Hepatitis A

1
Hepatitis A

• The virus that does not cause chronic liver
  disease

2
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

3
Risk Factors

• Sexual or household contact
• International travel
• Men who have sex w/ men (MSM)
• Intravenous drug abuse (IVDA)
• Daycare

4
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

5
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

6
Clinical Features

• Incubation is usually 2 to 4 weeks, rarely 6
  weeks
• Complete recovery within 2 months for gt 50
• Within 6 months for almost all others

7
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

8
Clinical Features

• Asymptomatic lt 2 year old
• Symptomatic 5 and older ill about 8 weeks
• Cholestatic jaundice lasts gt 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

9
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

10
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

11
PreventionImmunization

• 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

12
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

13
Hepatitis A Vaccine

• The vaccine is inactivated HAV
• Schedule for 2 18 years depends upon the
  manufacturer
• Havirx 720 EL U/.5mL _at_ 0, 6-12 mo
• Vaqta 25 U.5mL _at_ 0, 6-18 mo

14
Hepatitis A Vaccine

• For those over age 18
• Havirx 1440 EL U/1mL _at_ 0, 6-12 mo
• Vaqta 50 U/1mL _at_ 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

15
Questions?
16
Hepatitis B
17
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

18
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

19
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

20
Epidemiology

• Prevalence of HBV varies markedly around the
  world, w/ gt 75 of cases in Asia and the Western
  Pacific
• Vaccine available gt 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 gt 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 gt
  1 million deaths each year

21
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

22
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

23
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
  -gtchronic hepatitis and is the result of a
  compromised (newborn/HIV) or relatively tolerant
  immune system status

24
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

25
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)

26
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 lt 1 of cases.
  80 mortality without liver transplantation
• Enzyme elevations of 1,000-2,000 typical

27
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

28
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

29
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

30
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

31
Treatment

• Six approved medications as of July 2008
• Interferon alpha
• Pegylated interferon
• Lamivudine
• Adefovir Dipivoxil
• Entecavir
• Telbivudine
• Tenofovir approved
• Refer to hepatologist

32
The Cholestatic Liver Diseases

• Adults

33
Cholestatic Liver DiseaseEtiologies

• Immune Mediated PBC, PSC, autoimmune
  cholangitis, liver allograft rejection,
  graft-versus-host disease
• Infectious acute viral hepatitis
• Genetic and Developmental cystic fibrosis,
  Alagilles syndrome (syndrome w/ paucity of
  intrahepatic bile ducts), fibro polycystic liver
  disease

34
Cholestatic Liver DiseaseEtiologies

• Neoplastic Cholangiocarcinoma
• Drug-Induced Ductopenia amoxicillin,
  amitriptyline, cyproheptadine, erythromycin,
  tetracycline, thiabendazole
• Ischemic
• Idiopathic

35
Pathogenesis of Cholestatic Disorders

• Immune response (inflammation, auto-antibody) or
  hepatotoxic injury to bile ducts
• Bile duct injury by bile acids - gt
• Retention of bile acids in hepatocytes - gt
• Liver cell damage, apoptosis, necrosis, fibrosis,
  cirrhosis - gt liver failure

36
(No Transcript)
37
(No Transcript)
38
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)

39
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.

40
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

41
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

42
1. Primary Biliary CirrhosisA chronic and
progressive disease of unknown etiology affecting
primarily middle-aged women
43
Primary Biliary Cirrhosis

• Affects all races
• 91 ratio female gt male, age 20 65
• Characterized by small intrahepatic bile duct
  destruction and cholestasis
• In the presence of cirrhosis, male gt likely than
  female to develop hepatocellular carcinoma

44
PBCLaboratory Findings

• Alk Phos 2x to 20x ULN in gt 90 of patients
• AST-ALT 1x to 5x ULN gt 90
• Bilirubin variable. When elevated, may indicate
  advanced cirrhosis or 2nd condition
• Hypercholesterolemia in 80 of patients

45
Hypercholesterolemia Unique in PBC

• Hypercholesterolemia
• No obvious increase in heart disease
• Some lipid lowering agents cause rise
• Cholestyramine or Urso may mobilize cholesterol
  deposits

46
PBCLaboratory Findings

• IgM 1x to 5x ULN gt 90
• Anti mitochondrial antibody gt 120 titer gt90
• Anti nuclear and/or smooth muscle antibody gt 180
  may be seen in overlap syndrome
• Liver biopsy helpful to grade and stage disease,
  determine if cirrhosis present

47
PBC Treatment

• Slowly progressive, even if asymptomatic
• Ursodeoxycholic acid only effective therapy. May
  improve natural history
• Transplant curative
• Manage disease specific complications

48
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

49
Monitor for and Treat PBC Associated Disorders

• Keratoconjunctivitis Sicca
• Scleroderma, CREST syndrome
• Gallstones
• Arthropathies
• Rheumatoid, psoriatic arthritis, Raynauds
  phenomenon, Hypertrophic osteodystrophy,
  Avascular necrosis, Chondrocalcinosis
• Thyroid disease, renal tubular acidosis

50
PBC Associated Disorders

• Malabsorption
• Celiac Sprue
• 6 of PBC patients have Celiac Sprue
• 3 of Sprue patients have PBC
• Bile salt deficiency
• Pancreatic insufficiency

51
Manage PBC Complications

• Standard liver disease recommendations
• PBC specific symptom management
• Refer for liver transplantation

52
Primary Sclerosing CholangitisRare

• 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

53
Primary Sclerosing CholangitisPSC

• 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

54
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

55
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

56
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

57
(No Transcript)
58
PSC Clinical Features

• Histology
• Liver biopsy for staging the disease
• Liver biopsy to rule out other potentially
  treatable causes of cholestasis

59
(No Transcript)
60
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

61
PSCAssociated Diseases

• Inflammatory bowel disease, most often ulcerative
  colitis
• These patients have increased risk for colorectal
  carcinoma
• 25 have another autoimmune disease

62
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

63
PSC Disease Specific Complications

• Fever
• Abdominal pain
• Dominant stricture
• Gall stones
• Cholangiocarcinoma

64
PSC Prognosis

• Factors of Importance
• Older age
• Increasing bilirubin
• Histological advanced stage
• Child-Pugh-Turcotte Class C

65
PSC Treatment Goal Improve Quality of Life

• Medical support
• Endoscopic treatments
• Surgical interventions
• Liver transplantation PSC recurrence is more
  frequent than PSC

66
Case Study

• Asymptomatic elevation in AP noted on routine lab
• Middle aged male w/ Hx ulcerative colitis on
  mesalamine
• 59 209
• -----------------------------------------lt 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

67
Reference

• Broome, U and Berguist. Primary sclerosing
  cholangitis. In Zakim and Boyers Hepatology A
  textbook of liver disease, 5th Ed., Boyer, T.D.,
  Wright, T.L., Mans, M.P. Saunders Elsevier
  Canada, 821-854.