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Liver and intrahepatic bile ducts-nontumor
Hepatitis - noninfectious
Alcoholic liver disease

Author: Anthony W.H. Chan, BMedSc, MBChB, FRCPA (see Authors page)

Revised: 25 November 2015, last major update November 2015

Copyright: (c) 2003-2015, PathologyOutlines.com, Inc.

PubMed Search: Alcoholic liver disease [title]
Table of Contents
Definition / General | Epidemiology | Clinical Features | Prognostic Factors | Case Reports | Treatment | Micro Description | Micro Images | Differential Diagnosis
Definition / General
  • Alcohol is a psychoactive substance, which may lead to alcohol dependence, causing various physical, psychological and social problems
  • Excessive alcohol consumption causes a spectrum of alcoholic liver disease including steatosis, alcoholic hepatitis, fibrosis, alcoholic cirrhosis and hepatocellular carcinoma
Epidemiology
  • 90 - 95% of heavy drinkers develop steatosis; up to 35% develop advanced alcoholic liver diseases (i.e. alcoholic hepatitis, fibrosis, cirrhosis or hepatocellular carcinoma) (J Hepatol 2012;57:399)
Clinical Features
  • Global alcohol consumption among those > age 15 years is 6.2 liters of pure alcohol per year (13.5 g of pure ethanol per day) (WHO 2014 Status Report on Alcohol and Health)
  • Spirits account for 50.1% of global total recorded alcohol, and are the most common alcoholic beverage in Southeast Asia and Western Pacific regions
  • Beer accounts for 34.8% of global total recorded alcohol, and is the most common alcoholic beverage in the U.S. (WHO 2014 Status Report on Alcohol and Health)
  • 5.9% of global deaths are attributable to alcohol, mainly cardiovascular disease (33.4%), unintentional injury (17.1%) and liver cirrhosis (16.2%) (WHO 2014 Status Report on Alcohol and Health)
  • 5.1% of the global burden of disease and injury is attributable to alcohol, mainly neuropsychiatric disorders (24.6%), unintentional injury (20.4%), cardiovascular disease (15.5%) and liver cirrhosis (13.6%) (WHO 2014 Status Report on Alcohol and Health)
Prognostic Factors
  • Associated with disease progression (J Hepatol 2012;57:399):
    • Female gender
    • Obesity
    • Daily or nearly-daily heavy drinking
    • Drinking at early age
    • Concurrent chronic liver diseases, esp. HCV and genetic hemochromatosis
    • Genetic susceptibility PNPLA3 rs738409 (GG) genotype
Case Reports
Treatment
  • Abstinence is the most important measure
  • Prednisolone and Pentoxifylline are two drugs recommended in the treatment guidelines of severe alcoholic hepatitis by AASLD (Hepatology 2010;51:307) and EASL (J Hepatol 2012;57:399)
    • Efficacy is controversial
    • In a latest multicenter, double-blind, randomized trial of 1053 patients, Pentoxifylline did not improve survival whereas prednisolone was associated with a reduction in 28 day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year (N Engl J Med 2015;372:1619)
Micro Description
  • Steatosis:
    • Commonest and earliest from of alcoholic liver disease
    • Predominantly macrovesicular steatosis: large droplet (classical; a single large fat droplet displacing the nucleus to the periphery) and small / medium droplet
    • First appears in perivenular (zone 3) and spreads to other regions if drinking persists. May disappears within 1 month after cessation
    • Whether it is a benign, non-progressive lesion is controversial (J Hepatol 2012;57:399)
    • Association between degree of steatosis and disease progression is also controversial

  • Alcoholic hepatitis:
    • 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, ropey intracytoplasmic inclusion and represent aggregate of misfolded intermediate filaments with other different classes of proteins, including p62 and ubiquitin
      • Often but not necessarily found in ballooned hepatocyte (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 cirrhosis:
    • Classically micronodular cirrhosis
    • Steatosis and ballooned hepatocytes may burn out in advanced fibrosis or cirrhosis

  • Other pathological lesions in alcoholic liver disease:
    • 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 presented 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 Kupffer cells
Micro Images
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Liver biopsy

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Natural history of ALD

Differential Diagnosis
  • Non-alcoholic fatty liver disease:
    • Pathologically almost indistinguishable from ALD
    • Alcoholic liver disease tends to have more Mallory-Denk bodies and giant mitochondria, much less glycogenated nuclei, and the presence of satellitosis (ballooned hepatocyte surrounded by neutrophils)
      • All of them are nonspecific
    • Alcoholic liver disease has few specific pathological changes:
    • Key distinguishing feature is in fact the amount of alcohol consumption obtained from clinical history
    • Consumption of two standard drinks/day for men and one standard drink/day for women is endorsed as the acceptable threshold to define non-alcoholic
  • 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 NAFLD / NASH
  • Drug-induced liver injury: e.g. amiodarone, glucocorticoids, methotrexate, synthetic estrogens, tamoxifen
  • Wilson disease:
    • Mild steatosis, glycogenated nuclei and Mallory-Denk bodies mimic NAFLD / NASH
    • Deposition of copper-associated protein (particularly in hepatocytes out of periportal region) differentiates Wilson disease from NAFLD / NASH
  • Other uncommon inherited metabolic diseases
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