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Acute and Chronic Hepatitis:

still important in 2018

John Hart, M.D.

Sections of

Surgical Pathology

& Hepatology

University of

Chicago

Acute Hepatitis

• “Lobular disarray”:

– Ballooned hepatocytes and acidophil bodies

– Individual or confluent hepatocyte dropout

– Zonal, bridging, or panlobular necrosis

– Sinusoidal inflammatory cells

– Prominent Kupffer cells (PAS/D stain)

– +/- cholestasis

• Mild portal inflammation

• No fibrosis

Clinical HistoryCase Courtesy of Dr. John Nixon

OSF St. Francis Hospital, Peoria, IL

• 21 year old male presented with fatigue, anorexia, and abdominal pain

• AST = 1135, ALT = 1196

• Serologic tests for HAV, HBV, and HCV are all negative

• ANA and ASMA titers not elevated

• Serum ceruloplasmin was normal

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Acute hepatitis without distinctive features

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How to sign out this case?• DX: acute hepatitis

• Comment:

– No bridging necrosis

– No underlying chronic liver disease

– No features of autoimmune hepatitis or Wilson

disease

– Drug induced hepatotoxicity is a definite diagnostic

consideration

The patient admitted to taking large doses of Ecstasy (MDMA)

• Drugs and toxins•

•

•

•

• HAV infection

• Acute HCV infection

• Acute HBV infection

• Autoimmune hepatitis

• Exotic infections

DIAGNOSIS BY

SEROLOGIC

TESTING

ACUTE HEPATITIS

Symptoms: non-specific constitutional symptoms; jaundice

Liver chemistry tests: AST & ALT >>> Alk phos and TB

Histologic pattern: lobular disarray with minimal portal changes; no fibrosis

Chronic Hepatitis• Chronic HCV hepatitis

• Chronic HBV hepatitis (+/- HDV infection)

• Chronic autoimmune hepatitis

• Drug induced chronic hepatitis

• Differential diagnosis (mimics):– Wilson disease

– Primary biliary cholangitis (PBC)

– Hepatic involvement by lymphoma

– EBV hepatitis

– Non-specific portal inflammation

– [Acute hepatitis]

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Chronic Hepatitis Generic Histologic Features

• Portal mononuclear cell infiltrates

• +/- interface activity (piecemeal necrosis)

• +/- spotty lobular inflammation

• +/- foci of individual hepatocyte dropout

• +/- scattered acidophil bodies

• +/- portal fibrosis

• Significant lobular disarray suggests a second hepatic insult

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Interface Activity

Grading and Staging Chronic Hepatitis

• Knodell histology activity index

• Scheuer system

• Ishak modified HAI

• French METAVIR system

•Batts and Ludwig system

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Grading and Staging Chronic Hepatitis

• Use for grading HBV, HCV, AIH & drug induced CH

• Grade 0 and Stage 0 are permissible

• Stage is more important than grade to clinicians

• Comparison to previous biopsy is most helpful

• In the Batts/Ludwig: grade by worst component

• In the Batts/Ludwig: portal inflammation is ignored

• HCV should very rarely be graded as 3

• HBV and AIH are often grade 3 at presentation

1 2

3 4

Grade

Grade 1

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Grade 2

0%

10%

20%

30%

40%

50%

60%

5 10 15 20 25 30

HCV

HCV + HIV

Cir

rho

sis

Years of Infection

Sem Liver Dis 2011; 31:331-9

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1 2

3 4

Stage

Very small increment in fibrosis between stages 0 and 1

Stage 4

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Stage 4

Stage 4

Stage 4

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Stage 3

Stage 2-3

Stage 2

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Stage 2

Stage 1

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Staging Errors• Small fragmented biopsy

• Overcall of subcapsular fibrosis

• Overcall of densely inflamed portal tracts

• Overcall of normal portal fibrous extensions

• Overcall of large portal tracts

• Overcall of periportal collapse as fibrosis

Always compare to previous biopsy

Stage ?

Subcapsular

Fibrosis

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Stage ?

Subcapsular

Fibrosis

Stage 0

Subcapsular

Fibrosis

Stage 0

12 of these 1 of these

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Pseudo-periportal fibrosis

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53 y.o. male with endstage renal disease

Chronic HCV Hepatitis - Grade 1, Stage 1

08-25368

Previous liver biopsy in 1997

Chronic HCV hepatitis

Grade 1, Stage 3

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Chronic HCV Hepatitis – Grade 1, Stage 1

Severe chronic autoimmune hepatitis

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Natural History of HCV Infection

100 People

Resolve (15)

15%

Chronic (85)

85%

Cirrhosis (17)Stable (68)

80%

75%

Stable (13)

Mortality (4)

25%

Time

20%

Leading Indication for Liver Transplant

Direct Acting Antivirals

• Drugs that target HCV encoded proteins that

are vital to the replication of the virus

• Oral medications well tolerated by patients

• Extremely effective

• Extremely expensive - each pill is $1,000 (12

week course $80,000)

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The new chronic HCV hepatitis drugs

• HCV protease inhibitors

– Boceprevir (already licensed)

– Telaprevir (already licensed)

– Asunaprevir (Bristol-Myers Squibb)

– Danoprevir (Roche/Genentech)

– Faldaprevir (Boehringer Ingelheim)

– Simeprevir (Janssen/Vertex)

– MK-5172 (Merck)

– ABT-450 (AbbVie, formerly Abbott)

• Nucleotide/nucleoside polymerase

inhibitors– Sofosbuvir (Gilead)

– Mericitabine (Roche)

• Non-nucleoside polymerase

inhibitors– BI 207127 (Boehringer Ingelheim)

– BMS-791325 (Bristol-Myers Squibb)

– ABT-333 (AbbVie)

• HCV NS5A inhibitors– Daclatasvir (Bristol-Myers Squibb)

– Ledipasvir (Gilead)

– ABT-267 (AbbVie)

Au J et al. Clin Pharmacol Ther 2014

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“Recurrent chronic HCV hepatitis (G1, S1)”

Actually post-SVR

“Recurrent chronic HCV hepatitis (G2, S3)”

Actually post-SVR

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HCV-type necroinflammatory activityin liver biopsies by duration post-SVR24

Months Post-SVR Number of Biopsies HCV Activity*

0 - 6 25 20 (80%)

7 - 12 17 16 (94%)

13 - 36 26 16 (62%)

37 - 60 5 3 (60%)

> 60 8 6 (75%)

* HCV activity defined as apparent recurrent chronic HCV with a grade > 0

Chronic HCV Hepatitis• Characteristic histologic features:

– Portal lymphoid aggregates

– Lymphocytic infiltration of bile ducts (~ 5%)

– Macrovesicular steatosis (40%)

– Steatohepatitis (10%)

• Important considerations:– No more than grade 2 necro-inflammatory activity

– Steatosis > 33% or steatohepatitis decreases treatment response rate

– Hemosiderosis may decrease treatment response rate

– Comparison of grade & stage to any previous biopsy most important

Chronic HCV Hepatitis & NASH

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Chronic HCV Hepatitis & NASH

Chronic HCV Hepatitis & NASH

Chronic HBV Hepatitis

• Grade 3 necroinflammatory changes common at presentation

• Ground glass hepatocytes in about 50% of biopsies:– Finely acidophilic cytoplasm with clear peripheral halo

– Proliferation of ER and virion particles

– Usually scattered individually or in small clusters

– Reactive with the HBsAg immunostain

– Simulated by oncocytic change and Cyanimide

• HDV co-infection or superinfection

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HBV Phases of Infection• HBeAg+ chronic infection (immune tolerant state):

– High levels of HBV DNA but normal AST/ALT; high HBsAg

– Occurs often with perinatal infection

– Biopsy shows no or minimal necroinflammatory activity

• HBeAg+ chronic hepatitis (immune active state):

– High levels of HBV DNA and elevated AST/ALT; moderate/high HBsAg

– Biopsy shows significant necroinflammatory active, with fibrosis development

• HBeAg- chronic infection (inactive carrier state):

– Low levels of HBV DNA and normal AST/ALT; HBsAg very low

– Biopsy shows no necroinflammatory activity

• HBeAg- chronic hepatitis:

– Moderate levels of HBV DNA and fluctuating elevated AST/ALT; moderate HBsAg

– Escape mutations resulting in HBV variants

– Biopsy shows significant necroinflammatory activity

Immune active phase

Immune active phase

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Immune active phase

Immune active phase

Immune tolerant phase

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Immune tolerant phase

Autoimmune HepatitisDiagnosis

• Serum hypergammaglobulinemia

• Serum autoantibodies:

– antinuclear antibody (ANA)

– anti-smooth muscle antibody (ASMA)

– anti-liver kidney mitochondrial (LKM) antibody

– anti-soluble liver pancreas antigen (SLA/LP)

• Biopsy evidence of chronic hepatitis with interface activity

Autoimmune HepatitisHistologic Features

• Grade 3-4 necroinflammatory changes common at presentation

• Plasma cells are prominent in most cases (85%)

• Centrilobular necrosis can occur

• Giant cell transformation of hepatocytes in rare cases (not clinically significant)

• Hepatocyte rosettes and emperipolesis (?)

• Eosinophils raise the possibility of a drug trigger

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International Autoimmune Group Revised Criteria for Diagnosis of AIH

• Gender: Score

– Male 0

– Female +2

• Serum biochemistry (AP:AST/ALT)

– > 3.0 -2

– 1.5-3.0 0

– <1.5 +2

• Total serum globulin or IgG

– >2.0 +3

– 1.5-2.0 +2

– 1.0-1.5 +1

– <1.0 0

Alverez F et al. J Hepatology 1999; 31:929-38.

• Autoantibodies Score

– ANA, SMA, or LKM-1

• >1:80 +3

• 1:80 +2

• 1:40 +1

• <1:40 0

– AMA

• Positive -4

• Negative 0

• Viral Hepatitis Markers

– Negative +3

– Positive -3

International Autoimmune Group Revised Criteria for Diagnosis of AIH

• Other etiological factors Score

– History of drug use

• Yes -4

• No +1

– ETOH

• <25 g/day +2

• >60 g/day -2

– Genetics: HLA DR3 or DR4 +1

– Other autoimmune disease +2

– Response to therapy

• Complete +2

• Relapse +3

• Liver histologyScore

– Interface hepatitis +3

– Predominant lympho-

plasmacytic infiltrate +1

– Rosetting of liver cells +1

– None of the above -5

– Biliary changes -3

– Other changes -3

• Seropositivity for other defined autoantibodies+2

Scores: Pre-tx Post-txDefinite AIH: >15 pts >17 ptsProbable AIH: 10-15 pts 12-17 pts

Simplified AIH Diagnostic CriteriaVariable Cutoff Points

ANA or ASMA ≥1:40 1

ANA or ASMA ≥1:80

2*or LKM ≥1:40

or soluble liver antigen Positive

Serum IgG level

>Upper normal limit 1

>1.10 X upper normal limit 2

Liver histology

(evidence of hepatitis is

necessary)

Non-AIH features present 0

Compatible with AIH 1

Typical of AIH 2

≥6 points: probable AIH, ≥7 points: definite AIH (specificity of 95%) *Addition of points achieved for all autoantibodies (maximum, 2 points)

Typical histology: interface hepatitis with lymphocytic/lymphoplasmacyticinfiltrate, rosettes & emperipolesis

Hennes et al, Hepatology 2008;48:169-176

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• 68 y.o. M with persistently elevated liver chemistry tests

• AST & ALT 250 – 400, Alk phos – 325, TB 3.2 – 5.0.

• Serologic tests for HAV, HBV, HCV, ANA negative.

• Atorvastatin (Lipitor) started three months previously.

C07-1718

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Chronic Hepatitis• Chronic HCV hepatitis

• Chronic HBV hepatitis (+/- HDV infection)

• Chronic autoimmune hepatitis

• Drug induced chronic hepatitis

• Differential diagnosis:

– Wilson disease

– Primary biliary cholangitis (PBC)

– Hepatic involvement by lymphoma

– EBV hepatitis

– Non-specific portal inflammation

– [Acute hepatitis]

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Wilson Disease – “Chronic Hepatitis”

Chronic Hepatitis

versus

Wilson Disease

• Clinical features:

– Hemolytic anemia

– Fulminant presentation but cirrhosis by biopsy

• Histologic features:

– Periportal Mallory-Denk bodies

– Copper deposition

– ??? Glycogenated hepatocyte nuclei

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52 year old female with PBCCholestatic pattern of LCT elevation

Patchy quality of the portal inflammation

Lymphocytic cholangitis

Poorly formed granuloma

Clinical History

• 18 year old male with a 1 day history of jaundice

• Recently returned from a ski trip and developed fevers (103°F), chills, purulent nasal discharge, sore throat, nausea.

• Approx. 4.5g acetaminophen + several doses of ibuprofen during the 3 days prior to presentation

• 2 days of RUQ abd pain and acute onset of jaundice and very dark urine

• No meds (protein supplement); no travel outside U.S.

• Physical examination - hepatosplenomegaly

09-5444

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Laboratory Evaluation

• TB = 22.4, DB = 16.5

• AST = 236, ALT = 160, Alk phos = 181

• Acetaminophen = 11.7 mcg/mL

• PT = 15.7 INR = 1.3 PTT = 44.0

• Serologic tests for HAV, HBV, HCV all negative

• ANA = 1:80; anti-SMA = 1:25

• Serum ceruloplasmin is normal

09-5444

CT

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EBER

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• 71 y.o. F presented with jaundice, weight loss and confusion

• TB = 4.2, AST = 110, ALT = 144, alk phos = 333

• HAV, HBV and HCV negative

• ANA = 1:640

• Liver biopsy performed to confirm autoimmune hepatitis

• No response to steroids

• Patient transferred to University of Chicago

Clinical HistoryC09-26718

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Additional information

• Work-up reveals disseminated B-cell lymphoma

• Patient expired 2 days later

Non-specific Portal Inflammation

• Occult intermittent biliary tract disease

• Celiac disease

• Prior (burned-out) HCV or HBV hepatitis

• Autoimmune diseases (?)

• Prior drug exposure (??)

• Unknown viruses (???)

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Extrahepatic biliary obstruction

Case 11: Clinical History

• 34 y.o. F with abdominal pain, fatigue, and nausea & vomiting

• Physical exam – mild scleral icterus

• Travel to India for four weeks (mid Jan to mid-Feb)

• No medications except herbal remedy in India

S10-6043

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Laboratory Evaluation

• Serologic tests for HAV, HBV and HCV negative

• ANA = 1:160, anti-SMA & anti-dsDNA negative

• Ceruloplasmin = 30

• Urine toxicology screen negative

• EBV, CMV, HSV, HHV-6, Leptospira all negative

• TB = 11.0, AST = 4660, ALT = 4756, Alk phos = 192

S10-6043

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Serum HEV IgM positive

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0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

20-Mar 21-Mar 22-Mar 23-Mar 24-Mar 25-Mar

0

2

4

6

8

10

12

AST

ALT

TB

• Most outbreaks associated withfecally contaminated drinking water

• Minimal person-to-person transmission

• U.S. cases (6% seroprevalence):

– History of travel to HEV endemic areas

– Occupational contact with farm animals

– Sporadic exposure

Hepatitis EEpidemiologic Features

Ditah I et al. Hepatology 2014; 60:815-22.

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Acute Hepatitis Normal Liver Chronic Hepatitis

Summary

Chronic hepatitis:

- Diagnosis used for chronic HBV, HCV, AIH (& drug)

- Use a grading/staging scheme (Batts/Ludwig)

- Don’t forget grade 0 and stage 0

- Compare to previous biopsy if available

- Mention steatohepatitis if present

Mimics:

- Primary biliary cholangitis – cholestatic pattern of LCTs

Biopsy Adequacy in Chronic Hepatitis

How big does the biopsy have to be

for accurate grading and staging?

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Crawford AR et al. Hepatology 1998.

14 gauge needle

Conclusion: Biopsies for HCV must be -2.0 cm long and 1.4 mm wide

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1.4 mm Diameter Bx > 3 cm long 1.5 cm long 1.0 cm long

# of Portal Tracts

Complete 22.4 +/- 4.9 10.3 +/- 2.2 6.4 +/- 1.2

Incomplete 0.8 +/- 1.1 0.4 +/- 0.8 0.3 +/- 0.6

Grade

Mild 49.7 % 60.2 % 86.6 %

Moderate 38.5 % 39.1 % 17.4 %

Severe 11.8 % 0.60 % 0.00 %

Stage

One 59.0 % 68.3 % 80.1 %

Two 29.8 % 24.2 % 14.9 %

Three 11.2 % 7.4 % 4.9 %

Colloredo G et al. J Hepatol 2003; 39:239-44.

Klatskin 16 gauge needle

Menghini 20 gauge needle

Transjugular 20 gauge needle

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0.4 mm 0.5 mm 1.3 mm