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Chronic Hepatitis

Chronic Hepatitis. Cengiz Pata Gastroenterology Department Yeditepe University. Chronic Liver Disease : History.

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Chronic Hepatitis

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  1. Chronic Hepatitis Cengiz Pata Gastroenterology DepartmentYeditepe University

  2. Chronic Liver Disease: History • Symptoms of liver injury: fatigue, weakness, icterus, pruritis, dark urine, possible stool colour lightening, nausea, vomiting, RUQ discomfort, intolerance to dietary protein or cigarette smoke • Symptoms of the consequences of cirrhosis: bleeding, cachexia, edema, ascites, encephalopathy, skin changes, gynecomastia etc.

  3. Chronic Liver Disease:Physical • What physical exam features should be emphasized in a patient with chronic transaminitis ? (Can you identify the physical signs on the following slides ?)

  4. Chronic Liver Disease : Physical Obviously trivia….. • Dermatitis herpetiformis: chronic herpetiform lesions on extensor surfaces (in this case, elbows) in patients with Celiac Disease • Kayser-Fleischer Rings, best appreciated with a slit lamp, as brown pigmentary deposits on the periphery of the cornea, in patients with Wilson’s disease • Tendon xanthomata, on the Achilles, in patients with hyperlipidemia due to cholestasis in liver disease that also can have chronic transaminitis such as primary biliary cirrhosis

  5. Prevalence of Inherited Liver Diseases Leggett et al Brit J. Haem. 1990

  6. Genetics of Haemochromatosis • Autosomal recessive • Mutations in HFE gene (C282Y and H63D) • Cause increased intestinal absorption of Fe C282Y/C282Y and C282Y/H63D are responsible for 95% of genetic haemochromatosis

  7. Clinical Manifestations of haemochromatosis • Skin pigmentation • Liver disease • Diabetes mellitus • Arthropathy • Impotence • Fatigue • Cardiomegaly

  8. Screening Strategy for Haemochromatosis(HFE Associated) 1.Perform transferrin saturation (or UIBC) 2. If  45% - repeat fasting 3. If still  45% - perform HFE testing 4. If C282Y +/+ or C282Y/H63D +/+: - perform serum ferritin and LFT - if SF > 1000 and/or LFT abnormal - Liver biopsy essential 5. If C282Y +/- : - Counsel re:  Alcohol  NASH  HCV  PCT 6. Venesection and family screening

  9. The spectrum of Nonalcoholic Fatty Liver Disease • Type 1 Fat alone • Type 2 Fat + inflammation • Type 3 Fat + ballooning degeneration • Type 4 Fat + fibrosis and/or Mallory bodies • Only types 3 and 4 have been definitively shown to progress to advanced liver disease and can be classified as NASH

  10. NAFLD - Classification and Causes PRIMARY Increased insulin resistance syndrome Diabetes mellitus (type II) Obesity Hyperlipidemia

  11. NAFLD - Secondary Causes Drugs Surgical Procedures Miscellaneous Corticosteroids Gastroplexy Hepatitis C Synth oestrogens Jejunoileal bypass Abetalipoproteinaemia Amiodarone Extensive small bowel Weber-Christian Perhexiline resection disease Nifedipine Biliopancreatic diversionTPN with glucose Tamoxifen Environmental toxins Tetracycline S.bowel diverticulosis Chloroquine Wilson’s disease Salicylates Malnutrition IBD HIVinfection

  12. Prevalence of NAFLD and NASH • No good data - histological diagnosis • Car Crash post mortem study - 24% NAFL, 2.4% NASH- Hilden et al 1977 (n=503) • USS - 16.4- 23% NAFL (Italy, and Japan)

  13. Prevalence of NAFLD / NASHHigh risk groups • Severely obese subjects - 25% incidence of NASH at laparoscopy • Type 2 diabetes - 28-55% NAFL • Hyperlipidaemia - 20-90% NAFL • Approx 60% of NAFL occurs in females • Many patients are neither obese nor diabetic (Bacon et al 1994, George et al 1998)

  14. Obesity and Fatty liver • Prevalence increases with weight • Up to 80% of obese individuals • Up to 10-15% of normal subjects • Correspondingly, 15-20% of morbidly obese subjects and 3% of non-obese subjects have NASH • Increasing prevalence in children AGA, Gastroenterology 2002

  15. NAFLD - Clinical Features • Mostly an incidental finding in asymptomatic individuals • ALT 2-5x normal • AST:ALT < 1 except in severe injury • ALP, GGT 2-3x normal <50% • Bilirubin rarely raised • RUQ discomfort, fatigue and malaise in some patients

  16. NASH - Natural History • 15-50% of NASH patients have fibrosis or cirrhosis at index biopsy James and Day 1998 • In etiological studies NASH is now the most common cause of cryptogenic cirrhosis Caldwell et al 1999, Poonwala et al 2000 • In a 19 year follow up study, steatosis (alone) did not progess histologically Teli et al 1995

  17. . NASH - Natural History 10 year retrospective follow up studyn = 98 11% Liver Related deaths in types 3 and 480% of those developing cirrhosis had fibrosis at index biopsy % Developing Cirrhosis Matteoni et al 1999

  18. NASH-natural history • Steatosis only can progress to cirrhosis 1-2 % over 5-17yrs (Danish and Italian studies) • NASH + fibrosis – cirrhosis 0% at 5yrs 12% at 8ys • Prognosis in cirrhotics poor-30% developing liver-related morbidity or mortality (liver failure + HCC) over short period • Adams et al Gastroenterology 2005

  19. NASH - RISK FACTORS FOR FIBROSIS AND CIRRHOSIS Independent risk factors in several studies: • Age >45 • ALT > 2x normal • AST/ALT ratio > 1 • Obesity, particularly truncal • Type 2 diabetes • Insulin Resistance • Hyperlipdaemia (trigycerides > 1.7) • Hypertension • Iron overload NB: Studies are in selected groups; may not apply to all patients

  20. NASH - Who Should Have a Liver biopsy? To Identify Patients at Risk of Progression restrict biopsy to patients with some, if not all of: • ALT > 2x normal • AST > ALT • At least moderate central obesity • NIDDM or Impaired glucose tolerance • Hypertension • Hypertriglyceridaemia Day, Gut 2002;50:5585-588

  21. PATHOGENESIS OF NASHInsulin Resistance is the First Hit • NASH should be viewed as part of a multifactorial disease • Commonly associated with syndrome X - 85% in a retrospective study (Wilner et al 2001) • Treatment strategies may be directed at Insulin Resistance

  22. NASH - TREATMENT • Steady Weight Loss - logical treatment • Reduces fatty infiltration • Improves LFTs • CAUTION - In some patients, inflammation and fibrosis increase especially with rapid wt loss (cf gastric and intestinal bypass) • Improved diabetic control - little histological data • Exercise - patients with NAFLD have very poor respiratory quotients. LFTs and RQ improve with exercise Elias 2001

  23. NASHDRUG TREATMENT • No completed RCTs to date • CLOFIBRAT • No improvement in LFTs or histology over 1 year in NASH (n=16) Laurin et al 1996 • Gemfobrozil • One randomized study, improved LFTs after 4 weeks (n=46) Basaranoglu et al 1999 Metformin

  24. NASH - Drug TREATMENT 2 • Ursodeoxycholic Acid • 3 open label studies (n = 24, 24, 31) • One randomised (vs diet alone) • Improvement in aminotransferases • 12 month study demonstrated improvement in steatosis but not other histological features • RCT trial now underway * Laurin et al 1996, Guma et al 1997, Ceriani et al 1998

  25. NASH - DRUG TREATMENT 3ANTIOXIDANTS • Betaine (methionine) • Improved LFTs, steatosis and inflammation • n = 8, 12 months therapy, Abdelmalek et al 2000 • N-Acetylcysteine • Improved LFTs • n = 11, Gulbahar et al 2000 • Vitamin E - Tocopherol • Improved LFTs over 4-10 months • n = 11, Lavine et al 2000

  26. NASH - DRUG TREATMENT 4Insulin Resistance • Metformin • Improves sreatosis in ob/ob leptin deficient mouse • Decreased Transaminases in non-diabetic subjects with NASH compared with diet alone over 4m • Reduced liver volume • n = 20, Marchesini et al 2001 • RCT planned by BASL • Troglitazone • Improved LFTs but no histological change • n = 6, 4 months, Caldwell et al 2001

  27. Management of NAFLD

  28. NAFLD CONCLUSIONS • NAFLD is common • A small proportion progress to cirrhosis • NASH is the commonest cause of cryptogenic cirrhosis • More information needed on prevalence, pathogenesis and natural history • RCTs urgently needed - Metfomin, antioxidants and UDCA

  29. Hepatits C Most asymptomatic; acute hepatitis with jaundice is uncommon • 80% will have chronic / persistent infection. Of these, • 10% will develop cirrhosis of the liver 10 years after infection • 20-30% will develop cirrhosis of the liver 30 years after infection • 5% will develop hepatocellular carcinoma (liver cancer) 20 years after infection.

  30. Hepatitis C: Factors associated with progression of liver disease • The genotype of the virus -IB • Acquiring the infection at an older age • Alcohol misuse • Male gender • Co-infection with Hepatitis B or HIV

  31. Treatment of Hepatitis C Hep C RNA by PCR Liver biopsy for genotype I, treatment is recommended for patients with moderate to severe hepatitis Peg-interferon given by sc injection 1/ week, Ribavirin bd dose • Patients with genotypes II and III are treated with for 6 months. Response rate 70% • Patients with genotypes I, IV, V, and VI are treated with interferon and ribavirin for 12 months, if responsive on viral load at 3/12. Response rate 30%-40%. • Telaprevir(proteaseinh.

  32. NovelTreatmentforHepatitis C in 2011 PegIFN/RBV+Telaprevir(12w) + PegIFN/RBV (12w) PegIFN/RBV(4w) + PegIFN/RBV+Boceprevir (20w)

  33. Telaprevir vs. Boceprevir • First-generation direct-acting antivirals (DAAs) • NS3/4A serine proteaseinhibitors • Forpatientswithgenotype I • SVR %75 fortelaprevir, %65 forboceprevir • Side efects!!!

  34. NovelTreatmentforHepatitis C in 2014 • Sofosbufir: New nucleotideinhb. • Simeprevir: NS3/4A proteaseinhb • Daclatasvir: NS5B inhibitor • Forallgenotype • Withorwithout RBV and IFN • SVR %80-96 in genotype I • SVR %60- 95 in othergenotype

  35. Tedavi Secenekleri • İntreferon ( kalıcı cvp yüksek, düşük viral yük olmalı, HbeAg +, olmalı, dekompansasyon?) • Lamivudine (direnç, birinci ted.) • Adefovir (hepsera, direnç?) • Entecavir(Baraclude, direnç yok, ikinci ted.) • Tenofovir (viread, direnç yok, ikinci ted.) • Telbuvudine (sebivo, direnç?, ilk tedavi)

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