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
months
 Cirrhosis: Replacement of liver tissue fibrosis, scar
tissue
 Fulminant Hepatitis: severe impairment of hepatic
functions or severe necrosis of hepatocytes in the
absence of preexisting liver disease
Pathophysiology
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 Hepatitis
1. Prodromal phase:
 Patients experience anorexia, nausea, vomiting, alterations in taste, arthralgias,
malaise, fatigue, urticaria, and pruritus. Some develop an aversion to cigarette
smoke.
 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.
Acute hepatitis: histopathology
Lymphocytes
surround
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
disease.
* 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
encephalopathy.
* CBC: lymphocytosis
Differentials:
Abdominal Trauma, Blunt
Obstruction, Small Bowel
Aneurysm, Abdominal
Pancreatitis
Cholangitis
Pediatrics, Gastroenteritis
Cholecystitis and Biliary Colic
Pediatrics, Intussusception
Cholelithiasis
Gastritis and PUD
Gastroenteritis
Hepatitis A
 Common cause of acute hepatitis
 Single-stranded, positive-sense, linear RNA enterovirus
(Picornaviridae)
 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
weeks.
 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
exposure.
Diagnosis: HCV
 HCV: Anti-HCV; cannot distinguish acute from chronic
infection
 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
icterus.
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
countries.
 Symptoms of acute hepatitis
 Incubation period of hepatitis E virus is 2-9
weeks
 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)--EPIDEMIOLOGY
 HBV is a DNA virus that belongs to the hepadnavirus
family.
 2 billion people worldwide have past or present
infections
 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
it.
 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
facilities
 Health Care Workers
Pathophysiology
Transmission 3 main ways:
 Parenterally/percutaneous route----IV
Drug Users, needle sticks,
Hemodialysis patients
 Sexually
 Vertical/ Perinatal route
Serology
HBsAg
 Present in acute of chronic infection
 Detectable 1 to 2 weeks after infection
HBeAg
 Appears shortly after HBsAg
 Indicates viral Replication and Infectivity
HBsAB(Anti-HBS)
 Present after vaccination or clearance of HBsAg(Usually 1 to 3
months)
 Indicates immunity to HBV
Hb core Antibody (IgM anti-Hbc or IgG anti-HBc)
 Only Serological marker of HBV during "Window Period"
Clinical
Presentation
Acute Hepatitis B - less than 6 months; Based on significant aminotransferase activity


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
Replication
 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
Resolution
 Viral clearance of HBV DNA
Diagnosis
 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
Progression
 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
Treatment
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
SUB-Q
 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
transcriptase
 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
defined
 Interferon drugs don't have resistance
issues unlike the antivirals
When to Treat for Chronic
Hepatitis
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
ULN)
Oral Agents, not PEG IFN
+ or - and compensated
cirrhosis
Normal or elevated
Oral Agents, not PEG IFN
+ or - and uncompensated
cirrhosis
Normal or elevated
Oral agents and refer for
treatment
When to Treat for Chronic
2)HBeAG negative
Hepatitis
HBV DNA(copies/ml)
ALT
Recommendation
<104
Normal
No tx necessary, inactive
carrier
>104
Normal
Liver Biopsy , treat
if abnormal
>104
Elevated
Oral agents or PEG IFN
+ or - w/ compensated
cirrhosis
Elevated or normal
Oral agents, not PEG IFN
+ or - w/ uncompensated
cirrhosis
Elevated or normal
Oral agents, not PEG IFN
Prophylaxis
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.
Transplant
 Last resort for those with advanced
Liver Disease and HCC due to
infection
HEPATITIS D
Transmission
 Only as co-infection with acute HBV or with superinfection in
chronic HBV carrier
 Requires outer envelope of HBsAG for replication and
transmission
 Can progress to chronic disease
 Incubation Period 30to 150 days
Serology
 Hepatitis D antibody (Anti-HDV)
 Indicates HDV superinfection
 Ab not always present in acute infection---requires repeat
testing
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
Clinical
 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
TX:IFN-alpha
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
Sources
1)The Washington Manual of Medical
Therapeutics
2)Harrison's Principles of Internal
Medicine
3)Step up to Medicine