hepatitis. introduction hepatitis: inflammation of liver viral alcoholic immunedrugs toxins biliary...
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IntroductionHepatitis: Inflammation of Liver
viral
alcoholic immune DrugsToxins
biliary obstruction
- gall stones
Types: Acute
Chronic
Fulminant
Viral Hepatitis: Hepatitis A, B, C, D, E, & other
systemicsystemic
specificspecific
CMV, EBV& other
Pattern of Viral Hepatitis
Carrier state
asymptomatic phase
Acute hepatitis
Chronic Hepatitis Fulminant
hepatitis
Cirrhosis
HCCHCC
1 -Chronic Persistent Hepatitis (CPH)2 -Chronic Active Hepatitis (CAH)
ACUTE HEPATITISDef: Acute inflammation of the liver.
Etiology: 1 -Viral: A, B, C, D, E, F, G.
2 -Non viral: (inf.) - Toxoplasma. - Leptospira hegica.
3- Drugs: -Halothan. - Paracetamol .
- 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 Fatty changes S.Hepatitis C
Causes:Hepatitis A
HAVInfective hepatitis
Hepatitis BHBV
serum hepatitis
HepatitisD
HDV
Hepatitis CHCVPost
transfusion hepatitis
Hepatitis EHEV
Epidemic/ Entral
virus 27 nm RNA 42 nm DNAHepa virus
35 nm Incomplete
RNA+HBsAg
30 – 60 nmRNA flavi firus
32 nm RNA
transmission Feco-oral Paraentral and post transfusionSexual low risk 1-5 %Intrauterine low risk <5%
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 specificIg
Specific Ig IgM Non specificIg
-active HAV vaccine danger
Heptavax HBV vaccine
Heptavax HBV vaccine
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. - Lymphocytosis. - Haemolytic anaemia. -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: anti-HDV
PCR (HDV –RNA( .
HEV: Ag, Ab
CHRONIC HEPATITISDefinition: 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 - Moderate
inflammation - 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
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 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
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 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.
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?
Acute or fulminant presentation is possible 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 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 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 S-transferase, 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 DAMAGE1- 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 Malignant
oral contraceptive pills 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.
EtiologyViral hepatitis
Hepatitis A - rarelyHepatitis B - appx
1% of hep BHep C -- probably
not, but ??Hep D -- delta
agent coinfects with Hep B
Hep ECMV, HSV
Toxins Carbon
tetrachloridePhosphorusAmanita phalloides
(antidote penicillin and silybin)
Industrial cleaning solvents
EtiologyDrugs
AcetaminophenAcetaminophen 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, diffuse, extensive, resulting in caseating necrosis.
Cardiac -- similar, with particularly severe 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.
Clinical Presentation 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.
Clinical Presentation 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 HCV5 – 10% of HBV
&80% of HDV super infection
HAV & HEV infection never lead to chronic hepatitis
N.B: .
Clinical features & presentation
Patient may present an a variety of ways:
Patient may present an a varietyof ways:
- Clinical symptoms may range from non to mild fatigue or patient may present withcomplication of cirrhosis
-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 signsof chronic liver disease may be present
-there may be no signs but jaundice or signs of chronic liver disease may be present
chronic viral hepatitis
Chronic HCV
ChronicHBV
Patterns of viral hepatitis C
1- most patient with hepatitis C are asymptomaticmost 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.
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 Recovery
Transient subclinical infection 65%
Acute hepatitis 25%
death
Acute HBV
10%
Chronic HBV infection
Healthy HBsAg carier70-90%
HCC
Chronic hepatitis 10-30%
cirrhosis
100% 99% 1%
Table 3: Interpretation of HCV Assays
Utility of the Liver Biopsy
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 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 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)
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 %
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:
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.
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
Premanant Discontinuation (INF &
Ribavirin) Dose Reduction by 50%
<8.5 g/dl <10 g/ dl(only ribavirin )
HB Level
<1000 <1500(Only INF )
WBC
<500 <750(Only INF )
Neutrophils
<25,000 <50,000(Only INF )
Platelets
>1.5 UNL N/A Creatinine
2 ×Baseline OR <10 UNL N/A ALT-AST
>4 mg % )For <4 weeks( >5 mg% (only ribavirin )
Indirect Bil.
>2.5 UNL N/A Direct Bil.
NOVEL HCV
ANTIVIRAL
SOFOSBUVIR
(sovaldi)
