Non-Alcoholic Fatty Liver Disease1

8/13/2019 Non-Alcoholic Fatty Liver Disease1

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NON-ALCOHOLIC FATTY LIVERDISEASE


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Title :Pathology of Nonalcoholic Fatty LiverDisease

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 ofMedicine, Seattle


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Definition

Term NASH was coined by Ludwig et all in1980

It is steatohepatitis in absence of significantalcohol consumption

Alternate term :metabolic steatohepatitis ,not uniformly accepted


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Prevalence

NAFLD is most common liver disease

High incidence in cases of obesity

DMhyperlipidemia

insulin resistance

Females> males

Other predisposing conds: metabolicsyndromes HTN, hyperuricemia,PCOD


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Spectrum ranging from

Simple steatosis

Steatohepatitis Steatosis with fibrosis

cirrhosis


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Pathogenesis

Metabolic syndrome

Central obesity

Hyperglycemia(type II DM) Low HDL

Hypertriglyceridemia

HT

( 3 out of 5)


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Insulin resistance

TNF activates inhibitor Kinase Kappa-beta which causes downregulation ofphosphorylation of insulin receptor

substrate


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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


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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)


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Laboratory findings

Mild elevation of aspartate AST and ALT levels; levels seldomexceed 10X the upper level of normal and more typically are AST; AST > ALT suggests significant fibrosis or cirrhosis

(altered with antidiabetic therapy)

Glutamyltransferase and alkaline phosphatase levelelevation

Hyperglycemia (caused by the association with diabetespresent in about one third of patients)

Hyperlipidemia (usually triglycerides) in approximately 20%

to 25%


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IgA deposition has been described in histologicsections in NASH patients

Serum IgA level is elevated in about 25%

Antinuclear antibody in about one third of

patients

Abnormal iron indices (common but generallydo not indicate genetic hemochromatosis


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Histopathologic findings in

NASH Necessary components

- steatosis,macro> micro; accentuated in zone3

- mixed, mild lobular inflammation; scatteredneutrophils & mononuclear cells

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


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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 stainedKupffer cells

- fat cysts


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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 insinusoidal lining cells

- Megamitochondria in hepatocytes


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Unusual for NASH, consider other causes of livertest abnormalities

- macrovesicular steatosis:


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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


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Grade 2 (moderate)

- steatosis: any degree, usually mixed macrovesicular &microvesicular

- ballooning: present in zone 3

- lobular inflammation: polymorphs associated with balloonedhepatocytes and/or pericellular fibrosis; mild chronic

inflammation- portal inflammation :none, mild to moderate


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Grade 3, severe ( florid steatohepatitis)

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

- ballooning: predominantly zone 3; marked lobularinflammation :scattered acute & chronicinflammation; polymorphs concentrated in zone 3areas of ballooning and perisinusoidal fibrosis

- portal inflammation: mild or moderate; notpredominant or marked


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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


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NAFLD Activity Score(NAS)

Steatosis 0 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


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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 - stage1a/1b with periportal fibrosis

Stage 3 - bridging fibrosis

Stage 4 - cirrhosis


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NAS 5 Diagnostic of NASH

NAS > 2 to < 5 Indeterminate

NAS 2 Simple Steatosis


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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


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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 3predominance.


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Controversial areas for

research Risk factors for progression?

Most sensitive serum markers for diagnosis?

Relevant cytokines and peptide mediators ininsulin resistance?

role of FFA in cellular injury in NAFLD ?

Insulin signaling pathways affected? Best pharmacological approach?


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Points for best practice

Main histological components of NASH aresteatosis , ballooning degeneration , lobularinflammation & pericellular fibrosis. Mosthistopathologists rely on 3/4 components fordiagnosis of NASH.

Presence of Mallorys hyaline is helpful insupporting a diagnosis but its absence doesnot mitigate against a diagnosis of NASH.


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ASH & NASH are not identical. However they

share many features & it is often not possibleto distinguish them on histological groundsalone

A HPE diagnosis of steatosis , steatohepatitisshould be made & subsequently correlatedclinically.

Pediatric NASH more often shows portalbased fibrosis & inflammation together withsevere steatosis & less ballooning ,inflammation & pericellular fibrosis.


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Grading & staging of NAFLD is mainlyperformed in the context of epidemiologicalstudies & clinical trials.

NAS is a potentially valuable tool in thesystematic assessment of NAFLD in liver Bx &its components could be scored & described

in the report/


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Thank you

Documents

Non-Alcoholic Fatty Liver Disease1