chronic viral hepatitis - part 1 - kuwait

Neil D. Theise, MD

Depts. of Pathology and Medicine (Digestive Diseases)

Beth Israel Medical Center – Albert Einstein College of Medicine

New York City

www.neiltheise.com

Chronic Viral Hepatitis

Neil D. Theise, MD

Depts. of Pathology and Medicine (Digestive Diseases)

Beth Israel Medical Center – Albert Einstein College of Medicine

New York City

SLIDESHARE.NET

www.neiltheise.com

See: “Chronic Viral Hepatitis: A Personal, Practical Guide”

Chronic Viral Hepatitis

http://www.neiltheise.com/

The Viruses

Clinical Aspects

Role of Liver Biopsy, part 1

Histologic/Immunostaining features

ACUTE

HAV

HEV

ACUTE

HAV

HEV

Incidence in Kuwait: 13/100,000

Incidence in Kuwait: 1.4/100,000

RATE OF SPORADIC ENTERICALLY TRANSMITTED VIRAL HEPATITIS IN KUWAIT BETWEEN 1998 AND 2001AQ Al-Anezi, R Al-Awayesh, F Al-Ali, KM PeltekianKuwait Health Sciences Centre, Kuwait City, Kuwait & Division of Gastroenterology, Dalhousie University, Halifax, Nova Scotia

CHRONIC

C O N S O N A N T SHRONIC

HBVHCVHDV


HBVHCVHDV

Prevalence: 4.6%

Prevalence of Hepatitis B and C infection in patients admitted at Tertiary Eye Care Centre: A hospital based study. Junejo SA, Khan NA, Lodhi AA. Pak J Med Sci 2009;25(4):597-600.

Prevalence: 13%


HBVHCVHDV

Prevalence of Hepatitis B and C infection in patients admitted at Tertiary Eye Care Centre: A hospital based study. Junejo SA, Khan NA, Lodhi AA. Pak J Med Sci 2009;25(4):597-600.

Prevalence of co-infection: 3.9%


HBVHCVHDV

Hepatitis delta virus infection in acute hepatitis in Kuwait.Al-Kandari S, Nordenfelt E, Al-Nakib B, Hansson BG, Ljunggren K, Al-Nakib Scand J Infect Dis. 1988;20(1):15-9.

Prevalence: 4% in acute HBV31% in chronic HBV


The Viruses

Clinical Aspects

Role of Liver Biopsy, Part 1


Prevalence of HCV Antibody NHANES III

Adapted from Alter MJ, et al.,. N Engl J Med. 1999;341:556–562.

0

500,000

1,000,000

1,500,000

2,000,000

Pre

vale

nce

6-11 12-19 20-29 30-39 40-49 50-59 60-69 70-79 80+

Age distribution

90s 00s

Natural History of Hepatitis C

Acute Hepatitis C

Chronic Hepatitis 75%-85 %

Cirrhosis 20 %

10-20+ years

- Hoofnagle JH, Hepatology. 1997 - Di Bisceglie A, Hepatology, 2000

Decompensation,Decompensation,6%6%

HCC,HCC,4%4%

Death or Tx, 4%Death or Tx, 4%

Annual rate

- Hoofnagle JH, Hepatology. 1997 - Di Bisceglie A, Hepatology, 2000

Natural History of Hepatitis C

Cirrhosis, 20 %Cirrhosis, 20 %

Liver Fibrosis in Chronic Hepatitis C

Intermediate progressors

Slow progressors

Poynard et al, Hepatology 1999

n=1157n=1157

0

1

2

3

4

0 10 20 30 40 50

Years

F M

etav

ir

Rapid progressors

Factors Associated with Disease Progression

• Alcohol consumptionAlcohol consumption– 30 g/day in men30 g/day in men– 20 g/day in women20 g/day in women

• Disease acquisition at >40 yearsDisease acquisition at >40 years• Male genderMale gender• HIV co-infection HIV co-infection (treated vs. untreated)(treated vs. untreated)• Fatty liverFatty liver• Hepatitis B virus co-infectionHepatitis B virus co-infection• ImmunosuppressionImmunosuppression

NIH Consensus Development Conference Statement. 2002.Poynard et al. Lancet. 1997;349:825-832.

~ 2 drinks per day

Chronic hepatitis

with fibrosis10-50 years

Natural History of Chronic Liver Disease

Cirrhosis

Normal liver

HepatocellularCarcnoma

The Viruses

Clinical Aspects



Role of Liver Biopsy

Confirm clinical Confirm clinical diagnosisdiagnosis


Role of Liver Biopsy



Grade Grade necroinflammationnecroinflammation

Grade Grade necroinflammationnecroinflammation

StageStagefibrosisfibrosisStageStage

fibrosisfibrosis

The Normal LiverLobule:

The Limiting Plate

Portal inflammationDEFINES

Chronic Hepatitis

“Piecemeal Necrosis” or, better,

“Interface Hepatitis”

Chronic PersistentHepatitis

Chronic ActiveHepatitis

Chronic LobularHepatitis

RecoveryDeath/Transplant

Chronic Hepatitis

CPH CAH CLH


Chronic Hepatitis

CPH CAH CLH

CirrhosisProgression

Unlikely

Gnomes’ clinical problems:• Chronic hepatitis B• Autoimmune hepatitis


1968



Contemporary clinical problems:• Chronic hepatitis C• Mixed viral infections

Contemporary clinical problems:• Chronic hepatitis C• Mixed viral infections

1968

1990’s


Chronic Hepatitis

CPH CAH CLH

CirrhosisProgression

Unlikely


Chronic Hepatitis

STAGINGOf

Progression

GRADINGOf

Activity

GRADINGOf

Activity

• Portal inflammation• Interface hepatitis• Lobular hepatitis• Confluent necrosis

ConfluentNecrosis

Bridging confluent necrosis

Confluent necrosis, think about: - HBeAg to Ab conversion - HDV super-infection on HBV - HCV acute exacerbation - HIV co-infection - Autoimmune hepatitis - Drug induced injury, as always

LIVER: NEEDLE BIOPSY - Chronic hepatitis, ………. active with……. (stage …/4), compatible with hepatitis C.

Comment:A. Interface hepatitis: Absent (0/4).A. Interface hepatitis: Focal, few portal areas (1/4).A. Interface hepatitis: Focal, most portal areas, >5-50% (2/4).A. Interface hepatitis: Continuous around <50% of tracts/septa (3/4).A. Interface hepatitis: Continuous around >50% of tracts/septa (4/4).

B. Confluent necrosis: Absent (0/6).B. Confluent necrosis: Focal (1/6).B. Confluent necrosis: Zone 3 necrosis in some areas (2/6).B. Confluent necrosis: Zone 3 necrosis in most areas (3/6).B. Confluent necrosis: Occasional portal-central bridging necrosis (4/6).B. Confluent necrosis: Frequent portal-central bridging necrosis (5/6).B. Confluent necrosis: Panacinar or multiacinar collapse (6/6).

C. Lobular necrosis or inflammation: Absent (0/4)C. Lobular necrosis or inflammation: < 1 focus per acinus (1/4)C. Lobular necrosis or inflammation: 2-4 foci per acinus or nodule (2/4).C. Lobular necrosis or inflammation: 5-10 foci per acinus or nodule (3/4).C. Lobular necrosis or inflammation: >10 foci per acinus nodule (4/4).

D. Portal inflammation: None (0/4).D. Portal inflammation: Mild, some or all portal tracats (1/4).D. Portal inflammation: Moderate, some or all portal areas (2/4).D. Portal inflammation: Marked, not all portal areas (3/4).D. Portal inflammation: Marked, all portal areas (4/4).

E. Staging: No fibrosis (0/4).E. Staging: Fibrous portal enlargement (1/4).E. Staging: Fibrous septa (2/4).E. Staging: Transition to cirrhosis (3/4).E. Staging: Cirrhosis (4/4).

No fibrosis0

Fibrous expansion of some portal areas, with or without short fibrous septa

1Fibrous expansion of most portal areas, with or without

short fibrous septa 2Fibrous expansion of most portal areas, with occasionalportal to portal bridging

3Fibrous expansion of portal areas with marked bridging

portal-portal and/or portal-central 4Marked bridging (portal-portal and/or portal-central)

with occasional nodules (incomplete cirrhosis) 5Cirrhosis, probable or definite

6

So what do I do…?







MildModerateSevere

STAGING

No fibrosis0







6

No fibrosis 0

Fibrous expansion of some portal areas, with or without short fibrous septa 1

Fibrous expansion of most portal areas, with or without short fibrous septa 2

Fibrous expansion of most portal areas, with occasionalportal to portal bridging 3

Fibrous expansion of portal areas with marked bridging, portal-portal and/or portal-central 4

Marked bridging (portal-portal and/or portal-central)with occasional nodules (incomplete cirrhosis) 5

Cirrhosis, probable or definite 6

Ishak et al. staging scheme

No fibrosis0







6

No fibrosis 0

Portal fibrosis 1

Focal Septa 2

Frequent septa 3


METAVIR staging

No fibrosis 0

Portal fibrosis 1

Focal Septa 2

Frequent septa 3

?Cirrhosis, probable or definite 4

METAVIR staging

?

No fibrosis0







6

So what do I do…?

No fibrosis 0

Focal portal fibrosis, w or w/o short fibrous septa 1

Widespread portal fibrosis, w or w/o short fibrous septa 2

Focal portal-portal septa 3

Frequent septa (portal-central and/or portal portal) 4

Marked septa with occasional nodules 5


No fibrosis 0

Portal fibrosis 1

Focal Septa 2

Transition to cirrhosis 3


Theise modification of Ishak staging

?

Ishak et al. staging scheme

Stages of Fibrosis

Ishak

5 61 2focal frequent

1 2 3 4

PortalFibosis

FibrousSepta

Transitionto Cirrhosis

Cirrhosis

1 42 3focal frequent

Metavir

Theise ND. Human Pathology 2007

Modified Ishak Batts-Ludwig

3 4focal frequent

How much tissue is enough?How much tissue is enough?

How much tissue is enough?1.8 cm? 2.2 cm? 2.5 cm?



How much is too little???


How much is too little???

Case 1A

34 year old woman

Hepatitis C positive; biopsy for staging and grading.

Case 1A, 4x, H&E

Case 1A, 4x, Trichrome

Case 1A, 10x, Trichrome

For example:

LIVER: NEEDLE BIOPSY - Chronic hepatitis, mildly active with transition to cirrhosis (modified Ishak stage 3/4), compatible with hepatitis C.

For example:


Comment: There is a mild to moderate portal/septal mononuclear infiltrate associated with widespread interface hepatitis and focal lobular hepatitis.

For example:


Comment: There is a mild to moderate portal/septal mononuclear infiltrate associated with widespread interface hepatitis and focal lobular hepatitis. There is no confluent necrosis.

For example:

LIVER: NEEDLE BIOPSY - Chronic hepatitis, moderately active with transition to cirrhosis (modified Ishak stage 3/4), compatible with hepatitis C.

Comment: There is a mild to moderate portal/septal mononuclear infiltrate associated with widespread interface hepatitis and focal lobular hepatitis. There is no confluent necrosis. Trichrome and reticulin stains highlight focal fibrous septa, and focal nodularity Indicative of cirrhosis.

For example:


Comment: There is a mild to moderate portal/septal mononuclear infiltrate associated with widespread interface hepatitis and focal lobular hepatitis. There is no confluent necrosis. Trichrome and reticulin stains highlight focal fibrous septa, and focal nodularity Indicative of cirrhosis. There is focal steatosis in a pattern typical of that seen with chronic hepatitis C.

For example:


Comment: There is a mild to moderate portal/septal mononuclear infiltrate associated with widespread interface hepatitis and focal lobular hepatitis. There is no confluent necrosis. Trichrome and reticulin stains highlight focal fibrous septa, and focal nodularity Indicative of cirrhosis. There is focal steatosis in a pattern typical of that seen with chronic hepatitis C.

No significant hemosiderosis or alpha-1-antitrypsin globules are identified (iron, PAS-D stains).

Case 1B

47 year old man

Hepatitis C positive; ultrasound guided biopsy of left lobe, for staging and grading.

Case 1B, 2x, H&E

GLISSON’SCAPSULE

Case 1B, 4x, H&E

SUBCAPSULAR ZONE

Case 1B, 2x, H&E

LIVER: NEEDLE BIOPSY - Chronic hepatitis, mildly active with portal fibrosis

(modified Ishak stage 1/4), compatible with hepatitis C.

The Viruses

Clinical Aspects



HBV: Ground glass hepatocytes

HBV: Ground glass cells (surface antigen inclusions)

Immunostain: HBV Surface Antigen

HCV: lymphoid aggregates

Plasma cells in Autoimmune Hepatitis

Mixed Viral Infections

HBV + ?

= utility of immunostains

for HBV core Ag

Immunostain for HBcAG:Confirms active viral replication

Another example:

LIVER: NEEDLE BIOPSY - Chronic hepatitis B, mildly active with transition to cirrhosis (stage 3/4).

Comment: ….Ground glass hepatocytes (or immunostains for HBV surfaceantigen) confirm chronic hepatitis B virus infection. Immunostain for core antigen confirms hepatitis B viral replication….

No HBcAgSuspect:

HBV DNA neg., Spontaneously resolved or treated infection

orsampling

orCo-infection with HCV,HDV

Diffuse HBcAg

Suspect:Immunosuppression,

in particular: HBV + HIV!!!

HCV + HIV?

Increased ActivityDecreased Activity

Increase rate of progressionDecreased rate of progression

HCV + HIV?

On HAART: In large cohorts,

possibly more aggressive, but individual biopsies look the same

as HCV alone.

Beware: drug toxicity

HCV + HIV?

Untreated:Often more severe activity.

Often more advanced disease.

HCV + HIV?



Rare: fibrosing cholestatic hepatitis

HCV + HIV?



Rare: fibrosing cholestatic hepatitis

Beware: Infiltrating neoplasms, granulomas, HSV, CMV, biliary tract disease, etc.

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chronic viral hepatitis - part 1 - kuwait

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