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HEPATITIS
Introduction
Hepatitis: Inflammation of Liver
viral
alcoholic immune Drugs
Types :
biliary
obstruction
Toxins
- gall
stones
Acute
Chronic
Fulminant
specific
Hepatitis A, B, C, D, E, & other
Viral Hepatitis :
systemic
CMV, EBV& other
Pattern of Viral Hepatitis
Carrier
state
HCC
asymptomatic phase
Chronic
Hepatitis
Cirrhosis
Acute
Fulminant
hepatitis1- Chronic Persistent Hepatitis (CPH)hepatitis
2- Chronic Active Hepatitis (CAH)
ACUTE
HEPATITIS
Def:
Acute inflammation of the liver.
Etiology:
1- Viral: A, B, C, D, E, F, G.
2- Non viral: (inf.)
- Toxoplasma.
3- Drugs:
- Paracetamol.
- Leptospira hegica.
- Halothan.
- Mono Amino oxidase Inhibitor (MAOI).
4- Poisons:
- Aflatoxins
- Amanitaphaloids .
5- Misscellaneous:
-
pregnancy.
- Wilson’s disease.
- Circulatory insufficiency.
- Alcohol.
Pathology:
►
Hepatocytes  swollen and become granular with variable.
►
distribution:
►
►

* Centrizonal.
* Focal (spotty).
OR
* Massive.
Dead hepatocytes become shrunken.
Lobules: portal tract infiltration with lymphocytes.
N.B.: in
Pregnancy
Alcoholism
S.Hepatitis C
Fatty changes
Causes:
Hepatitis A
HAV
Infective
hepatitis
Hepatitis B
HBV
serum
hepatitis
Hepatitis
D
HDV
Hepatitis C
HCV
Post
transfusion
hepatitis
Hepatitis E
HEV
Epidemic/
Entral
virus
27 nm RNA
42 nm DNA
Hepa virus
35 nm
Incomplete
RNA+HBsAg
30 – 60 nm
RNA flavi firus
32 nm RNA
transmission
Feco-oral
Incubation p.
2 – 6 weeks
2 – 6 months
2 – 6 months
2 – 6 months
2 – 6 weeks
Chronicity
&liver cancer
no
Yes
Yes
Yes
No
Immunization
-passive
Non specific
Ig
Specific Ig
IgM
-active
HAV vaccine
danger
Heptavax
HBV vaccine
Heptavax
HBV vaccine
Paraentral and post transfusion
Sexual
low risk 1-5 %
Intrauterine
low risk <5%
Feco-oral
Non specific
Ig
CLINICAL PICTURE OF ACUTE HEPATITIS (VIRAL):
Variable from asymptomatic to fluminant hepatitis
A- Pre-icteric:
►
►
►
2 weeks
Anoraxia, Nausea, vomiting, diarrhea.
Fever, headache, malaise, abdominal pain.
Pruritis.
In Hepatitis B:
*Immunological manifestations as:
* maculopapular rash, polyarthritis,
vasculitis,
* glomerulonephritis.
B- Icteric phase (may not occur):
►
Jaundice: dark urine, pale stool.
►
Hepatomegally, splenomegally.
►
Tender lymphadenopathy.
►
Rarly  fulminant hepatic failure
C- Convalescent stage:
- Improvement occur (clinically and laboratory).
- Complete cure in A,E, chronecity in B,C, D,G.
Investigations:
1- Liver function tests:
- serum enzymes.
-serum bilirubin.
2- Haematological:
- Leucopenia.
- Haemolytic anaemia.
- Lymphocytosis.
-Aplastic anaemia.
3- Immunological:
- HAV:
IgM  acute infection.
IgG (alone)
* previous exposure.
* non infectivity.
* immunity.
- HBV:
* HBs Ag  infection, infectivity if persist after acute phase
 carrier state or chronicity.
* HBcAg  not detected in the serum. (in the liver).
* HBeAg 
- viral replication
- Infectivity after 3 months
* HBV Ab:
anti HBs +ve
Clearance of HBsAg.
After successful vaccination.
Recovery and non infectivity.
* Anti HBC:
IgM  persists for 3-6 months. appears shortly after
HBsAg (acute infection)
HBsAg –ve (HbsAb not get +).
Pt. is infective +ve anti HBC IgM.
* Anti-HBC IgG:
- Appear during acute illness
- Persists indefinitely.
* Anti-HBe  after anti HBC ( infectivity).
* HBV DNA:
The most sensitive index of viral replication and
infectivity (by PCR).
-HCV:
Anti HCV:
Detection of Anti HCV using C100antigen
(1st generation) (ELIZA).
2nd generation  using C22, 223 (RIBA).
PCR: detect HCV Ag qualitative and quantitative.
HDV :
HEV :
anti-HDV
PCR (HDV –RNA( .
Ag, Ab
CHRONIC HEPATITIS
Definition:
It is a chronic inflammatory reaction for 6
months or more.
Etiology:
1- Viral: B, C, D
2- Autoimmune.
3- Drugs: INH, ketoconazol,
Nitrofurantoin.
4- Heridetary: * 1 antitrypsin deficiency.
* Wilson’s disease.
Pathology:
Inflammatory cells infiltrate of the portal tracts
(lymphocytes, plasma cells, macrophages)  piece
meal necrosis  collagen deposition  bridging
necrosis  cirrhosis.
Classification:
According to the etiology.
Pathological classification
Chronic persistant
according to grade
stage of fibrosis
Chronic lobular
- Portal
Chronic active
- Peripheral
- Non
- Lobular
inflammation
- Moderate
- Severe
(minimal, moderate, severe)
CHRONIC VIRAL HEPATITIS
Clinical Picture:
□ Symptoms : Anorexia, vague abdominal pain,
past history of the cause and may be nothing at
all.
□ On Examination:
• Liver is enlarged and tender with smooth
surface.
• Spleen usually not enlarged or intercostally
enlarged.
INVESTIGATION:
• Serum enzymes [SGOT, SGPT, ALT] are all
normal or slightly elevated, bilirubin is normal.
• Viral markers may be +ve.
• Liver biopsy : normal hepatic architecture with
portal tract, infiltration with chronic inflammatory
cells.
Treatment:
• Symptomatic ttt only + Reassurance.
• Avoid hepatotoxic drugs.
CHRONIC AUTOIMMUNE HEPATITIS
c/o:
♣ Easy fatiguability, pruritis. jaundice, arthralgia ±
Ascites, etc....
♣ Multisystem manifestations:
◙ Polyarthopathy.
◙ Pallor, skin rashes,
◙ Glomerulonephntis
◙ D.M.
◙ Autoimmune Haem.An., neutropenia.
◙ Myxoedema, Thyrotoxicosis, Hashimoto's
thyroiditis.
0/E:
● Enlarged firm liver (usually smooth surface),
tender.
● Manifestations of LCF and portal hypertension.
AIH subtypes
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AIH type 1
AIH type 2
AIH type 3
on the basis of immunoserologic markers.
The International Autoimmune Hepatitis Group
has not endorsed this subclassification.
Used mainly for descriptive value
AIH type 1
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
Most common form worldwide
characterized by the presence or absence of SMA and/or
ANA in serum
Surrogate markers: Perinuclear antineutrophil cytoplasmic
antibodies which occur in PSC and chronic UC, are found
in 90% of patients who have type 1 AIH.
Bimodal age distribution (10-20; 45-70)
Female:male 3.6:1
Risk factors for type 1 AIH

in whites of northern European descent [HLA-DR3 (DRB1*0301)]
and –DR4 (DRB1*0401)]
AIH type 1

Associated with concurrent extrahepatic diseases

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
Autoimmune thyroiditis (12%)
Graves disease (6%)
Chronic UC (6%) * (cholangiography to exclude PSC)
<1% RA, pernicious anemia, systemic sclerosis, Coomb’s test-positive HA,
ITP, symptomatic cryoglobulinemia, leukocytoclastic vasculitis, nephritis,
erythema nodosum, SLE, fibrosing alveolitis.
40% of AIH type 1 presents with an acute onset of symptoms/signs
indistinguishable from that of acute viral or toxic hepatitis and the
disease may appear fulminant in fashion.
target autoantigen is unknown, but ASGPR (asialoglycoprotein
receptor) found on hepatocyte surface is a candidate
Responds well to glucocorticoids
AIH type 2
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
Characterized by presence of anti-LKM1 (liver/kidney microsome type 1) in serum
P-ANCA is not found
Mainly children (2-14 yo) but also seen in adults (in Europe, 20% of pts are adults; in US,
4% of pts are >18 yrs)
Only AIH with an identified target autoantigen: cytochrome monooxygenase P-450 IID6
(CYP2D6) found in the cytosol of hepatocytes.
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Acute or fulminant presentation is possible
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Recognized homologies b/w epitopes of CYP2D6 and genome of HCV.
<10% of Europeans with chronic Hep C have detectable anti-LKM1
Suggests molecular mimicry and antibody crossreactivity, multiple exposures to virus mimicking
self may be a way to break self-tolerance and induce AIH type 2.
Anti-LKM1 + pts with chronic Hep C in US pts is rare – differences in indigenous virus or host
susceptiblity?
Thus essential to screen all pts who have an acute decompensation for type-specific
autoantibodies.
Associated with HLQA-B14, -DR3, -C4A-QD
Susceptibility factor in German and Brazilians: DRB1*07
Like AIH type 1, also responds well to glucocorticoids
AIH type 2
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Distinct form of anti-LKM positive AIH
Occurs in association with autoimmune polyendocrinopathy disorder
(APECED) aka Polyglandular autoimmune syndrome type I (APS1)
rare autosomal recessive disorder
Caused by a signal gene mutation of the APS1 gene which encodes a
transcription factor, autoimmune regulator (AIRE) which is expressed
in epithelial and dendritic cells within the thymus where it regulates
clonal deletion of autoreactive T cells, thus can affect self tolerance
Features of this disease are ectodermal dystrophy, mucocutaneous
candidiasis, multiple endocrine gland failure (parathyroids, adrenals,
ovaries)
Marked by the presence of numerous organ and non-organ specific
autoantibodies and multiple concurrent autoimmune diseases.
most common among Finns, Sardinians, and Iranian Jews
Pts with APECED and AIH have an aggressive liver disease that does
not respond well to standard immunosuppressive regimens.
AIH type 3
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Least established form of the disease
Designation largely abandoned
Characterized by presence of antibodies to soluble liver
antigen and liver/pancreas (anti-SLA, anti- LP)
30-50 yo
Target autoantigens: thought to be Glutathione Stransferase, but a transfer ribonucleoprotein (tRNP) 50-kd
protein was described in 2000 as the more likely target.
Clinical and laboratory features that are indistinguishable
from AIH type 1
Also responds well to glucocorticoids
AIH subtypes
DRUG INDUCED LIVER DAMAGE
1- Hepatocellular damage:
Associated with history of drug intake.
Indistinguishable from acute or chronic
hepatitis.
Induced either by:
* Toxic metabolite.
or
* Immune response to drugs:
as - Thiazide
- Rifampicine
- Halothan
- Acetaminophan
- NSAIDs
- INH
2- Cholestatic liver damage:
as
* Estrogen
* Phenothiazine
* Tricyclic antidepressants.
* Erythromycin
* Sulphasalazine
* Tolbutamide
3- Drugs causing hepatic fibrosis:
Methotrexate, amiodarone
4- Drugs causing chronic active hepatitis:
Methyldopa, nitrofurantoins, sulphonamides .
5- Drugs causing hepatic tumours
Benign
oral contraceptive pills
Malignant
synthetic androgens
FULMINANT HEPATIC FAILURE
Fulminant Hepatic Failure
Definition - Altered mental status with
coagulopathy in setting of acute liver
disease. Hepatic encephalopathy occurring
within 8 weeks of onset of illness defines
FHF.
Etiology
 Viral hepatitis
 Hepatitis A - rarely
 Hepatitis B - appx 1%




of hep B
Hep C -- probably not,
but ??
Hep D -- delta agent
coinfects with Hep B
Hep E
CMV, HSV
 Toxins
 Carbon tetrachloride
 Phosphorus
 Amanita phalloides
(antidote penicillin
and silybin)
 Industrial cleaning
solvents
Etiology
 Drugs
 Acetaminophen
 Acetaminophen in Tx
doses with alcohol
 Idiosyncratic reaction
-- halothane,
sulfonamides,
phenytoin, and others.

Vascular
— Heart failure -centrolobular necrosis
— Sinusoidal
obstruction secondary
to metastates
— Budd Chiari
— Veno-occlusive
disease
Pathology

Viral, toxic -- hepatocellular necrosis,

Cardiac -- similar, with particularly severe
diffuse, extensive, resulting in caseating
necrosis.
centrolobular
necrosis
from
higher
intravascular pressure. Blood flows from
portal triad (hepatic artery and portal vein)
to central veins to hepatic vein. With poor
cardiac output, splanchnic flow markedly
decreased, resulting in markedly decreased
portal flow.
Pathology

Fatty liver of pregnancy and Reye’s show
microvesicular
collections
of
fat
in
hepatocytes and much less necrosis.

Special stains -- iron in hemochromatosis,
copper in Wilson’s, etc.



Typically -- nonspecific symptoms, nausea,
malaise, jaundice, altered mental status, coma -- all
over a few days.
The altered mental status occasionally precedes
clinical jaundice.
Mental status changes often start with agitation,
delusions, irritability before progressing to
lethargy, stupor, and coma.

Laboratory - Transaminases usually high (>1000)
 Bilirubin -- usually mixed hyperbilirubinemia
 Ammonia -- usually elevated
 Coagulopathy with prolonged PT, PTT, decreased
factors
 Low level DIC
 Low level fibrinolysis
 Respiratory alkalosis
 Metabolic acidosis, increased lactate
Chronic viral hepatitis
Etiology:-
This syndrome is induced by :
> 70% of HCV
5 – 10% of HBV
& 80% of HDV super
infection
N.B. :
HAV & HEV infection never
lead to chronic hepatitis
Clinical features & presentation
Patient may present an a variety
of ways :
- Clinical symptoms may range from non to
mild fatigue or patient may present with
complication of cirrhosis
- there may be no signs but jaundice or signs
of chronic liver disease may be present
chronic viral hepatitis
Chronic
HCV
Chronic
HBV
Patterns of viral hepatitis C
1-
most patient with hepatitis C are asymptomatic
( suspicious often with screening of risk factors which include :-
I.V. drug use
sharing of straws to snort cocaine
heamodialysis
& Bl. transfusion
in contrast to HBV sexual transmission is rare , vertical
transmission is uncommon )
2-
70-80% of all patients infected with HCV will
develop chronic hepatitis in the 10 years
following infection, within 20 years 30% of
those will develop cirrhosis & over 30 years of
those with cirrhosis may develop HCC .
Patterns of hepatitis B infection
death
1%
99 %
Recovery
Acute hepatitis
25 %
100 %
Transient subclinical infection
65%
Acute HBV
10%
Chronic HBV infection
Chronic hepatitis
Healthy HBsAg carier
10-30%
cirrhosis
70-90%
HCC
Table 3: Interpretation of HCV Assays
Utility of the Liver Biopsy
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It provides helpful information on the current status of the liver
injury (Grade, Stage).
It identifies features useful in the decision to embark on therapy
(steatosis and excess hepatocellular iron).
It may reveal advanced fibrosis or cirrhosis that necessitates
surveillance for hepatocellular carcinoma (HCC) and/or screening
for varices.
Comparison of Scoring Systems for Histological Stage
Characteristics of Persons for Whom
Therapy Is Widely Accepted
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Age 18 years or older, and
HCV RNA positive in serum, and
Liver biopsy showing chronic hepatitis with significant fibrosis
(bridging fibrosis or higher), and
Compensated liver disease (total serum bilirubin 1.5 g/dL; INR 1.5;
serum albumin _3.4, platelet count 75,000 mm with no evidence of
hepatic decompansation (hepatic encephalopathy or ascites), and
Acceptable hematological and biochemical indices (Hemoglobin 13
g/dL for men and 12 g/dL for women; neutrophil count 1500 /mm3
and serum creatinine _1.5 mg/dL, and
Willing to be treated and to adhere to treatment requirements, and
No contraindications
Characteristics of Persons for Whom
Therapy Is Currently Contraindicated
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Major uncontrolled depressive illness
Solid organ transplant (renal, heart, or lung)
Autoimmune hepatitis or other autoimmune condition known to be
exacerbated by peginterferon and ribavirin
Untreated thyroid disease
Pregnant or unwilling to comply with adequate contraception
Severe concurrent medical disease such as severe hypertension,
heart failure, significant coronary heart disease, poorly controlled
diabetes, chronic obstructive pulmonary disease
Age less than 2 years
Known hypersensitivity to drugs used to treat HCV
The Adisory Committee meeting report (28 December
2006, modified on 25 June 2007)
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Routine blood tests: CBC, LFTs (AST, ALT, T. Bil, Albumin, ALP,
Prothrombin time), S.creatinine, FBS, PCR for HCV.
Other blood tests: HB sAg, ANA, TSH, α FP, ABA.
Abdominal U/S.
Fundus examination.
ECG.
Liver biopsy.
BMI.

A liver biopsy may be unnecessary in:

Persons with genotypes 2 and 3 HCV infection, since more than 80% of
them achieve a sustained virological response (SVR) to standard of
care treatment.
 Medical & paramedical staffs.
 Extra-hepatic manifestations.

Compansated liver disease (Child A) will be treated if there is no
varices.
Liver biopsy >F0 &>A1 with elevated liver enzymes (Metavir
score).
Liver biopsy ≥ A2 & ≥ F2 with normal liver enzymes.

BMI <35 %
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
The Optimal Treatment of Chronic HCV:
Peginterferon Alfa and Ribavirin

There are two licensed pegylated interferons in the United States,
peginterferon alfa-2b (Peg-Intron, Schering Plough Corp.,
Kenilworth, NJ), with a 12-kd linear polyethylene glycol (PEG)
covalently linked to the standard interferon alfa-2b molecule, and
peginterferon alfa-2a (Pegasys, Hoffmann-La Roche, Nutley, NJ)
with a 40-kd branched PEG covalently linked to the standard
interferon alfa-2a molecule (Zeuzem et al, 2003).

The optimal dose of peginterferon alfa-2b, based on the original
registration trial is 1.5 µg/kg/week dosed according to body weight.

Weight-based ribavirin (800 mg for patients < 65 kg; 1,000 mg for
patients weighing 65 to 85 kg; 1,200 mg for patients weighing 85 to
105 kg; and 1,400 mg for patients weighting >105 kg but < 125
kg) was more effective (Jacobson et al, 2007).

Peginterferon alfa-2a is administered at a fixed dose of 180 µg/week
given subcutaneously together with ribavirin 1,000 to 1,200 mg
daily, 1,000 mg for those who weight < 75 kg and 1,200 mg for
those who weight > 75 kg.
Adverse Events:
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The most common adverse events in these trials were influenza- like
side effects such as fatigue, headache, fever and rigors, which
occurred in more than half of the patients.
Psychiatric side effects (depression, irritability, and insomnia), which
occurred in 22% to 31% of patients.
Laboratory abnormalities are the most common reasons for dose
reduction. Among these, neutropenia (absolute neutrophil count
[ANC] of 1500 mm3) was a frequent laboratory abnormality,
occurring in 18% to 20%. The dose was reduced 50% for an ANC of
750 mm3 and permanently discontinued for an ANC of <500
Despite the decline in the neutrophil count, serious infections are
uncommon (Suza et al 2002) and Granulocyte colony stimulating
factor is rarely necessary except in patients with advanced cirrhosis.
Anemia was observed in approximately one-third of patients, Dose
modification for anemia (hemoglobin level <10 g/dL) was required in
9% to 15%

Growth factors, such as erythropoietin, have been used to counter
the anemia associated with peginterferon and ribavirin. Although
growth factors improve a patient’s sense of well-being and have
reduced the requirement for ribavirin dose reduction, their use has
not been shown to improve SVR rates (Shiffman et al, 2007).

In one analysis, the use of a hematological growth factor nearly
doubled the cost of treatment for chronic hepatitis C (Del Rio et al,
2006). Although generally safe, erythropoietin use has been
associated with serious side effects including cardiovascular and
thromboembolic events, pure red cell aplasia, progression of certain
cancers, and death (Bennett et al, 2008). Therefore, routine use of
growth factors cannot be recommended at this time and dose
reduction is the primary mode for managing cytopenias.

Neuropsychiatric side effects include depression, anxiety,
insomnia, emotional lability, mood disorders, frank psychosis,
suicidal ideation, actual suicide, and homicide

The most consistent risk factors for developing depression are the
presence of mood and anxiety symptoms prior to therapy. A past history
of depression and of receiving higher doses of interferon, as well as
being female, have been identified as risk factors, but are less reliable
ones (Raison et al, 2005).
 Interferon-induced depression appears to be composed of two
overlapping
syndromes,
a
depression-specific
syndrome
characterized by mood, anxiety, and cognitive complaints, and
neurovegetative symptoms, characterized by fatigue, anorexia, pain
and psychomotor slowing (Capuron et al, 2002). Depression-specific
symptoms are highly responsive to serotonergic antidepressants
whereas neurovegatative symptoms are not. These symptoms may be
more effectively treated with agents that modulate catecholaminergic
function. When selecting an agent, consideration should be given to
drug– drug interactions, underlying hepatic function, the possibility of
drug-induced hepatotoxicity and other adverse side effects.
Consultation and follow up with a psychiatrist is advised.
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Pegylated interferon may induce autoimmune disorders, such as
autoimmune thyroiditis, or may worsen pre-existing autoimmune
disorders. Therefore, the presence of autoimmune conditions prior
to treatment is a relative contraindication to therapy.
With regard to ribavirin, the most common side effect is hemolytic
anemia.
Since ribavirin is cleared by the kidney, the drug should be used
with extreme caution in patients with renal disease and renal
failure.
Other side effects associated with ribavirin include mild
lymphopenia, hyperuricemia, itching, rash, cough and nasal
stuffiness.
Ribavirin is reported to cause fetal death and fetal abnormalities in
animals and thus it is imperative for persons who receive the drug to
use strict contraceptive methods both during treatment and for a
period of 6 months thereafter. The education of patients and
caregivers about side effects and their management is an integral
component of treatment and is important for a successful outcome.
Follow up pannel:


To detect response: PCR at 4, 12, 24, 36, 48 and 72 weeks.
To monitor complications :CBC (ANC), AST, ALT, Creatinine,
T.bilirubin after each injection in the first month, then monthly till end
of treatment.
Table 5: Virological Responses During Therapy and Definitions
Dose Reduction by 50 %
Premanant
Discontinuation (INF &
Ribavirin)
< 10 g/ dl
(only ribavirin)
<8.5 g/dl
WBC
< 1500
(Only INF)
< 1000
Neutrophils
< 750
(Only INF)
< 500
Platelets
< 50,000
(Only INF)
< 25,000
Creatinine
N/A
> 1.5 UNL
ALT-AST
N/A
2× Baseline OR >10 UNL
>5 mg %
(only ribavirin)
> 4 mg % (For >4 weeks)
N/A
> 2.5 UNL
HB Level
Indirect Bil.
Direct Bil.

NOVEL HCV
ANTIVIRAL

SOFOSBUVIR
(sovaldi)