Drug-Induced Acute Hepatic Failure

 INR is > 1.5, and there is no evidence of chronic liver disease

• Corresponding pathologic terms: Massive/submassive necrosis, fulminant hepatitis

Clinical Issues

• Acetaminophen is most common cause of acute liver failure (ALF) in USA, accounting for 40-50% of cases


• Massive/submassive necrosis with little or no inflammation: Acetaminophen, most toxins

• Massive/submassive necrosis with prominent inflammation: Most idiosyncratic drug reactions

• Microvesicular steatosis: Tetracycline, zidovudine

• Regenerative nodules can be seen later in course of disease and can be mistaken for cirrhosis

• Unlike fibrous septa of cirrhosis, necrotic areas show pale staining with trichrome stain and lack elastic fibers on elastic stain

Top Differential Diagnoses

• Necrosis with inflammation: Acute viral hepatitis A and B, autoimmune hepatitis, Wilson disease

• Necrosis with minimal inflammation: Herpes simplex and adenoviral hepatitis, acute ischemia, acute Budd-Chiari syndrome

• Microvesicular steatosis: Alcoholic foamy degeneration, acute fatty liver of pregnancy, Reye syndrome, Jamaican vomiting sickness, rare metabolic disorders like carnitine deficiency

Necrosis and Inflammation
This image shows confluent necrosis with lymphoplasmacytic inflammation image. Swelling, inflammation, and regenerative changes are seen in the remaining parenchyma image. Ductular reaction image is a common finding in the setting of necrosis and does not necessarily signify biliary disease.

Necrosis Without Inflammation
This image shows extensive panacinar necrosis image with negligible inflammation image, findings typical of toxic pattern of drug injury.

Acetaminophen-Related Acute Liver Failure
Multiacinar hemorrhagic necrosis image, congestion image, and lack of inflammation with sparing of periportal hepatocytes image are typical of acetaminophen toxicity but can also be seen in acute ischemia and acute Budd-Chiari syndrome.

Microvesicular Steatosis
Multiple small fat droplets are seen filling the cytoplasm image. There is no necrosis or inflammation.



• Acute liver failure (ALF)


• Hepatic encephalopathy and reduced synthetic function evidenced by INR > 1.5
• Duration of disease less than 26 weeks

• Absence of chronic liver disease

image Corresponding pathologic term is massive/submassive necrosis or fulminant hepatitis


Mechanisms of Injury

• Massive/submassive necrosis due to intrinsic hepatotoxins
image Most toxins fall in this category

– Carbon tetrachloride, mushroom poisoning, recreational drugs like cocaine and MDMA (ecstasy)

image Very few drugs cause this pattern of injury

– Acetaminophen, halothane

– Herbal medications: Pennyroyal, glue thistle, germander

• Massive/submassive necrosis due to idiosyncratic injury
image Most drugs fall in this category
– Drugs used for treatment of tuberculosis such as isoniazid are one of leading culprits of ALF in developing world

– Other implicated drugs: Monoamine oxidase inhibitors, anticonvulsants (valproate, phenytoin), antimicrobial agents (sulfonamides, co-trimoxazole, ketoconazole)

• Diffuse microvesicular steatosis due to acute mitochondrial injury
image Presents as ALF without histological necrosis

image Commonly implicated drugs: Tetracycline, zidovudine, valproic acid, amineptine



• Depends on specific drug or toxin
• Acetaminophen is most common cause of ALF in USA accounting for 40-50% of cases

image Dose-dependent toxicity occurs with accidental (1/3 of cases) or suicidal (2/3 of cases) overdose

image Minimum toxic dose in adults is 7.5-10 g, but severe liver damage occurs with ingestion of 15-25 g

image Chronic alcohol consumption, obesity, and drugs that induce P-450 cytochrome system can lower toxic threshold of acetaminophen

image Gastrointestinal symptoms for 1st 12-24 hours and latent phase of 24-48 hours is followed by ALF 72-96 hours after drug ingestion


• Drug withdrawal, supportive care, and liver resuscitation (hypothermia, albumin dialysis, artificial liver support)

• Liver transplantation is often necessary

• Acetaminophen hepatotoxicity can be prevented with acetylcysteine therapy within 12 hours of drug ingestion

Apr 20, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Drug-Induced Acute Hepatic Failure
Premium Wordpress Themes by UFO Themes
%d bloggers like this: