Liver and intrahepatic bile ducts - nontumor
Hepatitis - noninfectious
Nonalcoholic steatohepatitis (NASH)

Topic Completed: 1 August 2015

Revised: 23 March 2020

Revised: 23 January 2019, last major update August 2015

Copyright: (c) 2002-2018,, Inc.

PubMed Search: Nonalcoholic steatohepatitis[TI] liver[TI] free full text[sb]

Anthony W.H. Chan, F.R.C.P.A.
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Cite this page: Chan A. Nonalcoholic steatohepatitis (NASH). website. Accessed March 31st, 2020.
Definition / general
  • Nonalcoholic fatty liver disease (NAFLD) comprises a full spectrum of conditions from steatosis to steatohepatitis (NASH) and cirrhosis
  • Acquired factors:
    • Associated with overeating, consumption of energy dense, nutritionally imbalanced and appetite dysregulating food, lack of physical activity (Nat Rev Gastroenterol Hepatol 2013;10:307)
    • Prevalence and severity of fatty liver increases with the number of components of the metabolic syndrome: central obesity, hyperglycemia (≥ 5.6 mmol/L), hypertriglyceridemia, reduced HDL cholesterol (< 1.03 mmol/L in men, < 1.29 mmol/L in women) and hypertension (Gut 2012;61:409)
  • Inherited factors (Nat Rev Gastroenterol Hepatol 2013;10:307):
    • Polymorphisms of genes for lipid transport (e.g. PPARA, PPARG)
    • Polymorphisms of genes involving lipid metabolism (e.g. PNPLA3, APOC3 and adiponectin)
Clinical features
  • Most are asymptomatic with incidental findings of abnormal liver biochemistry or fatty liver in imaging
  • Various noninvasive tests, based on clinical, laboratory and radiological tests, have been developed to assess the degree of steatosis and fibrosis in NAFLD
  • Liver biopsy remains the gold standard for characterizing liver histology in patients with NAFLD and is recommended for those at high risk of steatohepatitis and advanced fibrosis (bridging fibrosis and cirrhosis) or with concurrent chronic liver disease of other etiology
Case reports
Microscopic (histologic) description
  • Five major histological patterns (Hepatology 2005;41:1313, Gastroenterology 2014;147:754)
  • Steatosis:
    • Predominantly macrovesicular steatosis: large droplet (classical; a single large fat droplet displacing the nucleus to the periphery) and small / medium droplet
    • Rarely microvesicular steatosis: multiple minute fat droplets (may be only highlighted by Oil Red O stain); usually only focal; associated with higher disease activity and progression
    • Degree of steatosis should be evaluated at low magnification (usually 4x, at most 10x); higher magnification may result in overestimation
    • < 5% (normal), 5 - 33% (mild), 34 - 66% (moderate), > 66% (severe)
    • Severity of steatosis is associated with lobular inflammation and perivenular fibrosis but not ballooning degeneration and portal / advanced fibrosis
  • Steatosis with inflammation
    • Not equivalent to steatohepatitis
    • Predominant lobular inflammation in form of spotty necrosis
    • Portal inflammation is typically absent or mild if present
    • Moderate to severe portal inflammation is associated with steatohepatitis and advanced fibrosis but should also raise the suspicion for other chronic hepatitis, particularly viral hepatitis C
    • Predominant portal inflammation is more common in pediatric patients (Hepatology 2005;42:641)
  • 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
    • Presence of Mallory-Denk bodies (MDB), also known as Mallory bodies or Mallory hyaline; a deeply eosinophilic, ropey intracytoplasmic inclusion; represents aggregates of misfolded intermediate filaments with different classes of proteins, including p62 and ubiquitin; it is often but not necessarily found in ballooned hepatocytes (Exp Cell Res 2007;313:2033)
    • Fibrosis is not a necessary diagnostic feature of steatohepatitis but is found in > 80% of adult and pediatric patients with NASH
    • Perivenular and pericellular (perisinusoidal) fibrosis is characteristic for fatty liver disease; as disease progresses, portal / periportal fibrosis, bridging fibrosis and cirrhosis develop
  • Borderline steatohepatitis:
    • Designated for those cases falling in the grey zone between steatosis with inflammation and definite steatohepatitis
    • Zone 3 borderline steatohepatitis is a controversial but widely accepted entity and includes those with perivenular / pericellular fibrosis in the absence of ballooning degeneration and those with equivocal ballooning degeneration
    • Zone 1 borderline steatohepatitis is a characteristic pattern in pediatric patients with NASH; it features portal based injury (periportal steatosis, predominantly portal inflammation and portal fibrosis) in the absence of ballooning degeneration
  • Cryptogenic cirrhosis
    • Cryptogenic cirrhosis accounts for 8 - 9% of liver transplants in the US; "burnt out" NAFLD / NASH is a common cause of cryptogenic cirrhosis (Hepatology 2000;32:689)
    • Steatosis in NAFLD / NASH may resolve as disease progresses to advanced fibrosis ("burnt out" NAFLD / NASH)
    • Recognition of residual ballooning degeneration, Mallory-Denk bodies, giant mitochondria and pericellular fibrosis, together with clinical evidence of metabolic risk factors, is helpful to diagnose "burnt out" NAFLD / NASH cirrhosis (Ann Hepatol 2009;8:346)
  • Other pathological lesions in fatty liver disease: lipogranuloma, glycogenated nuclei, giant mitochondria
  • NASH Clinical Research Network (CRN) published a NASH activity score (NAS) (Hepatology 2005;41:1313) to assess severity of NAFLD / NASH, using the sum of 3 components (total is 0 - 8 points)
    • Steatosis (0: < 5%; 1: 5 - 33%; 2: 34 - 66%; 3: > 66%), lobular inflammation (0: none; 1: < 2 foci/20x field; 2: 2 - 4 foci/20x field; 3: > 4 foci/20x field) and ballooning degeneration (0: none; 1: few; 2: many)
    • 86%, 41% and 1% of NAS with ≥ 5, 3 - 4 and ≤ 2 points are histologically confirmed NASH (Hepatology 2011;53:810)
    • However, NAS should not be used as the diagnostic criteria for steatohepatitis
Microscopic (histologic) images

Images hosted on other servers:
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Mild steatosis

Images contributed by Anthony W.H. Chan, FRCPA:
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Mallory-Denk bodies

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Glycogenated nuclei

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Macrovesicular steatosis, large droplet

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Macrovesicular steatosis, small droplet

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CK8 and 18

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Perivenular and pericellular fibrosis

Negative stains
  • CK8 / 18: loss of normal cytoplasmic stain in ballooned hepatocytes
  • Residual immunoreactivity is confined to Mallory-Denk bodies if present (J Hepatol 2008;48:821)
Differential diagnosis
  • Alcoholic liver disease
    • Pathologically almost indistinguishable from NAFLD / NASH
    • Alcoholic liver disease tends to have more Mallory-Denk bodies, much less glycogenated nuclei and the presence of satellitosis (ballooned hepatocyte surrounded by neutrophils) but these features are nonspecific
    • Alcoholic liver disease has a few specific but rare pathological changes: acute foamy degeneration, sclerosing hyaline sclerosis, acute / chronic cholestasis and sinusoidal obstruction syndrome
    • 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
  • 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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