HEPATOLOGY

Gatot Sugiharto, MD,

Internist
Faculty of Medicine, UWKS
Lecture - 2013

Hepatitis, introduction(1)
Generic

term for inflammations of the

liver
Caused by a number of viruses, other
infectious agents, and toxins

Viral Hepatitis
There

are 7 hepatitis viruses : A, B, C, D, E, F, G

Hepatitis A and E are transmitted primarily by
contaminated food and water, high-risk areas :
poor sanitation contamination of water.
Hepatitis B and C are spread by sexual contact,
exchange of body fluids, injections from
contaminated needles and syringes, and
unscreened blood transfusions.
Percutaneous

HBV 6-30%
HCV 0-7%
HIV 0.3

exposure and risk of infection

Symptoms
Can

vary, some cases completely unnoticed.

Because

the liver is involved with so many

metabolic functions, the symptoms is
generalized

Most

common : fever, fatigue, loss of

appetite, jaundice (yellow skin), dark urine,
abdominal pain, and aching joints.

May

occur weeks to months after exposure

and typically last from 2 to 6 weeks. .

Complete

recovery (most cases A and E), but

5% to 80% of B and C may progress to
chronic, sometimes fatal, liver disease.

Laboratory test
A

definite diagnosis : viral-specific hepatitis

test (serologic markers)
Viral hepatitis assays : detect the presence of
specific Vi antigens and/or antibodies in
serum.
The purposes of serologic marker test :
Diagnose, differentiate between virus,
differentiate stage & resolution of the
infection
Screening to prevent spreading, to test sex
partner etc
Monitor & evaluate seroconversion, success
of prophylaxis

Hepatitis A

Vaccine-preventable viral illnesses and the most frequently

diagnosed form of hepatitis in developing countries.

Very widespread and close to 100% of people in less

developed countries are infected by 10 years of age, in
contrast in US, about 33% has serologic evidence of previous
HAV infection

Accounts for 20-40% of all viral hepatitis

Spread fecal-oral route, results in acute, self-limited illness

or asymptomatic infection (majority of cases)

Fulminant disease when co-infected with HBV or HCV,

especially when older

Labs
ALT > AST usually >1000 IU/dl
Bilirubin >10 mg/dl is common
IgM anti-HAV-gold standard for diagnosis

Hepatitis A (Contd)
Treatment

supportive 85% full

Prevention

handwashing, good

clinical/biochemical recovery in 3 month

sanitation
Postexposure propylaxis

Immune globulin and HAV vaccination

Immune globulin effective within 2 weeks of
exposure
Vaccine recommended for higher risk groups

GI 9

Hepatitis B

The double-stranded circular

Hepadnaviridae family consists of a
central core nucleocapsid containing
viral DNA and a surrounding envelope
containing the surface protein antigen
Global public health problem
300 million HBV carriers
250,000 deaths yearly

GI 10

Routes of Transmission

Percutaneous :
Contaminated needle stick (injecting drug use and
occupational exposure/nosocomial) more
common from patient to health care provider
Hemodialysis, Human bite, Transplant or
transfusion, Sharing razors

Permucosal
Sexual intercourse (50% of cases in U.S)
Perinatal-infant born (infection at or after birth)
90% if mother HBeAg positive (30% if negative)
C/S doesnt prevent & breastfeeding doesnt
increase risk
Contact with infected household objects (toothbrush
or razor)

Individual at Risk

Sexual contacts, multiple sex partners,

Injecting drug users
Infants born to HBV infected mother
Individual who have occupational contact
with blood (medical workers, laboratory
personnel, public service employees
Recipients of unscreened blood
Hemodialysis patients
Household contacts of HBV infected
individuals
Institutionalized populations (i.e. prisoners)

Clinical Course
Incubation period averages 60-90 (range
45-180 days)
Onset is often insidious
HBV causes clinical illness in 30-50 % of
all individuals age five and older, but
less than 10 % of those aged under five
years
Symptoms may include anorexia,
fatigue, nausea, vomiting, abdominal
pains, muscle or joint aches, mild fever,
dark urine, skin rases, and jaundice

Clinical Course (cont)

Jaundice develops in 25-35 % of patients
with symptoms
Most of HBV-infected adults will recover
within six months and develop immunity
Of those infected with HBV, 30-90 % of
chlidren less than 5 years of age and 2-10
% of the population over 5 years of age
will progress to chronic infection
Among all age groups, 15-25 % of those
who become chronically infected with HBV
die prematurely as a result of chronic liver
disease

Diagnostic panels

Consists of 5 markers: HBsAg, HBeAg, anti-HBe antiHBc and anti-HBs

If HBSAg and anti-HBc IgM is positive Acute Hepatitis

B serial testing with the monitoring panel is indicated

Hepatitis B monitoring panels :

Determine the persistence of HBsAg (chronic HBV
infection)
Determine relative infectivity (HBeAg)
Monitor seroconversion from HBeAg to anti-Hbe
resolution of the disease
Monitor seroconversion from HBsAg to anti HBs
positivity resolution of the disease and
establishment of immunity

Chronic HBV Infection

Determine the stage of chronic infection:

HBsAg, HBeAg, Anti-HBc total
HBsAg and anti-HBc total will always be
present, HBe Ag may be positive or
negative depending on the stage of
disease progression or the existence of
pre- core mutant.
Two types of chronic HBV infection:
1. No seroconversion
2. Late seroconversion

Testing to Determine Immunity:

Anti-HBs
Recommended for: Healthcare workers, Babies born
to HBV infected mother, Sex partners of persons with
chronic HBV infection, Immunocompromised
individuals
The purposes of quantitative levels of anti-HBs are:
To determine the need for initial vaccination
To establish an initial level of anti-HBs after the
vaccination
To determine whether revaccination is needed
To assess recovery from HBv infection

Prevention/Prophylaxis

Screening of blood and blood products

Destruction of disposable needles, and adequate

sterilization of reusable medical equipment

Universal precautions and barrier techniques

Education

Treatment for chronic HBV

infections
Considered when HBsAg >6 months, evidence
of active virus replication (HBeAg and HBV
DNA positive) and active liver disease (chronic
hepatitis on biopsy, elevated ALT)

Interferon/Pegylated interferon Therapy

12-24 weeks in doses of 5 MU/daily or 10 MU
3x/week
Pegylated interferon may be helpful
Results
Supresses HBV replication ( HBV-DNA,
HBeAg)
Improvement in liver disease (normal ALT)
Prevention of cirrhosis,GI 20
hepatocellular

Hepatitis C

Acute process often asymptomatic;

80% develop chronic hepatitis liver

transplant cirrhosis10-15%, 10% may
develop decompensated disease or
hepatocellular carcinoma

Six genotypes (1 to 6 ) and multiple subtypes

(a,b,c etc)

Genotype 1 and 4 are more resistant to

therapy than genotype 2 and 3

Genotype 1b : more severe & agresive liver,

Southeast Asia : genotype 3b
GI 21

HEPATITIS C VIRUS
Single, positivestranded Flaviviridae
RNA virus
Individual at Risk
Injecting drug users
Persons occupationally
exposed to blood
Hemodialysis patients
Tranfusion and
transplant recipients
(prior to 1992)

Diagnostic Testing for Hep

C
HCV is diagnosed serologically by:
Detecting anti-HCV does not
distinguish between an acute, chronic or
resolved infection
Ruling out other viruses such as HAV or
HBV
If initial result is negative, but clinical
signs & symptoms suggest a HCV
infection retesting for anti-HCV
A supplemental test, RIBA (recombinant
immunoblot assay) confirm a positive EIA
anti-HCV test
HCV RNA test (Quantitative/Qualitative)
confirm acute or chronic infection +

Developments in HCV Testing

(HCV RNA)
Assess circulating virus
Evaluate suspect HCV infection before
seroconversion occurs
Asses viral load before & monitor the effectiveness
of antiviral therapy
Detect HCV infection in cases with ambiguous
serology

Hepatitis C transmission
Exposure to infected blood before 1992 (Screening
started in 1992)
Heterosexual monogamous relationships (Risk low 00.5%/year
Perinatal
2% when EIA positive, 7% when HCV RNA positive
NO data on preventive by C/S
Breastfeeding doesnt appear to transmit

Routes of Transmission
Percutaneous

Contaminated needle stick (injecting drug use

and occupational exposure)
Hemodialysis
Human bite
Transplant or transfusion of unscreened blood or
blood products
Acupuncture, tattooing, and body-piercing with
unsterilized needles

Permucosal

Sexual intercourse
Perinatal-infant born to an HBV infected mother
Contact with infected household objects (i.e
toothbrush or razor that may have blood on it)

Hepatitis C Treatment
Highest

response with Pegylated Interferon

and Ribavirin

Genotype

Treat for 48 weeks if minimum of 2 log decrease

detected at 12 weeks
Ribavirin 1000-1200 mg usual dose
Genotype

2,3 : Ribavirin 800 mg (24 weeks)

: Hepatitis C and cirrhosis

increased risk for hepatocellular carcinoma

Prognosis

GI 28

HEP D & E
HDV

depends on HBs-Ag for replication

and expression. Without the HBs-Ag
coating cannot infect on its own.

HEV

: non enveloped virus, similar with

HAV, in pregnant woman mortality
reaches 15-25% (2nd & 3rd trimester)

Large

outbreaks occur through

contaminated drinking water

More

than 50% of the patients with acut

Hepatitis E develop a cholestatic form

Hepatic injury
Patterns of Hepatic Injury
Inflammation = hepatitis
Degeneration (ballooning ) : swelling and edema of
hepatocytes
Necrosis - coagulative necrosis (ischemia), less common
( liver has dual blood supply)
Apoptosis = councilman body ( apoptotic bodies in the
liver caused by viral hepatitis)
Regeneration : possible in all but not in fulminate diseases
Fibrosis : seen in cirrhosis
Hepatic failure : fulminate damage (80 to 90% of liver is
damaged)

Portal HTN = 12 mm Hg or >, clinically :

1. Ascites (peritoneal fluid)
2. Varicosities
3. Congestive splenomegaly
4. Hepatic encephalopathy
Cholestasis = retention of bilirubin , bile salts &
cholesterol
Jaundice =Bilirubin production > hepatic clearance
Total bilirubin = conjugated + unconjugated.
Conjugated bilirubin is more soluble
Result from Hepatocellular dysfunction (Intrahepatic)
or Biliary obstruction (Extahepatic)
Symptoms ; jaundice- (Bilirubin), pruritus - retention
of bile acids, Xanthomas (skin accumulations of
cholesterol),

Jaundice
Unconjugated Hyperbilirubinemia
Bilirubin overproduction hemolytic anemias, resorption of
major hemorrhages, ineffective Erythropoiesis in the bone marrow

Hepatic uptake of bilirubin = drugs rifampin

Impaired hepatic conjugation of bilirubin
Physiological jaundice of newborns (neonatal jaundice)
Genetic diseases : Gilbert syndrome, Crigler-Najjar syndrome
type I-II

Conjugated hyperbilirubinemia associated with

cholestasis
Dubin-Johnson syndrome :defective canalicular
secretion of bilirubin
Rotor syndrome :

Cholestasis - Types
Intrahepatic
Hepatocellular
dysfunction or
intrahepatic bile duct
disease
Congenital
Transplantation is only
the treatment
if uncorrected- becomes
cirrhotic

Extrahepatic
resulting from
obstruction

Acquired
amenable

to surgical

correction
if uncorrected- becomes
cirrhotic

Liver Cirrhosis
Liver

Cirrhosis : histopathologic term (xirros =

shrunken & hard)
Major causes:
Alcohol (ASH)
Cryptogenic cirrhosis called NASH
Viral hepatitis B & C (tropical countries)
Diagnosed

based on two clinical syndromes:

Hepatocellular failure, or
Portal Hypertension syndrome
Three

characteristics

Fibrosis irreversible and result in Portal HTN

Nodules - regeneration of hepatocytes
Loss of architecture of the entire liver
GI 35

Clinical features
Jaundice,

hypoalbuminemia, hyperammonemia
Fetor hepaticus
Hyperestrogenemia : palmar erythema, spider
angiomas of the skin (one or two are normal
esp. in pregnancy), hypogonadism,
gynecomastia
Complications
Coagulopathy ( hepatic synthesis of clotting factors)
Multi- organ failure, hepatic encephalopathy ( excess
ammonia)
Hepatorenal syndrome

Patterns of Hepatic Injury

Normal Liver

Inflammation
(Hepatitis)

Fibrosis
(Cirrhosis)

Hepatocellular Failure Syndrome

(HFS)
Consists of : loss of hair, hyperpigmentation, Jaundice,
Spidernaevi, gynaecomastia, testis atrophi,
disturbance of periodicity, liver palm, white nail

Portal Hypertension Syndrome (PHS)

Consists of:
Varices of the esofagoes and rectum (haemorrhoid)
Hematemesis melena
Rectal bleeding (haematochezia/enterorrhagia)
Vascular collateral in the abdominal wall
Splenomegali , Ascites
Oedema of the lower extremeties

Palmar erythema

Spider
angiomas

The Complications of
Liver Cirrhosis

Hematemesis-melena
Ascites per magna
Peritonitis bacterial spontanea
Hepatorenal syndrome
Hepatic encephalopathy
Hepatoma

Ascites
In

patients with cirrhosis and Ascites:

Ascites is the most common form of

clinical decompensation
Carries a poor prognosis, 50% mortality
within 2 years
Prone to spontaneous bacterial peritonitis
(diagnostic tap is mandatory if suspect
infection)
Patients with new-onset ascites or clinical
deterioration should undergo paracentesis
Evaluation for liver transplantation should
be considered in all patients
GI 44

Ascites (Contd)

Follow a sodium-restricted diet

Diuresis, with spironolactone (Aldactone) as
first-line therapy and occasional use of a
supplemental loop diuretic
Diagnosis of spontaneous bacterial
peritonitis (SBP) heralds advanced liver
disease
Antibiotic prophylaxis for SBP as a
preventive strategy cannot be definitely
recommended
TIPSS (Transjugular intrahepatic portalsystemic stent-shunt) is an efficacious
treatment for patients with refractory ascites
GI 45

Hepatic Encephalopathy

Disorder of CNS & neuromuscular transmission

Disturbances of consciousness & sleep, (behavioral

abnormalities, confusion, stupor, coma, death)

EEG changes, limb rigidity and Hyperreflexia,

Seizures & asterixis (a flapping tremor of

outstretched hands)

Pathogenesis : Severe loss of Hepatocellular function

& Exposure of the brain to excess ammonia levels

Hepatorenal Syndrome

Renal insufficiency (Urea and creatinine)

secondary to severe liver disease
Decreased renal perfusion pressure renal
vasoconstriction
Oliguria with a hyperosmolar urine without
Proteinuria
Low urinary sodium (though kidney can still
concentrate Urine)
Kidney function promptly improves if hepatic
failure is reversed

Hepatoma

Hepatocellular carcinoma is a leading

cause of death in patients with
cirrhosis

Once cirrhosis has developed,

hepatitis C is the most common cause
of hepatocellular Ca

Screening with alpha-fetoprotein and

ultrasonography every six months
GI 48

Gallbladder Disease
Acute

Cholecystitis

90% of cases - gallstone obstructs the

cystic duct,10% of cases - absence of
gallstones (acalculous cholecystitis)
Diagnostic tests: Ultrasound (most useful),
Cholescintigraphy, Abdominal CT scanning
Management: definitive therapy
-cholecystectomy
Pregnant patient -conservative therapy
(antibiotics and supportive care)
GI 49

Gallbladder Disease
(Contd)
Choledocholithiasis

15% of patients with gallbladder stones

have stones in common bile duct
Tests: ERCP (gold standard),
cholangiography
Ultrasound visualizes about 50% of
common bile duct stones, can detect CBD
dilatation in 75% of cases
Complications: cholangitis, acute
pancreatitis
Management: stone removal by ERCP,
early cholecystectomy
GI 51

Cholangitis

85% of cases due to impacted stone in duct

Charcots Triad (RUQ abdominal pain, fever

and jaundice) present in 70% of cases

Diagnosis: increased WBC, increased LFTS,

blood cultures, ERCP(gold standard),
cholangiogram, ultrasound, MRCP

Management: ERCP with stone removal,

Antibiotics that cover gram-negative
organisms, consider cholecystectomy
GI 53