This document discusses various types of viral hepatitis including hepatitis A, B, C, D and E. It describes the causative viruses, modes of transmission, clinical features, diagnosis and potential outcomes of each type of viral hepatitis. Hepatitis A virus causes an acute, self-limiting form of hepatitis while hepatitis B, C and D can potentially lead to chronic liver disease and cirrhosis. Differentiating the types of viral hepatitis requires considering aspects such as incubation period, routes of transmission, risk factors and specific laboratory markers.

1. JAUNDICE PA25.1

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3.  Destruction of senescent RBC
 Cytochrome P450
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11. Causes
Intra hepatic Obstruction
1.Biliary atresia
2.Primary Biliary Cirrhosis
3.Malignant infiltration of ducts
Extra hepatic Obstruction
1.Gallstones impacted in the
bile ducts
2.Cancer (pancreatic and
gallbladder/bile duct
carcinoma)
3.Strictures of the bile ducts
4.Pressure on the common bile
duct from enlarged lymph
nodes
5.Cholangitis,
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12. Features of disease Crigler-Najjar
syndrome I
Crigler-Najjar
syndrome II
Gilbert’s
Syndrome
Mutation in UGT
gene
Present Present Present
Enzyme activity No activity is
recorded
Some activity 30 %
Bilirubin level Exceeds 20mg/dl less than
20mg/dl
Less than
5mg/dl
Prognosis Very bad, death
within 2 years
Good Harmless
Treatment Phototherapy
Liver
transplantation is
curative
Responds to
phenobarbitone
No treatment
needed
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13. DUBIN-JOHNSON
SYNDROME ROTOR SYNDROME
 This benign autosomal recessive
 Conjugatedhyperbilirubinemia in
childhood or during adult life.
 mutations in the gene encoding
MRP-2 the protein involved in the
secretion of conjugated bilirubin
into bile.
 The centrilobular hepatocytes
contain an abnormal black pigment
that may be derived from
epinephrine.
 This is a rare benign
condition characterized
by chronic conjugated
hyperbilirubinemia and
normal liver histology.
 Its precise cause has not
been identified, but it is
thought to be due to an
abnormality in hepatic
Storage
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14. Blood Parameters Prehepatic Post -Hepatic Hepatic
Total bilirubin Increased Increased Increased
Direct Bilirubin Normal / low Increased Depends on stage
Indirect Bilirubin Increased Normal /Low Depends on stage
ALT Normal Normal / + Elevated ++++
AST Normal Normal/+ Elevated++++
ALP Normal Elevated ++++ Normal/ ++
GGT Normal Elevated ++++ Normal /++
Prothrombin time Normal Elevated in marked
damage but responds
to Vit K inj
Elevated in marked
damage but won’t
respond to Vit K inj
ALT --- Alanine Transaminase
AST------Aspartate Transaminase
ALP -------Alkaline Phosphatase
GGT ----Gamma Glutamyl Transferase
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15. Urinary
parameters
Pre- Hepatic Post - Hepatic Hepatic
Color Colorless Coke color Dark yellow
Bilirubin Not present +++++ ++
Urobilinogen +++++ Absent Normal /++
Bile Salts Absent +++++ ++
Stool
Color Dark Brown Milky white Dark Brown
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16. Bilirubin
• It is a bile pigment derived from heme
• Detoxified and excreted by liver by conjugation
• It exists in two forms
• Conjugated
• Unconjugated
Reference range:
• Total- 0.2-1 mg/dl
• Conjugated -0.1-0.4 mg/dl
• Unconjugated-0.2-0.7 mg/dl

19. PA25.3
TOXIC AND VIRAL HEPATITIS

20. Competency 25.3
 Describe the etiology and
pathogenesis of viral and toxic
hepatitis: distinguish the causes of
hepatitis based on the clinical and
laboratory features. Describe the
pathology, complications and
consequences of hepatitis
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21. Specific learning Objectives
 List the organisms that causes
Hepatitis
 List the Hepatotropic and non –
hepatotropic viruses
 Describe the Etiology, Pathogenesis,
Morphology, Clinical features and
laboratory markers in viral hepatitis
 Drug induced hepatitis – types and
implicated drugs with a note on
morphology 10/10/2023

22. MICROBIAL INFECTIONS TO
LIVER
 Bacteria, Virus, fungi, helminths,
and other parasites/protozoa can
involve the liver and biliary tree as
localized infections or as part of a
systemic disease.
 Bacterial infections include
Staphylococcus aureus in toxic shock
syndrome, Salmonella typhi in typhoid
fever, Treponema pallidum in
secondary or tertiary syphilis, and
Bartonella henselae in cat scratch
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23. MICROBIAL INFECTIONS IN
LIVER
 Fungal (histoplamosis) and
mycobacterial infections
 Parasitic and helminthic infections
include malaria, schistosomiasis,
strongyloidiasis, cryptosporidiosis,
leishmaniasis, echinococcosis,
amebiasis
 Infections by the liver flukes Fasciola
hepatica, Opisthorchis species, and
Clonorchis sinensis
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24. VIRAL HEPATITIS
 HEPATOTROPIC
VIRUSES
 HEPATITIS A
 HEPATITIS B
 HEPATITIS C
 HEPATITIS D
 HEPATITIS E
 NON –
HEPATOTROPIC
VIRUSES
 Epstein-Barr
virus
 Cytomegalovirus
 herpes simplex
virus
 Adenovirus
 yellow fever virus
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25. viral hepatitis
 Acute viral hepatitis is diffuse liver inflammation
caused by specific hepatotropic viruses that have
diverse modes of transmission and epidemiologies.
 Most cases resolve spontaneously, but some
progress to chronic hepatitis or occasionally, to
acute hepatic failure (fulminant hepatitis).

26. Virus Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
Type of virus ssRNA
partially
dsDNA
ssRNA
Circular
defective ssRNA
ssRNA
Viral family
Hepatovirus;
related to
picornavirus
Hepadnavirus Flaviridae
Subviral particle
in Deltaviridae
family
Calicivirus
Route of
transmission
Faecal-oral
(contaminated
food or water)
Parenteral,
sexual contract,
perinatal
Parenteral;
intranasal
cocaine use is a
risk factor
Parenteral Fecal-oral
Mean
incubation
2–4 weeks 1–4 months 7–8 weeks Same as HBV 4–5 weeks
Frequency of
chronic liver
disease
Never 10% ~80%
5%(coinfection)
<70% for
superinfection
Never
Diagnosis
Detection of
serum IgM
antibodies
Detection of
HBsAg or
antibody to
HBcAg
PCR for HCV
RNA;
3rd-generation
ELISA for
antibody
detection
Detection of
IgM and IgG
antibodies; HDV
RNA serum;
HDAg in liver
PCR for HEV
RNA; detection
of serum IgM
and IgG
antibodies

27. Clinical syndromes
1. acute asymptomatic infection with recovery
(serologic evidence only);
2. acute symptomatic hepatitis with recovery,
anicteric or icteric;
a. an incubation period,
b. a symptomatic preicteric phase,
c. a symptomatic icteric phase, and
d. convalescence.
3. chronic hepatitis, without or with progression
to cirrhosis; and
4. fulminant hepatitis (massive/submassive
necrosis)

29. Hepatitis A
 Positive-strand RNA picornavirus (hepatovirus)
 A benign, self-limited disease with an incubation
period of 3 to 6 weeks.
 Most common cause of acute viral hepatitis particularly
among children and young adults
 HAV does not cause chronic hepatitis or a carrier
state and rarely causes fulminant hepatitis,
 The fatality rate associated with HAV is about 0.1%
 HAV vaccine, available since 1992, is effective in
preventing infection

30. Transmission of HAV
 HAV is spread by ingestion of contaminated
water and foods and is shed in the stool for 2 to
3 weeks before and 1 week after the onset of
jaundice.
 Close personal contact with an infected
individual or faecal-oral transmission
accounts for most cases (the outbreaks in
schools and nurseries, and the water-borne
epidemics in overcrowded places)
 Sporadic infection on consumption of raw
shellfish
 Because HAV viremia is transient, blood borne
transmission of HAV occurs only rarely;

31. Hepatitis A
Specific IgM
antibody appears at
the onset of
symptoms,
constituting a
reliable marker of
acute infection;
Fecal shedding of the
virus ends as the IgM
titer rises. The IgM is
followed by of IgG
anti-HAV conferring
lifelong immunity.

32. HBV
2nd most common cause of acute viral hepatitis.
It can produce
1. acute hepatitis with recovery & clearance of
the virus,
2. Non-progressive chronic hepatitis,
3. progressive chronic disease ending in
cirrhosis,
4. fulminant hepatitis with massive liver
necrosis, and
5. carrier state.
 HBV-induced chronic liver disease is an
important precursor for the development of
hepatocellular carcinoma.

33. Transmission
 In high prevalence regions of the world,
perinatal transmission during childbirth
accounts for 90% .
 In areas with intermediate prevalence,
horizontal transmission through minor cuts
and breaks in the skin or mucous
membranes among children with close bodily
contact.
 In low prevalence areas (US etc.), unprotected
heterosexual or homosexual intercourse and
IV drug abuse (sharing of needles and syringes).
 transfusion-related spread has become
uncommon

34. Hepatitis B
 One third of the world population (2 billion
people) have been infected with HBV,
 400 million people have chronic infection.
 75% of chronic carriers in Asia & Western
Pacific rim.
 Prevalence varies widely according to several
factors, including geography (e.g., < 0.5% in
North America and northern Europe, > 10% in
some regions of the Far East & Africa).
 HBV is sometimes associated polyarteritis
nodosa and other connective tissue diseases,
membranous glomerulonephritis,
cryoglobulinemia.

35.  Nucleocapsid “core”
protein (HBcAg)
 Longer polypeptide with
precore & core region
(HBeAg)
 Envelope glycoproteins
(HBsAg, surface Ag),
 A polymerase (Pol) with
DNA polymerase &
reverse transcriptase
activity.
 HBx protein, which is
necessary for virus
replication
The infective particle consists of a
viral core plus an outer surface
coat. The core contains circular
double-stranded DNA and DNA
polymerase, and it replicates within
the nuclei of infected hepatocytes

36. Potential outcomes of hepatitis B
infection in adults, with their
approximate frequencies

37. Anti-HBs antibody does not rise until the acute disease is
over. Anti-HBs may persist for life, conferring protection (the
basis for current vaccination strategies using non-infectious
HBsAg)
Persistence of HBeAg is an important indicator of continued
viral replication, infectivity, and probable progression to
chronic hepatitis. The appearance of anti-HBe antibodies implies
that an acute infection is on the wane.

38. HBV
 Strong response by virus-specific CD4+ and
CD8+ interferon γ-producing cells is associated
with the resolution of acute infection.
 HBV may not cause direct hepatocyte injury.
Hepatocyte damage is believed to result from
damage to the virus-infected cells by CD8+
cytotoxic T cells
 Can be prevented by vaccination & by the
screening of donor blood, organs, and tissues.
The vaccine is prepared from purified HbsAg
produced in yeast. Vaccination induces a
protective anti-HBs antibody response in 95% of
infants, children, adolescents

39. HCV
 Approximately 170 million people affected
 This makes HCV the most common chronic
blood-borne infection
 In contrast to HBV, progression to chronic
disease occurs in the majority of HCV-infected
individuals, and cirrhosis eventually occurs in
20% to 30% of individuals with chronic HCV
infection
 The most common indication for liver
transplantation.

40. Risk factors for HCV infection
1. Intravenous drug abuse (54%)
2. Multiple sex partners (36%)
3. Having had surgery within the last 6 month (16%)
4. Needle stick injury (10%)
5. Multiple contacts with HCV-infected person (10%)
6. Employment in medical or dental fields (1.5%)
7. Unknown (32%)
 The risk of acquiring HCV by needle sticks is
about six times higher than that for HIV (1.8 vs.
0.3%).

41. • HCV, is a member of the Flaviviridae family.
• Small, enveloped, single-stranded RNA virus with
a 9.6- kilobase (kb) genome that codes for a
single polyprotein, which is subsequently
processed into functional proteins
• nucleocapsid core protein;
• envelope proteins E1 and E2;
• Protein, p7, is believed to function as an ion channel;
• six nonstructural proteins: NS2, NS3, NS4A,
NS4B,NS5A, and NS5B.
• NS5B is the viral RNA-dependent RNA
polymerase.

42. LIFE CYCLE OF HEPATITIS
C
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43. HCV
 The virus is inherently unstable, giving rise to
multiple genotypes and subtypes
 The envelope E2 protein is the target of many
anti-HCV antibodies
 Genomic instability & antigenic variability have
hampered HCV vaccine development.
 Elevated titres of anti-HCV IgG occurring after an
active infection do not consistently confer
effective immunity. A characteristic feature of
HCV infection, therefore, is repeated bouts of
hepatic damage,

44. HCV
 The incubation period ranges from 2 to 26
weeks;
 In ~85% of cases, acute infection is
asymptomatic;
 The clinical course of acute HCV hepatitis is
milder than that of HBV; rare cases may be
severe and indistinguishable from HAV or HBV
hepatitis.
 Strong immune responses involving CD4+ &
CD8+ T cells are associated with self-limited
HCV infections,
 Persistent infection and chronic hepatitis are
the hallmarks of HCV infection (80% to 85% of

45. HCV
 Cirrhosis may develop 5 to 20 years after
acute infection in 20-30% of patients with
persistent infection.
 In chronic HCV infection, circulating HCV RNA
persists in many patients despite the presence of
neutralizing antibodies,
 A characteristic clinical feature of chronic HCV
infection is episodic elevations in serum
aminotransferases,
 in persons with chronic hepatitis, HCV RNA
testing must be performed

46. Hepatitis D virus
 HDV, or delta agent, is a defective RNA virus that
can replicate only in the presence of HBV.
 35-nm, double-shelled particle
 Replication is through
RNA-directed RNA synthesis
by host RNA polymerase (Pol II)
 Infection is worldwide with
~15 million affected individuals
(5% of HBV infected)
 Common in Amazonian basin
Africa, Middle East, Italy; rare in SE Asia and
China

47. Hepatitis D
 Acute coinfection following exposure to both
HDV and HBV results in acute hepatitis B + D
 Superinfection in chronic carrier of HBV may
present as severe acute hepatitis (acute phase)
or as chronic phase (may progress to cirrhosis or
HCC)
 independent latent infection occurs in the liver
transplant setting; During this latent phase, there
is no evidence of liver disease
 Elimination of hepatitis B leads to elimination of
HDV.
 IgM anti-HDV is the most reliable indicator of
recent HDV exposure

48. HEV
 A zoonotic disease with animal reservoirs, such as
monkeys, cats, pigs, and dogs; positive-stranded RNA
virus in the Hepevirus genus
 It is an enterically transmitted, water-borne infection
occurring primarily in young to middle-aged adults
 Epidemics have been reported in Asia, the Indian
subcontinent, sub-Saharan Africa, Mexico.
 30% to 60% of sporadic acute hepatitis in India
 high mortality rate among pregnant women, ~20%.
 not associated with chronic liver disease or
persistent viremia

49. Diagnosis
 Liver function tests
(AST and ALT
elevated out of
proportion to alkaline
phosphatase, with
hyperbilirubinemia)
 Viral serologic
testing
 PT measurement

50. Pathology
 “ballooning degeneration”
 Apoptosis, (arrow)
 Lobular disarray
 Cholestasis
 Inflammation (mainly
mononuclear cells) in
portal tract & lobules
 Kupffer cells hyperplasia

51. Chronic hepatitis
 Is defined as symptomatic, biochemical, or serologic
evidence of continuing or relapsing hepatic disease for
more than 6 months.
 HCV is by far the most common cause of chronic viral
hepatitis; HBV infrequently causes
 The most common symptom is fatigue; less common
are malaise, loss of appetite, mild jaundice.
 physical findings - spider angiomas, palmar erythema,
mild hepatosplenomegaly, tenderness,
 prolongation of the PT ; hyperglobulinemia,
hyperbilirubinemia, and mild elevations in alkaline
phosphatase levels.

52. Chronic Hepatitis
 IN HBV & HCV, immune complex vasculitis and
glomerulonephritis are often seen
 Cryoglobulinemia is found in ~ 35% with HCV
 With HBV, chronicity is more frequent in the young .
 Complete cure in HBV is difficult to achieve.
 HCV patients with even no symptoms are at high risk of
developing permanent liver damage. Therefore, any
individual with detectable HCV RNA in the serum
needs medical attention.
 Chronic HCV infection is potentially curable.
Treatment is IFN-α and ribavirin.

53. 10/10/2023
Figure 18.13 Diagrammatic representation of the morphologic features of acute and
chronic hepatitis. Acute hepatitis is characterized by lobular
inflammation and hepatocellular injury, and chronic hepatitis shows dense portal
inflammation. Bridging necrosis can occur in severe acute hepatitis, and
fibrosis is seen in chronic hepatitis. Ductular reaction is often present in areas of fibrosis
in chronic hepatitis.

54. HCV - Chronic Hepatitis
HBV - Hepatocytes with
Ground glass Cytoplasm;
IHC

55. Carrier State
1. Individuals who carry one of the viruses but have no
liver disease;
2. Those who harbour one of the viruses and have
non-progressive liver damage, but are essentially
free of symptoms or disability.
3. In the case of HBV infection, an individual without
HBeAg, but with presence of anti-HBe, normal
minotransferases, low or undetectable serum HBV
DNA, and a liver biopsy showing a lack of significant
inflammation and necrosis

56. Fulminant Hepatic Failure (FHF)
 Viral hepatitis is responsible for ~ 12% of FHF; (8% are
caused by HBV infection and the rest by HAV)
 Occasionally, HCV, herpesvirus infection, and Dengue
virus, acetaminophen toxicity cause FHF. In ~ 15% of
cases, the cause of is unknown.
 The mortality is ~ 80% (without transplant)

57. Characteristics of Hepatitis Viruses
Hepatitis A
Hepatitis
B
Hepatitis
C
Hepatitis
D
Hepatitis E
Nucleic acid RNA DNA RNA * RNA
Serologic
diagnosis
IgM anti-
HA
HBsAg Anti-HCV Anti-HDV Anti-HEV
Major
transmissio
n
Fecal–oral Blood Blood Needle Water
Incubation
period
(days)
15–45 40–180 20–120 30–180 14–60
Epidemics Yes No No No Yes
Chronicity No Yes Yes Yes No
Liver
cancer
No Yes Yes Yes No

58. DRUG INDUCED HEPATITIS
 Direct hepatotoxicity, a dose-
dependent phenomenon of the drug,
or its metabolite, which predictably
affects exposed individuals
 A typical example being
acetaminophen
 common cause of acute liver failure in
the United States.
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59. DRUG INDUCED HEPATITIS
 Idiosyncratic(hypersensitivity)respons
 not dose dependent
 accounts for the majority of drug-
induced liver injury
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60. DRUG INDUCED HEPATITIS
 Clinical features and morphology will
mimic other causes of hepatitis
 Is included in the differential diagnosis
of liver diseases in diverse clinical
setting
 Temporal profile of Drug intake and
duration of illness will help in
diagnosis
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