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NON-ALCOHOLIC DISEASE

FATTY LIVER

Title :Pathology of Nonalcoholic Fatty Liver Disease


Author : Mattew M Yeh , Elizabeth M Brunt

Journal : Am J Clin Pathol 2007;128:837-847


Type of article : review article Place of study : Washington School of

Medicine, Seattle

Definition
Term NASH was coined by Ludwig et all in 1980
It is steatohepatitis in absence of significant

alcohol consumption Alternate term :metabolic steatohepatitis , not uniformly accepted

Prevalence
NAFLD is most common liver disease High incidence in cases of obesity DM

hyperlipidemia insulin resistance


Females> males Other predisposing conds: metabolic

syndromes HTN, hyperuricemia,PCOD

Spectrum ranging from


Simple steatosis Steatohepatitis

Steatosis with fibrosis


cirrhosis

Pathogenesis
Metabolic syndrome
Central obesity Hyperglycemia(type II DM)

Low HDL
Hypertriglyceridemia HT

( 3 out of 5)

Insulin resistance
TNF activates inhibitor Kinase Kappa-

beta which causes downregulation of phosphorylation of insulin receptor substrate

NAFLD classification

Class 1: simple steatosis Class2 :steatosis with lobular inflammation Class3 : 2+ ballooned hepatocytes Class 4: 3+ mallory hyaline or fibrosis

NASH: class3 or 4

Symptoms and physical findings

-Fatigue (correlates poorly with histologic stage) -Right upper quadrant pain (usually mild but may be mistaken for gallstone disease) -Hepatomegaly -Bowel dysmotility and small bowel bacterial overgrowth

-Constipation (especially in children )


-Anthropometric (waist circumference indicates central adiposity)

Laboratory findings
Mild elevation of aspartate AST and ALT levels; levels seldom

exceed 10X the upper level of normal and more typically are <1.5 X the upper normal level (altered with antidiabetic therapy) elevation

ALT > AST; AST > ALT suggests significant fibrosis or cirrhosis Glutamyltransferase and alkaline phosphatase level

Hyperglycemia (caused by the association with diabetes

present in about one third of patients)

Hyperlipidemia (usually triglycerides) in approximately 20%

to 25%

IgA deposition has been described in histologic sections in NASH patients


Serum IgA level is elevated in about 25%

Antinuclear antibody in about one third of

patients

Abnormal iron indices (common but generally do not indicate genetic hemochromatosis

Histopathologic findings in NASH


Necessary components - steatosis,macro> micro; accentuated in zone 3

- mixed, mild lobular inflammation; scattered neutrophils & mononuclear cells

- hepatocellular ballooning; most apparent near steatotic liver cells, typically in zone 3

Usually present but not necessary for diagnosis:

- zone 3 perisinusoidal fibrosis - zone 1 hepatocellular glycogenated nuclei - lipogranulomas in the lobules; of varying size, but usually small - occasional acidophil bodies or PAS stained Kupffer cells - fat cysts

May be present but not necessary for diagnosis:

- Mallorys hyaline in ballooned hepatocytes *usually zone 3 in NASH, may be in zone 1 in diabetes, amiodarone
- Mild (1+) granular periportal (zone 1) hepatocellular iron or scattered iron granules in

sinusoidal lining cells


- Megamitochondria in hepatocytes

Unusual for NASH, consider other causes of liver test abnormalities - macrovesicular steatosis:<30% of parenchyma involved/ nonzonal distribution

- purely/ predominantly microvesicular steatosis

- sclerosing hyaline necrosis, veno occlusive lesions, perivenular fibrosis

Grading of NASH
Grade 1 (mild)

- steatosis : predominantly macrovesicular, range - < 33% upto 66% of lobules

- ballooning occasionally observed; zone 3 hepatocytes


- lobular inflammation: scattered & mild acute (polymorphs) and chronic inflammation (mononuclear cells) -portal inflammation: none or mild

Grade 2 (moderate)

- steatosis: any degree, usually mixed macrovesicular & microvesicular - ballooning: present in zone 3 - lobular inflammation: polymorphs associated with ballooned hepatocytes and/or pericellular fibrosis; mild chronic inflammation - portal inflammation :none, mild to moderate

Grade 3, severe ( florid steatohepatitis)

- steatosis: > 66%(zone 3 or panacinar); commonly mixed steatosis

- ballooning: predominantly zone 3; marked lobular inflammation :scattered acute & chronic inflammation; polymorphs concentrated in zone 3 areas of ballooning and perisinusoidal fibrosis
- portal inflammation: mild or moderate; not predominant or marked

Staging
Stage 1: zone 3 perivenular, perisinusoidal, or

pericellular fibrosis; focal or extensive


Stage 2: stage 1 + focal or extensive portal

fibrosis
Stage 3: bridging fibrosis, focal or extensive Stage 4: cirrhosis with or without residual

perisinusoidal fibrosis

NAFLD Activity Score(NAS)


Steatosis

0 <5% 1 0-33% 2 33-66% 3 >66%

Ballooning
0 none 1 few 2 many/prominent

Lobular inflammation

0 none 1 < 2 foci/200x 2 2-4 foci/200x 3 >4 foci/200x

Fibrosis
Stage 0 none Stage 1a - zone 3 perisinusoidal fibrosis ,MT Stage 1b - zone 3 perisinusoidal fibrosis Stage 1c - fibrosis limited to portal tracts Stage 2 Stage 3 Stage 4

- stage1a/1b with periportal fibrosis - bridging fibrosis - cirrhosis

NAS 5
NAS > 2 to < 5 NAS 2

Diagnostic of NASH
Indeterminate Simple Steatosis

NASH Vs ASH
More common in ASH
Sclerosing hyaline necrosis (bridging necrosis) Veno-occlusive lesions

Ductular reaction
Cholangiolitis Bilirubinostasis

Mallory hyaline

More common in NASH


Nuclear glycogenation/clearing

Pediatric NASH
Clinically
Obesity Hepatomegaly

Acanthosis nigricans

Histologically
More sever steatosis

Less ballooning, mallory hyaline,lobular inflammation


More portal based inflammation ,portal fibrosis

without perisinusoidal fibrosis, apperant zone 3 predominance.

Controversial areas for research


Risk factors for progression?
Most sensitive serum markers for diagnosis? Relevant cytokines and peptide mediators in

insulin resistance? role of FFA in cellular injury in NAFLD ? Insulin signaling pathways affected? Best pharmacological approach?

Points for best practice


Main histological components of NASH are steatosis , ballooning degeneration , lobular inflammation & pericellular fibrosis. Most

histopathologists rely on 3/4 components for diagnosis of NASH.


Presence of Mallorys hyaline is helpful in supporting a diagnosis but its absence does not mitigate against a diagnosis of NASH.

ASH & NASH are not identical. However they

share many features & it is often not possible to distinguish them on histological grounds alone A HPE diagnosis of steatosis , steatohepatitis should be made & subsequently correlated clinically. Pediatric NASH more often shows portal based fibrosis & inflammation together with severe steatosis & less ballooning , inflammation & pericellular fibrosis.

Grading & staging of NAFLD is mainly performed in the context of epidemiological studies & clinical trials. NAS is a potentially valuable tool in the systematic assessment of NAFLD in liver Bx & its components could be scored & described

in the report/

Thank you

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