Viral Hepatitis

Inflammation of the hepatocytes1 caused by hepatotropic viruses (viruses that infect primarily the hepatocytes) :
Virus
HAV
HBV

Nucleic acid
RNA
DNA

HCV

RNA

HDV

RNA
(Incomplete)
RNA

HEV

Virus family
Picornaviridae
Hepadnaviridae
Flaviviruses

Calciviridae

Shape
Sphere
Sphere
Tubules
Dane particles
Sphere

Sphere (doublewalled)

Transmission
Faecal-oral
Parenteral;
close
personal contact

IP
2 - 6 wks
1 - 5 mths

Parenteral;
close
personal contact
Parenteral;
close
personal contact
Faecal-oral
(@Water-borne)

Long
Intermediate
Short

Although these agents can be distinguished by their antigenic properties, all 5 types produce clinically similar
illnesses. These range from asymptomatic and inapparent to fulminant 2 and fatal acute infections common to
all 5 types, on the one hand, and from subclinical persistent infections to rapidly progressive chronic liver
disease with cirrhosis and even hepatocellular carcinoma, common to the blood-borne types (HBV, HCV,
HDV), on the other.
All 5 types asymptomatic & inapparent fulminant & fatal
B,C,D Subclinical persistent infections rapidly progressive CLDs. with cirrhosis & hepatocellular ca.
HEPATITIS A
Was formerly referred to as infectious hepatitis or short-incubation hepatitis. This it the commonest type of
viral hepatitis (20-40% of clinically apparent hepatitis).
Usually affects children and young adults.
Hepatitis A virus
Incubation period : 2 - 6 weeks
HAV causes a benign, acute, self-limited disorder that does not lead to chronicity or to a carrier state. Rarely,
it causes massive liver necrosis
HAV : RNA, picornaviridae family, spherical
MOT : Faecal-oral route (from contaminated food (e.g. shellfish 3) or water by acutely infected person - 3
week infective period.)
(HAV can be identified in the stool of pts. 2 weeks before and 1 week after the onset of clinical illness
(i.e. jaundice).)
Transmission favoured by : Poor personal hygiene, poor sanitation, overcrowding and promiscuous
homosexuals (Thats why lower socioeconomic group are affected more frequently)
Replication : In the gut and the liver
HEPATITIS B
Was formerly known as serum hepatitis or long-incubation hepatitis.
Hepatitis B virus
Incubation period : 1 - 5 months
MOT : Parenteral route - blood (& blood products) transfusion
- IV drug addicts
- hemodialysis and transplantation patients
1

Other viruses - CMV, EBV, Rubella and Yellow fever, can cause hepatitis but they are usually a/w primary
infection of extrahepatic organs. They only account for 1-2% of cases
2
Fulminant - Occurring suddenly, rapidly, and with great severity or intensity
3
Shellfish concentrates the virus from contaminated seawater

- dental & surgical instruments

Body secretion - saliva, seminal fluid, menstrual blood, urine & stool
close personal contact - sexual intercourse, esp. in homosexuals
Vertical transmission 4 - during parturition or soon after birth
Is it true that vertical transmission is not through placenta or milk but through close contact. Meaning to say
that the baby is born uninfected by gets infected post-natally. And is this why babies borned to hepatitis Bpositive mothers are given prophylactic passive immunization?
High risk groups:
1. Health care personnel
2. Patients in hemodialysis units
3. Drug addicts
4. Male homosexuals
5. Armed forces
6. Infants born to carrier mothers
HBV : DNA, hepadnaviridae family
When examined under the electron microscope, 3 types of particles can be seen:
Small spheres & tubules - are excess coat material of the virus. Contain HBsAg. NON-infectious
Dane particles. Infectious!!!
Dane particles are complete virions and hence are infectious. It consists of an outer surface coat and an inner
core.
Outer coat contains - HBV surface antigen (HBsAg).
Inner core contains
Core antigen (HBcAg)
e antigen (HBeAg)
double-stranded DNA
DNA polymerase
Replication : Only in the liver (there is evidence to suggest that the virus becomes integrated with the host
nuclear protein).
HBsAg - surface antigen
- is produced in abundance by infected liver cells and the excess can be visualized within their
cytoplasm and in the serum, both as spherical or tubular forms.
- it indicates :
Acute (Current) @ chronic infection
Carrier state
HBeAg - an internal component of HBcAg
- its presence in the serum is a marker for active viral replication
- correlates with the severity & infectivity of the disease.
- HBeAg is not present in the blood in the absence of HBsAg.
HBcAg - core antigen
- never found free in the circulation.
- present in liver cells indicates chronicity because HBcAg is not present in acute hepatitis.
Note : Carriers with HBeAg, viral DNA or DNA polymerase in the serum (and thus having active viral
replication) are highly infective.
HBsAg is first detected in blood during the incubation period (4-6th week) . Soon after that, complete virions
and HBeAg also appear in the blood. HBeAg disappears early in the acute illness. In typical case of acute
hepatitis B, the HBsAg level begins to decline after the onset of illness and is usually undetectable 3 months
after exposure. Persistence beyond 6 months usually indicates chronic disease.
HBsAg - 6 weeks to 3 months detectable in blood.
These antigens evoke specific antibodies : Anti-HBc, anti-HBe and anti-HBs.
These antibodies, together with viral-specific antigens, are important markers for determining the clinical
status of a patient exposed to the virus.
4

This mode of spread is believed to account for the high carrier rate of HBV

Anti-HBc - first antiviral antibodies detected

- appears toward the end of the incubation period
- persist during the acute illness and for several months to years thereafter.
- IgM initially (a valuable marker for recent exposure), IgG in 6-18 months
- not protective
Anti-HBe - appears in the serum as the HBeAg begins to disappear.
- its presence signals the onset of resolution of acute hepatitis infectivity low risk
Anti-HBs - detected during convalescence and usually persists for life
- indicates immunity
- There is a variable interval between the disappearance of HBsAg and the appearance of anti-HBs,
called the window period during which the presence of anti-HBc may be the only serum
marker of hepatitis B infection.
Summary : During the presymptomatic stage of acute hepatitis B, the principal serum markers of the infection
are first HBsAg and then HBeAg. As the symptoms appear, IgM anti-HBc becomes detectable, followed after a
variable period of weeks to months by anti-HBe and anti-HBs, in that order.
se (antigens) ces (antibodies)
HEPATITIS D
Hepatitis D occurs only in Hepatitis B carriers.
Hepatitis D virus
A unique RNA virus that is incomplete/defective. HDV is absolutely dependent upon the core DNA (genetic
information) provided by HBV for multiplication and causes hepatitis only in the presence of HBV.
MOT : Blood and secretions.
High mortality rate.
HEPATITIS C
Previously called parenterally-transmitted NANB
Similar in many respects to HBV, HCV causes acute and chronic hepatitis and chronic carrier states and is also
linked to the causation of hepatocellular carcinoma.
MOT : Same as Hepatitis B (Blood-borne)
The difference is that in Hepatitis C :
Acute hepatitis is mild (less severe that Hep. A or B)
Fulminant hepatitis is much less frequent
Has a higher propensity for transition to chronicity (in some studies over 50% of patients developed
chronic hepatitis!)
Cirrhosis develops in 20% of these.
HEPATITIS E
Previously known as water-borne NANB.
Causes sporadic and epidemic forms of acute hepatitis that share many features of HAV infections, including
transmission by the fecal-oral route and no risk of subsequent chronic liver disease. Its distinguishing feature is
the high mortality rate in pregnant women (20%) d/t the development of fulminant hepatitis (normal
mortality : 1-2%)
Hepatitis E virus
HEV : RNV virus, calcivirus, sphere

Age
Incubation
period
Transmission

A
Young
2-6 wks

B
Any
1-6 months

Fecal/oral
Blood

Blood
Sexual

C
Any
2 wks - 6
months
Sporadic
Blood

D
Any
3 wks - 3
months
Blood
Sexual

E
Any
3-6 wks
Fecal/oral

Sexual

Perinatal

Common
Mild

Uncommon
Mild moderate
Yes
Yes
Yes
Yes

0.1-0.2%

<5%

<0.5%

<1%

Immunization
Passive
Diagnosis
Acute

Anti-HAV IgM

Viral markers

Antibody

HbsAg
Anti-HBc IgM
Antibody
Antigen

Fever
Severity
Carrier state
Chronicity
Cirrhosis
Carcinoma
of
liver
Fulminant
Mortality
(acute)

Sexual
Perinatal
Uncommon
Mild-moderate

Perinatal
Common
Mild-moderate

Yes
Yes
Yes
Yes

Uncommon
Moderatesevere
Yes
Yes
Yes
Yes

<5%

5-20%

1-2%; 10-30%
in pregnant
women
1-2%
20% in
pregnant
women

<1%

Clinical

HDAg
Anti-HDV IgM

Clinical

Antibody
Antigen

PATHOGENESIS
2 mechanisms of liver injury:
Direct cytopathic effect (HAV)
Induction of immune responses against viral antigens or virus-modified hepatocyte antigens that damage
virus-infected hepatocytes (HBV).
The mechanism of liver cell injury caused by HCV, HDV and HEV is less clear.
The variable clinical expression of infection (i.e., hepatitis, fulminant hepatitis, chronic hepatitis, and the
chronic carrier state) are determined by the strength of the immune response :
Prompt host immune reaction acute viral hepatitis resulting in cellular injury but at the same time
eliminate the virus
Accelerated and excessive immune response fulminant liver necrosis, but the virus would be totally
eliminated
Inadequate immune response fail to eliminate the virus hepatocytes expressing viral antigens such
as HBcAg or virus-modified self antigens would persist, leading to continued low-level destruction
expressed as chronic hepatitis
Total failure of the immune response perpetuation of the viremia but little or no liver damage
carrier state.
Seductive as the preceding schema may be, it has not been possible to document suppression of specific
immune responsiveness in patients who exhibit either chronic hepatitis or the carrier state.
Note on carriers : Patients with immune deficiency e.g. Hodgkins disease, lymphmas, or Downs syndrome, or
immunosuppressive therapy or on long-erm dialysis may become carriers. Children are more likely to remain
carriers that adults.
Extrahepatic involvement
Antiviral antibodies are also undoubtedly involved in the pathogenesis of several extrahepatic manifestations.
Circulating immune complexes containing viral antigens & antibodies are responsible for such manifestations
as :
Vasculitis
Polyarthritis

Immune complex-mediated glomerulonephritis

Clinical syndromes
Hepatitis can manifest as follows:
1)
Asymptomatic infection (serologic evidence only)
2)
Acute hepatitis

Anicteric

Icteric
3)
Fulminant hepatitis (submassive to massive hepatic necrosis)
4)
Carrier state
5)
Chronic hepatitis

Chronic persistent hepatitis

Chronic active hepatitis

ACUTE VIRAL HEPATITIS
Acute hepatitis can be divided into 4 stages:
1. Incubation period
2. Preicteric stage
3. An icteric stage
4. Convalescence
Incubation period - patient is asymptomatic, but a few weeks before symptoms appear evidence of liver injury
can e detected as elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase
(ALT).
Preicteric phase - In some instances, particularly with Hepatitis A, no symptoms, or an extremely mild illness
similar to that of many other viral infections, may follow. In more severe cases, there is a preicteric phase for a
few days with:
Malaise, nausea & LOA
Distaste for cigarettes and coffee
Low-grade fever, headaches, myalgia, vomiting, or diarrhea
In 10% of patients with HBV, a serum sickness-like syndrome of fever, rash, and arthralgia develops (owing to
deposition of circulating viral antigen-antibody complexes. Indeed, if these circulating immune complexes
persist, glomerulonephritis, arthritis and systemic vasculitis may develop).
Onset of symptom tends to be more abrupt in pts. with hepatitis A & E than in those with hepatitis B & C.
From this point, 2 clinical patterns may emerge.
Anicteric hepatitis - No elevation of the serum bilirubin levels. Pts. recover after a few weeks.
Icteric hepatitis - Nonspecific symptoms are more marked, with higher fever, shaking chills, and headache,
sometimes + RUQ pain and tender hepatomegaly. Pale stools, dark urine. Pruritus
Note : When jaundice appear, other symptoms begin to abate. The jaundice is usually d/t elevated levels of
conjugated bilirubin predominantly.
Clinical features
Most of these persons were never aware that they had become infected, and probably had only trivial or
asymptomatic infection.
The pre-icteric @ prodromal phase lasts up to 2 weeks.
Viremia5 causes the patient to feel unwell with :
Anorexia, nausea, vomiting, diarrhea, headaches, malaise
Mild fever
Distaste for cigarettes
After 1 @ 2 weeks, the patient MAY become icteric and symptoms improve. Appetite returns and the patient
feels better. Other sign and symptoms at this time:
Dark urine, pale stools (d/t intrahepatic cholestasis)
5

Because the viremia is transient, blood-borne transmission of HAV only rarely occurs and, therefore, blood is
not specifically screened for this virus. This is in contrast to the screening of all blood donors for HBV and
HCV.

Tender hepatomegaly
Splenomegaly (10% of pts.)
Rash & lymphadenopathy mat occur

Pt. recover within 3 - 6 weeks. Relapses occ. occur, with the return of jaundice.
The disease rarely may be very severe with fulminant hepatitis, liver coma and death.
INVESTIGATION
Liver function test
Serum bilirubin - , reflects the level of jaundice
AST & ALT -
Serology
Hepatitis A - anti-HAV IgM (indicating an acute infection)
Hepatitis B - Check for HBsAg
If +ve HBeAg + Anti-HBeAg
If -ve HBcIgM (because of the window period)
FBP - leucopenia with a relative lymphocytosis
ESR -
PT - prolonged in severe cases
TREATMENT
No specific treatment.

FULMINANT VIRAL HEPATITIS @ FULMINANT HEPATIC FAILURE

A life-threatening syndrome d/t acute hepatitis from any cause.
Commonest cause:
Acute viral hepatitis
Drugs - paracetamol overdose, monoamine oxidase inhibitors, isoniazid, halothane anaesthesia
Histology - Submassive to massive necrosis of the liver
Characterized by hepatic failure (resulting from sudden severe impairment of hepatic function) hepatic
encephalopathy (drowsy, confuse, disorientated) stupor @ coma
INCIDENCE
HAV - < 1%
HBV - 1 - 4%
HEV - 0.5-3.0%
Pregnancy 20% (may be up to 50%!!!)
Prognosis : Poor. 70-90% mortality rate
INVESTIGATION
As for acute liver disease
Prothrombin time - d/t coagulopathy most useful index of severity
TREATMENT
No specific treatment. Supportive
CHRONIC HEPATITIS
Any hepatitis lasting > 6 months
3 types :
Chronic persistent hepatitis - minimal necrosis, basic architecture undisturbed, benign course
Chronic active hepatitis - c/b progressive liver destruction often leading to:
Cirrhosis
Chronic liver failure
Death
Chronic lobular hepatitis
CHRONIC PERSISTENT HEPATITIS
Usually asymptomatic, sometimes malaise, anorexia, nausea, mild jaundice
Minimal hepatomegaly
Lab Ix.
Persistent AST, ALT, ALP
Micro
Lobular architecture nearly normal
Dense portal infiltration by chronic inflammatory cells (Lymphocytes, plasma cells, macrophages)
necrosis
Treatment
Unnecessary. Months to years may pass before spontaneous resolution occurs
CHRONIC ACTIVE HEPATITIS
Progressive destruction of hepatocytes
May be :
Asymptomatic
Slowly progressing hepatitis
Chronic liver disease (50%)
Lab Ix.
bilirubin jaundice
AST, ALP

HBsAg & e antigen usually present

Micro
Hallmark of CAH : Piecemeal necrosis
necrosis of hepatocytes at the interface between the periportal inflammatory infiltrate & adjacent
hepatocytes.
Portal & periportal infiltrate of chronic inflammatory cells. Lymphoid follicles may appear
Bridging necrosis + fibrosis
The greater the necrosis, the more likely the progression to cirrhosis.
Causes
Virus - Hepatitis B, C, D
Autoimmune
Drugs - -methyldopa
Hereditary
1-antitrypsin deficiency
Wilsons disease
Hemochromatosis
Others
Infl. Bowel ds. - Ulcerative colitis
Alcohol - rarely