Viral & Toxic Hepatitis Trans

VIRAL and TOXIC HEPATITIS Dra. Valdellon

Sept 30, 2010

LEGEND Normal text :powerpoint Italics : Harrison’s + lecture notes OUTLINE Definition and types of hepatitis Viral hepatitis as a disease TYPES A, E, B, D, C - Diagnosis Transmission Prevention Treatment/management Spectrum of toxic hepatitis/drug-induced liver disease (DILI) • •

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E1

Types of Viral Hepatitis

Source of 

A

B

C

D

E

G

Feces

Blood, bo body fluids

Blood, body fluids

Blood, body fluids

F e ce s

Blood

FecalOral

Childbirth, needles, sex, blood transfusion

Needles,

Needles, sex, transfusion

Fecal-Oral

Blood transfusion

virus Route of  Transmission

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HEPATITIS • • •

means inflammation of the liver  It can be caused by viruses, drugs and toxins There are many different types of viruses that can cause hepatitis Hepatitis A, B, C, D, E Other transfusion transmitted agents e.g. hepatitis G virus and TT virus are identified which do not cause hepatitis.  All are RNA viruses viruses except except for Hep B which which is a DNA virus Each virus is prevented and transmitted differently with different symptoms

VIRAL HEPATITIS systemic infection affecting the liver    A systemic all caused by HAV, HBV, HCV, HDV or HEV   Almost all   All produce produce clinically clinically similar illnesses. illnesses.  asymptomatic & inapparent to fulminant & fatal acute infections common to all types subclinical persistent infections to rapidly  progressive chronic liver disease with cirrhosis & even hepatocellular carcinoma, common to those that are predominantly parenterally parenterally transmitted (HBV, HCV & HDV)   prodromal symptoms: symptoms: systemic systemic and  variable.Constitutional symptoms include anorexia, nausea, and vomiting, vomiting, fatigue, malaise, arthralgias, myalgias, headache, photophobia,  pharyngitis,  pharyngitis, cough, and coryza, coryza, which may  may   precede the onset onset of jaundice jaundice by 1-2 weeks. Low-grade fever more present in Hep A and E   types than Hep B, except when Hep B infection is heralded by a serum sickness-like syndrome  Dark urine and clay-colored stools may be noticed 1-5 days before the onset of clinical   jaundice.  jaundice.  The liver becomes enlarged and tender and may  be associated associated with right upper quadrant pain and  discomfort. Splenomagaly and cervical  adenopathy are present in10-20 % of patients  Posticteric Posticteric recovery phase is variable ranging 212 weeks in ans is usually more prolonged in Hep B and Hep C.  Complete recovery is to be expected 1-2 months for Hep A and Hep E and 3-4 months after the onset of jaundice for uncomplicated self-limited  infections infections of Hep B and Hep C.  Labs: increased ALT and AST; jaundice= bilirubin level: 2.5 mg/dL,; neutropenia, lymphopenia;  prolonged PT occasionally; occasionally; serum immunoglobulins IgG and IgM increased 

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Yes

Yes

No

No (whether it’s pathogenic to humans remains unclear)

Prevention

•

•

Yes

(requires HBV, HCV, or HIV coinfection)

(requires HBV coinfection)

Infection

•

•

No

Chronic

blood transfusion (sex, childbirth)

Vaccine

Vaccine

Immunoglobulin

Immunoglobulin

CDC fact sheets, available at www.cdc.gov

No vaccine available Blood donor  screening, risk management, education

HBV Vaccine

Ensure safe drinking water 

Blood donor  screening

HEPATITIS A

•

•

•

• •

• •

Incubation period of 4 weeks, replication is limited in the liver, but the virus is present in the liver, bile, stools and  blood during the late incubation period and acute preicteric  illness Despite persistence persistence of virus in the liver, viral shedding in the feces, viremia and infectivity diminish rapidly once  jaundice  jaundice is apparent. Feco-oral route; but has a stage of viremia, and if it  happens that patient donates blood, then patient can transmit via blood.  Asymptomatic  Asymptomatic (70%) in children children < 6 years Symptomatic Symptomatic among older children & adults; jaundice in 70% S/S lasts < 2 months Relapsing Relapsing disease/cholestatic in 10-15% of symptomatic patients

The figure shows that antibodies to HAV can be detected during  acute illness when serum aminotransferase activity is elevated and  fecal HAV shedding is still occurring. o ccurring. During early antibody response, Ig-M is the predominant pr edominant antibody and rarely persist after 6 months. During convalescence, the Ig-G class predominates. HAV: Prevention 1. General measures:

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Good hygiene Safe drinking water  * HAV inactivated by boiling for 1 minute, contact with formaldehyde and chlorine and ultraviolet radiation Proper disposal of sewage  2. Pre-exposure immunization with hepatitis A vaccine 3. Pre- and post-exposure with immune globulin 

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

• • •

8-9M hepatitis B carriers in the Philippines 10 – 40% progress to cirrhosis in 10 years 3 – 6% of cirrhotics transform to HCC 4 – 10% deaths annually

Geographical variation in mechanisms of HB V transmission

Active Immunization: Hepatitis A Vaccine Highly immunogenic  Administered in 2 doses Passively transferred maternal antibody interferes with immune response Recommended for patients with CLD Passive Immunization: Immune Globulin Effective pre-exposure or within 2 weeks post-exposure Maybe given to children < 2 years who are traveling to countries endemic to Hep A Concurrent administration with hepatitis A vaccine reduces vaccine immunogenicity •

Endemicity

Location

Age at time of  infection

Mode of  transmission

Low

N. America W. Europe

Early adulthood

Sexual Percutaneous Other 

Moderate

Mediterranean E. Europe

Childhood

Horizontal

High

Asia Pacific Africa

Birth Toddlers Preschool

Perinatal Horizontal

• •

•

• •

•

HAV: Management 1.  Activity 2. Diet: high protein diet can improve health status 3. Drugs 4. Hospitalization: not recommended unless obviously   jaundiced and vomiting 

•

HEPATITIS E

•

•

Serologic Course

Table shows that incidence varies with mode of transmission Low incidence countries: early adulthood  and sexual contact  Highly endemic: newborns and toddlershorizontal, sexual contact= rare, blood  transfusion as cause= effaced 

Geographic prevalence of chronic hepatitis B may be impacted by migration e.g. SF Bay Area prevalence: 5-6 %

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• • • •

•

Behaves like Hep A but with higher morbidity and mortality  especially in pregnant patients First described in India Increased ALT when symptomatic  Diagnosis done through inference Both IgM anti HEV and IgG HEV can be detected, but both fall rapidly after acute infection, reaching low levels within 9-12 months Serologic testing not available routinely 

Why Should Filipinos Be Aware of Hepatitis B? The Philippines is hyperendemic to HBV infection One in four carriers of the hepatitis B virus will eventually die of liver cancer or liver failure Hepatitis B is the most common cause of liver cancer and liver cirrhosis among Filipinos Liver cancer is the 4 th most common cause of cancer  among Filipinos(2nd among men and 7th among women) and is the 2nd leading cause of cancer-related deaths in the Philippines • •

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HEPATITIS B

HBV: Epidemiology & Transmission 350M chronically infected worldwide Especially endemic in Asia •

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Country

HBsAg Positive, %

Taiwan

10.0-13.8

Vietnam

5.7-10.0

China

5.3-12.0

 Africa

5.0-19.0

Philippines

5.0-16.0

Thailand

4.6-8.0

Japan

4.4-13.0

Indonesia

4.0

South Korea

2.6-5.1

India

2.4-4.7

Russia

1.4-8.0

US

0.2-0.5

Outcome of HBV Infection: effect of age at infection



Figure shows that infants are generally asymptomatic and  that as one ages, becomes symptomatic due to immune response

III. Disease Outcome In either case, the patient may recovery from the infection (>90 %) & develop lifelong immunity, fulminant hepatitis (1%) or develop a chronic infection (1-2 % of immunocompetent adults higher in neonates,elderly and immunocompromised) that usually lasts throughout life.

II. Transmission of HBV

IV. HBV Infection Markers

 Acute Infection

Chronic Infection

Recovery

HBsAg

HBsAg

Anti HBs

HBeAg

HBcAg

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HBeAg /  AntiHBe  AntiHBc

 Anti Hbe

 AntiHBc

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 After a person is infected with HBV,the first virologic marker detectable in serum isHBsAg. Circulating HBsAg precedes elevations of serum a minotransferase activity andclinical symptoms and remains detectable during the entire icteric or  symptomaticphase of acute hepatitis B and beyond. In typical cases, HBsAg becomes undetectable 1 to 2 months after the onset of   jaundice and rarely persists beyond 6 months. After HBsAg disappears, antibody  toHBsAg (anti-HBs) becomes detectable in serum and remains detectable indefinitely thereafter. Because HBcAg is sequestered within an HBsAg coat, HBcAg is notdetectable routinely in the serum of patients with HBV infection. By  contrast, anti-HBc is readily demonstrable in serum, beginning within the first 1 to 2  weeks after the appearance of HBsAg and preceding detectable levels of anti-H Bs by weeks to months. Because variability exists in the time of appearance of anti-H Bs after HBV  infection,occasionally a gap of several weeks or longer may separate the disappearance of HBsAg and the appearance of anti- HBs. During this “gap” or  “window” period, anti -HBc may represent serologic evidence of current or r ecent  HBV infection, and blood containing anti-HBc in the absence of HBsAg and antiHBs has been implicated in the development of transfusion-associated hepatitis B. In part because the sensitivity of immunoassays for HBsAg and anti-H Bs has increased, however, this window period I s rarely encountered. In some persons, years after HBV infection, anti-HBc may persist in the circulation longer than antiHBs. Therefore, isolated anti-HBc does not necessarily indicate active virus replication; most instances of isolated anti-HBc repr esent hepatitis B infection in the remote past. Rarely, however, isolated anti-HBc represents low level hepatitis B viremia, with HBsAg below the detection threshold; occasionally, isolated antiHBc represents a cross-reacting or false positive immunologic specificity. Recent  and remote HBV infections can be distinguished by determination of the immunoglobulin class of anti-HBc. Anti-HBc ofthe IgM class (IgM anti-HBc)  predominates during the first 6 months after acutei nfection, whereas IgG anti-HBc 

Figure shows HbsAg is the first serological marker to be detected with appearance of IgM anti-HBc weeks prior the appearance of anti -HBs

SALIENT POINTS: HBV DNA- detection in serum is the most sensitive test for Hep B infection HbSAg = acute or chronic HBV infection, do not denote severity of disease rather the degree of liver cell damage such that HbSAg titers would be highest among the immunocompromised than the chronically infected and  levels would be lowest for acute fulminant hepatitis, anti-HBs= protective antibody; its presence is thought to reflect the stimulation of a related clone of antibody-forming cells, but it has no clinical  relevance and does not signal imminent clearance of hepatitis B. IgM anti-HBc = early onset denotes acute or recent infection in cases where HbsAg in serum is too low.appears 1-2 weeks after the appearance of  HbsAg preceding detectable levels of anti-HBs by weeks to months IgG anti-Hbc =In patients who have recovered from hepatitis B in the remote  past as well as those with chronic HBV infection, anti-HBc is predominantly  of the IgG class. HbeAg = nucleocapsid protein,which is a qualitative marker of HBV  replication and relative infectivity. Mothers For example, HBsAg carrier  mothers who are HBeAg-positive almost invariably (>90%) transmit hepatitis B infection to their offspring, whereas HBsAg carrier mothers with anti-HBe rarely (10 to 15%) in fect their offspring.

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Figure shows a persistence of HbsAg and anti HBc beyond 6 months

V. HBV: Prevention Single most effective preventive measure is immunization (recombinant Hep B Vaccine IM) at 0, 1, 6 months on the deltoid . Protective anti-HBs response in 90% of healthy adults and >95% of infants, children and adolescents Host factors that contribute to decreased immunogenicity: age, smoking, obesity & immune suppression 0.06 mL/kg IM immediately HBIg (Hep B Immunoglobulin) after exposure in unvaccinated patients For perinatal exposure HBIg 0.05 mL in the thigh immediately after birth with the vaccine series started at 12  h of life •

Early during the course of acute hepatitis B, HBeAg appears transiently; its disappearance may be a harbinger of clinical improvement and resolution of  infection. Persistence of HBeAg in serum beyond the first 3 months of acute infection may be predictive of the development of chronic infection, and the  presence of HBeAg during chronic hepatitis B is associated with ongoing  viral replication, infectivity,and inflammatory liver injury.The replicative stage in the liver is thought to be the stage of highest infectivity.

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•

•

VI. Treatment Objectives for CHB Stop HBV replication, ideally permanently Improve hepatitis: normalize ALT’s, HBeAg seroconversion, improve symptoms  Arrest / reverse hepatic fibrosis: improve long term prognosis Treatment is available but not all individuals need it  • •

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•

•

Criteria: activity/progression of disease + increased  transaminases HBV infected individuals can work and 80-90 % do not  show disease activity.

VII. Treatment Options for CHB 1. Interferon α / PEG IFN α 2. Thymosin α 3. Lamivudine 4. Adefovir dipivoxil 5. Entecavir  6.Telbivudine 7. Clevudine

Simplified Approach in Patients Presenting with Acute Hepatitis HBsAg

IgM antiHAV

IgM antiHBc

AntiHCV

Diagnostic Interpretation

+

-

+

-

Acute hepatitis B

+

-

-

-

Chronic hepatitis B

-

-

+

-

Acute hepatitis B (HBsAg below detection threshold)

-

+

-

-

Acute hepatitis A

-

-

-

+

Acute hepatitis C

+

+

+

-

Acute hepatitis A & B

+

+

-

-

Acute hepatitis A superimposed on chronic hepatitis B

-

+

+

-

Acute hepatitis A & B (HBsAg below detection threshold)

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HEPATITIS D

TOXIC HEPATITIS AND DRUG-INDUCED LIVER INJURY

Incomplete virus that requires HBV for its replication. Either coinfects with HBV or superinfects a chronic Hep B carrier. Enhances severity  of HBV infection (acceleration of chronic hepatitis to cirrhosis, occasionally fulminant acute hepatitis)  A high index of suspicion is needed to determine infection. HDB RNA and HDB antibody tests are available but are seldom used. HEPATITIS C

Serologic Course

When to Suspect?  Appearance of symptoms and signs of liver disease in the setting of intake of prescription or non-prescription medications or dietary supplements anorexia, nausea, malaise, fatigue, abdominal pain, or jaundice Include DILI in the differential diagnoses of any patient who presents with liver dysfunction •

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Diagnosis: Challenging because there are no specific markers Straightforward o acute liver injury after overdosage to  known hepatotoxins such as acetaminophen or paracetamol Rechallenge with a drug suspected of   being the cause of previous episode of  acute liver injury Diagnosis of exclusion Dose-related(carbon tetrachloride, benzene derivatives, mushroom poisoning, acetaminophen, microvesicular  steatosis) or idiosyncratic ( isoniazid, halothane,  phenytoin, methyldopa, carbamazepine, diclofenac, oxacillin, sulfonamides) High index of suspicion Detailed medication history and compatible chronology  Awareness of a drug’s hepatotoxic potential Exclusion of other causes of liver damage Detection of the presence of subtle data that favors a toxic etiology 

 

Figure shows the mild clinical course of HCV marked by fluctuating  elevations of serum aminotransferases with 50% likelihood of  chronicity leading to cirrhosis. Serologic markers: Anti-HCV present  but problem presents because chronicity cannot be identified. Most  sensistive indicator of HCv infection is Anti-HCV RNA. Exposures Known to Be Associated With Hepatitis C (HCV) Infection • •

• • • •

Intravenous (IV) or injecting drug use; Transfusion and transplant from infected donor before routine screening implemented 1990s; mostly hemodialysis  patients Occupational exposure to blood (mostly needle sticks) Iatrogenic (unsafe injections) Birth to HCV-infected mother  Sex with infected partner  Multiple sex partners  –

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    

Types 

  

Hepatic adaptation  Mediated by survival genes (anti-oxidant, antiinflammatory and anti-apoptosis pathways) Drug-induced acute hepatitis or hepatocellular injury  Methotrexate, INH, paracetamol Fatty liver disease Ethanol, steroids, HAART  Granulomatous hepatitis

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 Allopurinol, quinidine, sulfonamides, pyrazinamide, captopril, TMP-SMZ Cholestasis Estrogen, amoxicillin-clavulanic acid  



 Anti-Tb Drug Toxicity Mainly idiosyncratic INH+RIF > INH > PZA > RIF RIF+PZA is extremely toxic when used alone PZA toxicity more prolonged Toxicity often in peripartum women and Asian men Higher risk with acetaminophen, elevated baseline transaminases, chronic HBV and HCV, possibly HIV • • • • • •

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