Transcript Hepatitis A - Michigan State University

Hepatitis A
The virus that does not
cause chronic liver disease
Hepatitis A
 “Infectious
Hepatitis”
 First characterized in 1973
 Detected in human feces
 Hepatovirus genus
 A reportable infectious disease
 U.S. rate of infection 4/100,000
 Highest among children
Risk Factors
 Sexual
or household contact
 International travel
 Men who have sex w/ men (MSM)
 Intravenous drug abuse (IVDA)
 Daycare
Transmission
 Unwitting
contact w/ infected person
 Most cases unknown
 Primary route is fecal oral either by
person to person contact or ingestion
of contaminated food or water
Pathogenesis
After ingestion, the HAV survives gastric
acid, moves to the small intestine and
reaches the liver via the portal vein
 Replicates in hepatocyte cytoplasm

– Not a cytopathic virus
– Immune mediated cell damage more likely

Once mature the HAV travels through
sinusoids and enters bile canaliculi,
released into the small intestine and
systemic circulation, excreted in feces
Clinical Features
 Incubation
is usually 2 to 4 weeks,
rarely 6 weeks
 Complete recovery within 2 months
for > 50%
 Within 6 months for almost all others
Clinical Features
 Low
mortality in healthy people
– High mortality when older than age 60
– High in presence of chronic liver disease
 High
morbidity
– Around 20% need hospitalization
– Lost work days
– Most become jaundiced
Clinical Features
 Asymptomatic
< 2 year old
 Symptomatic – 5 and older ill about
8 weeks
 Cholestatic – jaundice lasts > 10
weeks
 Relapsing w/ 2 or more bouts acute
HAV over a 6 to 10 week period
 Acute liver failure – rare in young.
When it occurs, is rapid i.e., within 4
weeks
Signs and Symptoms
 Prodrome
lasts 1-2 weeks: fatigue,
asthenia, anorexia, nausea,
vomiting, and abdominal pain
 Less common: fever, cephalgia,
arthralgia, myalgia, and diarrhea
 Dark urine is followed by jaundice
and hepatomegaly
 Less common: splenomegaly,
cervical lymphadenopathy
Diagnosis
 During
acute infection, anti HAV IgM
appears first
 HAV IgG antibody appears early in
the course of infection and remains
detectable for life, providing lifelong
immunity
Prevention
Immunization
 All
children 12 – 24 months
 Travelers, occupational exposure risk
 All patients w/ hepatitis B or C or
those awaiting liver transplantation
 HIV positive patients
 MSM
 IVD users
Immunize
 People
w/ clotting factor deficiencies
 Lab workers handling live hepatitis A
vaccine
 Need for post exposure prophylaxis
uncommon. Administration of the
vaccine is effective. If needed,
administer immune serum globulin
within 2 weeks 0.02 ml/Kg IM
Hepatitis A Vaccine
 The
vaccine is inactivated HAV
 Schedule for 2 – 18 years depends
upon the manufacturer:
– Havirx: 720 EL U/.5mL @ 0, 6-12 mo
– Vaqta: 25 U.5mL @ 0, 6-18 mo
Hepatitis A Vaccine

For those over age 18:
– Havirx: 1440 EL U/1mL @ 0, 6-12 mo
– Vaqta: 50 U/1mL @ 0, 6-18 mo
Adverse effects: rarely anaphylaxis,
injection site induration, erythema,
edema, fatigue, mild fever, malaise,
anorexia, nausea
 Twinrix:

– 720 El U/1mL 0, 1, 6 mo plus
– 20 mcg HBV
Questions?
Hepatitis B
The Virus
The hepatitis B virus is among the
smallest genomes of all known animal
viruses
 A DNA virus that infects only humans
 Belongs to the family Hepadnaviridae
 Knowledge of the viral proteins that are
perceived by the immune system as
“antigens” aids understanding of the
various tests used to diagnose acute,
chronic, and resolved infection and verify
response to immunization

HBV Antigens
Outer envelope contains a surface protein
called hepatitis B surface antigen
 HBsAg is a marker of viral replication
 Inner core contains the genome, the DNA
polymerase w/ reverse transcriptase
activity, hepatitis B core antigen (HBcAg)
particles. This antigen is not detectable in
serum
 A truncated form of the major core
polypeptide known as hepatitis e antigen
(HBeAg) is the third antigen generated by
virus activity. Marker of high infectivity

Hepatitis B Antibodies



Hepatitis B surface antibody is the antibody to
surface antigen. HBsAb is protective and
indicates either resolved infection or
immunization
HBcAb is the antibody to core antigen. This is not
a protective antibody. Only those who have been
exposed to the virus will have this antibody
HBcAb is measured in serum as:
– Anti HBc IgM (usually indicates new infection)
– Anti HBc IgG (appears later)

HBeAb is the antibody to e antigen. Loss of e
antigen w/ gain of e antibody is called
seroconversion. Not a protective antibody
Epidemiology

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


Prevalence of HBV varies markedly around the
world, w/ > 75% of cases in Asia and the
Western Pacific
Vaccine available > 20 years, but perinatal and
early life exposure continue to be a major source
of infection in endemic areas
Most acute HBV cases in the U.S. are seen among
young adults, males > females, who use injection
drugs and in those who engage in high risk
sexual behaviors
In the U.S., hundreds of people die each year of
fulminant HBV
World wide, chronic HBV and its complications
including hepatocellular carcinoma account for >
1 million deaths each year
Risk Factors

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


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Percutaneous and mucous membrane exposure.
The virus is 100 x more infectious than HIV, 10 x
more infectious than HCV and is present in all
body fluids. Present on horizontal surfaces,
eating utensils, personal hygiene items, etc.
Babies born to infected mother
Household contact
Hemodialysis
Receipt of blood products prior to the early 1970s
Receipt of previously infected donor liver
Markers of Exposure
 Surface
antigen appears as early as
1-2 weeks following exposure, as
late as 11-12 weeks
 HBV DNA measurable soon after
 HBeAg appears shortly after HBsAg
 Hepatitis occurs 1 – 7 weeks after
appearance of HBsAg
Pathophysiology
Governed by interaction between the virus
and host immune response
 Following inoculation by the HBV, cytokine
release, cell injury and viral clearance
follow
 HBsAg disappears by six months and is
accompanied by sero conversion to
protective HBsAb
 Persistent virus replication after six
months ->chronic hepatitis and is the
result of a compromised (newborn/HIV) or
relatively tolerant immune system status

Four Stages of Infection



Age at time of infection predicts chronicity in
most cases. Infants and young children usually
become chronically infected. When acquired in
adults, the virus is cleared by the healthy
immune system in about 95% of cases, leading
to natural immunity
Immune tolerant phase, there is active viral
replication. ALT and AST are normal. Immune
system does not recognize HBV as “foreign”
In the immune clearance phase, enzymes rise
reflecting immune mediated lysis of infected
hepatocytes. This phase can last for years.
Seroconversion of HBeAg to HBeAb occurs
Stages of Infection
Low or non-replicative phase. Also
known as inactive carrier (or
inappropriately “healthy carrier”).
Characterized by resolution of
necroinflammation, normalization of
enzymes and low levels of HBV DNA. This
stage may last for life
 Reactivation. Spontaneous or
immunosuppression mediated (cancer
chemotherapy or high dose corticosteroid
therapy)

Signs and Symptoms
 Incubation
period: a few weeks to 6
months
 About 30% develop jaundice
 10% to 20% of patients develop
serum sickness, i.e., fever,
arthralgias, rash
 Fulminant hepatitis B occurs in < 1%
of cases. 80% mortality without liver
transplantation
 Enzyme elevations of 1,000-2,000
typical
Signs and Symptoms
 Fatigue,
RUQ discomfort may be the
only symptoms
 Those in the immune tolerant phase
are usually asymptomatic. The phase
lasts until late puberty into adulthood
Signs of Decompensation
 See
section on Cirrhosis and Portal
Hypertension
 Refer to a liver transplantation center
 Patient education for people with
chronic liver disease should be
reinforced
 Refer to “Ten Tips for People w/
Chronic Liver Disease”
Prevention
 Two
forms of vaccine now available.
 Twinrix – contains both hepatitis A
and B vaccines available in an
accelerated schedule or standard
series
 Individual hepatitis B vaccine
 Standard schedule is given:
– Time 0
– 1 mo
– 6 mo
Prevention
Educate to avoid IVDU, high risk sexual
activity
 Prevent peri natal transmission. Serology
of pregnant women for HBsAg is standard
of practice in U.S.
 If pregnant female has high viremia, refer
to hepatologist for treatment during the
3rd trimester to reduce risk of transmission
to neonate
 Babies of HBsAg mothers receive hepatitis
B immune globulin with 12 hours of birth
and begin the vaccine series immediately

Treatment
 Six
approved medications as of July
2008
– Interferon alpha
– Pegylated interferon
– Lamivudine
– Adefovir Dipivoxil
– Entecavir
– Telbivudine
– Tenofovir approved
 Refer
to hepatologist
The Cholestatic Liver
Diseases
Adults
Cholestatic Liver Disease
Etiologies
 Immune
Mediated: PBC, PSC,
autoimmune cholangitis, liver
allograft rejection, graft-versus-host
disease
 Infectious: acute viral hepatitis
 Genetic and Developmental:
cystic fibrosis, Alagille’s syndrome
(syndrome w/ paucity of intrahepatic
bile ducts), fibro polycystic liver
disease
Cholestatic Liver Disease
Etiologies
 Neoplastic:
Cholangiocarcinoma
 Drug-Induced Ductopenia:
amoxicillin, amitriptyline,
cyproheptadine, erythromycin,
tetracycline, thiabendazole
 Ischemic
 Idiopathic
Pathogenesis of
Cholestatic Disorders
 Immune
response (inflammation,
auto-antibody) or hepatotoxic injury
to bile ducts
 Bile duct injury by bile acids - >
 Retention of bile acids in hepatocytes
->
 Liver cell damage, apoptosis,
necrosis, fibrosis, cirrhosis - > liver
failure
Complications of Chronic
Cholestasis
 Pruritis
believed to be 2/2 increased
opioid receptor tone, or centrally
mediated
 Fatigue
 Bone disease: osteopenia,
osteoporosis
 Fat soluble vitamin deficiency
 Malabsorption (Sprue, bile salt
deficiency, pancreatic insufficiency)
Pruritis in Cholestasis
 Therapy:
– Urso in AICP, PBC (15-30mg/Kg/day)
– Opiate antagonist naltrexone
(50mg/day)
– 5-HT3 antagonist odansetron
– SSRI sertaline
– Bile acid sequesterant cholestyramine
4gm t.i.d. to q.i.d.
– Antihistamines rarely effective
– Rifampin 150mg to 300mg b.i.d.
Fatigue in Cholestasis
 High
prevalence in Primary Biliary
Cirrhosis unrelated to disease
severity or duration
 Pathogenesis
– ?decreased hypothalamic cortico-tropinreleasing hormone
– ?CNS accumulation of manganese
 Prognosis
worse
 No effective treatment
Bone Disease in Cholestasis
 Clinical
manifestations: low bone
density, fractures of axial and/or
appendicular skeleton
 Pathogenesis: hyperbilirubinemia
impairs osteoblast proliferative
activity
 Therapy: bisphosphonates, calcium,
vitamin D, weight bearing exercise,
estrogens appear to be safe
1. Primary Biliary Cirrhosis
A chronic and progressive disease
of unknown etiology affecting
primarily middle-aged women
Primary Biliary Cirrhosis
 Affects
all races
 9:1 ratio female > male, age 20 – 65
 Characterized by small intrahepatic
bile duct destruction and cholestasis
 In the presence of cirrhosis, male >
likely than female to develop
hepatocellular carcinoma
PBC
Laboratory Findings
 Alk
Phos 2x to 20x ULN in > 90% of
patients
 AST-ALT 1x to 5x ULN > 90%
 Bilirubin – variable. When elevated,
may indicate advanced cirrhosis or
2nd condition
 Hypercholesterolemia in 80% of
patients
Hypercholesterolemia
Unique in PBC
 Hypercholesterolemia
– No obvious increase in heart disease
– Some lipid lowering agents cause rise
– Cholestyramine or Urso may mobilize
cholesterol deposits
PBC
Laboratory Findings
 IgM
1x to 5x ULN > 90%
 Anti mitochondrial antibody > 1:20
titer >90%
 Anti nuclear and/or smooth muscle
antibody > 1:80 may be seen in
“overlap syndrome”
 Liver biopsy helpful to grade and
stage disease, determine if cirrhosis
present
PBC Treatment
 Slowly
progressive, even if
asymptomatic
 Ursodeoxycholic acid only effective
therapy. May improve natural history
 Transplant curative
 Manage disease specific
complications
Effects of Ursodeoxycholate
 Urso
is a hydrophilic bile acid having
multiple anti-inflammatory and
immunomodulatory actions
 Urso administration in the setting of
pro-apoptotic stimuli (bile salts,
ethanol, TGF-beta, FAS ligand)
inhibits in vitro apoptosis
(programmed cell death)
 Reduces mitochondrial membrane
permeability
Monitor for and Treat PBC
Associated Disorders
 Keratoconjunctivitis
Sicca
 Scleroderma, CREST syndrome
 Gallstones
 Arthropathies:
– Rheumatoid, psoriatic arthritis,
Raynaud’s phenomenon, Hypertrophic
osteodystrophy, Avascular necrosis,
Chondrocalcinosis
 Thyroid
acidosis
disease, renal tubular
PBC Associated Disorders
 Malabsorption
 Celiac
Sprue
– 6% of PBC patients have Celiac Sprue
– 3% of Sprue patients have PBC
 Bile
salt deficiency
 Pancreatic insufficiency
Manage PBC Complications
 Standard
liver disease
recommendations
 PBC specific symptom management
 Refer for liver transplantation
2. Primary Sclerosing Cholangitis
Rare
 One
of the most important
cholestatic liver diseases in the
western world
 Chronic, cholestatic liver disease
characterized by
– Inflammation
– Obstruction
– Fibrosis of both intrahepatic and
extrahepatic bile ducts
Primary Sclerosing Cholangitis
PSC
 Many
patients will progress to
cirrhosis
 Highly variable in and between
individuals
 Usually fatal important complication
is cholangiocarcinoma
 Etiology largely unknown, though
evidence points to immune system
involvement
PSC
 No
specific treatment
 Treatment aimed at management of
disease associated conditions
 Prevalence unknown
 Almost half are asymptomatic at
diagnosis
 No specific diagnostic marker for PSC
PSC Clinical Features
 Labs:
– Two- fold increase in alk phos, most
have increased AST and ALT
– Albumin and protime normal in early
disease
– Bilirubin initially normal, but gradually
increases and fluctuates widely w/
extrahepatic biliary strictures, infection,
obstructing stone sludge or stone
PSC Clinical Features

Imaging
– Endoscopic retrograde cholangiography is the
gold standard

Magnetic resonance cholangiopancreatography demonstrates
intrahepatic duct changes
–
–
–
–
Diagnostic method of choice
Less invasive, lower risk
High cost
Claustrophobia, metal implants may preclude
PSC Clinical Features
 Histology
 Liver
biopsy for staging the disease
 Liver biopsy to rule out other
potentially treatable causes of
cholestasis
PSC Patient Presentation
 Large
bile duct PSC may have
asymptomatic elevation of LFTs. Can
be cirrhotic w/ no symptoms
 Symptomatic patients will have
cholestasis-type symptoms plus:
– Abdominal pain
– Weight loss
– Hepatomegaly
– Acute cholangitis
PSC
Associated Diseases
 Inflammatory
bowel disease, most
often ulcerative colitis
 These patients have increased risk
for colorectal carcinoma
 25% have another autoimmune
disease
PSC Complications
 Related
to cholestasis: pruritis,
fatigue, fat soluble vitamin
deficiency, osteoporosis
 Related to cirrhosis: liver failure,
peristomal varices
 Extra-hepatic disease: IBD,
pancreatitis, sprue, diabetes, thyroid
disease
 PSC specific
PSC Disease Specific
Complications
 Fever
 Abdominal
pain
 Dominant stricture
 Gall stones
 Cholangiocarcinoma
PSC Prognosis
 Factors
of Importance:
– Older age
– Increasing bilirubin
– Histological advanced stage
– Child-Pugh-Turcotte Class C
PSC Treatment Goal
Improve Quality of Life
 Medical
support
 Endoscopic treatments
 Surgical interventions
 Liver transplantation – PSC
recurrence is more frequent than
PSC
Case Study
Asymptomatic elevation in AP noted on routine
lab
 Middle aged male w/ Hx ulcerative colitis on
mesalamine
59
209
-----------------------------------------< 1.0
64
500
 Negative viral serologies; U/S normal
 MRCP reveal narrowing and strictures of
intrahepatic and extrahepatic biliary tree “Pruned
Tree” appearance
 High risk for cholangiocarcinoma, colon cancer
 Treatment is transplant

Reference
 Broome,
U and Berguist. Primary
sclerosing cholangitis. In Zakim and
Boyer’s Hepatology: A textbook of
liver disease, 5th Ed., Boyer, T.D.,
Wright, T.L., & Mans, M.P. Saunders
Elsevier: Canada, 821-854.