12. Smith Hepatitis Vietnam Sept 2012

Harvard Medical SchoolNonalcoholic Steatohepatitis NASH • A common cause of abnormal transaminase levels • Growing number of Vietnamese have nonalcoholic fatty liver • 50% of patients in

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Hepatitis for the General

Doctor: Diagnosis, Management and Prevention

C Christopher Smith, MD, FACP

Associate Professor of Medicine,

Harvard Medical School

Beth Israel Deaconess Medical Center

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Disclosure of Financial Relationships

C Christopher Smith, M.D.

Has no relationship with any entity producing,

marketing, reselling or distributing health care goods

or services consumed by, or used on patients.

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Case

A 67-year-old man just moved to your city and presents as a new patient He has no complaints His history is significant for type II diabetes (controlled with diet; last HgbA1c 6.9%)

He has never had more than one beer a day On

examination he is afebrile and is otherwise only remarkable for a BMI of 33

Laboratory studies of note include

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In addition to weight loss, which of the

following is the most appropriate next

step in managing this patient’s abnormal liver studies?

Audience Question

a Initiate insulin sensitizing medication (e.g., metoformin

or pioglitazone) and repeat liver studies in six months

b Refer for a liver biopsy

c Counsel patient on his alcohol consumption

d Send serum ceruloplasmin levels

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In addition to weight loss, which of the

following is the most appropriate next

step in managing this patient’s abnormal liver studies?

Audience Question

a Initiate insulin sensitizing medication (e.g., metoformin

or pioglitazone) and repeat liver studies in six months

b Refer for a liver biopsy

c Counsel patient on his alcohol consumption

d Send serum ceruloplasmin levels

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Case Highlights

 67-year-old obese patient with type II diabetes

 AST:ALT ratio > 1

 Limited alcohol intake

 Ultrasound with steatosis

 Reasonable evaluation of common causes of

liver abnormalities is unrevealing

 What is the best next step in management?

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First, make the diagnosis

 Differential Diagnosis includes:

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Alcohol Abuse

• AST:ALT greater than 2

–> 90% of patients with this ratio have alcoholic liver disease

–> 96% when ratio > 3:1

• Both less than 300 IU/L

• Ɣ-glutamyltransferase

–Twice the ULN strongly support the diagnosis

–Poorly specific so should not be used as a single

test

Cohen, Dig Dis Sci 1979

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Wilson’s Disease

• Rare genetic disorder of reduced biliary copper excretion and increased deposition

–Cognitive changes; hemolytic anemia, cardiomyopathy

• Rare in patients over the age 40

• Decreased ceruloplasmin levels (screening test)

–Reduced in 85% of affected patients

• Ophthalmologic examination for Kayser-Fleischer rings

• AST/ALT: mild elevation to fulminant hepatic failures

• 24 urine for quantitative copper excretion

• Frequently have low alkaline phosphate

• Low serum uric acid

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Causes of abnormal ALT/AST with normal liver biopsy

 Muscle

• Exercise induced or Metabolic Disorder

• Both ALT and AST can be elevated

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Nonalcoholic Steatohepatitis (NASH)

• A common cause of abnormal transaminase levels

• Growing number of Vietnamese have nonalcoholic fatty liver

• 50% of patients in Viet Nam over 40 years have NAFLD

–5% will develop nonalcoholic steatohepatitis

–8-26% of pts with NASH will develop cirrhosis

–Leading cause of cryptogenic cirrhosis

 No clinical or laboratory feature can predict progression

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Nonalcoholic Steatohepatitis (NASH)

• Diagnosis of NASH is one of exclusion

• Most patients are asymptomatic

• AST/ALT ratio less than 1

–If ratio reverses, worrisome for development of cirrhosis

–Normal serum aminotransferases do not exclude presence of advanced liver disease

• Liver ultrasound is highly sensitive for steatosis but not

specific for cause of steatosis or presence fibrosis or more advanced liver disease

• No distinguishing historical or laboratory features to

differentiate from other causes of chronic liver disease

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Nonalcoholic Steatohepatitis (NASH)

• Liver biopsy is only way to confirm NASH

–However, high risk to benefit ratio for biopsy as most

patients do not progress and frequently does not change management

–Consider biopsy if suspect NASH and one of the following:

•Laboratory or PE findings of chronic liver disease

•Unexplained findings (i.e., elevation of ANA or iron

studies)

•Other RF: Age > 45, Obesity, AST: ALT > 1, Type II DM

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Nonalcoholic Steatohepatitis (NASH)

 Treatment is directed at risk factor modification

 Weight loss, lipid control, diabetes control

 Insulin sensitizing drugs: pioglitazone or

metformin

• Limited data

Belfort, NEJM 2006

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A patient presents to your clinic…

A 34 year old female presents to your clinic to establish

care with her new PCP She has no complaints or

significant past medical history, but reports some family

members with ―liver problems.‖

She was born and raised in Viet Nam, and works in

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Questions

 How did she acquire HBV?

 Is she at risk for transmission to others?

 Does how and when she acquired HBV alter outcomes?

 How does HBV compare and contrast to HCV?

 What is the difference between HBV carrier and HBV

(chronic) infection and why does it matter?

 What other studies should be performed?

 Should her HBV be treated? If so, with which medicine(s)?

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Hepatitis B Worldwide

 HBV accounts for over a million deaths annually

• 2 billion with past/present infection

• 350 million actively infected worldwide (5% of world population)

• Leading cause of chronic hepatitis, cirrhosis and hepatocellular

carcinoma (15-40%)

 Hepatocellular carcinoma has increased worldwide, killing 300,000 to 500,000 each year

 Prevalence varies by region

• Greatest in Southeast Asia, China, Africa and Alaska

• More than half the population infected at some point

Maynard, Vaccine, 1990

www.cdc.gov

www.who.org

Prevalence of Chronic Hepatitis B

CDC Travelers’ Health: Yellow Book, 2008

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Hepatitis B Prevalence in Viet Nam

• General population: 10-20%

• Healthcare workers: 8-18%

• HIV-positive persons: 10-15%

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High Risk Groups for HBV

Injection drug use

Healthcare and public safety

workers

Hemodialysis patients

History of STD

Men who have sex with men

Sex contacts of infected

persons or multiple sex

partners

Infants born to infected mothers

Children of immigrants from endemic country

Household contact of chronically infected persons

CDC Hepatitis B Fact Sheet, 2004

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Age and Mode of Acquisition

 Development of chronic

infection varies by mode

and age of transmission

Neonate Infant Adult

Stevens, NEJM, 1975 Beasley, J Infect Dis 1983 Tassopoulos, Gastro, 1987

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Outcomes of Acute Hepatitis B

Acute Hepatitis

Recovery

Fulminant Hepatitis

Chronic Infection Subclinical

Ostapowicz, Ann Intern Med, 2002

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Outcomes of Chronic Hepatitis B

Chronic HBV

Inactive Carrier(nonreplicative)

Chronic Hepatitis(replicative)

Cirrhosis

Hepatocellular Carcinoma

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HBV vs HCV

 Much more contagious and easily spread than HCV

• 1,000,000 HBV virons for every HCV viron

• Present in all bodily secretions except for feces

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Sievert, Liver Intl, 2011

Epidemiology of HCV Infection

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Hepatitis C Prevalence in Viet Nam

• Injection-drug users: 60-90%

• Hemodialysis patients: 54%

• General population: 1-5%

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HCV Course

• Rarely fulminant and fatal

• Acute infection causes symptoms in <20%

• After acute infection, 20% clear virus from blood and have full recovery

• Remaining 80% have viremia that persists for life

• Seroconversion (positive antibody test) may take

3 months

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Cirrhosis 20%

Decompensation

6%

HCC4%

Death4%

Annual rate

Hoofnagle, Hepatology, 1997; Di Bisceglie, Hepatology, 2000

Natural History of Hepatitis C

20 years

80% Chronic HCV

InfectionExposure HCV

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Case Continued

Patient returns six months later reporting fatigue and

malaise Examination is remarkable for the liver edge two cm below the costal margin

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Causes of Acute Hepatitis in HBsAg positive Patients

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Liver Transaminase Levels > 500

Common

• Acute Viral Hepatitis

• Drug/toxin induced liver injury

• Common Bile Duct Stone

• Budd-Chiari or Veno-occlusive disease

• Acute Fatty Liver of Pregnancy or HELLP

• Wilson’s disease

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• Contaminated food or water (inadequate sanitation,

undercooked shellfish or infected food handlers)

 In Vietnam >97% seroconversion by adulthood

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Hepatitis A

 Usually acute, self-limited illness

• More symptomatic in adults

 Marked elevation aminotransferases and bilirubin

 <1% fulminant hepatic failure

• More common in patients with underlying liver disease

 Serum IgM anti-HAV in acute setting

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Hepatitis D

Parenteral transmission

Anti-HDV may appear late

• Especially true in immunodeficient patients

Defective virus

• Requires HBV to complete virion assembly and secretion

• Therefore, HBV must be present

Progresses to chronic HDV infection

• Suppression of HBV replication

• Accelerated course to cirrhosis

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Hepatitis E

 Spread by fecal-oral route

• Most common by fecally contaminated water

 Self-limited illness

• More severe course than HAV

• Fulminant hepatitis 0.5-3%

15-25% mortality in pregnancy

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• anti-HBc IgG & HBsAg

• anti-HBc IgG & anti-HBs

• HBV-DNA

Clinical SignificanceAcute/Chronic InfectionImmunity

High infectivityLow infectivityAcute InfectionChronic InfectionResolved InfectionViral replication/correlates with infectivity

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Which of the following would explain the above scenario?

A Low level HBV carrier

B Remote past infection (recovered HBV)

C False positive test result

D Window phase of acute hepatitis B

E Any of the above

Serology Cases

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Which of the following would explain the above scenario?

A Low level HBV carrier

B Remote past infection (recovered HBV)

C False positive test result

D Window phase of acute hepatitis B

E Any of the above

Serology Cases

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Carrier vs Chronic Infection

• Rate of spontaneous clearance of HBeAg averages 10% per year

• Rate of spontaneous HBsAg clearance estimated 0.5-1% per year in Western countries

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Carrier vs Chronic Infection

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Who to Treat?

 Patients with active disease

• HBeAg positive > 6 months

• > 90% of adults clear in 6 months

 HBV DNA > 2 x 104

 ALT > 2 x ULN or chronic hepatitis on biopsy

• Patients with normal ALT have low likelihood of seroconversion

• HBeAg negative but with HBV DNA > 2 x 103, histologic changes and ALT > 2 x ULN

 HBeAg negative with normal ALT should be followed clinically

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Treatment Guidelines

HBeAg HBV

DNA

ALT Eligibility for Treatment

Positive > 20,000 < 2xULN Observe

Positive > 20,000 > 2xULN Consider treatment

Negative > 20,000 > 2xULN Treat

Negative > 2,000 1-2xULN Biopsy; treat if

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HBV Treatment Algorithm

Lok ASF Overview of the management of hepatitis B and case examples UpToDate; February , 2011.

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Summary of HBV Treatment

Effectiveness

• Peg-interferon higher rate 1 year HBeAg seroconversion

(15-20%); finite course

• Oral nucleoside/nucleotide agents similar rate

seroconversion by two years

• Peg-interferon HbsAg seroconversion likely similar to newer agents (tenofovir)

• Oral agents associated with more profound HBV DNA

suppression, easier administration and favorable side-effect profile

• Oral agents are effective if peg-interferon fails

• Oral therapy has resulted in a 30% reduction in liver

transplantation

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Summary of Medications

Course

• Peg-interferon finite course

• Oral agents (nucleoside analogs) usually require ongoing therapy

 If discontinued prematurely associated with reactivation, risk of

resistance

• Interferon many side effects

• Oral agents well tolerated

 Monitor renal function with adefovir and tenofovir

Resistance

• No resistance to peg-interferon

• Marked risk of resistance with earlier oral agents (esp lamivudine)

• Resistance to entecavir and tenofovir remain low

 Adefovir and tenofovir not cross resistant with lamivudine, telbivudine

or lamivudine

• Combination therapy do not increase efficacy

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HCV Treatment Indications

• Positive HCV RNA

• Liver biopsy with chronic hepatitis and

significant fibrosis

• Clinically compensated liver disease

• Acceptable hematologic and biochemical

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HCV Treatment

• Genotype 1: peginterferon, ribavirin, and a

protease inhibitor (telaprevir or boceprevir)

• Genotype 2, 3, 4 or 6: peginterferon and ribavirin

• Duration of treatment: minimum of 24 weeks

• Side effects common

- Interferon: Fever, constitutional

symptoms, depression, myelosuppression

- Ribavirin: Hemolytic anemia, teratogenicity

- Telaprevir: Rash, pruritus, GI symptoms, anemia

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Prevention of Complications

Chronic HBV is an important risk for hepatocellular carcinoma

80% of patients with HCC have cirrhosis

In HBV age of acquisition and duration of active disease are important risk factors

Increased risk in Asia

• Two-thirds of all HCC deaths in Asia

• In HBV cirrhosis, annual risk of HCC

 Western countries: 3%

 Japan: 6%

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Hepatocellular Carcinoma

• 12,000 Taiwanese men with HBV

 HBsAg RR 9.6

 HBsAg and HBeAg RR 60.2

• Other RF independent of HBeAg:

 age > 60

 Tobacco

 Alcohol

 HBV DNA titer (> 105 copies/mL)

Yang, et al NEJM, 2002

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Hepatocellular Carcinoma Screening in

Patients with HBV

Ultrasound every six months in candidates for resection

Select those at greatest risk

• HBsAg and HBeAg

• HBV DNA titer (> 10 5 copies/mL)

• Cirrhosis—all patients regardless of etiology

• Asian men > 40 yo; women > 50 yo

• African patients > 20 yo

• Family history of hepatocellular carcinoma

• Long term carries, especially age > 60

In all patients watch for clinical stigmata of cirrhosis

Follow liver function tests and synthetic function

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General Health Recommendations

Hepatitis A vaccine

Avoid excessive alcohol

Avoid tobacco

• Stay well hydrated

Immunomodulatory medicines can cause flare

Liver toxicity from medications

Avoid obesity

Household contacts should be vaccinated

• No sharing of razors; safe sex at all times

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Hepatitis Prevention

• Avoid ingestion of contaminated foods (HAV), sexual

contact with infected persons (HAV, HBV, HCV), and

injection drug use (HBV, HCV)

• Vaccination against hepatitis A and B is recommended for persons at high risk who are seronegative for these infections

• Health care workers are a high-risk group for HBV

infection and should be tested and vaccinated, if

indicated

• There is no available vaccine to protect against HCV

infection