Liver & intrahepatic bile ducts

Noninfectious hepatitis

Nonalcoholic fatty liver disease / nonalcoholic steatohepatitis (NASH)

Deputy Editor-in-Chief: Raul S. Gonzalez, M.D.
Yoshihiro Ikura, M.D.

Last author update: 1 July 2020
Last staff update: 4 August 2022

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PubMed Search: Nonalcoholic fatty liver disease (NAFLD) pathology

Yoshihiro Ikura, M.D.
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Cite this page: Ikura Y. Nonalcoholic fatty liver disease / nonalcoholic steatohepatitis (NASH). website. Accessed September 30th, 2023.
Definition / general
  • Nonalcoholic fatty liver disease (NAFLD) is hepatic steatosis generated in association with overweight / obesity, type 2 diabetes mellitus or other metabolic dysregulations
  • Morphologically, NAFLD covers all forms of hepatic steatosis with or without inflammation / fibrosis
Essential features
  • Macrovesicular hepatosteatosis accentuated on zone 3, potentially accompanying fibroinflammatory changes in metabolic patients
  • Presence of concomitant liver disease does not become a reason for excluding metabolic (dysfunction) associated fatty liver disease (MAFLD) (NAFLD/NASH) (Gastroenterology 2020 May;158:1999)
  • Steatohepatitis is not the sole progressive form of NAFLD (J Hepatol 2015;62:1148)
  • Histologic grade is assessed using a scoring system including steatosis, lobular inflammation and ballooning degeneration (Hepatology 2005;41:1313)
  • Patients are at risk for fibrosis, cirrhosis and hepatocellular carcinoma
  • Nonalcoholic fatty liver disease (NAFLD) refers to any fatty liver disease caused by metabolic dysregulation, as above
  • Nonalcoholic steatohepatitis refers to an aggressive form of the disease characterized by inflammation and ballooning in addition to steatosis
  • Metabolic (dysfunction) associated fatty liver disease (MAFLD) has been proposed as a new, more accurate term for NAFLD (J Hepatol 2020 Apr 8 [Epub ahead of print])
  • Cytoplasmic inclusions known as Mallory-Denk bodies (see microscopic images) are also termed Mallory’s hyaline and intracytoplasmic hyaline
ICD coding
  • ICD-10: K76.0 - fatty (change of) liver, not elsewhere classified
  • Hepatic manifestation of metabolic disorders
  • Oxidative stress and lipotoxicity are considered key factors in disease progression (Hepatology 2006;43:506, J Atheroscler Thromb 2009;16:893)
  • Genetic variants in patatin-like phospholipase domain containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), membrane bound O-acyltransferase domain containing 7 (MBOA7) and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) are known modifiers of NAFLD (Clin Med (Lond) 2018;18:s54, J Hepatol 2018;68:268)
Diagrams / tables

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Diagnostic algorithm

Clinical features
Radiology description
Radiology images

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Bright liver

Hypodensity on CT

Increased signal on T1 weighted MRI

MRI based fat content evaluation

Prognostic factors
Case reports
  • Currently, there is no approved specific therapy
Gross description
  • Swollen soft liver with yellowish brown color
  • Surface of affected liver becomes irregular with progression of fibrosis
  • Some cases show cirrhosis or hepatocellular carcinoma
Gross images

Contributed by Yoshihiro Ikura, M.D.

NAFLD liver

Frozen section description
  • Lipid stain methods (Oil Red O, Sudan black B, filipin, etc.) to detect liver fat can be performed on frozen sections
Frozen section images

Contributed by Yoshihiro Ikura, M.D.

Lipid droplets

Microscopic (histologic) description
  • Predominantly macrovesicular steatosis in ≥ 5% hepatocytes under low magnification (4x or lower) observation is a sole histologic requirement for diagnosis of NAFLD
  • Disease severity is evaluated separately by grade of activity and stage of fibrosis
  • Activity grade is assessed according to nonalcoholic fatty liver disease activity score (NAS) using the sum of 3 components (total 0 - 8 points) (Hepatology 2005;41:1313)
    • 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)
    • Ballooning degeneration (0: none; 1: few; 2: many)
  • Fibrosis stage is assessed into 5 levels; stage 0, none; stage 1, perivenular (zone 3) fibrosis; stage 2, perivenular + portal fibrosis; stage 3, bridging fibrosis; stage 4, cirrhosis (Hepatology 2005;41:1313)
  • Other characteristic findings are Mallory-Denk bodies, glycogenated nuclei, giant mitochondria (megamitochondria) and lipogranuloma
  • Histologic changes of concomitant liver conditions may be seen
  • In NAFLD associated cirrhosis, steatotic hepatocytes may be burnt out, resulting in a loss of visible steatosis, but the term "cryptogenic cirrhosis" should not be used for this condition (J Hepatol 2020 Apr 8 [Epub ahead of print])
Microscopic (histologic) images

Contributed by Yoshihiro Ikura, M.D.

Zone 3 steatosis

Lobular inflammation

Hepatocellular ballooning and Mallory-Denk bodies

Mallory-Denk bodies (ubiquitin)

Hepatocellular ballooning (CK18)

Perivenular fibrosis (trichrome)

Glycogenated nuclei

Giant mitochondria


NAFLD associated cirrhosis (trichrome)

Positive stains
Negative stains
Sample pathology report
  • Liver, needle biopsy:
    • Fatty liver, consistent with nonalcoholic fatty liver disease
    • NAS 6 points = steatosis 2 + inflammation 2 + ballooning 2
    • Stage 2 (perivenular + portal fibrosis)
Differential diagnosis
Board review style question #1

A 78 year old woman with a > 10 year treatment history of rheumatoid arthritis shows elevated serum levels of liver enzymes (AST, 120 IU; ALT, 136 IU; GGT, 129 IU). She is an occasional drinker and does not have metabolic disorders. She is taking methotrexate (MTX). Hepatitis virus B and C are negative and antinuclear antibody is ×160. Liver biopsy, shown above, shows steatosis and inflammation. What should be done next in the diagnostic workup?

  1. Administration of steroids
  2. ATP7B gene testing
  3. Cessation of MTX
  4. Drug induced lymphocyte stimulation test
  5. Serum AMA
Board review style answer #1
C. Cessation of MTX. MTX is a first line therapy for rheumatoid arthritis and can cause steatohepatitis that mimics NAFLD.

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Reference: Nonalcoholic fatty liver disease (NAFLD) / nonalcoholic steatohepatitis (NASH)
Board review style question #2

Which of the following is correct concerning the intracellular inclusion seen in the figure above (arrow)?

  1. Actin positive
  2. CK18 negative
  3. Related to viral infection
  4. Specific for alcoholic liver damage
  5. Ubiquitin positive
Board review style answer #2
E. Ubiquitin positive. The inclusion shown is a Mallory-Denk body. It is a ubiquitinated aggregate of keratin filament that occurs in ballooned hepatocytes.

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Reference: Nonalcoholic fatty liver disease (NAFLD) / nonalcoholic steatohepatitis (NASH)
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