Liver & intrahepatic bile ducts

• Liver damage caused by excessive alcohol consumption

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• Nonspecific clinical features for any chronic liver disease
• Odor of alcohol on breath
• Alcohol withdrawal syndrome: fine tremor, psychomotor agitation, transient hallucinations or illusions, tachycardia
• Reference: J Hepatol 2018;69:154

• Increasing the risk of alcohol related liver injury (Hepatology 2020;71:306):
  • Drinking pattern: daily drinking, drinking while fasting, binge drinking
  • Female
  • Genetics: PNPLA3, TM6SF2, MBOAT7, HSD17B13
  • Smoking cigarettes
  • Increased BMI
  • Concurrent liver disease: chronic viral hepatitis, genetic hemochromatosis, nonalcoholic fatty liver disease
• Ameliorating the risk of alcohol related liver injury:
  • Coffee consumption

• 27 year old man with alcoholic hepatitis presenting with high levels of triglyceride, direct hyperbilirubinemia and elevated ALP without an obvious obstruction cause (Case Rep Gastroenterol 2020;14:448)
• 47 year old woman with alcoholic hepatitis masquerading as tumor infiltration (Clin Case Rep 2019;7:2174)
• 55 year old man with severe alcoholic hepatitis and superimposed Candida esophagitis, who was found to have leukemoid reaction during diagnostic workup (Cureus 2020;12:e9747)
• 67 year old man with acute liver injury and false positive results of enzymatic ethanol assay secondary to lactic acidosis due to intravascular large B cell lymphoma (BMJ Case Rep 2019;12:e229814)

Contributed by Anthony W.H. Chan, M.B.Ch.B. and @Andrew_Fltv on Twitter

• Steatosis:
  • Most common and earliest form of alcoholic liver disease
  • Predominantly macrovesicular steatosis: large droplet (classical; a single large fat droplet displacing the nucleus to the periphery) and small / medium droplets
  • First appears in perivenular region (zone 3) and spreads to other regions if drinking persists; may disappear within 1 month after alcohol cessation
  • Whether it is a benign, nonprogressive lesion is controversial (J Hepatol 2012;57:399)
  • Association between degree of steatosis and disease progression is also controversial
• Alcoholic steatohepatitis:
  • Steatosis with inflammation and ballooning degeneration, which is the hallmark of hepatocellular injury in steatohepatitis
  • Ballooning degeneration is characterized by cellular swelling, rarefaction of the hepatocytic cytoplasm and clumped strands of intermediate filaments
  • Satellitosis is featured by ballooned hepatocyte surrounded by neutrophils
  • Mallory-Denk body, also known as Mallory body or Mallory hyaline, is a deeply eosinophilic, ropy intracytoplasmic inclusion that represents aggregates of misfolded intermediate filaments with other different classes of proteins, including p62 and ubiquitin
    • Often but not necessarily found in ballooned hepatocytes (Exp Cell Res 2007;313:2033)
    • Persists for several months after cessation of drinking
    • Associated with increased risk of progression to cirrhosis
  • Fibrosis is not a necessary diagnostic feature; perivenular and pericellular (perisinusoidal) fibrosis is characteristic for fatty liver disease; as disease progresses, portal / periportal fibrosis, bridging fibrosis and cirrhosis will develop
  • Alcoholic hepatitis histologic score is proposed to predict 90 day mortality based on 4 parameters: fibrosis, bilirubinostasis, neutrophilic infiltration and giant mitochondria (Gastroenterology 2014;146:1231)
• Alcoholic cirrhosis:
  • Classically micronodular cirrhosis
  • Steatosis and ballooned hepatocytes may burn out in advanced fibrosis or cirrhosis
• Other pathological lesions:
  • Lipogranuloma
  • Giant mitochondria: associated with recent heavy alcohol intake and disease progression (J Clin Pathol 1992;45:412)
  • Acute foamy degeneration: rare, extensive microvesicular steatosis with no / minimal inflammatory activity; clinically presents with jaundice, abdominal pain and hepatomegaly (Gastroenterology 1983;84:683)
  • Sclerosing hyaline necrosis: fibrous obliteration of terminal hepatic venule (phlebosclerosis) due to perivenular fibrosis; severe form of alcoholic hepatitis associated with noncirrhotic portal hypertension
  • Iron deposition: usually mild; mainly in hepatocytes (grade 1 - 2) and occasionally in Kupffer cells

Contributed by Anthony W.H. Chan, M.B.Ch.B.

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• Chronic viral hepatitis C:
  • Steatosis is typically mild at most
  • Presence of lymphocyte predominant portal inflammation, portal lymph follicle, bead-like sinusoidal lymphocyte infiltration and mild bile duct injury differentiates hepatitis C from alcoholic liver disease
• Drug induced liver injury (e.g., amiodarone, glucocorticoids, methotrexate, synthetic estrogens, tamoxifen)
• Nonalcoholic fatty liver disease:
  • Pathologically almost indistinguishable from alcoholic liver disease
  • Alcoholic liver disease has few specific pathological changes and all are rare:
    • Acute foamy degeneration
    • Sclerosing hyaline sclerosis
    • Acute / chronic cholestasis and sinusoidal obstruction syndrome
  • Alcoholic liver disease tends to have more Mallory-Denk bodies and giant mitochondria, much less glycogenated nuclei and has satellitosis (ballooned hepatocyte surrounded by neutrophils), although all of these are nonspecific
  • Key distinguishing feature is in fact the amount of alcohol consumption obtained from clinical history
  • Consumption of 2 standard drinks/day for men and 1 standard drink/day for women is endorsed as the acceptable threshold to define nonalcoholic
• Wilson disease:
  • Mild steatosis, glycogenated nuclei and Mallory-Denk bodies
  • Deposition of copper associated protein (particularly in hepatocytes out of periportal region) differentiates Wilson disease from alcoholic liver disease
• Other uncommon inherited metabolic diseases

Which of the following histological features is useful to differentiate alcoholic liver disease from nonalcoholic fatty liver disease?

1. Acute foamy degeneration
2. Ballooning degeneration
3. Mallory-Denk body
4. Satellitosis
5. Severe steatosis

A. Acute foamy degeneration. Acute foamy degeneration (diffuse microvesicular steatosis) is a rare presentation of severe acute alcoholic hepatitis presenting with jaundice and hepatomegaly. Rapid recovery occurs on abstinence from alcohol. Diffuse microvesicular steatosis is not a histological feature of nonalcoholic fatty liver disease.

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Reference: Alcoholic liver disease

Which stain is helpful in highlighting the structures indicated by arrows in the image shown above?

1. Alpha-1 antitrypsin
2. CK5/6
3. HepPar1
4. Orcein
5. p62

E. p62. The highlighted structures are Mallory-Denk bodies, which are misfolded and aggregated intermediate filaments combined with other different classes of proteins, including p62 and ubiquitin. They are immunoreactive to CK8/18, p62 and ubiquitin.

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Reference: Alcoholic liver disease