015:1285.
  5. United States National Library of Medicine. https://livertox.nlm.nih.gov Accessed January 18, 2017.

Author

H. Parry Dilworth, MD
CAP Surgical Pathology Committee
Hospital Pathology Associates
Minneapolis, MN


Answer Key

  1. If this patient were to have a liver biopsy, knowing the exact medication would be helpful, as each specific drug tends to consistently induce the same or narrow range of histologic patterns. (c)
  2. The patient’s alcoholism increases her susceptibility to APAP injury by enhancing the expression of cytochrome P450 2E1 in liver cells. (e)
  3. The typical histologic manifestation of APAP DILI is zone 3 (centrilobular) coagulative necrosis with no or only minimal neutrophilic inflammation. (d)