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									     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
   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
   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
    approved medications as of July
 Six
 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
 Pruritisbelieved 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-tropin-
    releasing 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
                    Sicca
 Keratoconjunctivitis

 Scleroderma, CREST syndrome

 Gallstones

 Arthropathies:
  – Rheumatoid, psoriatic arthritis,
    Raynaud’s phenomenon, Hypertrophic
    osteodystrophy, Avascular necrosis,
    Chondrocalcinosis
 Thyroid   disease, renal tubular
 acidosis
    PBC Associated Disorders
 Malabsorption

 Celiac   Sprue
  – 6% of PBC patients have Celiac Sprue
  – 3% of Sprue patients have PBC
 Bilesalt 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 cholangio-
    pancreatography 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.

								
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