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The ABCs of Hepatitis

Ian Williams, PhD, MS Division of Viral Hepatitis Centers for Disease Control and Prevention

Bibliografa Emedecine

Hepatitis A Author: Richard K Gilroy, MBBS, FRACP; Chief Editor: Julian Katz, MD , updated:25agosto 2011

Hepatology - A Clinical Textbook Second Edition Editors:Stefan Mauss ,Thomas Berg,Jrgen Rockstroh Christoph Sarrazin,Heiner Wedemeyer. Wedemeyer.

Consideraciones generales


One of the more common causes of acute hepatitis is (HAV), which was isolated by Purcell in 1973. Humans appear to be the only reservoir for this virus. Since the application of accurate serologic investigations in the 1980s, the epidemiology, clinical manifestations, and natural history of hepatitis A have become apparent.

Hepatitis A
Ictericia
Manifested here as icterus, or jaundice of the icterus, conjunctivae and facial skin Source: Centers for Disease Control and Prevention

Man with jaundice (yellowing of skin and eyes)Source: Centers for Disease Control and Prevention

Hepatitis A Virus
    

Naked RNA virus Related to enteroviruses, formerly known as enterovirus 72, 72, now put in its own family: heptovirus family: One stable serotype only Difficult to grow in cell culture: primary marmoset cell culture: culture and also in vivo in chimpanzees and marmosets 4 genotypes exist, but in practice most of them are group 1

Hepatitis A virus as viewed through electron microscopy.

Hervir el agua de tomar, Agregar cloro, iodo

Etiologa Epidemiologa
Most patients have no defined risk factors for hepatitis A. Risk factors for the acquisition of hepatitis A include the following: Personal contacts Institutionalization Occupation (eg, daycare) Foreign travel Male homosexuality ( Ano - lingual) Illicit parenteral drug use

Epidemiologa


Problema sobre todo en estacin lluviosa, las innundaciones provocan mezcla de aguas pluviales con aguas negras , ambas contaminan los pozos y la red de agua potable Promiscuidad, sobretodo, prostitucin infantil aumento en homosexuales , no hay datos oficiales del MINSA

Hepatitis A Virus Transmission



Close personal contact (e.g., household contact, sex contact, child day care centers) Contaminated food, water (e.g., infected (e.g., food handlers, raw shellfish) . Conchas negras de los esteros, Nicaragua) esteros, Blood exposure (rare) (e.g., injecting drug use, transfusion)

Global Patterns of Hepatitis A Virus Transmission

Disease Peak Age Endemicity Rate of Infection Transmission Patterns High Moderate Low to High High Early Person to person; childhood outbreaks uncommon Person to person; Late childhood/ food and waterborne young adultsoutbreaks

Low

Very low

Low Young adultsPerson to person; food and waterborne outbreaks Very low Adults Travelers; outbreaks uncommon

Viral Hepatitis Historical Perspective

Infectious Viral hepatitis A Enterically E transmitted

NANB
Parenterally C transmitted F, G, ? other

Serum

B D

Classification of Hepatitis Viruses

Virus HAV HBV HCV HDV HEV Family Picornaviridae Hepadnaviridae Flaviviridae Deltavirus (genus) ?
(Previously classified as a calicivirus)

DNA or RNA RNA* DNA** RNA* RNA*** RNA*

Envelope no yes yes yes no

*linear, single strand; ** circular, double strand; *** circular, single strand

Basic Features of Hepatitis Viruses

Virus A B C D E
* Weeks

Transmission fecal-oral parenteral parenteral parenteral fecal-oral

Incubation Period* 4 (2-6) 8-12 (6-24) 6-9 (2-24) ? (2-10) 4-5 (2-9)

Chronic Infection No Yes Yes Yes No

Acute Viral Hepatitis, United States, 19911991-1998

63% 28% 8%
Hepatitis A Hepatitis B Hepatitis C Non-ABCDE

1%
Source: Sentinel Counties Study, CDC

Reported Risk Factors for Hepatitis A in the United States

Household or sexual contact (12%) Unknown* (51%) Day care related (11%)

Male homosexual activity (7%)

Injection drug use (14%) Travel (4%)

* Most "unknowns" probably related to person-to-person transmission Source: Sentinel Counties Surveillance System for Acute Viral Hepatitis, CDC

PATOFISIOLOGIA

Hepatitis A - Clinical Features



Incubation period: days Jaundice by age group: Complications: hepatitis hepatitis

Average 30 Range 15-50 days <6 yrs, <10% 6-14 yrs, 40%-50% >14 yrs, 70%-80% Fulminant Cholestatic

Chronic sequelae:

Relapsing hepatitis None

Evolucin Hepatitis A

Diagnstico Estudios, Paraclnicos Laboratorio

Laboratory Diagnosis


Acute infection is diagnosed by the detection of HAV-IgM HAVin serum by EIA. EIA. Past Infection i.e. immunity is determined by the detection of HAV-IgG by EIA. HAVEIA. Cell culture difficult and take up to 4 weeks, not routinely performed Direct Detection EM, RT-PCR of faeces. Can RTfaeces.

detect illness earlier than serology but rarely performed. performed.

Laboratory Findings in Acute Viral Hepatitis

Laboratory indicators of liver pathology Elevated ALT (SGPT) and AST (SGOT) Elevated bilirubin Elevated alkaline phosphatase Laboratory indicators of infection Increased WBC

All non-specific with regard to making an etiologic diagnosis

Immunologic Markers Used for Serologic Diagnosis

Immune globulin of the M sublcass (IgM): Produced in early infection Immune globulin of the G subclass (IgG): Produced in later infection Total immune globulin (Total Ig): Combination of IgM and IgG Early infection - primarily IgM Late infection - primarily IgG

Hepatitis A Virus (HAV)

Differential Diagnosis of Acute Hepatitis

Viral infections Bacterial infections hepatitis A, B, C, D, and E, CMV, EBV, HSV, VZV, yellow fever typhoid fever, Q fever, RMSF, leptospirosis, secondary syphillis, sepsis toxocariasis, liver flukes ASA, acetaminophen, INH, rifampin, oral contraceptives, anti-seizure meds, carbenicillin, sulfonamides Alcohol, carbon tetrachloride Autoimmune hepatitis, SLE

Parasitic infections Drugs

Toxins Autoimmune diseases

Diagnstico diferencial
Hepatitis de otra etiologa
      

Embarazo edad peditrica

Alcoholic Hepatitis Autoimmune Hepatitis Dermatologic Manifestations of Hepatitis C Hepatitis B Hepatitis C Hepatitis D Hepatitis E

    

Hepatitis in Pregnancy Pediatric Hepatitis A Pediatric Hepatitis B Pediatric Hepatitis C Viral Hepatitis

Mechanism of Injury

Hepatotropic viruses Acute infection:

direct cytotoxicity vs. immune response to infection vs. combination of the two

Chronic infection:
immune response probably more important

Hepatitis A infection in a child

Copyright Dr. CW Leung, Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong

Clinical Features of Hepatitis A

Incubation period Mean:28-30 days Range:2-6 weeks <6 years: 10% 6-14 years: 40-50% >14 years: 70-80% Overall: 0.3% >50 years: 1.8% No

Jaundice

Case fatality

Chronic infection

Extrahepatic manifestations


Cutaneous vasculitis, artrhitis..related to artrhitis..related cryoglobulinemia Hematological complications: complications: thrombocytopenia, thrombocytopenia, red cell aplasia,

Prognstico
Excelente


100 Muertes en USA



Raras las formas fulminantes de hepatitis A. En nios

Itericia 80% de los casos

Hepatitis C mortalidad

Acetaminofen dosis peligrosa ms de 3 gramos en adulto. N-acetyl cysteina

Emedecine
RELATED NEWS AND ARTICLES Updated 2011


What Factors Determine the Severity of Hepatitis AArelated Acute Liver Failure? Hepatitis A Infection Risk in ForeignForeign-Born Adoptees, Their Contacts

Clinical Features of Acute Renal Failure Associated with Hepatitis AVirus Infection

Hepatitis A Prevention - Immune Globulin



PrePre-exposure
travelers to intermediate HAVHAV-endemic regions and high

PostPost-exposure (within 14 days)

Routine household and other intimate contacts Selected situations institutions (e.g., day care centers) common source exposure (e.g., food prepared by infected food handler)

Clinical Manifestations of Acute Viral Hepatitis

Asymptomatic Symptomatic Fulminant liver failure and death

Typical Signs and Symptoms

Fever Malaise Anorexia Nausea Vomiting Jaundice Scleral icterus Abdominal/RUQ pain Hepatomegaly Arthritis

Immune Globulin (IG)

  

Prepared from pooled human plasma Mechanism of action: passive transfer action: of neutralizing antibodies Prevents infection or clinical expression of disease

Prevention of Hepatitis A with IG

PrePre-Exposure Prophylaxis
Protection lasts 3-5 months 3 Used for travelers

PostPost-Exposure Prophylaxis
Must be given within 14 days of exposure Used for household and sexual exposures Sometimes used for common source exposures (e.g., infected food handler)

Prevention of Hepatitis A with Hepatitis A Vaccine

 Used

for pre-exposure prophylaxis pre Given as 2-dose series 2 Licensed for use for persons >2 years old  Duration of protection: at least 20 years possibly lifelong  Unresolved issues:
use for post-exposure prophylaxis post use in community-wide outbreaks community-

Recommendations for Hepatitis A Vaccination

 Travelers

to HAV endemic countries  Homosexual and bisexual men  Drug users (IDU and other street drugs)  Persons with chronic liver disease (disease more server in these persons not necessarily at higher risk)  Children living in states with high rates of hepatitis A

Algoritmos diagnosticos


 

1. Clinical Features of Typical Hepatitis A Viral Hepatitis 2. Complications and Extrahepatic Manifestations of Hepatitis A 3. Risk Factors for Becoming Infected with Hepatitis A Virus

Transmission of Bloodborne Viral Infections

Route


Mode
injection drug use needle stick injury blood/ serous fluid sex perinatal

Percutaneous  Apparent

 Inapparent

 Permucosal

Relative Transmission Efficiency of Bloodborne Viral Infections

HBV
Injection drug use Sexual Perinatal Occupational +++ +++ ++++ +++

HCV
++++ + + +/-

HIV
++ ++ ++ +/-

Risk Factors for Transmission of Hepatitis Viruses and HIV

Proportion of Infections

Risk Factor
Injection drug use MSM Heterosexual partners Transfusion Occupational No Identified Risk

HBV
14% 15% 40% rare 5-7% (past) 30%

HCV
60% 1% 20% Past 7- 20% <<1% 10%

HIV
31% 47% 10% Past 2% <<1% 9%

Disease Burden from Bloodborne Viral Infections

Outcome
Chronic infections

HBV
~1.2 (million)

HCV
~2.7 (million) ~40,000 8,000

HIV
~0.8 (million) ~40,000 18,000

New infections /yr Deaths /yr

~120,000 5,000

Hepatitis B Virus (HBV)

Hepatology - A Clinical Textbook Second Edition

 


Chapter 5:The human hepatitis B virus Classification, biology, life cycle, in vitro
and in vivo models Jessika Lsebrink, Verena Schildgen, Oliver Schildgen Lsebrink, Schildgen,

the Dane particle, is of a spherical shape with a diameter of 4242-47 nm these proteins, known by their sizes as small (HBsAg), middle (HBmAg), or large (HBlAg), are HBsAg), (HBmAg), (HBlAg), acquired during budding into the ER

Emedecine.Hepatitis Emedecine.Hepatitis B
Blumberg et al reported the discovery of the hepatitis B surface antigen (HBsAg), also known as Australia
In 1965, antigen, and its antibody,

hepatitis B surface antibody (HBsAb).

A few years later, in 1970, Dane visualized the hepatitis B virus (HBV) virion.[1]

Patofisiologa

Hepatitis B Author: Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP; Chief Editor: Julian Katz, MD , updated Nov.2011

Patofisiologa

Liver biopsy specimen showing the ground-glass appearance groundof hepatocytes in a patient with hepatitis B.

Epidemiologa

Geographic Distribution of Chronic HBV Infection

HBsAg Prevalence >=8% - High 2-7% - Intermediate <2% - Low

Who is at Risk for HBV Infection?

         

HighHigh-risk heterosexual men and women Sexually active homosexual men Injection drug users Health care workers Household and sex partners of persons with chronic infection Hemodialysis patients Recipients of blood products Clients and employees of institution for developmentally disabled Families of adoptees from HBV endemic countries Inmates of correctional facilities

HBV Prevalence Among Various Risk Groups

General population >10 sex partners >50 sex partners MSM IDU 0 20 40 60

(4.9%) (6%) (12%) (20-40%) (60-80%)

80 100

Percent Infected (Anti-HBc positive)

HighHigh-Risk Heterosexual Men & Women

   

>1 sex partner in the past 6 months STD clinic patients Recently acquired STD Commercial sex workers

Reported Risk Factors for Acute Hepatitis B in the U.S. (1991-2000) (1991IDU (20%) MSM (12%)

Other1 (5%) Heterosexual (43%)

1

Unrecognized (14%)

Other: Household contact, institutionalization, hemodialysis, blood transfusion, occupational exposure

Source: Sentinel Counties Study of Acute Viral Hepatitis, CDC

Modes of Transmission of HBV

  

Percutaneous and permucosal e.g., IDU, needle stick injuries Sexual homosexual and heterosexual Perinatal From mother to child during labor and delivery (in utero (in transmission rare)

Concentration of HBV in Body Fluids

High blood serum wound exudate Moderate semen vaginal fluid saliva Low/not Detectable urine feces sweat tears breast milk

Clinical Features of Hepatitis B

Incubation period
Average: 60-90 days Range: 45-180 days

Clinical illness (jaundice) < 5 years: <10%

>5 years: 30-50%

CaseCase-fatality rate Chronic infection

0.5-1.0% YES <5 years: 30-90% 5 years: 6-10%

History
 

Acute phase Hyperacute phase Chronic phase Hepatic decompensation See notes

HepatitisB
Hepatitis aguda  Physical Examination  Low-grade fever Low Jaundice (10 d after the appearance of
constitutional symptomatology and lasting for 1-3 1mo)

Hepatitis Crnica  Hepatomegaly  Palmar erythema  Spider angioma

   
  

Hepatomegaly Splenomegaly (5-15%) (5Palmar erythema (rarely) Spider nevi (rarely)

Gynecomastia Testicular atrophy Abdominal collateral veins (caput medusa)

Cirrosis
      

Ascites Jaundice History of variceal bleeding Peripheral edema Gynecomastia Testicular atrophy Abdominal collateral veins (caput medusa)

Chronic Hepatitis
  

 

High vs low replicative state AlfaAlfa-fetoprotein (AFP) concentrations correlate with disease activity. In exacerbations of hepatitis B concentrations as high as 1000 ng/mL may ng/ be seen. HBeAg (+) ( -) , and HBeAb HBsAg HBsAg clearance favorable prognosis

Chronic HBV Infection, Vietnam

Staging Estadios
Grados de inflamacion  Grade 0  Grade 1  Grade 2  Grade 3  Grade 4


Estadios de cirrosis
   

Stage 0 No fibrosis Stage 1 Portal fibrosis Stage 2 Periportal fibrosis Stage 3 Septal, bridging Septal, fibrosis

Ver las notas pie de pag, pag,

Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

Biopsy with hematoxylin stain showing stage 4 fibrosis (Cirrosis ) in a patient with hepatitis B.

Extrahepatic manifestations


Polyarteritis nodosa Nephropathy/ Nephropathy/ membranous glomerulonephritis ( proteinuria) most cases occurs in childrens. childrens.

Outcome of HBV Infection by Age at Infection

100 100

Symptomatic Infection (%)

Chronic Infection (%)

80 Chronic Infection 60

80

60

40

40

20

Symptomatic Acute Hepatitis B

20

0 Birth 1-6 months 7-12 months 1-4 years

0 >5 years

Age at Infection

Outcome of HBV Infection

Liver cancer and cirrhosis Chronic infection Asymptomatic acute hepatitis B Resolved & immune Infection Liver cancer and cirrhosis Chronic infection Symptomatic acute hepatitis B Resolved & immune Asymptomatic carrier Asymptomatic carrier

Hepatology - A Clinical Textbook Second Edition

Chapter 9: Standard of care for hepatitis B virus infection Florian van Bmmel, Johannes Bmmel, Wiegand, Wiegand, Thomas Berg.. Updated 2010 Berg..

 

Treatment indication: Summary of the recommendations of the German Guidelines

Treatment

Diagnstico diferencial
Autoimmune Hepatitis Cholangitis Cirrhosis Hemochromatosis Hepatic Carcinoma, Primary Hepatitis A Hepatitis C Hepatitis D Hepatitis E Hepatitis, Viral

Differential Diagnosis of Acute Hepatitis

Viral infections Bacterial infections hepatitis A, B, C, D, and E, CMV, EBV, HSV, VZV, yellow fever typhoid fever, Q fever, RMSF, leptospirosis, secondary syphillis, sepsis toxocariasis, liver flukes ASA, acetaminophen, INH, rifampin, oral contraceptives, anti-seizure meds, carbenicillin, sulfonamides Alcohol, carbon tetrachloride Autoimmune hepatitis, SLE

Parasitic infections Drugs

Toxins Autoimmune diseases

Workup Diagnstico



Approach Considerations
Laboratory evaluation for hepatitis B disease: Liver disease: function tests (LFTs), including levels of alanine LFTs), aminotransferase (ALT) and/or aspartate aminotransferase and/or (AST), alkaline phosphatase (ALP), total and direct serum bilirubin, bilirubin, and urine bilirubin and urobilinogen. urobilinogen. Hematologic and coagulation studies include prothrombin time (PT), total protein level, albumin level, complete level, level, blood cell (CBC) count. Platelets count. Platelets In severe cases, serum ammonia levels may be obtained.

Test diagnsticos
    

De acuerdo al estadio. Acute Chronic inactive hepatitis B disease Chronic active hepatitis B disease (TissueTissuenonspecific antibodies). Cirrhosis
Radiologic studies, US, MRI (ferrumoxides) for SRE tumors identifications

Treatment aproach consideration



Medications ( INF a, Lamivudine,Telbivudine,Adefovir, Lamivudine,Telbivudine,Adefovir, Tentecavir, Tentecavir, Tenofovir Algoritms (American Association for the Study of Liver Diseases (AASLD). pdf Transplantation Notes at bottom page

 

Prognosis

Hepatitis B Prognosis


9% de pacientes con cirrosis desarrollan cancer a 73 meses de seguimiento. HBsAg, HbsAb, HBsAg, HbsAb, HBV, aumento riesgo de cancer. cancer. Variables and survival ( albumin, albumin, plaquetas, splenomegalia, bilirubina, splenomegalia, bilirubina, HB eAg. eAg.

 

Prevention of HBV Infection

Hepatitis B Immune Globulin (HBIG)
Post-exposure prophylaxis Post-

Hepatitis B Vaccine
Pre-exposure prophylaxis Pre Post-exposure prophylaxis Post-

Hepatitis B Immune Globulin (HBIG)

Prepared from plasma containing high titers antianti-HBs  Used for post-exposure prophylaxis to postprevent infection from:

- Perinatal exposure - Sexual exposure - Occupational exposure

Must be given soon after exposure to be effective  Does not protect against future exposures


Hepatitis B Vaccine


Primary component of vaccine is HBsAg

HBsAg elicits devolvement of anti-HBs anti anti-HBs protective antibody anti-

Worldwide, plasma-derived and recombinant plasmaformulations available  Only recombinant available in U.S.  Given as a 3-dose series 3 Highly immunogenic seroconversion ~95%  Protection long-lasting booster doses of vaccine longnot recommended


Elimination of HBV Transmission in the United States

Current Strategy
  

Routine vaccination of infants Routine vaccination of adolescents not vaccinated in infancy Vaccination of high-risk children, highadolescents, and adults

HepB3, DTP3, and Hib3 Coverage, Among 19-35 Month-Old Children, 1992-2000
100 90 80 70 60 50 40 30 20 10 0

DTP3 Hib3
Routine HepB vaccination recommended

Coverage, %

HepB3

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

Year

Reported Cases of Acute Hepatitis B in Children United States, 1985-2000 19851 to 4 yrs 200 Reported Cases 150 100 50 0
85 19 86 19 87 19 88 19

5 to 9 yrs

Routine HepB vaccination recommended

89 19 90 19 91 19 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 19 00 20

Year

Estimated Incidence of Acute Hepatitis B in the United States (1982-2001)

Estimated Acute Cases 350,000 300,000 250,000 Number 200,000 150,000 100,000 50,000 0 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 Year
Vaccine licensed

Estimated Acute Infections

Infant immunization recommended

Children Playing with Medical Waste, Bangladesh

Viral Hepatitis - Overview

A Source of virus Route of transmission Chronic infection Vaccine Pre/Post prophylaxis Feces B Blood* C Blood* D Blood* E Feces

fecal-oral

Percutaneous yes

Percutanous yes

Percutaneous yes

fecaloral no

no

yes pre/post (IG)

yes post (HBIG)

no no

yes** no

no no

* Blood and blood-derived body fluids

**Prevention of Hep B with vaccine

Chapter 11. Hepatitis D Diagnostic procedures and therapy

Diagnstico D hepatitis

Hepatitis E


Epidemiology, Epidemiology, transmission , natural history history Zoonotic transmission transmission

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