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					Viral Hepatitis:
  A C E
                Clinical Terms
 Hepatitis: inflammation of liver; presence of
  inflammatory cells in organ tissue
 Acute Viral Hepatitis: symptoms last less than 6 months
 Acute Hepatic Failure: Massive hepatic necrosis with
  impaired consciousness within 8 wks of onset of illness.
 Chronic Hepatitis: Inflammation of liver for at least 6
 Cirrhosis: Replacement of liver tissue fibrosis, scar
 Fulminant Hepatitis: severe impairment of hepatic
  functions or severe necrosis of hepatocytes in the
  absence of preexisting liver disease
Targets of the Hep viruses are hepatocytes:
 Hepatocyte uptake involves a receptor on the
   plasma membrane of the cell
 After entry into the cell, viral RNA is uncoated, and
   host ribosomes bind to form polysomes. Viral
   proteins are synthesized, and the viral genome is
   copied by a viral RNA polymerase
 Minimal cellular morphologic changes result from
   hepatocyte infection
 Lymphocytic infiltrate; varying degree of necrosis.
     Classic presentation:
      infectious hepatitis
 Phase 1 - Viral replication; Patients are
  asymptomatic during this phase.
 Phase 2 – Prodromal
 Phase 3 - Icteric phase
 Phase 4 - Convalescent phase;
  symptoms and icterus resolve. Liver
  enzymes return to normal.
          Clinical Evaluation: Acute Viral
1. Prodromal phase:
 Patients experience anorexia, nausea, vomiting, alterations in taste, arthralgias,
     malaise, fatigue, urticaria, and pruritus. Some develop an aversion to cigarette
 When seen by a health care provider during this phase, patients are often
     diagnosed as having gastroenteritis or a viral syndrome.

2. Icteric Phase
 Jaundice, Patients may note dark urine, followed by pale-colored stools.
 In addition to the predominant gastrointestinal symptoms and malaise, patients
     become icteric and may develop right upper quadrant pain with hepatomegaly.

 Severe cases may result in Fulminant Hepatitis:
 1.Hepatic Encephalopathy: B/L asterixis, palmar erythema
 2.Hepatorenal syndrome
 3.Bleeding diathesis
      Clinical Evaluation:
       Chronic Hepatitis
- Occurs after acute Hepatitis in >80% of
  people with HCV
- Some are asymptomatic, or have mild
  symptoms; others may only present
  with late complications (cirrhosis/HCC)
- Categorized based on grade of
  inflammation, stage of fibrosis, and
  etiology of disease
               Physical Exam
 Low-grade fever.

 Significant vomiting and anorexia  dehydration such as
  tachycardia, dry mucous membranes, loss of skin turgor, and
  delayed capillary refill.

 Icteric phase: icterus of the sclerae or mucous membranes
  or discoloration of the tympanic membranes.

 The skin may be jaundiced and may reveal urticarial rashes.
 Liver may be tender and diffusely enlarged with a firm, sharp,
  smooth edge.
Imaging Studies
 No specific imaging studies needed for diagnosis
 Obtain the appropriate diagnostic imaging studies (eg, ultrasound, CT) if
   the differential diagnosis favors gallbladder disease, biliary obstruction,
   or liver abscess.

Liver biopsy usually in cases of:
     o The diagnosis is uncertain.
     o Other coinfections or disease may be present.
     o The patient is immunocompromised.
     o Asses severity of chronic hepatitis B or chronic hepatitis C.

Histologic Findings
Lymphocytic infiltration, moderate degrees of inflammation and necrosis, and
    portal or bridging fibrosis are noted. Regenerative nodules are seen in
    patients with cirrhosis.
apoptotic   Clustered hepatocytes with ballooning
hepatocytes degeneration (clear vacuolated cytoplasm)
                 Lab Studies:
•LFT: Elevation of serum transaminases not diagnostic, but useful
a)ALT elevated more than AST
b)Acute Hepatitis: ALT > 1000
c)Chronic HCV: ALT is generally lower than 1000

   * Urine analysis: presence of bilirubin.
   * Serum bilirubin: Total bilirubin may be elevated in infectious
hepatitis. Bilirubin levels higher than 30 mg/dL indicate more severe
   * Alkaline phosphatase: if elevated significantly, consider abscess or
biliary obstruction.
   * Prothrombin time (PT) if prolonged  impaired synthetic function of
the liver.
   * BUN & serum creatinine  decreased renal function suggests
fulminant hepatic disease.
   * Serum ammonia in patients with AMS or other evidence of hepatic
* CBC: lymphocytosis
Abdominal Trauma, Blunt
  Obstruction, Small Bowel
   Aneurysm, Abdominal
 Pediatrics, Gastroenteritis
Cholecystitis and Biliary Colic
 Pediatrics, Intussusception
     Gastritis and PUD
                     Hepatitis A
 Common cause of acute hepatitis
 Single-stranded, positive-sense, linear RNA enterovirus
 Transmission fecal-oral route; Contaminated water and food
 The incubation period of hepatitis A virus is 2-7 weeks,
 AST & ALT levels usually return to reference ranges over 5-20
 High risk  Travellers: vaccinations; passive immunoglobins
  given to those exposed
 Mild self-limited disease and confers lifelong immunity to
  hepatitis A virus. Chronic infection with hepatitis A virus does
  not occur.
 Treatment: supportive
           Diagnosis: HAV
 **Serum Serology: presence of serum
  antigens and immunoglobins
 HAV: IgM anti-HAV: positive at the time of
  onset of symptoms; results remain positive
  for 3-6 months after the primary infection
 Anti-HAV IgG appears soon after IgM and
  generally persists for many years.
               Hepatitis C
 Spherical, enveloped, single-stranded RNA virus
  (Flavivirus genus)
 Incubation period: 7-8 wks
 170 million infected worldwide
 Major cause of chronic hepatitis in U.S.
 More common in Hispanic, AA population;
  females have better outcome
 Parenteral Transmission: IV drug users
 Most common indication for liver transplantation
                  Hepatitis C
 Usually clinically mild, does not cause significant
  acute illness
 Fluctuating elevations of AST & ALT
 20% likelihood of developing cirrhosis
 50% likelihood of developing chronic hepatitis
 Incubation period: 15-150 days, with symptoms
  developing anywhere from 5-12 weeks after
              Diagnosis: HCV
 HCV: Anti-HCV; cannot distinguish acute from chronic
 EIA: antibodies against core protein and nonstructural
   proteins; may appear 3 – 5 months after infection
PCR: used to detect viral RNA  HCV
80% of cases: patients are asymptomatic and do not develop
Treatment: Interferon alpha, Ribavirin; PEG-IFNs (better
   sustained absorption, a slower rate of clearance, and a
   longer half-life than those of unmodified IFN)
              Hepatitis E
 Hepatitis E virus (HEV) RNA virus of the
  genus Hepevirus
 Enterically transmitted infection; fecal-oral
  route, typically self-limited
 Most outbreaks occur in developing
 Symptoms of acute hepatitis
 Incubation period of hepatitis E virus is 2-9
 Case fatality rate is 4%
     Hepatitis E: diagnosis
 Serum, liver, and stool samples can be
  tested for HEV RNA
 Anti-HEV antibodies:
- IgM (acute)
- IgG (chronic)
AST & ALT are elevated several days before
  the onset of symptoms; return to normal
  within 1-2 months after the peak severity
  of disease.
Treatment: supportive
A 61 yo F is brought to the ER, drowsy and disoriented,
only able to follow simple commands. On PE, her
abdomen is distended and non-tender and she is
jaundiced. In her purse, the physician finds
prescriptions for peginterferon and ribavirin. When
asked to raise her hands, the physician notes a coarse
tremor. Lab values show ALT = 93U/L, AST = 89U/L,
total bilirubin = 3.1 mg/dL, and ammonia =
124microg/dL. What is the most likely diagnosis?

A. Bleeding esophageal varices
B. Hepatic encephalopathy
C. Hepatocellular carcinoma
D. Hepatorenal syndrome
E. Spontaneous bacterial peritonitis
Hepatitis: B & D
   Robert Leahy
           Hepatitis B(HBV)--
 HBV is a DNA virus that belongs to the hepadnavirus
 2 billion people worldwide have past or present
 400 million people are chronic HBV carriers.
 Eight genotypes of HBV identified and re-labeled A
  through H.
 HBV is the cause of 60% to 80% of worldwide
  Hepatocellular Carcinoma(HCC).
 500,000 to 1 million deaths worldwide are attributed to
 5% to 10% of all liver transplants are attributed to HBV.
          AT Risk Groups
 IV drug users
 People receiving multiple blood transfusions
 Sexual promiscuity
 People in contact with HBV carriers
 Travelers to endemic areas of South
  America, Southern Asia, and Africa
 Resident and employees of residential care
 Health Care Workers
Transmission 3 main ways:

 Parenterally/percutaneous route----IV
  Drug Users, needle sticks,
  Hemodialysis patients

 Sexually

 Vertical/ Perinatal route
HBsAg                   Serology
 Present in acute of chronic infection
 Detectable 1 to 2 weeks after infection

 Appears shortly after HBsAg
 Indicates viral Replication and Infectivity

 Present after vaccination or clearance of HBsAg(Usually 1 to 3
 Indicates immunity to HBV

Hb core Antibody (IgM anti-Hbc or IgG anti-HBc)
 Only Serological marker of HBV during "Window Period"
                Clinical Presentation activity
Acute Hepatitis B - less than 6 months; Based on significant aminotransferase
    due to necro inflammatory injury
    Symptoms are often non-specific symptoms such as myalgia, malaise , nausea,
    fatigue , pruritus, abdominal pain, RUQ, jaundice
    Fulminant Hepatitis--Acute HBV results in Liver Failure

Chronic Hepatitis B - greater than 6 months; Based on grade, stage, and etiology.
    Fibrosis and Necroinflammatory processes; can last for decades
 Immune tolerant--High viral replication, NL liver enzymes, low inflammation and
    fibrosis. Seen in children or those affected early in life.
 Immune active--High Liver enzymes and High HBV DNA and HBeAg, Active
 Carrier State with low replication
       Seroconversion from HBeAg to HBeAB
       Low HBV levels, NL liver enzymes, Reduced Liver inflammation
       Low risk for developing of HCC
 Clinical Presentation cont.
Chronic HbeAg negative
 HBV DNA high, Liver enzymes high,
  No HbeAg
 Seen in late phase of HBV

 Viral clearance of HBV DNA
 Serology

 Liver Chemistry tests
    AST, ALT, ALP, and total Bilirubin

 Histology--Immunoperoxidase staining

 HBV Viral DNA--Most accurate marker of viral
  DNA and detected by PCR

 Liver Biopsy--to determine grade(Inflammation)
  and stage(Fibrosis) in chronic Hepatitis
 Incubation Period: 30-180 days

 Acute HBV Infection: 90% resolve by themselves; less
  than 1% develop fulminant hepatitic failure

 Chronic HBV Infection: 2-10% progress to chronic state
    90% in children less than five progress to chronic state
    Risk of Liver Cirrhosis: 5 year accumulation risk of 8%
     to 20%
    5% to 10% of people progress to HCC with or without
     preceding cirrhosis; less than 5% achieve a chronic
     carrier state
1) Interferon therapy – First Line

 Method of action is the inhibition of viral replication of cells thus
  assisting the immune system

 Interferon alpha: TX: SUB-Q 5 million units q D or 10 million
  units 3x weekly Sub-Q

 Side effects: "Flulike Symptoms", alopecia, rash, diarrhea
    pINF-alpha(pegylated interferon-alpha): 180ug q weekly
    Better Choice than IFN-Alpha--Greater
      Bioavailability, Longer half life, Better treatment schedule
                        Treatment cont.
2) Nucleoside Analogues -- Lamivudine, Entecavir, Telbivudine
     Method of action is the inhibition of viral reverse transcriptase

     Lamivudine
        Dose : 100 mg PO q daily
        Good for reducing the risk of progression to hepatic decompensation in patients with
           cirrhosis or advanced fibrosis
        Pregnancy category B--Not teratogenic in animal studies and successful use with
           pregnant women
        Problem: High rates of resistant mutations
        Side effect: lactic acidosis

     Entecavir – 1st line
        0.5 to 1mg PO
        very effective; low resistance and greater than 90% HBV DNA clearance rate in HBeAG
            positive Px's.
        more effective than lamivudine
        Side effect: lactic acidosis
     Telbivudine
        Dose: 600mg q daily
        Worse resistant profile than Entecavir
        Side effect: lactic acidosis
             Treatment cont.
3) Nucleotide analogues
    Method of action is the inhibition of viral reverse
 Tenovir
      Dose: 300mg qd
      Highly effective with low resistance
      Well tolerated

 Adefovir – 1st line
    Dose: 10mg daily
    Resistance less than Tenovir
    Side effect: nephrotoxicity and lactic acid
    Medication Guidelines
 Optimal treatment duration not yet

 Interferon drugs don't have resistance
  issues unlike the antivirals
    When to Treat for Chronic
1) HBeAg positive
  HBV DNA(copies/ml)                 ALT                    Recommendation
<105                       Normal                       No treatment , monitor,
                                                        considered inactive
>105                       Normal                       No treatment, current tx is
                                                        limited benefit
>105                       Elevated (greater than 2 x   Oral Agents, not PEG IFN
+ or - and compensated     Normal or elevated           Oral Agents, not PEG IFN
+ or - and uncompensated   Normal or elevated           Oral agents and refer for
cirrhosis                                               treatment
   When to Treat for Chronic
2)HBeAG negative Hepatitis
  HBV DNA(copies/ml)                 ALT           Recommendation

<104                      Normal               No tx necessary, inactive
>104                      Normal               Liver Biopsy , treat
                                               if abnormal
>104                      Elevated             Oral agents or PEG IFN
+ or - w/ compensated     Elevated or normal   Oral agents, not PEG IFN
+ or - w/ uncompensated   Elevated or normal   Oral agents, not PEG IFN
HBV Vaccine
 Indicated for everyone and especially those in high risk groups
      IM injection at 0,1,6 months in infants and adults
      Response greater than 90% after 3rd dose

HBV Pregnant Mothers
 Give 1st dose of Hip B vaccine and Hip B Immunoglobulin(HBIG) o.5 ml within
    12 hours of birth.
      2nd dose at 1 month, 3rd at 6 months
      Recheck at 12 months for active infection
      95% lifetime immunity
      Not Done---leads to 90% chronic HBV
      Transmitted through birth canal during birth or through umbilical cord.

Others i.e. those receiving a needle stick
 Should receive 0.04 to 0.7 ml/kg of HBIG and 1st dose vaccine within 48 and
    no later than a week.

 Last resort for those with advanced
  Liver Disease and HCC due to
                HEPATITIS D
 Only as co-infection with acute HBV or with superinfection in
    chronic HBV carrier
      Requires outer envelope of HBsAG for replication and
      Can progress to chronic disease
      Incubation Period 30to 150 days

 Hepatitis D antibody (Anti-HDV)
      Indicates HDV superinfection
      Ab not always present in acute infection---requires repeat
                     HEPATITIS D
Risk Factors - Same high risk groups as those for Hip B

Prevention - Avoidance of Hip B and/or Hip B vaccine

DX - HDV antigen in serum or finding Ab to HDV antigen

 Coinfection-self limited
 Superinfection-acute HBV carriers present with severe acute hepatitis
      infection w/ increased risk for HDV infection.

Fatality Rate - 2% to 10%

Cirrhosis – None

 Other Causes of Hepatitis

 Alcoholic Hepatitis
 Drug induced Hepatitis
 Autoimmune Hepatitis
 Ischemic Hepatitis
A hepatitis panel is ordered for a 27 year old
   female as part of a routine workup for
   abdominal pain. Results of serological
   testing a negative for HBeAg and HBsAg,
   but positive for HBsAb and IgG HBcAb. The
   patient has been exposed to Hep B.
a. Patient has recovered
b. Patient is in acute infective disease state
c. Window period
d. Chronically infected
e. Patient was never infected
1)The Washington Manual of Medical

2)Harrison's Principles of Internal

3)Step up to Medicine