Aryabhata

Liver biopsy with minimal histological changes Solving a crossword with cryptic clues Sanjay Kakar, MD UCSF

Two interpretations • Nothing • Number ‘zero’ • 000,000,000 • 1,000,000,000 • $ 1,000,000,000

• What is the contribution of Aryabhata to mathematics? • ZERO

Liver biopsy: minimal changes • Nothing 000,000,000 • Proper clinical context 1,000,000,000 • Subtle histologic findings ($) $1,000,000,000

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Liver biopsy: mild or nonspecific histological changes • Viral serologies negative • Classic features are absent Autoimmune hepatitis Steatohepatitis PBC/PSC

Case 1

Hepatitic diseases

Metabolic disorders

Resolving hepatitis Nonspecific reactive hepatitis Viral hepatitis Adverse drug reaction Autoimmune diseases -Connective tissue diseases -Celiac disease

Glycogenic hepatopathy Hypervitaminosis A Wilson disease Alpha-1-antitrysin deficiency

Biliary diseases Primary biliary cirrhosis Primary sclerosing cholangitis Mast cell disorders Vanishing bile duct syndrome

Vascular disorders Idiopathic portal hypertension Venous outflow obstruction Nodular regenerative hyperplasia

Other Amyloidosis Diabetic hepatosclerosis

Mild portal inflammation

• • • • •

40/M with mild abdominal pain Atorvastatin (Lipitor) for hyperlipidemia ALT 400 IU/L, AST 390 IU/L Alk Phos normal Viral markers, ANA, SMA, AMA negative • Two months later, ALT and AST 150 IU/L

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Prominent macrophages

Macrophages along the sinusoids PASD+

Fig 7.3

Macrophage collection: ‘microgranuloma’

Morphological features • Mild portal and/or lobular inflammation • Mild hepatocellular damage • Microgranulomas • PASD+ macrophages

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Differential diagnosis Resolving hepatitis • • • •

Hepatitis C Adverse drug reaction Autoimmune hepatitis Wilson disease

Nonspecific reactive hepatitis Portal tracts • Lymphocytes, few eos, plasma cells • Normal bile ducts, mild ductular reaction can be present

Lobule • Mild inflammation • Focal necrosis • Macrophages

Nonspecific reactive hepatitis • • • •

Febrile illness Inflammation in the abdomen Systemic autoimmune disorders Adjacent to tumors

Case 1 diagnosis • Hepatitis C was negative • No systemic illness • Lipitor Diagnosis: Resolving hepatitis, most likely due to adverse drug reaction

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Mild portal inflammation

Case 2 • • • •

35/F with history of SLE ALT and AST 200 IU/L ANA and SMA positive Biopsy done to rule out autoimmune hepatitis

Lymphocytes, rare plasma cells

Mild lobular inflammation

Fig 9.1

Fig 9.2

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Is this AIH? • Mild hepatitis can occur in autoimmune diseases • ANA and SMA present in SLE • AIH and SLE rare • Both treated with steroids Cirrhosis and liver failure in AIH Survival 10% at 10 years

Case 2 diagnosis Additional information • Anti dsDNA + • ALT and AST levels 200 U/L • Biopsy: mild inflammation minimal periportal activity Diagnosis: Mild portal and lobular hepatitis, most consistent with lupus-related hepatitis

Lupus-related hepatitis vs. AIH Lupus-related hepatitis

Serology SMA dsDNA Ribosomal P

Histology Inflammation Plasma cells Necrosis Cirrhosis

Autoimmune hepatitis

.

.

+ (30%) + Often + (40%)

+ (60-80%) Uncommon Negative

. Mild Not periportal Not prominent Absent Rare

. Moderate/marked Periportal Prominent Often prominent Common

Other autoimmune disorders • RA, Sjogren syndrome • Celiac disease Asymptomatic elevation: ALT, AST Nonspecific reactive hepatitis Acute/chronic hepatitis Cirrhosis Association with PBC

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Hepatitic diseases

Metabolic disorders

Resolving hepatitis Nonspecific reactive hepatitis Viral hepatitis Adverse drug reaction Autoimmune diseases -Connective tissue diseases -Celiac disease

Glycogenic hepatopathy Hypervitaminosis A Wilson disease Alpha-1-antitrysin deficiency

Biliary diseases Primary biliary cirrhosis Primary sclerosing cholangitis Mast cell disorders Vanishing bile duct syndrome

Vascular disorders Idiopathic portal hypertension Venous outflow obstruction Nodular regenerative hyperplasia

Case 3 • 42/F asymptomatic with elevated ALP on pre-employment screening • ALT and AST normal • Antimitochondrial antibodies (AMA) positive

Other Amyloidosis Diabetic hepatosclerosis

Mild lobular inflammation

Portal inflammation, no bile duct injury

Fig 8.1

Fig 8.2

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PBC: bile duct damage, florid duct lesion

Is this primary biliary cirrhosis? • Significance of histologic findings • Specificity of positive AMA

Two common errors • Portal inflammation is not equivalent to chronic hepatitis • Lobular inflammation does not necessarily indicate hepatitic disease

Diagnostic dilemma Is this primary biliary cirrhosis? • Significance of histological findings The findings are nonspecific • Specificity of positive AMA

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Specificity of AMA • High specificity for PBC Autoimmune hepatitis Infections like TB • ELISA-based assay more specific

Diagnosis • Diagnosis: • Positive AMA: asymptomatic, normal ALP • Bx: Classic 12/29, consistent 12/29, N=2 • Most progressed to symptomatic PBC 50% at 5 years, 95% at 20 years

Mild portal and lobular inflammation, cannot rule out early PBC

Note: • Patchy bile duct involvement in early PBC, can be missed on biopsy • Majority of AMA+ develop features typical of PBC on follow-up

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45M, HIV positive

“Report: Nonspecific changes”

Few months later

Vanishing bile duct syndrome Category Drugs Biliary diseases Infections Systemic Unknown

Specific etiologies Antibiotics, anticonvulsants, neuroleptics PBC, sclerosing cholangitis HIV, CMV Sarcoidosis, Hodgkin lymphoma, ischemic injury Idiopathic adulthood ductopenia

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Hepatitic diseases

Metabolic disorders

Resolving hepatitis Nonspecific reactive hepatitis Viral hepatitis Adverse drug reaction Autoimmune diseases -Connective tissue diseases -Celiac disease

Glycogenic hepatopathy Alpha-1-antitrysin deficiency Hypervitaminosis A Wilson disease

Biliary diseases Primary biliary cirrhosis Primary sclerosing cholangitis Mast cell disorders Vanishing bile duct syndrome

Vascular disorders Idiopathic portal hypertension Venous outflow obstruction Nodular regenerative hyperplasia

Other Amyloidosis Diabetic hepatosclerosis

Glycogenic hepatopathy • • • •

Glycogenic hepatopathy

Type 1 diabetes Elevated transaminases Hepatomegaly Glycogen storage disease More swelling, fibrosis Clinical setting

Torbenson/Chen/Ferrell, AJSP,2003

Glycogen inclusions (‘pseudo ground glass’) -HBsAg neg -Immunosuppressive -Cyanamide -Glycogen storage IV -Lafora disease -Hypo(a)fibrinogenemia

Wisell, AJSP, 2006; Bejarano, Virchow Arch, 2006

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Alpha-1-antrypsin deficiency

A1AT deficiency Homozygous Heterozygous

Homozygous state (PiZZ) • Low serum levels • Chronic hepatitis and cirrhosis • PAS-D positive globules Heterozygous state (PiMZ) • Globules: fewer, smaller • ? role in liver disease

Alpha-1-antirypsin deficiency

Alpha-1-antitrypsin deficiency

Pitfalls in diagnosis • Serum levels unreliable • Cytoplasmic globules can be subtle on HE stain • Presence of globules is not specific for diagnosis

• PAS-D stain in all cases of unexplained liver disease • Immunohistochemistry: peripheral accentuation

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A1AT immunohistochemistry

Alpha-1-antitrypsin deficiency Pitfalls in diagnosis • Serum levels unreliable • Cytoplasmic globules can be subtle on HE stain

• Presence of globules is not specific for diagnosis -Nonspecific in setting of acute illness -Fibrinogen deficiency -Alpha-1-antitrypsin deficiency -Giant mitochondria

Giant mitochondria

Wilson disease • Acute hepatitis, acute liver failure chronic hepatitis, cirrhosis • Steatosis, glycogenated nuclei • Portal inflammation • Serum ceruloplasmin, urinary copper, quantitative copper from the block

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Portal inflammation, ?steatosis

Case 4 • 30/M with headache and muscle soreness • Health enthusiast on several multivitamins for many years • Persistent increase in ALT and AST 100-150 IU/L

Vacuolated cells along sinusoids

Ito cell (stellate cell) lipidosis

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Ito cell lipidosis • Normal liver: Ito cells store lipid • Ito cell lipidosis: excessive lipid Hypervitaminosis A -increased intake -retinoid drugs: etretinate Other conditions: cholestasis, alcohol, steroids, methotrexate

Case 4 diagnosis • History of vitamin A intake • Morphological features • Diagnosis: Ito cell lipidosis related to hypervitaminosis A

Hypervitaminosis A • • • •

Perivenular fibrosis Portal hypertension Chronic hepatitis Cirrhosis

Hepatitic diseases

Metabolic disorders Glycogenic hepatopathy Alpha-1-antitrysin deficiency Hypervitaminosis A Wilson disease

Resolving hepatitis Nonspecific reactive hepatitis Viral hepatitis Adverse drug reaction Autoimmune diseases Vascular disorders Venous outflow obstruction -Connective tissue Idiopathic portal hypertension diseases -Celiac disease Nodular regenerative

Biliary diseases Primary biliary cirrhosis Primary sclerosing cholangitis

hyperplasia

Other Amyloidosis Diabetic hepatosclerosis

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Sinusoidal dilatation and congestion

Case 5 • 40/F with abdominal pain and jaundice • Mild hepatomegaly and ascites • ALT 120 IU/L, AST 125 IU/L • ALP 610 IU/L • ANA,SMA,AMA: negative • Imaging: normal bile ducts

RBC extravasation into the space of Disse

Sinusoidal dilatation and congestion Venous outflow obstruction • Budd-Chiari syndrome • Heart disease Right heart failure Constrictive pericarditis • Veno-occlusive disease (sinusoidal obstruction syndrome)

Fig 10.2

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Diagnostic pitfalls Sinusoidal dilatation: is it real? • Mechanical artifact • Cirrhosis, adjacent to tumor • Transplant biopsies • Intraoperative biopsies

Sinusoidal dilatation: other causes Venous outflow obstruction 60-70% Other causes • Portal vein thrombosis • Inflammatory/granulomatous RA, Castleman disease • Malignant neoplasms Renal cell carcinoma, lymphoma

Ductular reaction

Case 5 diagnosis • Venogram showed hepatic vein thrombosis • Diagnosis: Venous outflow obstruction due to Budd-Chiari syndrome

Fig 10.4

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Suspicion of biliary disease • Ductular reaction • Lymphocytic infiltration of bile duct • Bile ducts normal on imaging • Possibly due to ischemic injury

Do not necessarily indicate biliary disease

Case 6 • 60/F with long history of rheumatoid arthritis • Sudden onset of hematemesis • Splenomegaly • Endoscopy: esophageal varices • Ultrasound: cirrhosis

Biopsy • Normal portal tracts • Hepatocellular damage: none • No inflammation • No fibrosis

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Nodular architecture: reticulin

Nodular regenerative hyperplasia Wanless criteria • Hepatocellular nodules, generally