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 µvesicular
- 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