fatty liver disease - ucsf departments of pathology...
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Fatty Liver DiseaseDiagnostic Challenges & Updates
Ryan M. Gill
Current Issues 2014
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Definitions• NAFLD – Fat in the liver (imaging or histology) in a patient without secondary fat accumulation.
• NASH‐NAFLD with histologic evidence of liver injury in the form of ballooned hepatocytes, inflammation and fibrosis
• NAFL – NAFLD without the above histologic findings associated with NASH
• NASH cirrhosis – Cirrhosis with current or previous evidence of NASH
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Secondary Hepatic Fat• Macrovesicular
– Excess alcohol– HCV– Wilson Disease– Starvation/TPN– Abetalipoproteinemia– Medications (amiodarone, methotrexate, tamoxifen, corticosteroids)
• Microvesicular
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Secondary Hepatic Fat• Macrovesicular• Microvesicular
– Reye Syndrome– Acute Fatty Liver of pregnancy– Medications (e.g. antiretrovirals, valproate)
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NAFLD: Extent of the problem• 6.3-33% (median = 20%) in various populations• 3-5% NAFLD represent NASH• Prevalence of NASH cirrhosis in general
population not known (in bariatric surgery population: 90% NAFLD and 5% unsuspected cirrhosis)
• Obesity (2009-2010, CDC)– US adults: 35.7%, 78 million; highest rate in women
over age 60 (42.3%)– US children: 16.9%, 12.5 million; highest rate in boys
age 6-11 (20.1%)
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Outline
1. Clinical considerations2. Essential histologic criteria for diagnosis of
steatohepatitis3. Staging4. Histologic variations 5. Diagnostic challenges
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Clinical Considerations
• When to biopsy a NAFLD patient?– All NAFLD patients at risk for NASH and advanced fibrosis (based on metabolic syndrome and “NAFLD fibrosis score”)
– Competing etiologies for steatosis– Co‐existing chronic liver disease possible
• Non‐invasive testing?– No clinical or imaging tests can distinguish NAFL from NASH
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Metabolic Syndrome
• Three or more of the following:– BP >130/85– Increased waist circumference (>102 cm M, >88 cm F)
– Fasting blood sugar (>110 mg/dL)– Triglycerides >150 mg/dL– Low HDL (<40 mg/dL M, <50 mg/dL F)
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Histologic pattern and outcome
• Steatosis alone• Steatosis + inflammation
Progression to cirrhosis <5%
• Steatosis + ballooning• Steatosis + fibrosis
Progression to cirrhosis ~25%
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Treatment Options• Weight loss • Exercise• Vitamin E is a first line treatment for non‐diabetic patients
• Pioglitazone, omega‐3 FA, and bariatric surgery may also be effective
• Screening for esophageal varices and HCC is appropriate
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Steatohepatitis: essential features
AASLD and NASH Clinical Research Network
• Steatosis (>5%)• Inflammation (lobular)• Hepatocellular injury
Ballooned hepatocytesPericellular fibrosis
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Steatohepatitis: essential features
AASLD and NASH Clinical Research Network
• Steatosis (>5%)• Inflammation (lobular)• Hepatocellular injury
Ballooned hepatocytesPericellular fibrosis
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Mild Steatosis (Grade 1, scale 0‐3)
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Moderate Steatosis (Grade 2, scale 0‐3)
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Severe Steatosis (Grade 3, scale 0‐3)
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Steatohepatitis: essential features
AASLD and NASH Clinical Research Network
• Steatosis (>5%)• Inflammation (lobular)• Hepatocellular injury
Ballooned hepatocytesPericellular fibrosis
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Lobular Inflammation in NASH
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Portal Inflammation in NASH
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Neutrophil Satellitosis
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Steatohepatitis: essential features
AASLD and NASH Clinical Research Network
• Steatosis (>5%)• Inflammation (lobular)• Hepatocellular injury
Ballooned hepatocytesPericellular fibrosis
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Ballooned Hepatocyte
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Heptocellular Ballooning
• Large size
• Cytoplasmic clearing
• Eosinophilic globules
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Multiple Ballooned Hepatocytes
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BH Mimic – Small Droplet Fat
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BH Mimic ‐ Glycogenosis
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BH Mimic ‐ Processing
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Steatohepatitis: essential features
AASLD and NASH Clinical Research Network
• Steatosis (>5%)• Inflammation (lobular)• Hepatocellular injury
Ballooned hepatocytesPericellular fibrosis
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Staging ‐ Brunt/Kleiner Method
Stage 1A Pericentral/sinusoidal Fibrosis –Delicate
Stage 1B Pericentral/sinusoidal Fibrosis – DenseStage 1C Periportal FibrosisStage 2 Pericentral/sinusoidal and Periportal
FibrosisStage 3 Bridging FibrosisStage 4 Cirrhosis
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Stage 1
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Stage 2
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Stage 3
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Stage 3
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Stage 4
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Fibrosis Pitfall – Tangential
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Fibrosis Pitfall ‐ Subcapsular
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Fibrosis Pitfall ‐ Overstained
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Fibrosis Pitfall – Overstained
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Fibrosis Pitfall ‐ Nodular Perivenular Collagen
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Fibrosis Pitfall – Branching Portal Tract
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Fibrosis Pitfall – HistiocyteAggregate
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Fibrosis Pitfall – HistiocyteAggregate
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Steatohepatitis: non-essential features
• Mallory hyaline in Zone 3• Mild iron deposits in hepatocytes or
sinusoidal cells• Megamitochondria• Glycogenated nuclei• Lipogranulomas• Acidophil bodies (occasional)
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Mallory Hyaline
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Lipogranuloma
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Spotty HepatocyteNecrosis/Acidophil bodies
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NASH Activity Score (NAS)
• Steatosis (0‐3) – none, mild, moderate, severe
• Lobular inflammation (0‐3) – 0, <2, 2‐4, >4 foci/20x
• Hepatocellular ballooning (0‐2) – none, few, many
• Total = 0‐8
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Histologic Variation
PATTERN 1: CLASSIC STEATOHEPATITIS
Steatosis with mild inflammation, hepatocellular ballooning, and pericellular fibrosis
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Histologic Variation
PATTERN 2: STEATOSIS WITHOUT HEPATOCELLULAR INJURY
Steatosis without hepatocyte ballooning or pericellular fibrosis is insufficient for a diagnosis of steatohepatitis and represents NAFL
Low rate of progression (~5%) to significant fibrosis
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Histologic Variation
PATTERN 3: STEATOSIS WITH SWOLLEN HEPATOCYTES/NON‐CLASSIC BALLOONED HEPATOCYTES
Borderline for steatohepatitis; if clinical risk factors are present, it is best to manage the patient as appropriate for steatohepatitis
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Non‐Classic Ballooned Hepatocyte
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Histologic Variation
PATTERN 4: BALLOONED HEPATOCYTES OR PERICELULAR FIBROSIS WITHOUT STEATOSIS
Uncommon in patients with metabolic risk factors
Ballooned Hepatocytes Only Pericellular Fibrosis OnlyRecent cessation of Alcohol Chronic venous outflow
obstructionAmiodarone Remote CZ injury
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Chronic Venous Outflow Obstruction
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Histologic Variation
PATTERN 5: STEATOSIS WITH PERICELLULAR FIBROSIS, BUT NO BALLOONED HEPATOCYTES
Chronic steatohepatitis in the appropriate clinical context
Other considerations: chronic venous outflow obstruction, drug (e.g. oxaliplatin), remote parenchymal rejection (post‐transplant)
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Histologic Variation
PATTERN 6: CIRRHOSIS WITH STEATOSIS AND/OR BALLOONED HEPATOCYTES
Cirrhosis with histologic features of NAFLD is best considered NASH cirrhosis. Some cases may show residual pericellular fibrosis.
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Diagnostic Challenges
1. Alcoholic steatohepatitis2. Burnt out NASH cirrhosis3. Centrizonal Arteries4. Drug induced steatohepatitis5. Hereditary hemochromatosis6. Metabolic disorders7. Microvesicular steatosis8. More than mild portal inflammation
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Alcoholic Steatohepatitis
• Alcoholic steatohepatitis can not be definitively distinguished from NASH by histology
NASH ASH
Steatosis ++ +
Ballooned hepatocytes + ++
Lobular inflammation + ++
Mallory hyaline + ++
Neutrophil infiltrate + ++
Cholestasis +/‐ +
Obliterated CV +/‐ +
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Burnt‐out NASH Cirrhosis
• Typical steatohepatitis features regress with progression of fibrosis and may be lost with cirrhosis
• Many cases labeled as cryptogenic cirrhosis; since this population has a high incidence of type 2 DM, NASH is considered to be the most likely etiology
• Rule out other etiologies and correlate with NASH risk factors
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Centrizonal Arteries
• Identification of arterioles is used to orient the pathologist to lobular architecture
• Centrizonal arterialization is common and is under‐recognized
• Mis‐identification of a central zone as a portal tract can lead to erroneous classifcation as a portal based disease
• Glutamine synthetase can be helpful in problem cases (stains pericentral hepatocytes)
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Centrizonal Artery
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Centrizonal Artery
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Centrizonal Artery
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Drug Induced Steatohepatitis
• Histologic changes identical to NASH have been identified in patients without NASH risk factors exposed to certain drugs
Definite Association Possible Association
Amiodarone Tamoxifen
Irinotecan Steroids
Methotrexate Estrogen
PerhexilineMaleate/Diethylaminoethoxyhexesterol
Diethylstilbestrol
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Amiodarone Toxicity
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Methotrexate
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Methotrexate with Portal Fibrosis
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Hereditary Hemochromatosis• A mild to moderate hepatocyte siderosis(generally nonzonal) and/or Kupffer cell siderosis is seen in ~20% of NAFLD patients
• Serum ferritin is an acute phase reactant that is commonly increased in NAFLD patients
• Increased iron saturation would more strongly suggest hereditary hemochromatosis
• C282Y HFE mutation in an established NASH patient may warrant biopsy to evaluate iron overload
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Periportal Siderosis in HH
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Unrelated Steatosis in HH
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Periportal Siderosis in NAFLD
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Secondary Siderosis in NAFLD
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Metabolic Disorders
• Glycogenic hepatopathy– Type 1 DM with poor glycemic control– Glycogenosis, minimal fat, and abundant megamitochondria
• Diabetic hepatosclerosis– Non‐zonal perisinusoidal fibrosis and BM deposition in patients with long standing insulin dependent DM, minimal steatosis, no ballooning
• Wilson disease– Steatosis (non‐zonal), glycogenated nuclei, Mallory hyaline, swollen hepatocytes, portal inflammation and fibrosis
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Glycogenic Hepatopathy
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Glycogenic Hepatopathy
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Diabetic Hepatosclerosis
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Steatosis and Portal Inflammation in Wilson Disease
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Periportal Fibrosis in Wilson Disease
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Wilson Disease with Swollen Hepatocytes
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Wilson Disease with Pericellular Fibrosis
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Microvesicular Steatosis
• Pure microvesicular steatosis does not occur in NASH and indicates severe mitochondrial injury
• Reye syndrome, acute fatty liver of pregnancy, alcoholic foamy liver degeneration, drug (cocaine, tetracycline, valproic acid, zidovudine), and rare genetic disorders.
• Many NAFLD cases will have a minor component of microvesicular fat
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Diffuse Microvesicular Steatosis
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More than Mild Portal Inflammation
• NASH portal inflammation is typically mild• Prominent portal inflammation raises consideration of other causes (HBV, HCV, AIH, PBC, Wilson disease)
• If other etiologies are excluded, this can be considered NASH with prominent portal inflammation
• May be associated with a higher degree of fibrosis
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More than Mild Portal Inflammation
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Pediatric NASH
• NASH cirrhosis seen as young as 8 years of age• AST/ALT screening has been considered for obese children starting at age 10
• Type 1 pediatric NASH: Identical to adult type NASH• Type 2 pediatric NASH: Severe panacinar steatosis, no ballooned hepatocytes, early portal based fibrosis (stage 1C)
• Children younger than age 2 with fatty liver should be evaluated for rare genetic disorders
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Severe Pan‐acinar Steatosis
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Tumors Arising in NAFLD
• Hepatocellular Adenomas– Adenomas, especially the inflammatory variant, occur commonly in obese and diabetic patients
• Focal Nodular Hyperplasia – May be fatty
• Hepatocellular carcinoma – HCC in NASH explants had less aggressive features and longer recurrence free survival compared to HCC in HCV explants
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Hepatocellular Adenoma
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Serum Amyloid A (SAA) Immunostain
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QUESTIONS?
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What causes ballooning• Oxidative damage to cytoskeleton• Intermediate filaments K 8 and 18
Loss of K8/K18 in ballooned cellsLackner, J Hepatol 2008
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Hepatitis C with steatohepatitis
• Steatohepatitis increases the risk of disease progression in hepatitis C
• Reduces efficacy of antiviral therapy• Hepatitis C increases insulin resistance
and exacerbates steatohepatitis
Younossi, Liver Int 2009