Chronic Hepatitis

Chronic hepatitis
Liver function tests

many of the tests reflecting the health of
the liver are not direct measures of its

function
the commonly used liver function tests may
be abnormal even in patients with a
healthy liver
Liver function tests

enzyme tests
serum aminotransferases
alkaline phosphatase
gamma glutamyl transpeptidase
tests of synthetic function

serum albumin concentration
prothrombin time
serum bilirubin (measures the liver's ability
to detoxify metabolites and transport

organic anions into bile)
ALT
Cutoff values chosen to define an abnormal test
for men 29 IU/L had the highest degree of correct
classification, with a sensitivity of 88 percent and a

specificity of 83 percent
for women22 IU/L with a sensitivity of 89 percent and
a specificity of 82 percent
Applying these cutoffs to the entire population, 36%
of men and 28% of women would be classified as

having an elevated ALT
ALT levels correlate with the degree of trunk fat, and
at least two large studies suggested that the cutoff
values should be adjusted for body mass index
ALT
There is wide variability of what is
considered to be the upper limit of normal

for ALT across different laboratories, likely
due to the references used for different
chemical analyzers.
Thus, comparing values across different
labs may not be straightforward.

In addition, cutoff levels for recognition of
liver disease differ based on the reference
used at the specific laboratory.
LABORATORY TESTING
Patterns predominantly reflecting
hepatocellular injury
Patterns predominantly reflecting
cholestasis
MILD CHRONIC ELEVATION IN

SERUM AMINOTRANSFERASES
chronic (defined as six months or greater)
mild elevation (defined approximately as
less than four times the upper limit of

normal)
of one or both of the aminotransferases is
best achieved in a stepwise fashion to
eliminate unnecessary testing
the order of the testing may change if the
history and physical examination raise the

pretest probability of a particular diagnosis
Step one
Medications
almost any medication can cause an
elevation of liver enzymes

common causes include nonsteroidal antiinflammatory drugs, antibiotics, statins,
antiepileptic drugs, and antituberculous
drugs
in addition, herbal preparations and illicit
drug use may also be the cause.
However, the diagnosis of drug-induced
liver injury can be difficult.
Step one
Alcohol abuse
the diagnosis of alcohol abuse can be difficult
because many patients conceal this information

the diagnosis is supported by an AST to ALT
ratio of 2:1 or greater (Se 90%; if greater than
3:1 Se 96%)
However, the AST/ALT ratio may also be
occasionally elevated in an alcoholic pattern:

in patients with nonalcoholic steatohepatitis,
in patients with hepatitis C who have developed
cirrhosis.
Step one
Hepatitis B
the pretest probability for hepatitis B is
increased in patients with a history of

parenteral exposures and in patients from
parts of the world where a high disease
prevalence exists
The proper initial testing includes:
Hepatitis B surface antigen (HBsAg)
Hepatitis B surface antibody (HBsAb)
HBV
Hepatitis B core antibody (HBcAb) DNA
Step one
Hepatitis C
the risk is highest in individuals with a history
of parenteral exposure (blood transfusions,

intravenous drug use, occupational), cocaine
use, tattoos, body piercing, and high risk
sexual behavior.
Initial evaluation typically begins with an
antibody test.
Step one
Hereditary hemochromatosis
the frequency of heterozygotes is about 10% in
Caucasian populations, with a frequency of about

5/1000 (0.5%) for the homozygous state
Screening should begin with a fasting serum
iron and total iron binding capacity (TIBC).

An iron saturation of greater than 45% warrants
obtaining a serum ferritin (greater than 400
ng/mL in men and 300 ng/mL in women).
Step one
Hepatic steatosis and steatohepatitis
NASH is a condition more common in women
and associated with obesity and type 2

diabetes mellitus.
The initial evaluation is imaging:
Ultrasonography has a lower sensitivity than
CT or MRI scanning, but is less expensive.

However, radiologic imaging cannot identify
inflammation. Thus, the differentiation
between steatosis and NASH should require a
liver biopsy.
Step two
The next set of tests should look for non-
hepatic causes of elevated

aminotransferases:
Muscle disorders(creatine kinase or aldolase
levels should be determined)

Thyroid disorders(unclear mechanisms)
Celiac disease
Adrenal insufficiency (due to Addison's
disease or secondary causes)

Anorexia nervosa
Step three
Set of tests is aimed at identifying rarer
liver conditions:
Autoimmune hepatitis
Wilson disease(should be considered in
patients less than 40y)

Alpha-1 antitrypsin deficiency
Adult bile ductopenia
Step four
A liver biopsy is often considered in
patients in whom all of the above testing

has been unyielding.
However, in some settings, the best course
may be observation.
Step four
Whom to observe
only in patients in whom the ALT and AST are less
than twofold elevated and no chronic liver condition

has been identified by the above noninvasive testing
(negative viral, metabolic, and autoimmune markers )
Whom to biopsy
in patients in whom the ALT and AST are persistently
greater than twofold elevated (but it remains unlikely

that the biopsy will provide a diagnosis or lead to
changes in management; it is often reassuring to the
patient and clinician to know that there is no serious
disorder)
Chronic HBV hepatitis
Epidemiology
more than 350 million HBV carriers in the
world
of whom roughly one million die annually
from HBV-related liver disease
Prevalence of
chronic
infection with
HBV, 2006
Epidemiology
The rate of progression from acute to chronic HBV
infection:
approximately 90% for perinatally acquired infection,
20-50% for infections between the age of 1 and 5 years,
less than 5% for adult acquired infection.
Despite the decrease in incidence of acute HBV
infection, an analysis of hospitalization records found

that the rate of HBV-related hospitalizations, cancers,
and deaths in the United States have more than
doubled during the past decade, due to
the delay in implementation of universal vaccination
(instituted in 1991),
the influx of immigrants from endemic areas,
improved diagnosis and better documentation of infection.
MODES OF TRANSMISSION
Perinatal transmission
The infection rate among infants born to
HBeAg-positive mothers is as high as 90%.

There is no evidence that cesarean section
prevents maternal-infant transmission.
The high protective efficacy (95%) of
neonatal vaccination suggests that most
infections occur predominantly at or before
birth.
Transplacental passage of HBV is rare.
The risk of transmission during
amniocentesis is also low.
Breastfeeding does not appear to increase
the risk of transmission (with appropriate
Paternal transmission
infection rate was 65 percent among
neonates born to HBsAg-negative mothers

with HBsAg-positive fathers
transmissions were believed to be from
exposure of the unprotected infants to
infected blood and body fluids of the fathers
through close contact
Horizontal transmission
children may acquire HBV infection through
horizontal transmission via minor breaks in

the skin or mucous membranes or close
bodily contacts with other children
transmission via contaminated household
articles such as toys may be possible
Transfusion
In a retrospective review of records of posttransfusion
hepatitis B from 1991 to 1997 in the United Kingdom, the

risk of acquiring posttransfusion hepatitis B was 0.6
percent
In the United States, the risk of posttransfusion hepatitis
B is estimated to be 1-4 per million blood component
transfused
In China (where HBV is endemic), the risk of
posttransfusion HBV infection is higher: 1 in 17,501
Patients requiring multiple transfusions, such as those
with hemophilia and thalassemia, are at increased risk

of contracting HBV infection.
Sexual transmission
remains the major mode of spread of HBV in
developed countries
heterosexual transmission accounts for
approximately 39 percent of new HBV
infection among adults in the United States
can be prevented by vaccination of spouses
and steady sex partners in individuals with
monogamous partners, and safe sex practice
including use of condoms in subjects with
multiple partners
Percutaneous inoculation
intravenous drug users who share syringes and
needles
household contacts can also transmit hepatitis B
through the sharing of razors or toothbrushes
acupuncture
tattooing
body piercing
Nosocomial infection
HBV is the most commonly transmitted blood-borne
virus in the healthcare setting

particularly surgeons, pathologists, and clinicians
working in hemodialysis and oncology units.
Organ transplantation
Transmission of HBV infection has been
reported after transplantation of extrahepatic

organs, such as kidneys and even cornea,
from HBsAg positive donors
Increased risk of posttransplant hepatitis B is
seen primarily among seronegative liver
recipients; the importance of serological
testing and HBV vaccination among potential
transplant recipients!
Serologic diagnosis
Serologic diagnosis
HBsAg
appears in serum 1 to 10 weeks after an acute exposure
to HBV, prior to the onset of hepatitic symptoms or

elevation of serum alanine aminotransferase
in patients who subsequently recover, HBsAg usually
becomes undetectable after four to six months
Persistence of HBsAg for more than six months implies
chronic infection.
it is estimated that less than 1 percent of
immunocompetent adult patients with genuine acute

hepatitis B progress to chronic infection
among patients with chronic HBV infection, the rate of
clearance of HBsAg is approximately 0.5 percent per year
Serologic diagnosis
anti-HBs
the disappearance of HBsAg is followed by
the appearance of hepatitis B surface

antibody
in some patients, however, anti-HBs may not
be detectable until after a window period of

several weeks to months
coexistence of HBsAg and anti-HBs has been
reported in approximately 24 percent of
HBsAg positive individuals
Serologic diagnosis
HBcAg
an intracellular antigen that is expressed in infected
hepatocytes; it is notdetectable in serum

Anti-HBc can be detected throughout the course
of HBV infection.
The detection of IgM anti-HBc is usually regarded
as an indication of acute HBV infection. However,

IgM anti-HBc may remain detectable up to two years after
the acute infection.

The titer of IgM anti-HBc may increase to detectable levels
during exacerbations of chronic hepatitis B.
IgG anti-HBc persists along with anti-HBs in patients
who recover from acute hepatitis B. It also persists

in association with HBsAg in those who progress to
chronic HBV infection.
Serologic diagnosis
HBeAg
a secretory protein that is processed from the
precore protein.
generally considered to be a marker of HBV
replication and infectivity - usually associated
with high levels of HBV DNA in serum and
higher rates of transmission of HBV infection
HBeAg to anti-HBe seroconversion
occurs early in patients with acute infection,
prior to HBsAg to anti-HBs seroconversion

HBeAg seroconversion may be delayed for
years to decades in patients with chronic HBV
Serologic diagnosis
Seroconversion from HBeAg to anti-HBe
is usually associated with a decrease in serum
HBV DNA and remission of liver disease.

some patients continue to have active liver
disease after HBeAg seroconversion. Such

individuals may have low levels of wild type HBV
or HBV variants with a stop codon in the precore
or dual nucleotide substitutions in the core
promoter region that prevent or decrease the
production of HBeAg
Serologic diagnosis
SERUM HBV DNA ASSAYS
qualitative and quantitative tests
currently, most HBV DNA assays use real-
time PCR techniques, report results in IU/mL,

have lower limit of detection around 20 IU/mL
Serologic diagnosis
Recovery from acute hepatitis B is usually
accompanied by the disappearance of HBV DNA in

serum as determined by hybridization assays.
However, HBV DNA may remain detectable in serum
for many years if tested by PCR assays. This
observation suggests that the virus persists after
"recovery" but is controlled by the immune system.
Similar findings have been noted in patients with
chronic HBV infection. Spontaneous or treatmentinduced HBeAg seroconversion is usually accompanied

by the disappearance of HBV DNA from serum by
hybridization methods, but PCR assays usually remain
positive except in patients with HBsAg seroconversion .
Serologic diagnosis
A serum HBV DNA level of >10(5)
copies/mL has been proposed as a cutoff

level to differentiate patients with HBeAg
negative chronic hepatitis from those in an
inactive carrier state (ie, HBeAg negative,
persistently normal ALT)
Serologic diagnosis
Occult HBV infection: presence of detectable HBV DNA
by PCR in patients who are negative for HBsAg.

"seropositive"
"seronegative" (depending upon whether they are positive or
negative for other HBV markers, most commonly anti-HBc)

Most of these patients have very low or undetectable
serum HBV DNA levels accounting for the failure to detect

HBsAg. Occult HBV infection should be considered in
patients with apparent cryptogenic chronic liver disease.
Infections with HBV variants that decrease HBsAg
production or have mutations in the S gene with altered S
epitopes that evade detection in serology assays for
HBsAg are uncommon.
The spectrum of clinical

manifestations of HBV infection
During the acute phase
subclinical or anicteric hepatitis
icteric hepatitis
fulminant hepatitis.
During the chronic phase

asymptomatic carrier state
chronic hepatitis,
cirrhosis,
hepatocellular carcinoma.
Extrahepatic manifestations also can occur
with both acute and chronic infection.
CHRONIC HEPATITIS
In low or intermediate prevalence areas,
30-50% of patients with chronic HBV

infection have a past history of acute
hepatitis;
Such a history is lacking in the remaining
patients in these areas and in the majority
of patients in high prevalence areas
(predominantly perinatal infection)
Symptoms
Many patients with chronic hepatitis B are
asymptomatic (unless they progress to

decompensated cirrhosis or have extrahepatic
manifestations),
Others have nonspecific symptoms such as fatigue.
Some patients experience exacerbations of the
infection which may be:

asymptomatic,
mimic acute hepatitis,
or
manifest as hepatic failure.
Extrahepatic manifestations
are thought to be mediated by circulating
immune complexes,
occur in 10-20 percent of patients with
chronic HBV infection
Acute hepatitis may be heralded by a
serum sickness-like syndrome manifested

as fever, skin rashes, arthralgia, and
arthritis, which usually subsides with the
onset of jaundice.
The two major extrahepatic complications
of chronic HBV are
polyarteritis nodosa
glomerular disease.
PHASES OF CHRONIC HBV

INFECTION
The natural course of chronic hepatitis B virus
(HBV) infection is determined by the interplay

between virus replication and the host immune
response.
Other factors that may play a role in the
progression of HBV-related liver disease include

gender, alcohol consumption, and concomitant
infection with other hepatitis virus(es).
The outcome of chronic HBV infection depends
upon the severity of liver disease at the time
HBV replication is arrested.

INFECTION

INFECTION
HBeAg seroconversion is frequently, but
not always, accompanied by biochemical

exacerbations (abrupt increases in serum
ALT).
Not all exacerbations lead to HBeAg
seroconversion and clearance of HBV DNA
from the serum, a phenomenon termed
abortiveimmune clearance.
The rate of spontaneous HBeAg clearance
appears to be similar10 percent to 20
percent per year.
Resolution of chronic HBV

infection
Some patients with chronic HBV infection become
HBsAg negative.
The annual rate of delayed clearance of HBsAg has
been estimated to be 0.5-2 percent in Western

patients and much lower (0.1-0.8 percent) in Asian
countries. A study from Taiwan estimated that the
cumulative probability of HBsAg seroclearance was
only 8 percent after 10 years, but increased to 25
and 45 percent, respectively, after 20 and 25 years.
Clearance was preceded by a decrease in HBV DNA.
Reactivation following
seroconversion
A subset of patients who achieve HBeAg
seroconversion experience reactivation.

Reactivation can occur in patients who
receive immunosuppressive therapy, but
can also occur spontaneously.
PROGNOSIS OF CHRONIC HBV

INFECTION
The estimated five-year rates of
progression are:
Chronic hepatitis to cirrhosis - 12-20%
Compensated cirrhosis to hepatic
decompensation - 20-23%
Compensated cirrhosis to HCC - 6-15%
The cumulative survival rate at each of
these stages of progressive disease is:

Compensated cirrhosis - 85% at five years
Decompensated cirrhosis - 55-70% at one
year
-14-35% at five years
TREATMENT
the immunization of all patients with
chronic liver disease against hepatitis A

virus (HAV)
However,
countries with a high prevalence of HBV
also have a high prevalence of HAV. Thus,
testing for the HAV antibody should be
performed, with the vaccine being given
only to patients who are HAV antibodynegative.
TREATMENT
Heavy use of alcohol (>40 g/d), has been
associated with worsening liver disease and

an increased risk of HCC.
The exact amount of alcohol that can be
safely consumed is unclear.

Thus, advising patients to be completely
abstinent is reasonable in those who have

substantial liver injury.
WHO SHOULD BE TREATED AND

HOW
The rationale for treatment in patients with
chronic HBV is to reduce the risk of

progressive chronic liver disease,
transmission to others, and other long-term
complications from chronic HBV such as
cirrhosis and hepatocellular carcinoma.
HBeAg-positive patients
Treatment is recommended for:
those with HBV DNA >20,000 IU/mL and ALT >2 x ULN
in patients without cirrhosis.

patients with compensated cirrhosis and HBV DNA
>2,000 IU/mL and those with decompensated
cirrhosis and detectable HBV DNA by PCR assay,
regardless of the serum ALT level.
Treatment should be delayed for three to six
months in newly diagnosed HBeAg positive patients

with compensated liver disease to determine
whether spontaneous HBeAg seroconversion will
occur.
Patients with chronic hepatitis whose serum ALT is
persistently below two times the upper limit of

normal can be observed, considering treatment if
and when the serum ALT becomes higher.
Possible exceptions to this rule are:
those who have recurrent hepatitis flares that fail to
clear HBeAg,
patients with icteric flares,
those with active or advanced histologic findings
(such as moderate/severe inflammation or bridging
fibrosis/cirrhosis),
patients above the age of 40 who remain HBeAg
positive with persistently high HBV DNA levels.
In HBeAg positive patients with normal ALT,
the likelihood of HBeAg seroconversion is low.

The benefits of long-term treatment in such
patients, most of whom are young Asians with
perinatally acquired HBV infection, must be
balanced against the risks of drug-resistance,
side effects, and costs, particularly since some
of these individuals will undergo spontaneous
HBeAg seroconversion and remain in
remission for many years afterwards.
HBeAg-negative patients
Treatment may be initiated once a diagnosis of HBeAg
negative chronic hepatitis (ALT >2 x ULN and HBV

DNA >2000 IU/mL) is established because sustained
remission is rare in the absence of treatment.
Because of the fluctuating course of HBeAg negative
chronic hepatitis, serial follow-up is needed to

differentiate an inactive carrier state from HBeAg
negative chronic hepatitis.
Liver biopsy should be considered in HBeAg negative
patients who have serum HBV DNA levels >2000
IU/mL and normal or mildly elevated ALT to determine
if treatment is warranted.
Choosing among the available

options
Interferon
the advantages of interferon compared to the other options are
its finite duration (4-24 months) of treatment, the absence of

selection of resistant mutants, and a more durable response.
side effects from interferon are troubling for many patients, and
(less commonly) can be severe.
cannot be used in patients with decompensated disease.
Treatment of young patients with well compensated liver
disease, who do not wish to be on long-term treatment or

are planning to be pregnant within the next two to three
years, and in whom drug resistance may limit their
treatment options in the future.
Interferon is also an attractive option for patients with HBV
genotype A infection.

options
Lamivudine
lower cost compared to the other oral agents
many years of experience confirming its safety, including
its use during pregnancy.

main disadvantage the high rate of drug resistance
Adefovir
main advantage of adefoviris its activity against
lamivudine-resistant HBV and a lower rate of drug

resistance compared to lamivudine
virus suppression is slow and up to 25% of patients
nonresponsive.
at high doses has been associated with nephrotoxicity

options
Entecavir
potent antiviral activity
a low rate of drug resistance.
may also have an important role in patients
with decompensated cirrhosis

may be a better option in patients with renal
insufficiency
Telbivudine
Tenofovir
DURATION AND TREATMENT

ENDPOINTS
Most patients receiving nucleos/tide
analogue therapy will require at least four

to five years of treatment, and some may
require indefinite treatment.
DURATION AND TREATMENT

ENDPOINTS
HBeAg-positive chronic hepatitis
after HBeAg seroconversion has occurred and serum
HBV DNA has become undetectable should be treated

for at least 12 more months after HBeAg
seroconversion has been confirmed
roughly 50% of patients enrolled in clinical trials achieve
HBeAg seroconversion after five years of treatment
HBeAg-negative chronic hepatitis
The endpoint of treatment has not been established.
Treatment may be discontinued in patients who have
confirmed loss of HBsAg (5% of patients lose HBsAg

after five years of continued therapy)
HEPATITIS B REACTIVATION AND

IMMUNOSUPPRESSIVE THERAPY
immunosuppressive therapy (including prednisone
monotherapy at doses 20 mg/day administered for

more than four weeks);
Patients with serologic evidence of HBV infection
(HBsAg- or anti-HBc-positive) are at risk for HBV
reactivation if they receive immunosuppressive
therapy;
Most patients with HBV reactivation are asymptomatic,
and the only manifestation is an increase in the HBV
DNA level.
For patients who are at moderate to very high risk of
HBV reactivation, we recommend that antiviral therapy
be administered prior to initiating immunosuppressive
therapy. For such patients, we suggest tenofovir or
entecavir be administered, rather than lamivudine.

very high risk of reactivation (>20 percent risk of
reactivation) if they are HBsAg-positive and are going

to receive anti-CD20 therapy (ie, rituximab,
ofatumumab, obinutuzumab) or undergo
hematopoietic cell transplantation.
high risk for reactivation (11 to 20 percent risk of
reactivation) if they are HBsAg-positive and are going
to receive high-dose glucocorticoids (eg, 20 mg/day
for at least four weeks) or the anti-CD52 agent,
alemtuzumab.
moderate risk of reactivation (1 to 10 percent) if they
are going to receive any of the following: cytotoxic
chemotherapy without glucocorticoids; anti-TNF
therapy; or anti-rejection therapy for solid organ
transplants.

Treatment be maintained for at least 6 months
after withdrawal of immunosuppression (with

the exception of anti-CD20 therapy).
Treatment be maintained for at least 12
months after stoppinganti-CD20
agentssincethere is a lag in the recovery of B
cell function among such patients.
Antiviral therapy may need to be continued
long-term for patients who have undergone
hematopoietic stem cell or solid organ
transplantation since they often remain on
chronic immunosuppressive medications.
HDV hepatitis
HDV INFECTION
Individuals with hepatitis D are
alwaysdually infected with HDV and HBV.

Due to interference mechanisms that are
not well understood, HBV replication is

suppressed in most HDV-infected
individuals.
Coinfection
coinfection of HBV and HDV is clinically
indistinguishable from classical acute

hepatitis B
usually transient and self-limited.
however, a high incidence of liver failure
has been reported among drug addicts
Superinfection
HDV superinfection of a chronic HBsAg
carrier may present as a usually severe

acute hepatitis in a previously
unrecognized HBV carrier, or as an
exacerbation of preexisting chronic
hepatitis B.
Progression to chronic HDV infection occurs
in almost all patients
NATURAL HISTORY
The clinical manifestations of hepatitis D
virus (HDV) infection vary from benign acute

hepatitis to fulminant hepatitis, and from an
asymptomatic carrier state to rapidly
progressive chronic liver disease.
Persistent HDV replication was associated
with annual rates of development of cirrhosis

and HCC of 4% and 2.8%, respectively.
The only predictor of liver-related mortality
was persistent HDV replication.
EPIDEMIOLOGY
Data on HDV epidemiology have mostly been
gathered in chronic HBV carriers superinfected

with HDV in whom HDV infection has progressed
to chronicity.
Anti-HDV is present in high titers in these
patients, and the prevalence of chronic HDV
infection can be reliably determined.
Approximately 5% of the HBV carriers worldwide
may be infected with HDV

Thus, the number of individuals infected with
HDV worldwide is estimated to be 15 million.
EPIDEMIOLOGY
The geographical distribution of HDV infection,
however, does not parallel that of HBV, as areas

endemic for HBV may be almost HDV-free. The level
of HDV endemicity is partly related to the route of
transmission.
The Mediterranean basin - endemic (main route of
transmission is inapparent, permucosal, or

percutaneous spread and intrafamilial transmission is
common )
The Far East - 90% in the Pacific islands to 5% in Japan
(predominantly transmitted sexually, vs. confined to
intravenous drug users)
Western countries- uncommon (confined to high-risk
groups: intravenous drug addicts and multiply
transfused individuals )
AIMS OF TREATMENT
The primary endpoint of treatment is the
suppression of HDV replication

accompanied by normalization of the serum
aminotransferase (ALT) level

amelioration of necroinflammatory activity on
liver biopsy.
Suppression of HDV replication is
documented by loss of detectable HDV RNA

in serum and of HDAg in the liver.
AIMS OF TREATMENT
A secondary endpoint is the eradication of
HBV infection, with HBsAg to anti-HBs

seroconversion.
Patients who have cleared HDV but who
remain HBsAg positive are still at risk of

reinfection with HDV.
TREATMENT
INTERFERON ALFA
the only drug approved at present for
treatment of chronic hepatitis D

Peginterferon appears to be more effective
than standard interferon
only a minority of patients treated with
interferon clear HDV infection.
PREVENTION OF HDV
INFECTION
The mainstay of prevention of HDV
infection is vaccination against its helper

virus, the HBV.
Animal studies show that partial protection
of HBsAg carriers from HDV infection

through active immunization is feasible.
Chronic HCV hepatitis
HCV infection
can result in both:

acute hepatitis
chronic hepatitis.
HCV infection
The acute infection
is most often asymptomatic (fewer than 25
percent being clinically apparent); if

symptoms are present, they usually abate
within a few weeks.
rarely causes hepatic failure.
typically leads to chronic infection; 60 to 80
percent of cases develop chronic hepatitis.
HCV infection
Chronic HCV infection
usually slowly progressive and may not result in
clinically apparent liver disease in many

patients if the infection is acquired later in life.
approximately 20 to 30 percent of chronically
infected individuals develop cirrhosis over a 20to 30-year period of time.
the most common cause of chronic liver disease
and the most frequent indication for liver

transplantation in the United States.
Epidemiology
the prevalence of antibodies to HCV (anti-
HCV) in the United States is approximately

1.6% (about 4.1 million),
while the prevalence of positive HCV RNA is
approximately 1.3 percent (about 3.2
million).
The peak prevalence is observed among
persons age 40 to 49 years.

The strongest risk factor for infection is a
history of injection drug use.
TRANSMISSION
Most patients infected with HCV in the
United States and Europe acquired the

disease through:
intravenous drug use
or
blood transfusion
the latter of which has become rare since

routine testing of the blood supply for HCV
was begun in 1990.
HCV risk factors

Intravenous drug use odds ratio 49.6
Blood transfusion odds ratio 10.9 (in the past,
estimated risk is now less than one in a million per

unit transfused)
Sex with an intravenous drug user odds ratio 6.3
Having been in jail more than three days odds
ratio 2.9
Religious scarification odds ratio 2.8
Having been struck or cut with a bloody object
odds ratio 2.1
Pierced ears or body parts odds ratio 2.0
Immunoglobulin injection odds ratio 1.6
HCV risk factors

Health care workers
Hospitalization(nosocomial transmission of HCV)
Organ transplantation(transplant recipients who
receive organs from HCV-positive donors )

Sexual or household contact(approximately
0.1% annually ; shared razors or toothbrushes!)
Perinatal transmission(about 5% of infants born
to anti-HCV positive women; there is no evidence
that breastfeeding is a risk for infection among
infants born to HCV-infected women )
Hemodialysis (0.4-15% incidence of anti-HCV
positivity in hemodialysis units )
HCV risk factors

Surprisingly high rates of HCV infection
(approx.30%) have been found in patients

with alcohol abuse, even in the absence of
other risk factors for infection.
HCV may accelerate the liver injury in
patients who drink heavily

alcohol use appears to decrease the efficacy
of interferon therapy for HCV
patients with alcohol and HCV-induced liver
injury have a greater risk for hepatocellular
carcinoma
Symptoms
Most patients with chronic infection are
asymptomatic or have only mild nonspecific

symptoms
the most frequent complaint is fatigue
other less common manifestations include:
nausea,
anorexia
myalgia
arthralgia
weakness,
weight
loss
They may lead to a decrease in the quality of life.
Symptoms
The symptoms of chronic HCV infection
do not reliably reflect disease activity.

lack of correlation between the symptoms of
HCV infection and either the serum ALT

concentration or liver histology
however, symptoms appear to be more
common once cirrhosis develops
HCV infection has been associated with
cognitive impairment.
Serum aminotransferases
There is wide variability in serum aminotransferase
concentrations among individual patients with

chronic HCV infection over time.
Up to one-third of patients have a normal serum ALT.
Slight enzyme elevations are usually seen in the
remaining patients.
Only about 25 percent have a serum ALT
concentration more than twice normal.
It is rare to find elevations more than 10 times
normal.
There is generally a poor correlation between
aminotransferase levels and liver histology
Natural history
long course of the disease

the prevalence of cirrhosis 20 years after
infection was 16%

the disease may not be progressive in all
patients (31 percent of patients would
show no evidence of cirrhosis for at least 50
years)
Natural history
host and viral factors may be significant
Cirrhosis
cirrhosis eventually occurs in up to 50
percent of chronically infected patients

complications of hepatitis C are mostly
confined to patients who have developed
cirrhosis.
the risk of developing hepatic
decompensation of 3.9% per year

the probability of survival after
diagnosis of decompensated
HCV-related cirrhosis of 50%
at five years
Factors predictive of disease

progression
Host factors
production of profibrogenic cytokines (TGF B1 and
angiotensin phenotype )
acquisition of HCV infection after the age of 40 to 55 may
be associated with a more rapid progression of liver
injury
children appear to have a relatively decreased risk of
disease progression.
male sex has been associated with faster fibrosis
progression
patients with high body mass index and hepatic steatosis
are at increased risk for the development of fibrosis
daily use of marijuana
coffee consumption
hepatocellular carcinoma - more common in Japan

progression
Host factors
alcohol intake - promotes the progression of
chronic HCV, even in patients with relatively

low alcohol intake
alcohol increases HCV replication, and has
also been linked to the acceleration of liver
injury

progression
Viral factors
the size of the infectious inoculum (viral
dose) does not appear to be important

infection with more than one HCV genotype
coinfection with hepatitis B and C (some
patients with HCV who are infected with HBV
lack HBsAg !!)

progression
Liver biopsy
the best clinical predictor of disease
progression in chronic HCV infection is the

amount of inflammation and fibrosis on liver
biopsy
EXTRAHEPATIC MANIFESTATIONS OF
CHRONIC HEPATITIS C
At least one in 38% of cases:
Hematologic diseases such as essential
mixed cryoglobulinemia and lymphoma

Renal disease, particularly
membranoproliferative glomerulonephritis
Autoimmune disorders such as thyroiditis and
the presence of autoantibodies
Dermatologic conditions such as porphyria
cutanea tarda and lichen planus
Diabetes mellitus
Sicca syndrome
DIAGNOSIS
Serologic assays that detect antibodies to hepatitis C
SCREENING - enzyme-linked immunosorbent assay or
ELISA (sensitivity as high as 95 %)

CONFIRMATORY - recombinant immunoblot assay (RIBA)
; usually used to identify false positive ELISA test results
Molecular assays that detect or quantify HCV RNA
Qualitative tests(lower limit of detection of <IU/mL )
Quantitative tests(real-time PCR methods with limits of
detection of approximately 10 to 15 international

units /mL)
HCV GENOTYPE TESTING

at least six genotypes and numerous
subtypes have been identified

genotype (and subtype) are used in making
clinical decisions regarding treatment.
LIVER BIOPSY
not necessary for the diagnosis of hepatitis
C virus (HCV) infection

useful for:
determining the stage of disease
excluding other causes of liver test elevation
guiding decisions regarding treatment
(including treatment duration) and

surveillance
A minimal length of 25 mm and more than
10 portal triads are desirable to evaluate
fibrosis accurately
NONINVASIVE MEASURES OF
FIBROSIS
LIVER STIFFNESS(elastography)
For cirrhosis, sensitivity was 87 percent (95% CI 84-
90%) and specificity was 91 percent (95% CI 89-92%).

For stages II-IV fibrosis, sensitivity was 70 percent (95%
CI 67-73%) and specificity was 84 percent (95% CI 8088%).
examines a large mass of liver tissue thereby reducing
sampling error
however, the technique may be limited in patients with
ascites, patients with elevated central venous pressure
(such as heart failure), and those who are obese since
fluid and adipose tissues attenuate the elastic wave
hepatic inflammation and steatosis can reduce accuracy
FIBROSIS
SERUM BIO-MARKERS
Fibrotest and Fibrosure (INDIRECT MARKERS
OF FIBROSIS)
assessment of alpha 2 macroglobulin, alpha
2 globulin (haptoglobin), gamma globulin,

apolipoprotein A1, gamma glutamyl
transferase and total bilirubin
sensitivity and specificity for detection of
significant fibrosis (F2 or greater) are
approximately 75 and 85 percent
FIBROSIS
SERUM
BIO-MARKERS
FIBROSIS
SERUM BIO-MARKERS
FIBROSIS
SERUM BIO-MARKERS
DIRECT MARKERS OF FIBROSIS
Markers associated with matrix deposition

Markers associated with matrix degradation
Cytokines and chemokines associated with fibrogenesis
TREATMENT
Patients do not need to avoid acetaminophen, but
we suggest that the dose of acetaminophen not

exceed 2 g per 24 hours.
While statins are frequently withheld from patients
with chronic liver disease, available data fail to show

an increased risk of adverse effects in patients with
compensated chronic liver disease, suggesting that
statin use is safe in patients with stable HCV
infection.
In addition, there are some data that suggest statin
use is associated with increased sustained virologic
response rates following treatment with
peginterferon and ribavirin.
TREATMENT
Antiviral therapy
GOAL OF ANTIVIRAL THERAPY
eradicate HCV RNA
sustained virologic response (SVR),
associated with a 98-100% chance of being

HCV RNA negative during long-term follow-up
attaining an SVR has been associated with
decreases in all-cause mortality, liver-related
death, need for liver transplantation,
hepatocellular carcinoma rates, and liverrelated complications
PATIENT SELECTION FOR ANTIVIRAL

THERAPY
Are 18 years of age or older
Have HCV RNA detectable in the serum
Have a liver biopsy with chronic hepatitis
and significant fibrosis

Have compensated liver disease
Have acceptable hematologic and
biochemical indices
Are willing to be treated and conform to
treatment requirements
Have no contraindications to treatment
SIDE EFFECTS OF TREATMENT

(Interferon-based)
Flu-like symptoms
Anemia
Neutropenia
Thrombocytopenia
Rashes
Hair loss
Thyroid dysfunction
Depression
Fatigue
Irritability and mania
Nonproductive cough
Dyspnea
Ophthalmologic disorders such as retinal hemorrhages
Teratogenicity
Exacerbations of autoimmune diseases
SIDE EFFECTS OF TREATMENT

(Interferon-based)
CHOICE OF PEGINTERFERON
Peginterferon alfa-2a was superior to
peginterferon alfa-2b (SVR rates of 47

versus 41 percent; relative risk [RR] 1.11,
95% confidence interval [CI] 1.04-1.19)
DOSES OF PEGINTERFERON AND

RIBAVIRIN (1st generation therapy)
For patients receiving peginterferon alfa-2a, the
ribavirin dose is 1000 mg for patients who weigh

75 kg or 1200 mg for those who weigh >75 kg.
For patients receiving peginterferon alfa-2b, the
ribavirin dose is 800 mg for patients weighing
<65 kg, 1000 mg for 65 to 85 kg, 1200 mg for
>85 to 105 kg, and 1400 mg for >105 kg.
For peginterferon alfa-2a, the dose is 180
micrograms subcutaneously per week.

For peginterferon alfa-2b, the dose is 1.5
microgram/kg subcutaneously per week.
First-generation direct-acting antiviral therapies.

Telaprevir
protease inhibitor (NS3/4A). It is currently licensed
in the treatment of genotype 1-infected individuals
and when used in combination with pegylated
interferon and ribavirin has an improved SVR rate.
The most common adverse events associated with
telaprevir are rash and anaemia which can be

significant leading to discontinuation of treatment.
Anorectal discomfort is also more frequent.
CYP3A4 inducers may significantly decrease
plasma concentrations of telaprevir.
First-generation direct-acting antiviral therapies.

Boceprevir
serine protease inhibitor. It is licensed in
the treatment of genotype 1 HCV-infected
individuals, in combination with pegylated
interferon and ribavirin.
Anaemia is the most common and in some
treatment limiting adverse event, although
dysgeusia is also reported. CYP3A4
inducers may significantly decrease plasma
concentrations of boceprevir.
TREATMENT OPTIONS
(2nd generation therapy)
Patients with genotype 1 should be treated
with peginterferon, ribavirin, and a

protease inhibitor (telaprevir and
boceprevir).
Patients with other genotypes are treated
with peginterferon and ribavirin.
Protease inhibitors
Telaprevir is given as 750 mg (two 375 mg
tablets) three times per day with food
Protease inhibitors
Boceprevir is given as 800 mg (four 200 mg
capsules) three times per day starting at

week four of treatment, following a fourweek lead-in period of treatment with
peginterferon and ribavirin.
Protease inhibitors
DRUG INTERACTIONS!!
Telaprevirand boceprevirare cleared by
CYP3A4/5 and numerous drug interactions

have been noted .
The drugs should not be given in conjunction
with medications that are CYP3A4/5 inducers
or with drugs that are highly dependent on
CYP3A4/5 for clearance and that are
associated with serious and/or life-threatening
events when plasma concentrations are high.
ADDITIONAL SIDE-EFFECTS!!
EFFICACY OF PROTEASE INHIBITOR

CONTAINING REGIMENS
Prior to the introduction of the NS3/4A
protease inhibitors telaprevirand

boceprevir, only 40 to 50 percent of
patients with chronic HCV genotype 1
would achieve an SVR.
With the addition of these protease
inhibitors, the rate has increased to 70 to

80 percent.
Second-generation direct-acting
anti-viral therapies
Sofosbuvir
HCV-specific uridine nucleotide NS5B polymerase
inhibitor with potent pan-genotypic activity. It is a
once daily preparation, usually taken at a dose of 400
mg. It is licensed for use in combination with other
HCV therapeutic agents, including ribavirin and
interferon. There is no associated food effect and
CYP3A/4 metabolism of the drug.
Sofosbuvir is associated with a well-tolerated safety
profile. The most commonly reported adverse events
associated with sofosbuvir are headache, anaemia,
fatigue and nausea but the rates are little more than
placebo.
Sofosbuvir is predominantly renal eliminated thus use
should be cautioned in severe renal impairment.
Simeprevir
HCV NS3/4A protease inhibitor with efficacy in
genotype 1, 4, 5 and 6. It is a once daily
preparation.
Simeprevir is well tolerated with a favourable
safety profile.
The most frequently reported adverse events
in patients treated with simeprevir are fatigue,
influenza like symptoms, pruritus, headache
and nausea, but at rates not dissimilar to
placebo. CYP3A4 inducers may significantly
decrease plasma concentrations of simeprevir.
Faldaprevir
HCV NS3/4A protease inhibitor with efficacy
in genotype 1, 4, 5 and 6; it is a once daily
preparation.
The most common adverse events
associated with faldaprevir are mild
gastrointestinal upset, rash, pruritus and
jaundice, but at rates not dissimilar to
placebo.
Therapies for chronic HCV have evolved
dramatically in recent years.

All three drugs are well tolerated with safety profiles
more favourable than interferon ribavirin and firstgeneration protease inhibitor-based regimens.
Interferon-free regimens are now possible without
compromise in the rate of sustained viral response.
The decision as to which regimen is most
appropriate is multifactorial, and based on efficacy,

safety and cost.
Medications
PREDICTORS OF A TREATMENT
RESPONSE
HCV genotype (genotypes 2 and 3 are
more responsive to treatment than

genotypes 1 and 4)
Baseline viral load (600,000 to 800,000
IU/mL)
Race (whites have higher response rates
than African Americans and Latino whites)
Host genetic factors (eg, IL28B
polymorphisms)
Use of combination therapy with
peginterferon and ribavirin/ novel direct
antiviral therapies
ASSESSING A TREATMENT
RESPONSE
Rapid virologic response (RVR): HCV RNA
negativity after four weeks of treatment; if

the HCV RNA remains negative at 12 weeks
it is known as an extended rapid virologic
response (eRVR)
Early virologic response (EVR): at least a 2
log10reduction in HCV RNA (a partial EVR)
or HCV RNA negativity (a complete EVR) by
week 12 of treatment
Delayed virologic response: HCV RNA
negativity at week 24 in patients who fail to
achieve a complete EVR (such patients are
also known as "slow responders")
TREATMENT OF EXTRAHEPATIC
MANIFESTATIONS
Some of the manifestations that may
respond to treatment for HCV include:

Cryoglobulinemia
Porphyria cutanea tarda
Leukocytoclastic vasculitis
Necrolytic acral erythema
Glomerulonephritis
Question
Ac anti HBs positive

Ac anti HBc IgG positive
Question
Ac anti HBs positive

Ac anti HBc IgG negative
Autoimmune hepatitis
Designation
Since it was first described in the 1950s,
the disorder has been known by a variety

of terms:
lupoid hepatitis,
plasma cell hepatitis,
autoimmune chronic active hepatitis
CLINICAL MANIFESTATIONS
The spectrum includes
asymptomatic patients,
those with considerable and sometimes
debilitating symptoms,
those with acute liver failure.
Furthermore, long periods of subclinical
disease may occur before or after

presentation.
Asymptomatic patients
the finding of an elevated aminotransferase
level may be the only clue to the presence

of liver disease
on occasion, the asymptomatic patient is
discovered when abdominal surgery is

performed for some other reason and the
surgeon notes an abnormal, sometimes
frankly cirrhotic-appearing liver
Acute liver failure

profound jaundice,
an elevated prothrombin time,
aminotransferase values >1000 U/L
Such a presentation is uncommon with autoimmune

hepatitis.
Many patients with an acute presentation have
established cirrhosis when biopsied. Thus, they must
have had subclinical disease for some period of time.
In between
fatigue,
lethargy,
malaise,
anorexia,
nausea,
abdominal pain
itching.
Although not specific to autoimmune
hepatitis, arthralgia involving the small joints

is a characteristic clinical feature
hemolytic anemia,
idiopathic thrombocytopenic purpura,
type 1 diabetes mellitus,
thyroiditis,
celiac sprue,
ulcerative colitis (which is more often
associated with primary sclerosing

cholangitis)
in addition, a polyglandular autoimmune
syndrome can occur in children with type 2
autoimmune hepatitis.
Physical examination
Physical findings range from
a normal physical examination
to
the presence of
hepatomegaly,
splenomegaly,
stigmata of chronic liver disease
jaundice.
Complications
those seen in any progressive liver disease
occur in patients with untreated or
unresponsive disease
Primary hepatocellular carcinoma - less

frequent than in chronic viral hepatitis.
DIAGNOSIS
characteristic serologic and histologic
findings
the exclusion of other forms of chronic liver
disease
Compatible laboratory and

histological abnormalities
abnormal liver biochemical tests,
an increased total IgG or gamma-globulin
levels,
serologic markers (ANA, SMA, anti-LKM-1,
or anti-LC1),
interface hepatitis.
additional autoantibodies (anti-SLA and
pANCA).
cholangiographic studies should be
considered to exclude primary sclerosing
cholangitis in patients who do not respond
Laboratory features
aminotransferase elevations are more
striking in autoimmune hepatitis than those

of bilirubin and alkaline phosphatase
In some cases, however, autoimmune
hepatitis has a cholestatic picture marked

by high levels of conjugated bilirubin and
alkaline phosphatase.
Extrahepatic obstruction (diagnosed by imaging
studies), and cholestatic forms of viral hepatitis,

primary biliary cirrhosis, primary sclerosing
cholangitis, and the variant syndromes must be
considered in this setting.
Laboratory features
an elevation in serum globulins, particularly
gamma globulins and, generally, IgG, not

universally present,
Histology
A portal mononuclear cell infiltrate
Piecemeal necrosis or interface hepatitis
An exuberant plasma cell infiltrate (plasma cell
hepatitis), rosettes of hepatocytes, and

multinucleated giant cells, may be seen,
Emperipolesis (active penetration of one cell into and
through a large cell)
Bile duct changes (destructive and nondestructive
cholangitis and ductopenia)
Fibrosis
Nonspecific nature of the histologic changes!!!
Autoantibodies
type 1 autoimmune hepatitis
antinuclear,
anti-smooth muscle,
and/or antiactin antibodies
anti SLA (10 -30% of adults and 60% of children)
on occasion, antimitochondrial antibodies
anti- single-stranded (anti-ssDNA) and double-
stranded (anti-dsDNA) DNA

p ANCA
type 2 autoimmune hepatitis
anti LKM-1
anti SLA
anti liver cytosol antigen (LC-1)
Diagnosis
There are some patients who present with
all the features of autoimmune hepatitis

but lack circulating ANA, ASMA, anti SLA/LP,
ANCA, or ALKM-1 antibodies.
At present, they are considered to have
cryptogenic chronic hepatitis or cryptogenic
cirrhosis.
A therapeutic response to antiinflammatory therapy may be the only
indication that autoimmune hepatitis is the
underlying disease in these patients.
Scoring systems
Autoantibodies - ANA, ASMA - 1:40 (1p);
1:80 (2p)
OR
- LKM 1:40 or SLA positive
(2p)
IgG > ULN (1p); > 1.1 ULN (2p)
Liver histology: compatible (1p); typical
(2p)
Absence of viral hepatitis (2p)
88% sensitivity, 97% specificity for a score

6 (probable)
DIFFERENTIAL DIAGNOSIS
the other autoimmune liver diseases
(primary biliary cirrhosis, primary sclerosing

cholangitis, and overlap syndromes)
acute hepatitis
chronic hepatitis C
Treatment
AIH = in general, a "steroid-responsive"
condition.
Appropriate management can improve
quality of life, prolong survival, and delay

the need for liver transplantation.
The life-expectancy of treated patients is
similar to age- and gender-matched

controls in patients who have been followed
for up to 20 years
Vaccination
Vaccinations of patients with autoimmune
hepatitis, including hepatitis A and B,

before starting immunosuppressive therapy
INDICATIONS FOR
TREATMENT
The decision to treat should be
individualized based upon

the severity of symptoms,
the degree of elevation of serum
aminotransferases and IgG,

histologic findings,
the potential for side effects.
The magnitude of aminotransferase and
gamma globulin elevations do not

necessarily correlate with histologic injury.
As a result, histologic changes more
accurately reflect disease severity.
INDICATIONS FOR
TREATMENT
Immunosuppressive treatment should be
instituted :
in patients with serum aminotransferases
greater than 10-fold the upper limit of

normal,
at least five-fold the upper limit of normal in
conjunction with serum gamma-globulin
levels at least two-fold the upper limit of
normal,
and/or histologic features of bridging necrosis
or multilobular necrosis.
INDICATIONS FOR
TREATMENT
Treatment should not be withheld from
patients with decompensated cirrhosis who

have active disease.
The response may be excellent even in
those who have already experienced
bleeding from esophageal varices or who
have significant ascites.
Many patients respond when treatment is
initiated, and the 10-year survival for
treated patients exceeds 90%.
INDICATIONS FOR
TREATMENT
Immunosuppressive treatment can be
considered :
in adults without symptoms and mild
laboratory and histological changes.

The decision should be individualized and
balanced against the risks of therapy.
INDICATIONS FOR
TREATMENT
Immunosuppressive treatment should NOT
be instituted in patients:
with minimal or no disease activity or
inactive cirrhosis,
Such patients should be followed every
three to six months.
INDICATIONS FOR
TREATMENT
Immunosuppressive treatment should NOT
be instituted in patients :
with serious preexisting comorbid conditions
(vertebral compression, psychosis, brittle

diabetes, uncontrolled hypertension) or
previous known intolerances to prednisone;
unless the disease is severe and progressive
and adequate control measures for the
comorbid conditions can be instituted.
INDICATIONS FOR
TREATMENT
Azatioprine should NOT be started
in patients with severe pretreatment
cytopenia (white blood cell counts below 2.5

X 10(9)/L or platelet counts below 50 X
10(9)/L)
or known complete deficiency of thiopurine
methyltransferase activity.
Special situations
AIH tends to be more severe in children
compared with adults, possibly because of

a delay in diagnosis.
Up to one-half of children have cirrhosis at
the time of diagnosis; thus, treatment is
usually recommended at the time of
diagnosis
Special situations
In the rare instances in which autoimmune
hepatitis is accompanied by chronic

hepatitis C virus (HCV) infection, treatment
should first be directed toward autoimmune
hepatitis because of the danger of
exacerbating autoimmune hepatitis with
interferon.
Although this approach may result in
raising viral levels of HCV, it is the safer
initial strategy.
CHOICE OF INITIAL THERAPY

Glucocorticoids
Azathioprine
Combination regimens permit the use of

lower doses of glucocorticoids, thereby
reducing glucocorticoid-related side effects.
Cyclosporine may be a reasonable initial
alternative in children
Budesonide
DOSES
Two initial treatment regimens are considered to
be equally effective in severe AIH:

prednisone(60 mg daily) alone
or
lower dose prednisone (30 mg daily) in
combination with azathioprine(50 mg daily is
used most commonly in the United States, while
in Europe the dose is often given as 1 to 2 mg/kg
body weight).
Prednisoneshould be tapered to an individual
level sufficient to maintain remission.
Treatment endpoints
Consensus has not been achieved on the optimal
duration of treatment.
As a general rule, treatment is continued until
remission, treatment failure, or the development of
drug toxicity.
Remission can be defined as the
resolution of symptoms,
reduction in serum aminotransferase levels to less than
twice the upper limit of normal,

normalization of serum bilirubin and gamma globulin
levels,
improvement in liver histology to normal or only mild
portal hepatitis (or minimal or no activity in patients with
cirrhosis)
Treatment endpoints
Approximately 90% of patients have
improvement in serum aminotransferases,

bilirubin, and gamma globulin within two weeks;
Histologic improvement lags biochemical
improvement by three to eight months.
Serum levels of autoantibodies do not appear to
parallel disease activity and should not be used
to monitor activity.
Approximately 65 and 80% of patients achieve
remission by 18 months and three years,

respectively.
LIVER TRANSPLANTATION
Patients who are refractory to or intolerant
of immunosuppressive therapy and develop

end stage liver disease require liver
transplantation
Despite the intensive immunosuppression
following liver transplantation, patients are

at risk for recurrent autoimmune hepatitis
Wilson disease
Epidemiology
hepatolenticular degeneration
autosomal recessive defect in cellular
coppertransport,
prevalence of approximately 1 case in
30,000 live births in most populations.
PATHOGENESIS
An impairment in biliary excretion leads to
the accumulation of copper in the liver.

Over time the liver is progressively
damaged and eventually becomes cirrhotic.
The genetic defect in Wilson disease,
localized to chromosome 13, involves a

coppertransporting protein in the liver
(ATP7B).
Genetics
Multiple mutations in the gene have
already been identified in patients with

Wilson disease.
The H1069Q mutation is one of the most
frequent with an allelic frequency of 10 to
40 percent.
Most patients are compound
heterozygotes, carrying two different

mutations on each of their two
chromosomes
PATHOLOGY
The earliest lesion in Wilson disease occurs
in the liver, the site of initial

copperaccumulation.
fatty infiltration within hepatocytes,
glycogen inclusions within nuclei
portal fibrosis.
PATHOLOGY
As the disease progresses, frank
hepatocellular necrosis occurs and the

histologic lesion resembles that of
autoimmune chronic hepatitis.
There is portal inflammation and fibrosis,
piecemeal necrosis, with marked swelling
and necrosis of periportal hepatocytes and
eventually frank cirrhosis.
PATHOLOGY
Histological stains for copperdemonstrate
increased deposits of copper within the

liver, renal tubular cells, and brain. The
deposition in the liver is initially diffuse but
may be patchy if cirrhosis is present.
With electron microscopy, striking changes
are noted in mitochondria, with dilatation of
the tips of the mitochondrial cristae
Infants and children with Wilson disease have silent
but ongoing hepatic deposition of copper, gradually

producing clinical disease. Clinical manifestations
arise as hepatic and extrahepatic copper deposition
progresses.
They are rare before age 6 and almost always
present before the age of 30, although it has been
described in those as young as age 3 and patients
presenting in their seventies.
The variability in age at onset of the various
manifestations of Wilson disease probably reflects

differences in mutations and penetrance as well as
extragenic factors.
Children may present incidentally with
elevated liver enzymes without overt

clinical symptoms.
Liver disease may progress silently until
adolescence, when patients present with

complications of cirrhosis or acute liver
failure.
In some cases, extrahepatic manifestations
precede overt liver disease, although liver

disease is invariably already established.
Some studies have suggested that
adolescents tend to present with liver

disease while young adults are more likely
to present with neuropsychiatric disease.
Virtually all patients with neuropsychiatric
disease have compensated cirrhosis, which

is often not detected until Wilson disease is
diagnosed.
Hepatic disease
Chronic hepatitis - approximately 40 percent of Wilson
disease patients present with signs and symptoms of

chronic hepatocellular disease, either chronic
hepatitis or cirrhosis.
Asymptomatic liver function abnormalities
Portal hypertension
Acute/fulminant liver failure (often children or young
adults)(usually have an associated hemolytic anemia )
Neurologic disease
Young patients whose disease is not detected at the
stage of hepatic dysfunction may present with

neuropsychiatric symptoms.
Neurologic disorders are present in up to 35 percent
of patients with Wilson disease.
Signs:
Parkinsonian-like tremor,
rigidity,
clumsiness of gait,
slurring of speech,
inappropriate and uncontrollable grinning (risus
sardonicus),
drooling.
Neurologic disease
Cerebrospinal fluid (CSF)
copperconcentrations in these patients are

elevated three to fourfold compared to
controls and to patients with Wilson disease
without neurologic signs.
These values fall with treatment and
represent a quantitative parameter for
monitoring therapy
Psychiatric disease
Approximately 10 percent of patients
present with psychiatric problems

subtle personality changes
deteriorating performance at school,
mood disorders
overt depression,
paranoia,
catatonia
Other manifestations
Copper deposition in other organs:
Fanconi syndrome (proximal tubular
dysfunction - glucosuria, aminoaciduria,

hypouricemia, and proximal renal tubular
acidosis)
Nephrolithiasis (may be secondary to distal
renal tubular acidosis)
Arthropathy (occasionally chondrocalcinosis,
most commonly in the knee)
Impotence
Cardiac arrhythmias
DIAGNOSIS
Age-most patients present between the
ages of 5 and 40.

Kayser-Fleischer rings(fine pigmented
granular deposits of copperin Descemet's
membrane in the cornea) - rings are
present in approximately 50 to 60% of
patients who present with isolated hepatic
involvement compared with more than 90%
of patients who present with neurologic
involvement
DIAGNOSIS
Kayser-Fleischer rings are not absolutely
specific for Wilson disease, having been

rarely reported in other chronic cholestatic
diseases such as primary biliary cirrhosis
and in children with neonatal cholestasis
Sunflower cataracts- copperdeposits in
the lens; may also be seen by slit-lamp

examination; like Kayser-Fleischer rings,
the cataracts gradually disappear with
treatment of the Wilson disease.
Diagnosis
Neuropsychiatric disease
Serum aminotransferases- usually mildly
to moderately elevated
Confirmation
Serum ceruloplasmin concentration
Most patients (85-90%) with Wilson disease
have low serum ceruloplasmin levels.

A very low level (<50 mg/L or <5 mg/dL)
provides strong evidence for the diagnosis of
Wilson disease.
However, the serum ceruloplasmin level
alone does not reliably establish or exclude
the diagnosis.
There are conditions that can increase serum
ceruloplasmin levels (cholestatic liver
diseases, the use of birth control pills).
Confirmation
Serum ceruloplasmin concentration
a serum ceruloplasmin concentration less
than 20 mg/dL in a patient who also has

Kayser-Fleischer rings is considered to be
diagnostic.
Confirmation
Serum copper concentration
while total copperbody stores are increased
in Wilson disease, serum copper is decreased

in proportion to the reduction in serum
ceruloplasmin.
serum nonceruloplasmin-bound copper levels
are greater than 25 mcg/dL in the majority of
untreated patients with Wilson disease
(normal <15 mcg/dL). Marked elevation may
be seen in fulminant hepatic failure due to
Wilson disease, where copper is released
suddenly from tissue stores.
Confirmation
Urinary copper excretion
Wilson disease is typically associated with 24-hour
urinary copper excretion of >100 mcg, although

lower values have been described in up to 25% of
presymptomatic patients with confirmed disease
Values in the Wilson disease range can also be seen
in patients with other forms of chronic active liver
disease
Penicillamine challenge- greatly increases urinary
copper excretion in patients with Wilson disease
(greater than 1600 mcg per 24 hours) and to a
lesser extent in patients with other forms of liver
disease.
Confirmation
Hepatic copper concentration
Quantitative hepatic copperdetermination in
patients with Wilson disease usually reveals

more than 250 mcg of copper per gram of
dry weight (normal <50 mcg per gram of dry
weight)
However, normal hepatic copper
concentration has been described in patients
with Wilson disease .
Confirmation
Liver histology
similar to those of autoimmune hepatitis and
nonalcoholic steatohepatitis!!! Wilson disease

should be considered in patients who respond
poorly to standard therapy for autoimmune
hepatitis.
a histologic stain for copperdeposition can
be suggestive. However, copper stains have

limited sensitivity; and the absence of copper
staining does not exclude the diagnosis.
Confirmation
Genetic testing
Mutation analysis difficult.
SCREENING FAMILY MEMBERS

First-degree relatives of patients diagnosed
with Wilson disease should be screened.
Treatment
Lifetime therapy is required in patients with
Wilson disease
Treatment should be given in two phases:
removing the tissue copperthat has
accumulated
then preventing reaccumulation.
Potent chelators
D-penicillamine
30% of patients do not tolerate long-term therapy
because of side-effects
incremental doses of 250 to 500 mg/day
increased by 250 mg increments every four to
seven days to a maximum of 1000 to 1500 mg
daily in two to four divided doses.
Trientine
a reasonable option for primary therapy
lower incidence of side effects
750 to 1500 mg daily in two to three divided
Maintenance phase
D-penicillamine
A lower dose (750 to 1000 mg daily in two divided
doses) is sufficient during the maintenance phase

(usually after four to six months).
Trientine
750 to 1000 mg daily.
Oral zinc - interferes with the absorption of copper

zinc acetate 150 mg daily given in three divided doses.
Ammonium tetrathiomolybdate
not yet commercially available
D-penicillamine
Early sensitivity reactions (occurring within one to
three weeks of beginning therapy) are characterized

by:
fever,
cutaneous eruptions,
lymphadenopathy,
neutropenia,
thrombocytopenia,
proteinuria.
The drug should be discontinued immediately in
such patients and alternative treatment (principally

trientine) begun.
D-penicillamine
Late reactions
proteinuria (nephrotic syndrome) - necessitates cessation of the drug.
crescentic glomerulonephritis.
Goodpasture syndrome,
bone marrow toxicity (severe thrombocytopenia or total aplasia),
myasthenia gravis,
polymyositis,
hepatotoxicity,
loss of taste,
lupus-like syndrome characterized by hematuria, proteinuria, and a
positive antinuclear antibody.

Skin changes have been described including elastosis perforans
serpiginosa pemphigus, lichen planus, and aphthous stomatitis
Nausea, vomiting, and anorexia
The neurologic status of patients with predominantly neurologic
symptoms worsens in approximately 10% of patients after

beginning treatment
Diet
Low copperdiet
avoid copper-rich foods such as liver, kidney,
shellfish, nuts, dried fruits or beans, peas,

unprocessed wheat, chocolate, cocoa, and
mushrooms
Monitoring therapy
Measuring 24-hour urinary copperexcretion
; initial goal is urinary copperexcretion of

2000 mcg/day
Once patients have been decoppered, they
can be switched to maintenance therapy

(24-hour urinary copper repeatedly in the
range of 200 to 500 mcg) per day on
treatment; most patients require one to five
years of therapy to achieve these goals.
PROGNOSIS
The prognosis in patients with Wilson
disease is excellent in all but those with

advanced disease and those who present
with rapidly progressive liver failure and
hemolysis.
The neurologic, psychiatric, and hepatic
abnormalities gradually improve with

treatment, and liver biochemical tests
results usually return to normal.
There does not appear to be an increased
Hemochromatosis
Epidemiology
Hereditary hemochromatosis is an
autosomal recessive disorder in which

mutations in the HFE gene cause increased
intestinal iron absorption.
The frequency of heterozygotes is about
10% in Caucasian populations in the United

States and western Europe, with a
frequency of about 5/1000 (0.5%) for the
homozygous state
PATHOPHYSIOLOGY
In normal subjects, absorption of heme and
non-heme iron is inversely correlated with

iron stores, as reflected by the serum
ferritin concentration.
Homozygous HH is characterized by
increased absorption of both heme and

non-heme iron .
A few simple calculations explain why
clinical manifestations of HH typically occur

after age 40 in males and later in females.
A patient absorbs 4 mg/day.
Retention of 3 mg of iron more per day
Net iron accumulation of approximately 1 g
per year.
It will not be until age 40 or 50 that total iron
accumulation will reach more than 20 g of

iron.
The retained iron in HH is primarily deposited
in parenchymal cells, with reticuloendothelial

cell accumulation occurring very late in the
disease.
liver disease,
skin pigmentation,
diabetes mellitus,
arthropathy,
impotence in males,
cardiac enlargement with or without heart
failure or conduction defects
Liver disease
hepatomegaly, elevated liver enzymes, and
the eventual development of increasing

fibrosis and cirrhosis
reversibility of these changes following
therapeutic iron removal is more likely

early in the course of the disease, but can
occur even in patients with cirrhosis and
varices
Hepatocellular carcinoma
increased risk of HCC in patients with
hereditary hemochromatosis,
estimates of the magnitude of risk have
varied considerably ranging from a 20-fold
to up to a 200-fold increase
Diabetes mellitus
present in approximately 50 percent of
patients with HH who present with

symptoms
patients with HH and DM who require
insulin may note a fall in insulin

requirements following therapeutic iron
removal.
Arthropathy
displays the full spectrum of calcium
pyrophosphate crystal deposition disease

symptoms of arthropathy do not generally
respond to iron removal.
Heart disease
heart failure
conduction disturbances such as the sick
sinus syndrome
Treatment has been associated with reversal
of the left ventricular dysfunction. However,

irreversible myocardial dysfunction can occur
in subjects with advanced disease
Hypogonadism
Iron accumulation is mostly in the anterior
pituitary, while involvement of the posterior

portion is rare.
Secondary hypogonadism
Other pituitary deficiencies may occur, but
are much less frequent.
Susceptibility to specific
infections
Risk factors for infection with Listeria
iron overload of macrophages can diminish phagocytosis
high serum iron levels may increase bacterial virulence.
Yersinia enterocolitica
siderophoric (iron-loving) organism
contains several pathways to facilitate iron uptake, which
is essential for its growth

Septicemia from Vibrio vulnificus, (iron-requiring
bacterium), is more common in patients with HH who

ingest uncooked seafood
Total iron body stores

3 to 4 grams. It exists in the following forms:
Hemoglobin in circulating red cells
approximately 2.5 grams

Iron containing proteins, such as myoglobin,
cytochromes, and catalase 400 mg
Iron bound to transferrin in plasma 3 to 7 mg
The remainder is storage iron in the form of
ferritin or hemosiderin. Adult men have about 1
g of storage iron (mostly in liver, spleen, and
bone marrow).
DIAGNOSIS
Routine iron studies
Plasma (or serum) iron concentration
normal 60 to 150 microg/dL.
Transferrin concentration (plasma total iron
binding capacity, TIBC) normal 300 to 360
microg/dL. The ratio of plasma iron to
transferrin permits calculation of the
transferrin saturation normal 20-50%.
Plasma ferritin normal 40 to 200 ng/mL
(microg/L)
DIAGNOSIS
Routine iron studies
Cutoff levels for screening purposes
fasting transferrin saturation 60% in men or
50% in women has been accurate in
detecting over 90% of patients with
homozygous HH who have clinical symptoms
and/or documented iron overload
plasma ferritin concentration above 300
ng/mL in men and 200 ng/mL in women
provides further support for the diagnosis of
iron overload, provided that acute
inflammation is not also present
Ferritin
Only patients with HH and serum ferritin levels
>1000 ng/mL have been shown to be at

increased risk for the development of cirrhosis
High levels of ferritin in the absence of iron
overload
chronic viral hepatitis,
alcoholic liver disease,
nonalcoholic steatohepatitis
inflammatory cytokines (inflammatory diseases,
the metabolic syndrome, and malignancy) can

raise the plasma ferritin concentration
DEFINITIVE TEST
for the diagnosis of hepatic iron overload
and its consequences (cirrhosis) is liver

biopsy,
noninvasive imaging studies, such as CT as
well as T2* and R2* measurements by MRI
have become increasingly accurate for
determining both hepatic as well as cardiac
iron deposition
Liver biopsy
parenchymal iron loading can be
demonstrated by Perls' Prussian blue

staining of a liver biopsy specimen,
standard histologic examination can detect
the presence of fibrosis.
Liver biopsy
Hepatic tissue can also be directly analyzed
for iron content, the majority of which is

nonheme iron (normal values are <36
micromol/g, while values >71 micromol/g
are highly suggestive of homozygous HH )
Patients who may not need a liver

biopsy
the diagnosis has been clearly established
based upon genetic testing (see below),

and
there is a low likelihood of finding
significant hepatic fibrosis or cirrhosis
Response to phlebotomy
If there are reasons why a liver biopsy
cannot be performed but iron overload is

suspected, one can clinically confirm the
presence of iron overload in most patients
by determining the number of weekly 500
mL phlebotomies, each of which removes
200 to 250 mg of elemental iron, which are
required to produce iron deficient
erythropoiesis.
This procedure is called quantitative
phlebotomy.
Genetic testing for HH (HFE

gene)
C282Y and H63D mutation analysis
Treatment
PHLEBOTOMY
The simplest, cheapest, and most effective
way to remove accumulated iron in nonanemic patients with iron overload is via
therapeutic phlebotomy.
for a patient with HH and estimated iron
stores of 10 grams, one phlebotomy per
week for 50 weeks should fully deplete the
patient's accumulated iron stores.
Endpoints
serum ferritin (< 50 ng/mL) and the
transferrin saturation (< 50%) can be used to
Treatment
For maintenance, most patients require a
500 mL phlebotomy every two to four

months.
Treatment
Erythrocytapheresis
red cells are removed in an isovolemic
manner and the patients plasma is also

returned to the patient.
larger amounts of iron can be removed per
session than by phlebotomy.
Treatment
IRON CHELATION
deferoxamine
Ethanol
Consumption of 40-60 g of alcohol per day
(the amount contained in approximately

four glasses of wine or beer) was
associated with a ninefold increase in the
likelihood of developing cirrhosis in a cohort
of 224 C282Y homozygous patients with
documented iron overload.
PROGNOSIS
the presence or absence of cirrhosis
appears to be a major determinant of

prognosis
Granulomatous liver disease
Granulomas can be present in the liver in a
variety of conditions.
Their detection in the liver may be the first
clue to an ongoing systemic disease.
HISTOPATHOLOGY
Noncaseating such as seen with sarcoidosis.
Caseating characterized by central necrosis
(tuberculosis).
Fibrin-ring in which epithelioid cells surround a
vacuole that often has an encircling fibrin ring

(Hodgkin lymphoma, cytomegalovirus infection,
leishmaniasis, hepatitis A, toxoplasmosis, giant cell
arteritis, Boutonneuse fever, Q fever, and use of
allopurinol).
Lipogranulomas which contain a central lipid
vacuole (ingestion of mineral oil).
The clinical manifestations

depend upon the underlying cause and its
severity
Fever
Night sweats and weight loss
Hepatomegaly
Portal hypertension (only in cases of sarcoid,
primary biliary cirrhosis, and schistosomiasis)

In many patients, minor elevations in serum
aminotransferases and/or alkaline
phosphatase may be the initial clue
Autoimmune disorders
Sarcoidosis
Primary biliary cirrhosis
Wegener's granulomatosis
Polymyalgia rheumatica
Systemic infections
Tuberculosis
AIDS related causes(mycobacteria,
Cryptococcus neoformans, CMV,

histoplasmosis, toxoplasmosis)
Fungal diseases(histoplasmosis,
coccidioidomycosis, cryptococcosis,
candidiasis, blastomycosis)
Q fever
Brucellosis
Malignancy
Hodgkin lymphoma
non-Hodgkin lymphoma
renal cell carcinoma
Lesions are distinct from lymphomatous

areas and are not thought to reflect a
concomitant infectious etiology.
Drugs
allopurinol,
sulfa drugs,
chlorpropamide,
quinidine,
among others
Idiopathic
The term "granulomatous hepatitis" refers to
a syndrome characterized by a prolonged

febrile illness, myalgias,
hepatosplenomegaly, and arthralgias of
unclear etiology.
The treatment of symptomatic idiopathic
granulomatous hepatitis involves

immunosuppression.
Drugs and the liver
Liver injury can develop following the use
of many drugs, both prescription and overthe-counter, through a variety of

mechanisms.
A high index of suspicion is often necessary
to expeditiously establish the diagnosis.
EPIDEMIOLOGY
Drug-induced liver injury
annual incidence between one in 10,000 to
100,000
represents up to 10 percent of consultations
by hepatologists
over 1000 medications and herbal products
have been implicated in the development of

DILI
Mechanism of hepatotoxicity
Drugs associated with DILI may cause
injury:
in a dose-dependent, predictable way (eg,
acetaminophen)
in an unpredictable (idiosyncratic) fashion.
Idiosyncratic reactions may be immune-
mediated or metabolic.
SPECTRUM OF DRUG-INDUCED
LIVER INJURY
Subclinical
asymptomatic elevations in liver enzymes
without producing overt clinical disease

certain antibiotics, antidepressants, lipid-
lowering drugs, sulfonamides, salicylates,

sulfonylureas, and quinidine, generally in
fewer than 5-10% of individuals
isoniazid(up to 20%)
tacrine(up to 50%)
LIVER INJURY
Subclinical
Most subclinical ALT elevations are benign
and resolve once the offending agent has

been discontinued.
The time course of resolution can be variable
but generally occurs over weeks to months.
LIVER INJURY
Acute liver injury
accounting for approximately 10% of all
cases of acute hepatitis

patterns:
cholestasis,
hepatocellular (cytotoxic) damage,
a mixed pattern of cytotoxic and cholestatic injury,
less commonly, steatosis
LIVER INJURY
Acute liver injury
Discontinuation of the offending agent
usually results in complete recovery,

although the prognosis is generally worse in
patients with hepatocellular injury presenting
with jaundice.
In the setting of cholestatic injury, jaundice
can take months to resolve.
LIVER INJURY
Acute liver injury
Acute hepatitis
hepatocellular injury is similar to that seen in viral hepatitis.
halothane, carbon tetrachloride, acetaminophen, yellow
phosphorus, beryllium, iron sulfate; phenytoin, methyldopa,

isoniazid, and diclofenac, aspirin
mortality rate of up to 10% overall and up to 80% or
higher if acute liver failure develops.

the best predictor of mortality in the setting of acute
hepatocellular injury is a serum bilirubin level >3 times
the upper limit of normal
LIVER INJURY
Acute liver injury
Cholestatic injury
amoxicillin-clavulanate, captopril, carbamazepine,
chlorpromazine, efavirenz, ezetimibe, estradiol,

flutamide, diclofenac, erythromycinestolate,
nafcillin, ketoconazole, nevirapine, rifampin,
rosiglitazone, trimethoprim-sulfamethoxazole,
troglitazone,
rarely, amiodarone
LIVER INJURY
Acute liver injury
Mixed patterns
phenytoin, fluoroquinolones
LIVER INJURY
Acute liver injury
Acute steatosis
Jaundice is usually mild, and serum aminotransferases are
lower than that seen in cytotoxic injury.
The illness can be severe and the prognosis poor with high
mortality
Clinical features are similar to non-drug causes of
steatosis, including Reye's syndrome, or acute fatty liver of

pregnancy
high-dose intravenous tetracycline, amiodarone,camphor,
cocaine, piroxicam, tolmetin, valproic acid,
zidovudine(AZT), stavudine, and didanosine
LIVER INJURY
Chronic hepatic injury
generally refers to the presence of persistently
abnormal liver enzymes for over three to six months

resemble other causes of chronic liver disease such
as autoimmune hepatitis or alcoholic liver disease
generally resolves upon discontinuation of the
offending drug, but this pattern of liver injury may
progress to cirrhosis and liver failure
A progression to chronic disease is reported to occur
in approximately 5 -10% of adverse drug reactions
and is more common among the cholestatic/mixed
types of injury
LIVER INJURY
Chronic hepatitis
Autoimmune-like (methyldopa, minocycline,
nitrofurantoin, diclofenac, fenofibrate, papaverine,
phenytoin, propylthiouracil, statins, ecstasy)
Viral hepatitis-like (phenytoin, dihydralazine)
Chronic hepatitis with negative autoimmune
markers (lisinopril, sulfonamides, trazodone, uracil,
and tamoxifen)
Rarely, chronic toxicity without active
necroinflammatory disease (dantrolene, aspirin, and
isoniazid)
LIVER INJURY
Chronic steatosis
L-asparaginase, valproate, perhexilinemaleate, and
amiodarone
Steatohepatitis
amiodarone, diethylaminoethoxyhexestrol,
irinotecan, and perhexilinemaleate
LIVER INJURY
Fibrosis and cirrhosis FROM
steatosis (amiodarone)
chronic hepatitis
without any manifestation of clinical illness (as with
methotrexateor methyldopa)
chronic cholestasis (floxuridine)
chronic congestive hepatopathy with sinusoidal
obstruction syndrome (azathioprine,
mercaptopurine, oral contraceptives)
noncirrhotic portal hypertension (vitamin A)
LIVER INJURY
Chronic cholestasis
Chronic intrahepatic cholestasis (amitriptyline, ampicillin,
amoxicillin-clavulanate, carbamazepine, chlorpromazine,
cyproheptadine, erythromycinestolate, haloperidol,
imipramine, organic arsenicals, prochlorperazine,
phenytoin, trimethoprim-sulfamethoxazole, thiabendazole,
tolbutamide, tetracycline, oral contraceptives, and anabolic
steroids)
Vanishing bile duct syndrome (amoxicillin, carbamazepine,
chlorpromazine, chlorpropamide, clindamycin, flucloxacillin,
haloperidol, sulpiride, tenoxicam, thiabendazole, tricyclic
antidepressants, trimethoprim-sulfamethoxazole)
Biliary sclerosis(floxuridine)
LIVER INJURY
Vascular disease
Hepatic vein thrombosis(oral contraceptives)
Sinusoidal obstruction syndrome (pyrrolizidine
alkaloids - found in herbal remedies,
azathioprine, mercaptopurine, vitamin A, oral
contraceptives, cyclophosphamide, tetracycline,
and a number of chemotherapeutic agents oxaliplatin)
Peliosis hepatis (anabolic steroids, arsenic,
azathioprine, mercaptopurine, oral
contraceptives, danazol, diethylstilbestrol,
tamoxifen, vitamin A, and hydroxyurea)
LIVER INJURY
Granulomatous hepatitis
allopurinol, amiodarone, carbamazepine,
cephalexin, dapsone, diazepam, diclofenac,
diltiazem, gold, interferon, isoniazid,
mesalamine, methyldopa, nitrofurantoin,
penicillin, phenytoin, procainamide,
quinidine, sulfonamides, and sulfonylureas
DIAGNOSIS
can be difficult
careful drug history
review of pharmacy records
underlying liver disease should be excluded
the relationship between exposure to the
drug and hepatic toxicity is not always clear
DIAGNOSIS
The key elements for attributing liver injury
to a drug include :
Drug exposure preceded the onset of liver
injury (although the latent period is highly

variable)
Underlying liver disease is excluded
Stopping the drug leads to improvement in
the liver injury
Rapid and severe recurrence may occur if
there is repeated exposure to the drug
(however, rechallenge is not advised)
TREATMENT
withdrawal of the offending drug
early recognition of drug toxicity is
important to permit assessment of severity

and monitoring for acute liver failure
recovery should be expected in the
majority of patients after discontinuing the

drug.
Specific therapies
N-acetylcysteine for
acetaminophentoxicity
L-carnitinefor cases of valproic acid
overdose

Chronic Hepatitis

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Chronic Hepatitis

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Chronic hepatitis

Liver function tests

the liver are not direct measures of its

Liver function tests

tests of synthetic function

serum bilirubin (measures the liver's ability

to detoxify metabolites and transport

classification, with a sensitivity of 88 percent and a

of men and 28% of women would be classified as

considered to be the upper limit of normal

labs may not be straightforward.

MILD CHRONIC ELEVATION IN

less than four times the upper limit of

history and physical examination raise the

elevation of liver enzymes

liver injury can be difficult.

because many patients conceal this information

occasionally elevated in an alcoholic pattern:

increased in patients with a history of

of parenteral exposure (blood transfusions,

Caucasian populations, with a frequency of about

iron and total iron binding capacity (TIBC).

and associated with obesity and type 2

CT or MRI scanning, but is less expensive.

hepatic causes of elevated

levels should be determined)

disease or secondary causes)

patients less than 40y)

patients in whom all of the above testing

than twofold elevated and no chronic liver condition

greater than twofold elevated (but it remains unlikely

Chronic HBV hepatitis

Despite the decrease in incidence of acute HBV

infection, an analysis of hospitalization records found

HBeAg-positive mothers is as high as 90%.

neonates born to HBsAg-negative mothers

horizontal transmission via minor breaks in

hepatitis B from 1991 to 1997 in the United Kingdom, the

with hemophilia and thalassemia, are at increased risk

virus in the healthcare setting

reported after transplantation of extrahepatic

to HBV, prior to the onset of hepatitic symptoms or

immunocompetent adult patients with genuine acute

the appearance of hepatitis B surface

be detectable until after a window period of

hepatocytes; it is notdetectable in serum

as an indication of acute HBV infection. However,

the acute infection.

IgG anti-HBc persists along with anti-HBs in patients

who recover from acute hepatitis B. It also persists

prior to HBsAg to anti-HBs seroconversion

HBV DNA and remission of liver disease.

disease after HBeAg seroconversion. Such

time PCR techniques, report results in IU/mL,

accompanied by the disappearance of HBV DNA in

chronic HBV infection. Spontaneous or treatmentinduced HBeAg seroconversion is usually accompanied

copies/mL has been proposed as a cutoff

by PCR in patients who are negative for HBsAg.

negative for other HBV markers, most commonly anti-HBc)