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

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

Revised: 1 November 2017, last major update November 2015

Copyright: (c) 2002-2017, PathologyOutlines.com, Inc.

PubMed Search: Alcoholic liver disease[TI] hepatitis free full text[sb]
Table of Contents
Definition / general | Epidemiology | Pathophysiology | Clinical features | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Differential diagnosis
Cite this page: Chan, A.W.H. Alcoholic liver disease. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/liveralcoholichep.html. Accessed April 27th, 2018.
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)
Pathophysiology
  • Alcohol consumption results in translocation of gut bacteria into the portal system along with lipopolysaccharides that interact with toll-like receptors and results in production of inflammatory and immunogenic mediators such as tumor necrosis factor α and interferons (World J Hepatol 2011;3:114)
  • Alcohol consumption causes shunting of normal substrates away from catabolism and toward lipid biosynthesis due to:
    1. Excess NADH generation from alcohol dehydrogenase and acetaldehyde dehydrogenase
    2. Impaired assembly / secretion of lipoproteins and
    3. Increased peripheral fat catabolism
  • P450 induction causes other drugs to be transformed to toxic metabolites; free radicals, from microsomal oxidation of alcohol, damage proteins and membranes
  • Alcohol directly affects microtubular and mitochondrial function, also induces immunologic attack on hepatic neoantigens
  • Acetaldehyde (alcohol metabolite) causes lipid peroxidation and acetaldehyde protein adduct formation
  • Collagen deposition by perisinusoidal hepatic stellate (Ito) cells is due to Kupffer cell activation (release of TNF alpha, IL1 / 6, TGF-beta), platelet activating factor, influx of neutrophils into parenchyma
  • Alcohol also causes derangements of vascular perfusion
Clinical features
Prognostic factors
  • Associated with disease progression (J Hepatol 2012;57:399):
    • Female gender
    • Obesity
    • Daily or nearly daily heavy drinking
    • Drinking at an early age
    • Concurrent chronic liver diseases, especially HCV and genetic hemochromatosis
    • Genetic susceptibility genotype PNPLA3 rs738409 (GG)
Case reports
Treatment
  • Abstinence is the most important treatment
  • Prednisolone and pentoxifylline are recommended to treat severe alcoholic hepatitis by AASLD (Hepatology 2010;51:307) and EASL (J Hepatol 2012;57:399), although efficacy is controversial
  • In a recent multicenter, double blind, randomized trial of 1,053 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)
Gross description
  • Initially liver is 4 - 6 kg, yellow, greasy, easily fractured
  • Later liver becomes red with bile stained areas
  • May contain visible nodules and fibrosis
Microscopic (histologic) description
  • 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 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, 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 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 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
Microscopic (histologic) images

Images hosted on other servers:
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Liver biopsy

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Natural history of ALD

Differential diagnosis
  • 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
  • Nonalcoholic fatty liver disease:
    • Pathologically almost indistinguishable from ALD
    • Alcoholic liver disease has few specific pathological changes and all are rare:
    • 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 two standard drinks/day for men and one standard drink/day for women is endorsed as the acceptable threshold to define nonalcoholic
  • 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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