anti-HBe, antibody to hepatitis B e; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma. Regarding HBV genotyping, genotype C appears to be associated with a higher risk of development of cirrhosis and HCC, compared with genotype B. These are the 2 dominant genotypes in Asia. Conversely, genotype B is associated with a higher rate of seroconversion from HBeAg positivity to HBeAg negativity and is associated with greater HBV DNA suppression when treated. Genotype A and B are associated with a higher rate of response to interferon-based therapy, which is an important issue when managing adult-acquired hepatitis B.
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How do we identify patients with hepatitis C? There are a couple of ways. First, we find patients with elevated serum liver transaminases either during routine physical examination or routine blood testing after starting certain medications. Patients may also test positive for anti-HCV during volunteer blood donations or for life or health insurance physicals. However, one of the most important ways that physicians can identify patients with hepatitis C is to inquire about previous risk behaviors and screen patients who disclose these behaviors.
As previously mentioned, the majority of individuals exposed to HCV will develop chronic infection; however, 15% of patients exposed to HCV are somehow capable of spontaneously resolving this infection. Research is currently ongoing to better understand how these people can resolve their infection, and this may shed some light on how to better treat hepatitis C in the future.
The next slide illustrates the natural history of HCV infection. As previously mentioned, a small percentage of individuals will go on to spontaneous resolution—about 15%—whereas 85% develop chronic disease. Of this 85% who develop chronic disease, about 80%, (68% of all infected individuals), will have stable chronic hepatitis without significant progression over the next 20 years. By contrast, 20% of those who develop chronic disease (17% of all infected individuals) will develop cirrhosis over the next 20-25 years. Of these cirrhotic patients, many will continue to progress slowly, and about 25% will rapidly develop hepatocellular carcinoma (HCC) or liver failure. Thus, liver cancer and liver failure occur in approximately 4% of patients who are exposed to HCV over a 20- to 25-year period.
This first slide looks at the tests that are used to identify patients with hepatitis C and assess disease severity and response to therapy. The first, aspartate aminotransferase and ALT tests, are not really liver function tests although many physicians refer to them as such. Rather, they measure liver transaminases, which are indicative of inflammation or irritation to the liver. The true tests to measure liver function include bilirubin, albumin, and prothrombin time or international normalized ratio. When the liver has dysfunction, these tests start to show abnormalities. Unfortunately, that does not occur until patients develop cirrhosis. Therefore, the majority of patients with chronic hepatitis C show normal liver function based upon these liver function tests. One of the most sensitive tests of advanced liver disease is the platelet count. A large number of studies have now demonstrated that thrombocytopenia—platelet counts below the lower limit of normal—is indicative of cirrhosis in individuals who do not have some sort of primary platelet or bone marrow disorder. Identifying thrombocytopenia is an easy way to identify patients with cirrhosis, and clearly liver histology represents the gold standard of determining the severity of disease and histologically can identify cirrhosis and the degree of scarring or fibrosis is present in the liver. One test we monitor to determine treatment response is serum ALT. If treatment is working effectively, we expect that the ALT levels will drop back down into the normal range on therapy. We also monitor the level of HCV RNA, and the goal is to have virus levels become undetectable during treatment. Hepatitis C virus genotype determines how long we need to treat patients, and liver histology can be used as a marker to show that the liver has improved after therapy.
The final way to assess liver disease severity in hepatitis C is with liver biopsy. This is the only test able to accurately assess severity of inflammation and degree of fibrosis. The baseline degree of inflammation and fibrosis are able to determine risk of cirrhosis development in the future, the need for therapy, and the need for ongoing therapy if initial treatment has failed. For example, an individual who failed interferon therapy and has mild liver disease and no apparent cirrhosis based on liver biopsy, has little urgency to undergo retreatment with new or more aggressive therapies. In contrast, an individual with more scarring and bridging fibrosis on biopsy may request such treatments. The biopsy is very useful for managing patients in these scenarios.
If you ask patients with hepatitis C how they feel, about 56% of them say they are asymptomatic, about 37% say they have symptoms, and about 7% have complications of cirrhosis. Of those who have symptoms, the most common symptom is simply fatigue—80% of symptomatic patients complain of fatigue. The symptoms can be very, very subtle indeed.
If you examine patients with cirrhosis who achieve a sustained virologic response after interferon therapy, the risk of developing liver cancer is significantly reduced. Compared with untreated controls where the risk of developing cancer was 38% over long-term follow-up, the risk was reduced to 4% in patients treated with interferon, a highly significant risk reduction.
The 2 studies shown in this slide illustrate the effectiveness of the 2 peginterferons approved for treatment of hepatitis C—peginterferon alfa-2a and peginterferon alfa-2b. Approximately 80% of individuals with genotype 2 or 3 HCV achieve a sustained virologic response with peginterferon combined with ribavirin, meaning 80% are cured of hepatitis C. Unfortunately, genotype 1 is more resistant to treatment, yet 40% to 45% of patients with genotype 1 achieve a sustained virologic response after treatment with peginterferon and ribavirin.
Acute Hepatitis B Virus Infection with RecoveryTypical Serologic Course Symptoms HBeAg anti-HBe Total anti-HBcTitre HBsAg IgM anti-HBc anti-HBs 0 4 8 12 16 20 24 28 32 36 52 100 Weeks after Exposure
Progression to Chronic Hepatitis B VirusInfection Typical Serologic Course Acute Chronic (6 months) (Years) HBeAg anti-HBe HBsAg Total anti-HBcTitre IgM anti-HBc 0 4 8 12 16 20 24 28 32 36 52 Years Weeks after
Outcome of Hepatitis B Virus Infection 100 by Age at Infection 100 80 80 Symptomatic Infection (%) 60 60 Chronic Infection 40 Chronic Infection (%) 40) % not ce n c no h C ( i f I i r 20 20 Symptomatic Infection 0 0 Birth 1-6 months 7-12 months 1-4 years Older Children and Adults Age at Infection
Factors of chronicityAgeImmune statusImmunological response
Definition-HBeAg +ve Diagnostic criteria HBsAg + >6 months, HBeAg +ve Serum HBV DNA >20,000 IU (1,00,000 copies) Persistent or intermittent elevation of ALT/AST Liver biopsy showing chronic hepatitis with moderate or severe necro-inflammationLok AS, et al. Hepatology. 2007;45:507-539.
HBeAg-ve - Definition Diagnostic critieria – HBsAg+ >6 months HBeAg-ve , anti-HBe + Serum HBV DNA <2000 IU (10,000 copies ) Persistently normal ALT levels Liver biopsy confirms absence of significant hepatitisLok AS, et al. Hepatology. 2007;45:507-539.
Natural history of chronic infection Chronic Hepatitis B (All HBsAg +) 8-12% per yr HBeAg - HBeAg + Anti-HBeAg + 67-80% 10-30% 4-20% Inactive carrier Elevated ALT Undetectable DNA Detectable HBV DNA •Lifelong follow-up of patients No inflammation •0.5% of HBsAg carriers clear 10-20% yearly Reactivation •Clearing HBeAg associated with HBeAg – increased survival and decreased chronic hepatitis risk of hepatic decompensationLok AS, et al. Hepatology. 2007;45:507-539.
Impact of HBV Genotype on Disease Progression HBV Genotyping Line Probe Assay Genotype C marker line conj. control 1 – More frequently associated with amp. control 2 3 severe liver disease and HCC than Genotype A 4 5 with genotype B Genotype B 6 7 8 Genotype B Genotype C 9 Genotype D 10 – Associated with seroconversion 11 Genotype E 12 13 from HBeAg to anti-HBe at younger Genotype F 14 15 age than with genotype C Genotype G 16 Genotypes A and B – Higher rates of antiviral response and HBeAg loss following peginterferon alfa-2b than with genotypes D and C, respectivelySlide courtesy of Clincal Care OptionsKeeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
Differences Between the Treatment Algorithm and AASLD 2007 Guidelines: HBeAg-Positive Patients Treatment Algorithm 1 AASLD 20072 ALT <1 × ULN ALT >2 × ULNALT <1 × ULN HBV DNA (HBV DNA (HBV DNA (HBV DNA >20,000 IU/mL 20,000 IU/mL) >20,000 IU/mL)<20,000 IU/mL) Observe Observe 3–6 mo No Rx No Rx Rx if persistent ALT <1 × ULN ALT >1 × ULN ALT 1–2 × ULN Biopsy if age Rx (HBV DNA >20,000 IU/mL) >35–40 yr; Rx if significant disease Observe Biopsy if age >40 yr, ALT persistently high, family history of HCC; Rx if biopsy shows moderate/severe1. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936–962. inflammation, significant fibrosis2. Lok AS, McMahon BJ. Hepatology. 2007;45:507–539. Courtesy of Dr. Ira Jacobson
Differences Between the Treatment Algorithm and AASLD 2007 Guidelines: HBeAg-Negative Patients Treatment Algorithm1 AASLD 20072 HBV DNA HBV DNA ALT <1 × ULN ALT ≥2 × ULN<2,000 IU/mL >2,000 IU/mL HBV DNA HBV DNA No Rx <20,000 IU/mL ≥20,000 IU/mL ALT <1 × ULN ALT >1 × ULN No Rx Rx Consider biopsy; Rx ALT 1–2 × ULN Rx if needed HBV DNA 2,000–20,000 IU/mL Biopsy; Rx if needed1. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936–962.2. Lok AS, McMahon BJ. Hepatology. 2007;45:507–539. Courtesy of Dr. Ira Jacobson
Therapy for Chronic Hepatitis B: 2008 2008 and 1992 1998 2002 2005 2006 beyond…interferon- lamivudine adefovir entecavir telbivudine Tenofovir* alfa Clevudine** pegylated Combination Rx “The New Era” IFN-α ORAL Therapy *FDA-approved for HIV and in review by FDA for HBV indication ** in phase III trial
HEPATITIS D Acute co-infection with hepatitis- D does not increase the incidence of chronicity Superinfection with hep-D in chronic hep-B worsening of the liver disease occurs
Hepatitis C Virus Infection Typical Serologic Course anti- HCV SymptomsTitre ALT Normal 0 1 2 3 4 5 6 1 2 3 4 Mont Years hsTime after Exposure
Hepatitis C Virus Infection Identification of Patients Found to have elevated serum ALT during – Routine physical examination – Routine blood testing after starting certain medications Test positive for anti-HCV during – Volunteer blood donation – Health or life insurance applications Physician – Inquires about previous risk behaviors
Hepatitis C Virus Fate of Acute Infection Spontaneous resolution 15% Chronic 85%Alter MJ, et al. N Eng J Med. 1999;341:556-562.
Alcoholic HepatitisCan be chronicRisk of cirrhosis variable…genetics, sex (women more susceptible,)Possibe nutritional factorPresentation can range from an asymptomatic person to a critically ill one
SGOT / SGPT rarely over 400 U/L Ratio SGOT / SGPT >2 - GGT elevated Bilirubin level quite variable depending on severity…can be 10 or higher Fig20.jpg PT/INR also may be elevated PMN - > 5500 / Ml Discriminant function > 32
Autoimmune Hepatitis Generally affects young females -viral,drugs,alcohol and genetical causes excluded Hypergammaglobulinemia Extrahepatic manifestations are clues… amenorrhea, thyroiditis, acne, Sjogrens, arthritis, Coomb-positive hemolytic anemia, nephritis
ANA , anti-smooth muscle antibodies (SMA),anti LKM and SLA – soluble liver antigen are presentOld name was Lupoid HepatitisLiver histology-cytotoxic T cells and plasma cellsResponds well to steroids and immunosuppressive therapy
Nonalcoholic Steatohepatitis- NASH Asymptomatic patient with chronic mild transaminase elevations in the absence of viral hepatitis, drug hepatotoxicity or alcohol use. Classically middle aged with syndrome X Often seen with DM, obesity, high lipids TPN, Protien malnutrition, steroids
NASH continuedAge > 45, ↑ BMI ,SGOT /SGPT > 1 & DM Course usually benign, a few may 15- 30%progress to fibrosis and cirrhosis No specific treatment exists Focus on control of DM-insulin sensitizers, weight loss and treatment of lipid disorder
Wilson’s disease -Clinical Presentation Liver disease in adolescents (abnormal liver enzymes to cirrhosis and portal HTN) Half present this way. Neuropsychiatric disease in young adults (tremors, movement disorders, bulbar dysfunction, behavior and personalitychanges) Kayser-Fleischer rings (pathognomonic) Renal disorders (calculi, RTA))
Alpha-1 Antitrypsin Deficiency Patients with homozygous deficiency may develop emphysema as adults. About 10% of homozygous patients develop neonatal hepatitis which can progress to cirrhosis In adults the most common manifestation is asymptomatic which may progress and develop hepatocellular carcinoma
HIVCAH-coinfection with B or CHepatotoxic effects of HAART NNRI PISystemic diseases
LESS COMMON DISEASES Reticuloendothelial disorders Granulomatous infiltrations Hemochromatosis Amyloidosis
Hemochromatosis• Liver…mildly abnormal liver tests,• eventually cirrhosis• Skin pigmentation…slate-gray or brown• Pancreas…glucose intolerance, diabetes• Joints…arthralgias, especially 2nd and 3rd• MCP joints• Restrictive cardiomyopathy +/- CHF• Amenorrhea, impotence
Primary Biliary Cirrhosis• Liver studies reflect cholestasis• Mostly elevated alkaline phosphatase and cholesterol, later bilirubin• 95% have Anti Mitichondrial Antibodies• Elevated serum IgM levels• Treat with ursodeoxycholic acid, possibly MTX• Many need liver transplantation
Algorithm in HIV positive HBV DNA <2000 HBV DNA >2000 ALT Normal ALT elevated Mild fibrosis Significant fibrosis No Treatment TreatmentSoriano et al. AIDS 2008;21(12):1399-410
• Treatment should be offered in patients who meet the following criteria, regardless of CD4 count: – hepatitis B e antigen positive – raised ALT (more than twice upper limit of normal) – evidence of fibrosis on biopsy or on appropriate imaging – hepatitis B viral load >10 000 copies/ml.• The ART regimen should include tenofovir (TDF) and lamivudine (3TC) or emtricitabine (FTC).
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