GASTROENTEROLOGY—1
Acute HA
Chronic HB
VIRAL HEPATITS Prior exposure
Infections and EtOH are dominant causes of hepatitis. To Hep C (+) (+) (-) (+) (-) (-)
Wide variety of infections involve the liver, viral
Acute HB
infections, especially those by a small group of
Chronic HC(-) (-) (+) (+) (+) (-)
viruses with a particular affinity for the liver are the
principal cause of hepatitis. Chronic viral hepatitis
Term viral hepatitis disorder caused by their infection Subjective symptoms
with Hep A, B, and C. Early: Myalgia, flu-like symptoms, nausea, anorexia,
Other viral infections, CMV and EBV, involve the liver fatigue, occasionally arthralgia
less often, and only as a part of systemic Later: Continued fatigue, anorexia
involvement. Chronic: Fatigue, weight loss
Clinico Pathologic Syndromes Objective signs
1. Fever
Hepatitis viruses may cause one or some of the
2. Jaundice, dark urine
following clinical syndromes:
3. Large tender liver, often splenomegaly (often with
1) Asymptomatic infection: Infection resolves without
onset of cirrhosis with portal HTN)
giving rise to a clinical illness.
4. Rarely, arthritis, lymphadenopathy, nephrotic
2) Carrier state: Infection persists without clinically
syndrome (Ag-Ab complex dz/almost exclusively
apparent disease or with mild chronic hepatitis.
hepatitis B)
Individual with this condition constitute reservoirs of
5. Chronic: Often edema. With onset of cirrhosis, all of
infection.
the signs of cirrhosis.
3) Acute viral hepatitis: Clinical manifestations 6 months in the absence extent of tissue injury and inflammation:
of reexposure.
1. Chronic persistent hepatitis Inflammation is confined
Hepatitis B, C , D and G have potential to to portal tracts
become chronic. Clinical experience has been that 2. Chronic active hepatitis
if laboratory and / or clinical manifestations of Portal tract inflammation spills into parenchyma and
viral hepatitis are present continuously for 6 or surrounds apoptotic hepatocytes.
more months, the process tends to continue a long Primary determinant of dz progression is the type of
time and is unlikely to resolve spontaneously etiologic virus. Classification of chronic hepatitis
(although occasionally it does). It may progress strictly by histologic criteria is obsolete. Information
into cirrhosis. on tissue injury is still useful to assess the severity
5. Fulminant viral hepatitis. and progression of the dz.
Acute viral hepatitis Histologic hallmarks include:
Tissue injuries vary little among different subtypes of 1) Piecemeal necrosis: Apoptotic cell death with breach
acute viral hepatitis. They are characterized by the of "limiting plate", i.e. parenchyma-portal tract
following changes: interface. Viral hepatitis is very random. Does not
1) Diffuse liver cell injury: cellular swelling results affect every lobule equally. Some are surrounded by
in disarray of liver cell cords fibrous septa and others not. Then can say that this
2) Apoptosis: acidophilic bodies / Councilman bodies of cirrhosis occurred from virus. Rule of
random, isolated liver cells, or small cell clusters. 2) Spilling of chronic inflammatory cells** into
This represents a programmed cell death accentuated parenchyma. Mainly lymphocytes and macrophages
by viral hepatitis. Not to be confused with Mallory 3) Fibrosis - Continued tissue injury results in formation
bodies. Nature of tissue injury is different of fibrous septum, which, accompanied by
3) Inflammatory cellular infiltrates mainly lymphocytic parenchymal regeneration, results in cirrhosis
(Lymphocytic infiltrates tend to be more prominent
in hepatitis C than in other types) in portal tracts and Why biopsy (tissue pathology)?
focally within parenchyma Viral hepatitis: serologic studies are sufficient to
4) Prominence of hepatic macrophages: due to reactive establish diagnosis. This is why biopsy is not needed
changes Kupffer cells and sinusoid-lining cells for the diagnosis of acute viral hepatitis, unless other
hepatic injuries need to be differentiated.
Clinical Picture: Chronic hepatitis: biopsies are useful in assessing the
levels of aminotransferases. In EtOH hepatitis are only severity and progression (i.e. extent of tissue injury
raised to mid 300. Hep mainly parenchamyl dz: and fibrosis), and in establishing diagnosis of
cirrhosis. It also helps to monitor the effectiveness of
AST , ALT
treatment.
Bilirubin
Duration of hepatitis can not be made by biopsy because
ALPase (only modest) the rate of progression does not correlate with
Impaired synthetic formation. histopathology. Therefore, duration of the dz must be
PT: Prolonged with near normal serum albumin. PT has dated clinically.
a shorter half-life than albumin
Interpretation of Serologic Tests In Diag of
Acute Hepatitis
HEPATITIS A
Fecal oral in origin and transmission or ingestion of
IgM Anti- IgM HCV IgM
HAV HBsAg Anti-HBc Anti-HCV RNA Anti-HDV
fecally contaminated water or food.
PicoRNA virus: Only one human serotype with multiple
Acute HA (+) (-) (-) (-) (-) (-) genotypes.
Acute HB (-) (+) (+) (-) (-) (-) Replicates within hepatocyte cytoplasm.
Acute HC (-) (-) (-) seroconversion(+) (-)
Acute HD (-) (-) (-) (-) (-) (+) Clinical Presentation:
2—GASTROENTEROLOGY
Acute Self Limited Infection: Antigens:
HAV progresses through normal life cycle and is usually Puts out enormous amount of virus into blood.
terminated by immune system. Excess surface antigen (HbsAg)
Virus is shed in largest amounts and for the longest time
Transmission
in the stool. May also be shed in serum, urine, or
semen. Parenteral and mucous membrane exposure to infectious
IgG to capsid protein persists and protects host for life. fluids (blood, serum, semen, and saliva.)
Time course: Infects prolonged replication period Only need to transmit a very low viral load to cause
shed great amount in stool. infection. Most of the transmission is covert. Can
transmit very easily.
Symptoms: Hyperendemic in sub-Saharan Africa.
Nausea and vomiting If infected as infant have 15% chance of getting
Jaundice hepatocellular carcinoma.
Diarrhea Risk factors:
Dark urine
Close personal or intimate contact with infected person
Light colored stool
IV drug abuse
Abd pain
Homosexual activity.
Malaise/fatigue Healthcare workers.
Fever/Chills Tattooing and body piercing
appetite Inapparent blood inoculations
Myalgias. Blood transfusions or exposure to blood products
Hemophilia
Less frequently and less severely infected children than Hemodialysis.
adults.
In adults HAV manifests as clinical cases with Serologic Markers of Infection:
mortality. SGOT in the 1,000. HBsAg: surface antigen of HBV virus
HAV does not cause chronic infection and long term HBcAg: Ag from core of HBV. Never available in
sequelae blood, but produced in hepatocytes that lyse.
Transmission Important for cell mediated immunity and antibody
development.
Fecal-oral transmission. Anti-HBs
Absence of Chronic carrier state Anti-HBc
Absence of transmission via blood: 10 day period before Anti-Hbe
symptoms in which HAV is in blood. After that DNA polymerase
very little in the blood.
Acute Hepatitis:
Diagnosis:
90% of HBV infections with subsequent resolution of dz
Exposure History: in 3 to 6 months.
Daycare based epidemics are relatively common Will usually lead to recovery with persistent antibody
Homosexual men or alternative sexual practices vs.
International Travel HBsAb
Confirmed by IgM Ab to HAV. HBcAg
Seroconvert to IgM then IgG HBeAg.
Control Measures: Levels of antibody can fall below detectable levels, but
Antibody: are still present.
HAV has long incubation period get neutralizing Ab Production of HBV DNA parallels rise in HBsAg.
will prevent dz. Have preexposure Ig prophylaxis. HBsAg disappears “Window” HBcAg Rise in
Standard practice for those in peace corp. Can also Anti-HBsAg. Look for HBcAg to indicate
give to household contacts of pts that have been infection.
infected. Symptoms:
Take from pooled blood products. Levels used now are Non specific
much lower. May raise the levels. Light colored stool
Totally prevents infection in many. Are not protective Jaundice
in the long term after the Ig is metabolized. Flu like disease
GN
Vaccine: Rash
Groups in whom vaccination recommended: Arthritis
Travelers Vasculitis
Children and employees at daycare centers Chronic Hepatitis:
Military 5% of patients infected with HBV
Homosexual males Asymptomatic Carrier: 5%
IV drug users May be asymptomatic or may lead to damage, cirrhosis,
Food Handlers and hepatocellular carcinoma.
Liver Transplant recipients Continued production of HBsAg and Anti-HBcAg Ab;
Lab Techs possible Anti-HBeAg.
Healthcare workers Usually no detectable Anti-HBsAg Ab.
Native Americans
Sewage workers Symptoms:
Virus inactivated with formyl killed vaccine that is Progression to Cirrhosis ~25% of chronic infection.
highly effective. GN
Within 5 to 18 days There were cases in the Rash
vaccinated group. Too late to have an effect. After Arthritis
20 days was effective. Vasculitis
Fulminant Hepatitis:
HEPATITIS B 1 to 2% of patients
Mode of Replication: Reverse transcription in liver and
other tissues. Immunization:
GASTROENTEROLOGY—3
Exposure: Give high levels of Ig. From needle stick, 15 to 20% of pts Severe complications and death
acute sexual contact, perinatal transmission. occur only in persons with cirrhosis.
Vaccine: Can proceed to cirrhosis and/or hepatocellular
Immunity is long lasting and most likely for life. carcinoma.
Break the cycle: Liver function tests cannot predict who gets cirrhosis or
1. Need to intervene in delivery room. Need to know if HCC.
pregnant woman is carrier
2. Give baby Hep B Ig
Diagnostic Tests:
3. Start 3 dose immunization process on first day of life.
Serologic Assays:
Vaccine: No Anti-HBcAg Only Anti-HBsAg antibody. Enzyme immunoassay: Core protein, and nonstructural
proteins 3 and 4.
Can detect Ab w/in 4 to 10 weeks after infection.
HEPATITIS C False positives: Pts w/out risk factors, w/out signs or
Infects 170 million persons worldwide. Highest number liver dz. Also pts with immune compromise, pt
of infections in Egypt. w/renal failure, and pts w/HCV associated essential
In the US 1.8% of population is (+) for HCV antibodies mixed cryoglobinemia.
with 3 of 4 with active viremia ~2.7 million in US Recombinant Immunoblot: used to confirm (+) enzyme
with active HCV. immunoassay.
Shorter incubation period and less symptoms than HBV
infection. More often asymptomatic. Molecular Tests:
Qualitative: PCR testing. Lower limit of detection is
Risk Factors: than HIV (1 in
Genotyping: helps to predict outcome of therapy. Now
493,000). Now PCR screening window to 3 only clinical relevant distinction is between
weeks. genotype 1, and 2 and 3.
Vertical transmission: infrequent. Often associated
with co-infection with HIV-1 in the mother. Liver function Tests: Can use alanine
Nosocomial: aminotransferases level to monitor HCV infection
--Reported from pt to pt by a colonoscopy. and efficacy of treatment in the intervals between
--Needle stick: HBV transmitted in 30% of molecular testing.
exposures, HCV in 3%, and HIV in 0.3%.
40% cannot tell. Treatment:
Acute Infection: Not clear.
Pathogenesis:
RNA virus. Natural targets are hepatocytes and possibly Chronic Infection:
B lymphocytes. liver enzymes, detectable HCV levels, liver biopsy
Robust viral replication: more than 10 TRILLION virion shows fibrosis or moderate necrosis and
particles are produced per day, even in chronic inflammation. Treatment.
infection liver enzymes, but with minimal or mild necrotic
RNA polymerase does not have proofreading function changes on biopsy:
rapid evolution.
may benefit from Tx, but are at risk of
Genotypes: progressive liver dz
Six distinct, but related HCV genotypes. Genotype is
Can follow up w/serial liver enzyme, & biopsy at 3
important because it has predictive value in
to 5 yrs.
response to viral therapy.
liver enzymes, but no histologic evidence of necrosis
US and Western Europe: 1a and 1b most common.
or inflammatory changes on biopsy excellent
Followed by 2 and 3.
prognosis w/out therapy.
Egypt: Type 4
South Africa: Type 5 Initial Therapy:
South East Asia: Type 6. Combination Therapy:
Type 2 and 3 have better response than Type 1. Interferon Alfa and Ribavirin.
Acute Infection Virologic response should be assessed at 24 weeks.
Infrequently diagnosed during this stage. Clinical (+) PCR assay for HCV RNA: No response to
manifestations occur in 7 to 8 weeks w/mild therapy. Treatment should be stopped Controlled
symptoms or no symptoms. clinical trials.
74% to 86% will have persistent viremia. (-) PCR and Genotype 2 and 3. Can stop.
(-) PCR and other genotypes require 24 weeks
Chronic Infection: additional therapy.
Will happen in most of infected pts. Spontaneous
clearance of viremia is rare. Contraindications to therapy:
Most chronic infections hepatitis and some degree of Interferon Alfa:
fibrosis.
4—GASTROENTEROLOGY
Absolute: Current psychosis or Hx of psychosis,
severe depression, neutropenia or
thrombocytopenia, symptomatic heart dz,
decompensated cirrhosis, uncontrolled sz, and organ
transplantation other than liver.
Relative: Autoimmune disorders, and uncontrolled
DM.
Ribavirin:
Absolute: Pregnancy, absence of reliable form of
contraception, ESRD, anemia, Hemoglobinopathies,
and severe heart disease.
Relative: Uncontrolled HTN, and Old age.
Side Effects of Combo therapy:
Very Common: >30%
Influenza like symptoms
HA
Fatigue
Fever
Rigors
Myalgia
Thrombocytopenia
Induction of autoantibodies.
Pegylated Interferon: Extends half-life and duration of
therapeutic activity. Only needs to be given once a
week.
Liver Transplantation
Hepatitis D: Delta agent
Chronic active Hep B. Noticed that a pt would get a
tremendous aggravation of dz and sometime survive.
Took convalescent serum to stain healthy liver.
There was antibody to some protein in nuclei. Called
this the Hep D antigen.
Not independent virus. Satellite. Coat is Hep B surface
antigen
Small circular ss RNA.
Can only replicate in cells that are actively replicating
Hep B virus. Pt has superimposed Hep D on top of
Hep B infection. Also to provide the coat.
Two ways to get infected:
1. Unlucky to get donation from IV user with both
viruses in it acute hepatitis. More fulminant
hepatitis.
2. Chronic infection with Hep B is super infected with
Hep D. Severe aggravation of hepatitis. Will have
HbsAg and Anti-HBc protein. Then infected and
will anti-HBd Ag.
Prevention:
If HBV susceptible get vaccinated with HBV. Will
prevent infection with HBV and HBD.
If chronic carrier: little to do. Avoid exposures. Limit
exchange of fluids.
Hepatitis E:
Epidemic traced to sewage contamination. Mean age
27. Over all mortality is low like Hep A. Very high
mortality in pregnant women.
Hit and run. Waterborne epidemics Water borne
transmission
40 day incubation.
Young adults mostly infected.
In pregnancy mortality 20% in third trimester.
Endemic in Mexico. Not endemic in the US.
Immunity is life long. Distinct from Hep A and Hep B
Control: Do not drink sewage.
Our immune serum Ig is not protective. If use local
globulin may be more effective.