Best Dx/Best Rx: Chronic Hepatitis

From: Subject: Best Dx/Best Rx: Chronic Hepatitis Date: Wed, 3 Jun 2009 21:10:35 -0700 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_012B_01C9E48F.BCCF5390" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_012B_01C9E48F.BCCF5390 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.acpmedicine.com/acp/newrxdx/rxdx/dxrx0408.htm Best Dx/Best Rx: Chronic Hepatitis

Chronic=20 Hepatitis

Peter F. Malet, M.D., = F.A.C.P.
University of=20 Texas Southwestern Medical Center at Dallas

Defin= ition/Key=20 Clinical Features
Diffe= rential=20 Diagnosis
Best = Tests
Best = Therapy
Best = References

Definition/Key Clinical=20 Features

Liver disease lasting 6 mo or longer, mainly = manifested=20 by hepatocellular injury/necrosis=20
Most common etiologies
- Chronic hepatitis C=20
- Chronic hepatitis B=20
- Autoimmune hepatitis
Highly variable presentation and course =
- Asymptomatic to rapidly progressive with = fulminant=20 hepatic failure
Most common symptoms
- Fatigue=20
- Malaise=20
- Mild abdominal pain
Symptoms of advanced disease
- Variceal bleeding=20
- Jaundice=20
- Spider angiomas=20
- Palmar erythema=20
- Ascites=20
- Edema=20
- Hepatomegaly=20
- Encephalopathy
Extrahepatic manifestations
- Arthralgias=20
- Arthritis=20
- Glomerulonephritis=20
- Skin rashes

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Differential = Diagnosis

Primary biliary cirrhosis=20
Primary sclerosing cholangitis=20
Alcoholic liver disease=20
Fatty liver and nonalcoholic steatohepatitis=20 (NASH)=20
Drug-induced chronic hepatitis=20
Wilson disease
α₁-Antitrypsin = deficiency

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Best=20 Tests

Serologic = Testing

Autoimmune Hepatitis=20

Type 1=20
- Hypergammaglobulinemia=20
- Presence of antinuclear antibody (ANA), = anti=96smooth=20 muscle antibody (ASMA), or both
Type 2
- Absence of ANA and ASMA=20
- Presence of antibody to liver/kidney = microsome=20 (anti-LKM) type 1
Type 3
- Presence of antibody to soluble liver = antigen,=20 liver/pancreas antigen, or both=20
- Some patients also positive for ASMA,=20 antimitochondrial antibody, or both
Some patients have no serologic markers = (marker-negative=20 autoimmune hepatitis) or have overlap syndromes

Chronic Hepatitis B=20

Inactive HBsAg carrier=20
- Positive HBsAg=20
- Positive anti-HBc
- Negative anti-HBs
- Negative HBeAg
- Positive anti-HBe=20
- HBV DNA usually < 100,000 = copies/ml
High replicative state=20
- Positive HBsAg=20
- Positive anti-HBc=20
- Negative anti-HBs=20
- Positive or negative HBeAg=20
- If HBeAg positive, Anti-HBe is = negative=20
- HBV DNA > 100,000 copies/ml=20

Chronic Hepatitis = C=20

Positive anti-HCV ELISA
Detectable HCV RNA=20
Determination of genotype
- 75% genotype 1
- 20% genotypes 2 or 3
- < 5% genotypes 4 to 6 =

Routine Laboratory Tests=20

Serum ALT and AST usually elevated, often only = minimally=20 elevated or even normal in chronic hepatitis B (inactive carrier) and = C=20
Serum bilirubin usually normal in chronic = viral=20 hepatitis but often > 3 mg/dl in autoimmune hepatitis=20
Increased γ-globulin level in autoimmune=20 hepatitis=20
Low serum albumin level and prolonged PT = suggest=20 advanced disease=20
Abdominal CT, MRI, or ultrasound to determine = the=20 following:=20
- Liver and spleen size and contour=20
- Evidence of portal hypertension=20
- Presence of ascites=20
- Presence or absence of hepatocellular = carcinoma=20

Liver Biopsy=20

Help confirm diagnosis=20
Establish grade of inflammation=20
Establish stage of fibrosis=20
Exclude coexistent liver disease =

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Best=20 Therapy

Drug Therapy for Autoimmune = Hepatitis

Corticosteroids=20

65% remission in 18 mo=20
80% remission in 3 yr=20
20%=9690% relapse within 3=966 mo of tapering = to lower doses=20 (≤ 10 mg/day) or discontinuance of therapy
Long-term therapy needed in many cases=20
Prednisone alone=20

Dose: initial, 40 mg/day p.o., tapered over = 4 wk;=20 maintenance, 20 mg/day p.o. until biochemical remission; then slower = tapering to 10 mg/day maintenance=20
Cost/mo: $8

Prednisone + azathioprine: azathioprine helps = maintain=20 remission but may not be appropriate in cases of severe cytopenias, = pregnancy,=20 or active malignancy=20

Dose=20

Prednisone: initial, 30 mg/day, tapered = over 6 wk to=20 20 mg/day until biochemical remission; then slower tapering to 10 = mg/day=20 maintenance
Azathioprine: initial, 50 mg/day; = maintenance,=20 50=96150 mg/day (2 mg/kg/day)

Cost/mo: $8 + $71

Begin tapering drugs when clinical and = biochemical=20 remission is achieved; taper over a period of months; taper prednisone = first,=20 keeping azathioprine dose constant=20
First relapse: increase medication doses =
≥ 2 relapses: maintain disease = quiescence (serum=20 transaminases elevated ~ twofold) with lower doses=20

Prednisone alone: ≤ 10 mg/day (as low = a dose as=20 possible), or=20
Prednisone, gradually tapered + = azathioprine, 2=20 mg/kg/day

Drug = Therapy for=20 Chronic Hepatitis B

Interferon alfa-2a or 2b=20

Often difficult to tolerate=20
Patients with cirrhosis need low, titrated = doses with=20 careful monitoring=20
Seroconversion: loss of HBeAg and appearance = of anti-HBe=20 in ~ 35%; loss of HBsAg and appearance of anti-HBs in ~ 8%=20
Dose: 5 million U/day s.c. or 10 million U 3 = times/wk=20 s.c. for 16=9624 wk=20
Use of peginterferon for chronic hepatitis B = is still=20 under study but is generally accepted in the U.S. at present=20
Side effects=20

Depression, other psychiatric = symptoms=20
Leukopenia and thrombocytopenia=20
Thyroid dysfunction=20
Insomnia=20
Headaches=20
Weight loss=20
Neurologic dysfunctions=20
Death from sepsis, suicide, or = cardiovascular disease=20 can occur

Contraindications=20

History of hypersensitivity to = interferon=20
Decompensated cirrhosis=20
Immunosuppression associated with organ=20 transplantation=20
Active autoimmune disease=20
Severe psychiatric disease=20
Elderly or frail =
Lamivudine=20

Well tolerated=20
Safe in end-stage liver disease (ESLD)
Dose adjustments n?eded for patients with = significant=20 renal failure=20
Resistance common

14%=9632% at 1 yr, increasing to 69% at 5 = yr=20
HBeAg seroconversion in 17% at 1 yr, 50% at = 5=20 yr

Long-term therapy often needed, especially in=20 HBeAg-negative patients
Dose: 100 mg/day p.o.=20
Cost/mo: $181
Adefovir=20

Well tolerated
Safe in ESLD; dose adjustments needed for = patients with=20 significant renal failure=20
Resistance in 2%=963% at 2 yr when used as = primary=20 therapy, higher after 4=965 yr; resistance more frequent when used in = patients=20 who developed resistance to lamivudine=20
HBeAg seroconversion in 12% at 1 yr
Long-term therapy often needed, especially in=20 HBeAg-negative patients
Dose: 10 mg/day p.o.=20
Cost/mo: $532
Entecavir

Well tolerated=20
Safe in ESLD=20
Resistance data limited=20
HBeAg seroconversion in 21% at 1 yr
Long-term therapy often needed, especially in=20 HBeAg-negative patients
Dose: 0.5 mg/day p.o. in treatment-naive = patients, 1=20 mg/day in lamivudine-resistant patients=20
Cost/mo: $700 (0.5 mg/day)

Liver Transplantation for Chronic = Hepatitis=20 B=20

HBV infects allograft in 80%=96100% of cases = if antiviral=20 prophylaxis not given=20
Use of HBIG and lamivudine/adefovir reduces = reinfection=20 to 10%=9620%=20
Long-term survival good in absence of=20 reinfection
Reactivation in = Inactive=20 Carriers

May occur spontaneously or after cessation of=20 chemotherapy for malignancy and may be severe=20
Monitor and treat prophylactically with = lamivudine or=20 adefovir
Drug Therapy for = Chronic=20 Hepatitis C

Pegylated Interferon and Ribavirin Combination = Therapy=20

HCV genotype 1=20

Sustained virologic response (SVR) = 42%=9652%; if HCV RNA=20 still detectable after 24 wk of treatment, stop treatment=20
Dose: pegylated interferon alfa-2a, 180 =B5g = s.c. weekly=20 for 48 wk, plus ribavirin, 1,000=961,200 mg/day p.o. for 48 = wk=20
Cost/mo: $1,316 + $780 =
HCV genotype 1: alternate regimen=20

SVR 42%=9652%; if HCV RNA still detectable = after 24 wk=20 of treatment, stop treatment=20
Dose: pegylated interferon alfa-2b, 1.5 = =B5g/kg s.c.=20 weekly for 48 wk, plus ribavirin, 800=961,200 mg/day p.o. for 48 wk =

HCV genotype 2 or 3=20

SVR 76%=9684%=20
Pegylated interferon alfa-2a, 180 =B5g s.c. = weekly for=20 24 wk, plus ribavirin, 800 mg/day for 24 wk=20
Cost/mo: $1,316 + $520

HCV genotype 2 or 3: alternate regimen=20

SVR 76%=9684%=20
Pegylated interferon alfa-2b, 1.5 = =B5g/kg s.c.=20 weekly for 24 wk, plus ribavirin, 800=961,200 mg/day for 24 = wk

Factors that reduce likelihood of successful=20 therapy=20

High viral load (> 2 =D7 10⁶=20 copies/ml)=20
African-American ethnicity=20
Advanced fibrosis

Side effects of interferon (see above)=20
Contraindications of interferon

Severe psychiatric illness=20
Poorly controlled seizure disorder=20
Poorly controlled diabetes mellitus=20
Active malignancy=20
Hemoglobin < 10=9612 g/dl
WBC < 1,500/=B5l=20
Platelet count < = 60,000=9675,000/=B5l=20
Pregnant or at risk of pregnancy=20
Decompensated cirrhosis

Side effects of ribavirin=20

Reversible, dose-dependent hemolytic = anemia=20

Mild anema: temporarily reduce dose =
Greater degrees of anemia: epoetin or=20 darbepoetin=20
Severe anemia: discontinue ribavarin =

Teratogenic; avoid in pregnancy=20
Rash=20
Nasal or sinus problems =
Liver Transplantation for Chronic Hepatitis = C

HCV reinfects allograft in nearly 100% of = cases, but=20 subsequent illness is usually mild
A small percentage progress to cirrhosis and = liver=20 failure=20
Post-transplant treatment is possible but=20 difficult

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Best References

Chang TT, et al: N Engl J Med 354:1001, 2006 = [PMID=20 16525137]

Craxi A, et al: J Hepatol 44(1 suppl):S77, 2006 = [PMID=20 16356581]

Czaja AJ, et al: Hepatology 36:479, 2002 [PMID=20 12143059]

Keeffe EB, et al: Clin Gastroenterol Hepatol = 4:936, 2006=20 [PMID 16844425]

Strader DB, et al: Hepatology 39:1147, 2004 [PMID = 15057920]

The author has received grants for clinical = research=20 from Roche Pharmaceuticals and Schering-Plough Corporation.
March=20 2007

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