Management of cirrhosis for improving survival

medicine

1. Management of cirrhosis of liver for improving survival Moderator- Presenter- Dr. P. Dihingia Dr. Mahendra Debbarma Associate professor 2 nd yr. PGT

2. Introduction The term cirrhosis was first used by Rene Laennec (1781-1826) to describe the abnormal liver color of individuals with alcohol induced liver disease. Derived from Greek word Kirrhos means Yellowish brown color.

3. Definition: Cirrhosis is a chronic progressive disease of the liver characterized by extensive degeneration and destruction of the liver parenchymal cells,resulting in abnormal blood vessels and bile duct architecture.

4. Contd. Scarring also impairs the liver's ability to: control infections remove bacteria and toxins from the blood process nutrients, hormones, and drugs make proteins that regulate blood clotting produce bile to help absorb fats—including cholesterol—and fat-soluble vitamins

5. Liver biopsy Determines the degree of scarring and architectural distortion (disease stage), T he nature of the disease process. Thus liver biopsy is felt to represent the gold standard for assessing the degree of liver injury and fibrosis . A normal liver lobule consists of portal (zone 1), lobular ( midzonal or zone 2), and central (zone 3) zones. The portal tract contains the hepatic artery (HA) and portal vein (PV ) & bile duct (BD)

6. Causes of Cirrhosis

7. Cirrhosis ( percentage wise) Alcoholic cirrhosis 60- 70% Viral hepatitis 10 % Billiary disease 5-10 % Primary hemochromatosis 5% Cryptogenic cirrhosis 10-15%

8. Clinical cirrhosis: Compensated Asymptomatic Abnormal liver test on routine examination Mild hepato -splenomegaly on palpation Prognosis: 50 % 10 years survival Decompensated Complicated cirrhosis Jaundice Ascites Hepatic encephalopathy Bleeding varices 50 % survival at 18 months

9. Factor 1 point 2 points 3 points Total bilirubin (mg/dl, μ mol /L) <2 /<34 2-3 /34-50 >3 />50 Serum albumin (g/L) >3.5 />35 3-3.5 /28-35 <3 /<28 PT INR <1.7 1.71-2.30 >2.30 Ascites None Mild Moderate to Severe Hepatic encephalopathy None Grade I-II (or suppressed with medication) Grade III-IV (or refractory) Prognostic indicators Child-Pugh Score   Class A Class B Class C Total points 5-6 7-9 10-15 1-year survival 100% 80% 45%

10. Prognostic indicators MELD SCORE(Model for end-stage liver disease) Introduced in Feb 2002. The MELD score originally was developed and validated to assess the short-term prognosis of patients with cirrhosis undergoing TIPS. Developed by the Mayo Clinic. Estimated 3-month survival for a score of 6 is 90%, and for a score of 40 is 7%. MELD SCORE - O.957x log(CREAT)+0.378xlog(TBIL)+1.12xlog(INR)+0.643

11. Prognostic indicators Maddrey’s Discriminant Factor= TBIL + prolongation of PT in secs compared to controls x4.6

12. Aetiology -abstinence in alcohlic cirrhosis & antiviral treatment in viral cirrhosis has better prognosis If decompensation has followed haemorrhage,infection,alcoholism ,the prognosis is better than if it is spontaneous The response to therapy- if failed to improve within 1 month of starting hospital treatment,the outlook is poor Jaundice - if persistent is a serious sign Neurological complications- spontaneous or chronic hepatic encephalopathy Clinical Prognostic Indicators

13. Ascites worsens the prognosis if resistant to diuretic therapy Liver size -large liver carries a better prognosis as its likely to contain more functioning cells Poratal venous pressure- in many studies prediction of survival by child pugh score is improved by adding portal presure Biochemical test- if serum albumin is less than 25g/L(<3g/dl & s. sodium <120 mmol /l persistent hypotension- SBP <100 mm Hg Prognostic indicators

14. Management General- symtomatic measures, adequate balanced diet, avoidance of alcohol & obesity Specific- antivirals for hepatitis B & C , steroids and immuno suppressive drugs for autoimmune hepatitis, chellation therapy in Wilsons disease, abstinence in alcohol, weight loss in NASH Precipitating factors- Treating bleeding varices , ascites, encephalopathy, sepsis, electrolyte imbalances

15. Management Nutrition- diet containing 35-40 kcal and 1.2-1.5 g of protein /kg body weight Oral or enteral feeding is preferable to parenteral nutririon Protein restriction is not recommended in hepatic encephalopathy Late evening or nocturnal feeding is beneficial. Surgical & other interventional procedures- Liver transpalnts TIPS Endoscopic banding ligation Sengstaken-Blackemore tube & self-expanding esophageal stent.

16. Alcoholic cirrhosis Can be present without alcohol related hepatitis Irreversible,therapy usually directed towards complications. Propyltiouracil - alcohol induces a hypermetabolic state & it is reduced by its use A long term beneficial effect has been shown in cirrhosis pts. Who continue to drink. Orrego H,Blake JE et al .Long term treatment of alcoholic liver disease with propylthiouracil . N . Engl. J. Med.1987;317:1421-1427 S Adenosyl methionine- a significant beneficial effect has been found in pts. With Child’s A & B cirrhosis.further studies are awaited . Mato  JM, Camara J, Fernandez de Paz J, et al. S- Adenosylmethionine in alcoholic liver cirrhosis: a randomized , placebo- contolled ,double blind,multicenter clinical trial J. Hepatol . 1999;30:1081-1089

17. Hepatitis B An estimated 240 million people are chronically infected with hepatitis B (defined as hepatitis B surface antigen positive for at least 6 months). More than 780 000 people die every year due to complications of hepatitis B, including cirrhosis and liver cancer. Geographical distribution Hepatitis B prevalence is highest in sub-Saharan Africa and East Asia, where between 5–10% of the adult population is chronically infected. An estimated 2–5% of the general population is chronically infected. Less than 1% of the population in Western Europe and North America is chronically infected.

18. Hepatitis B

19. Recommendations for treatment of chronic hepatitis B based on American Association for study of liver diseases(AASLD) According to the EASL (European Association for the Study of the Liver guidelines), treat if HBV DNA is >2 × 10^3 IU/mL and ALT >ULN.

20. Hepatitis C The  incidence  of HCV on a global scale is not well known, because acute infection is generally asymptomatic. As many as 2 to 4 million persons may be chronically infected in the United States, 5 to 10 million in Europe, and about 12 million in India, and most do not know they are infected. Of these, about 25% are symptomatic, but 60 to 80% may progress to chronic liver disease, and 20% of these develop  cirrhosis . About 5%-7% of patients may ultimately die of the consequences of the infection . Most European countries report a  prevalence  of HCV in the general population of between 0.5 and 2 %. WHO estimates that about 3% of the world’s population has been infected with HCV and that there are more than 170 million chronic  carriers  who are at risk of developing liver cirrhosis and/or liver cancer.

21. Hepatitis C

22. Hepatitis C TREATMENT (HCV genotype 1) PEG IFN-α2a 180 μg weekly plus weight-based ribavirin 1000 mg/d (<75 kg) to 1200 mg/d (≥75 kg) or PEG IFN- α2 b 1.5 μ g/kg weekly plus weight-based ribavirin 800 mg/d (≤65kg), 1000 mg/d (>65–85 kg), 1200 mg/d (>85–105 kg), or 1400 mg/d (>105 kg) Plus Response-guided therapy with a protease inhibitor consisting of either: with boceprevir 800 mg three times daily with food started after a lead-in treatment of 4 weeks with PEG IFN– ribavirin Telaprevir 750 mg three times daily with fatty food started at the beginning of therapy without a PEG IFN– ribavirin lead-in

23. Hepatitis C Treatment HCV genotype 4: 48 weeks of PEG IFN–ribavirin therapy Treatment should be discontinued if patients do not achieve an early virologic response at week 12. Patients who do achieve an early virologic response should be retested at week 24, and treatment should be discontinued if HCV RNA remains detectable . HCV genotypes 2 and 3: 24 weeks of therapy For HCV/HIV co-infected patients : 48 weeks, regardless of genotype, of weekly PEG IFN-α2a (180 μg ) or PEG IFN-α2b (1.5 μg /kg) plus a daily ribavirin dose of at least 600–800 mg.

24. Autoimmune hepatitis is a chronic disorder characterized by continuing hepatocellular necrosis and inflammation when untreated, may have a 6-month mortality of as high as 40%. The natural history of autoimmune hepatitis, the 10-year survival is 80−98% for treated and 67% for untreated patients . AUTOIMMUNE HEPATITIS

25. Prednisolone 60 mg/d , tapered successively over the course of a month down to a maintenance level of 20 mg/d . An alternative , prednisone dose (30 mg/d) along with azathioprine (50 mg/d). With azathioprine maintained at 50 mg/d , Prednisone dose tapered over a month down to a maintenance level of 10 mg/d . Treatment

26. Treatment of precipitaing factors 1. Esophageal varices bleed- Approximately 5–15% of cirrhotics per year develop varices , and it is estimated that the majority of patients with cirrhosis will develop varices over their lifetimes. The medical management of acute variceal hemorrhage includes the use of vasoconstricting agents, usually somatostatin or octreotide . Octreotide , a direct splanchnic vasoconstrictor, is given at dosages of 50–100 μg /h by continuous infusion.

27. Esophageal varices bleed- Terlipressin ( 2mg bolus followed by 1mg every 4-6 hrly for 3- 5 days) is a semisynthetic analog of vasopressin Compared with vasopressin, terlipressin results in lower circulatory levels of the vasopressin analog and a lower rate of systemic side effects. Terlipressin is the first choice in many countries because it the only drug that has been associated with improved survival . ( Levacher  S,  Letoumelin  P,  Pateron  D, et al Lancet   1995; 346:865-8)

28. Esophageal varices bleed- β-Adrenergic Blocking Agents Nonselective β-adrenergic blocking agents have been used extensively in preventing variceal rebleeding .( Lebrec  D,  Poynard  T,  Hillon  P, et al:   N Engl J Med   1981; 305:1371-4. ) Nonselective beta blockers such as propranolol or nadolol are preferred. The usual method of monitoring the efficacy of beta blockers is to observe a decrease in the heart rate . The dose of propranolol or nadolol can be increased gradually every three to five days until the target heart rate of 25% below baseline or 55 to 60 beats per minute or the maximum tolerated dose is reached, provided that the systolic blood pressure remains above 90 mm Hg . The usual starting dose of long-acting propranolol is 40 mg once daily and that of nadolol is 20 mg once daily. Because the risk of bleeding is greatest at night, the beta blocker should probably be administered in the evening .( Sugan  OS, Yamamoto K,  Sasao  K, et al: Hepatol   2001; 34:26-31) .

29. Pressure techniques Esophageal balloon Sengstaken blakemore tube, Minnesota tube Linton Nicholas tube(only gastric balloon with gastric aspiration) Balloon should be inflated for less than 24 hrs. 75% rebleeding rate after balloon deflation . Most reports suggest that balloon tamponade provides initial control of bleeding in 85% to 98% of cases. Sleisenger and Fordtran's Gastrointestinal and Liver Disease Ninth Edition

30. variceal rebleeding recurs soon after the balloon is deflated in 21% to 60% of patients. The major problem with tamponade balloons is a 30% rate of serious complications, such as aspiration pneumonia, esophageal rupture, and airway obstruction. Clinical studies have not shown a significant difference in efficacy between vasopressin administration and balloon tamponade . ( Pitcher JL: Safety and effectiveness of the modified Sengstaken -Blakemore tube: A prospective study.  Gastroenterology 1971 Sep;61(3):291–298  ) Sleisenger and Fordtran's Gastrointestinal and Liver Disease Ninth Edition

31. Esophageal varices Sclerotherapy Endoscopic sclerotherapy has largely been supplanted by endoscopic band ligation, except when poor visualization precludes effective band ligation of bleeding varices . Available evidence does not support emergency sclerotherapy as first-line treatment of variceal bleeding. ( D’Amico G, Pietras G, Tarantino I, Pagliaro L: Gastroenterology  2003; 124:1277-91 ). * The technique involves injection of a sclerosant into ( intravariceal ) or adjacent to ( paravariceal ) a varix . * The sclerosants used : sodium tetradecyl sulfate , ( Sotradecol ). sodium morrhuate , (  Scleromate ) ethanolamine oleate (  Ethamolin ) Polidocanol (3%) { lauromacrogol } absolute alcohol the choice of a sclerosant is based on availability, rather than on superior efficacy of one agent over another.

32. Endoscopic variceal ligation * is the preferred endoscopic modality * the utility of band ligation in the treatment of gastric varices is limited. * Variceal ligation is simpler to perform than injection sclerotherapy . * Endoscopic variceal ligation is associated with fewer complications than sclerotherapy . - Varices at the gastroesophageal junction are banded initially, and then more proximal varices are banded in a spiral manner at intervals of approximately 2 cm; the endoscope is then withdrawn. -The procedure involves suctioning of the varix into the channel of an endoscope and deploying a band around the varix . -The band strangulates the varix , thereby causing thrombosis. -Multi-band devices can be used to apply several bands without requiring withdrawal and reinsertion of the endoscope. -.

33. TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT(TIPS) TIPS reduces elevated portal pressure by creating a communication between the hepatic vein and an intrahepatic branch of the portal vein. TIPS is used to treat complications of portal hypertension, mainly * mainly refactory variceal bleeding and refractory ascites , * as well as Budd- Chiari syndrome, * hepatic hydrothorax, and * hepatorenal syndrome. Procedure, the hepatic vein is cannulated through a transjugular approach, and by using a Rosch needle , the portal vein is cannulated,then a guidewire is passed to connect the hepatic vein and a branch of the portal vein. Dilate the tract and a metallic stent is placed. Dilate the tract at the confluence of the hepatic vein if required to reduce the portacaval pressure gradient (the pressure difference between the portal vein and the inferior vena cava) to below 12 mm Hg

34. 2. Hepatorenal syndrome The hepatorenal syndrome (HRS) is a form of functional renal failure without renal pathology that occurs in about 10% of patients with advanced cirrhosis or acute liver failure Type 1 HRS characterized by progressive impairment in renal function. significant reduction in creatinine clearance within 1–2 weeks of presentation. Type 2 HRS characterized by a reduction in glomerular filtration rate with an elevation of serum creatinine level, Fairly stable and is associated with a better outcome than that of type 1 HRS

35. HRS Treatment has, unfortunately, been difficult in the past, dopamine or prostaglandin analogues were used as renal vasodilating medications. Currently , patients are treated with midodrine , an α-agonist , along with octreotide and intravenous albumin. The best therapy for HRS is liver transplantation; recovery of renal function

36. 3.HEPATIC ENCEPHALOPATHY Portosystemic encephalopathy is a serious complication of chronic liver disease and is broadly defined as – alteration in mental status and cognitive function occurring in the presence of liver failure. Ammonia levels are typically elevated in patients with hepatic encephalopathy the correlation between severity of liver disease and height of ammonia levels is often poor, and most hepatologists do not rely on ammonia levels to make a diagnosis. Other compounds and metabolites that may contribute to the development of encephalopathy- F alse neurotransmitters and mercaptans . Survival probability after 1 st episode of HE is 42% at 1 year & 23% at 3 years.

37. Treatment of HE Treatment is multifactorial and includes management of the precipitating factors.- hydration and Correction of electrolyte imbalance In the past , restriction of dietary protein was considered for patients with encephalopathy; however, the negative impact of that maneuver on overall nutrition is thought to outweigh the benefit when treating encephalopathy , and it is thus discouraged.

38. Treatment of HE U se of lactulose(40-120ml/day), a nonabsorbable disaccharide , which results in colonic acidification . The goal of lactulose therapy is to promote 2–3 soft stools per day . R ifaximin at 550 mg twice daily has been very effective in treating Encephalopathy. Bass NM,Mullen KD, Sanyal A et al Rifaximin Treatment in Hepatic Encephalopathy N Engl J Med 2010; 362:1071-1081 LOLA (l-ornithine –L-aspartate) –dose 0f 6g three time a day promotes hepatic removal of ammonia by stimulating residual urea & promoting glutamine synthesis A critical analysis of studies assessing Lornithine -L-aspartate (LOLA) in hepatic encephalopathy treatment ARTICLE in ARQUIVOS DE GASTROENTEROLOGIA · JANUARY 2009 Zinc supplementation is sometimes helpful in patients with encephalopathy and is relatively harmless.

39. Liver transplantation- Liver transplantation—the replacement of the native The preferred and technically most advanced approach orthotopic transplantation , in which the native organ is removed and the donor organ is inserted in the same anatomic location . Success measured as 1-year survival which has improved from ~30% in the 1970s to >90% today Currently, the 5-year survival rate exceeds 60%.

40. Primary indications & diseases leading to liver transplantation in Europe between Janaury 1988 and June 2006 ( E uropean liver transplant Registry)

41. Proportion of liver transplants performed for specific indications O'Leary JG, Lepe R, Davis Gastroenterology 2008; 134:1764-76 ,

42. Indications of liver transplantation

43. Contraindications of transplantation

44. When….? Patients who are too well should not be transplanted. Likewise, transplantation of patients who are too sick is associated with poor outcomes. The goal of transplantation is to prolong survival. Thus, liver transplantation should be performed at the time point when the patient is expected to have greater survival with a liver transplant than without.

45. Prognostication Survival of a patient with ‘‘Child’s C cirrhosis’’ is about 20–30% at 1 year and less than 5% at 5 years. In contrast, the survival rate after transplantation is 85–90% at 1 year and over 70% at 5 years. By the time the patient has evidence of advanced clinical liver disease (Child’s C cirrhosis), the patient may not survive long enough to get a transplant.

46. Guidelines for Organ Allocation Organs should be allocated to transplant candidates in the order of medical urgency The role of waiting times in determining allocation order should be minimized Every attempt should be made to promote efficient use of donor organs

47. Requirements for Transplantation End stage liver disease Physiologic ability to tolerate surgery: Cardiac, pulmonary, renal, cerebral function Anatomy – status of vessels (PV/HA/HV) Social support/ psychological support No extra-hepatic infection or malignancy Alcohol abstinence for 6 months/ no substance abuse

48. Liver Transplant Procedure The surgery is quite an extensive procedure and entails removing either left or right lobe of the liver. Usually right lobe is taken for adults and left for children. Post donor’s surgery, diseased liver from the recipient is removed and replaced with the part taken from the donor. The blood vessels and bile ducts are connected to the liver lobe. After the surgery, the transplanted lobe regenerates to 85% of original liver within a week.

49. Donor selection Cadaveric/ living donor. Blood group match. (HLA not required/ cross matching not required). Size match.

50. Immunosuppression CNIs: tacrolimus / cysclosporine mTOR inhibitors: Sirolimus , everolimus Steroids Mycophenolate Azathioprine Antibodies: daclizumab , basiliximab , ATG, ALG, OKT3 Newer agents: Efalizumab , Enlimomab , Campath ( Alemtuzumab ), Natalizumab , Betalacept , abatacept , etc.

51. Expected Outcomes of Liver Transplant Surgery The outcomes of liver transplant surgery are quite satisfying. After a successful liver transplant the patient is expected to return to regular lifestyle after six months. Patients with liver transplants are expected to live a healthy and active life provided they are put on healthy diet, a regular exercise regime and medication.

52. Disease Recurrence If antiviral therapy not used Hepatitis B appears at 2-12 months and may lead to cirrhosis & liver failure in 1-3 yrs. Hepatitis C may occur any time after first 4 weeks. Hepatitis B & liver transplant- The current 5 yr. survival rate is 80 % The absence of prophylactic measure risk of reinfection after LT is 80% overall,and largely related to level of HBV replication. Hepatitis C & liver transplant- current 5 yr. patient survival rate is 66% & 10 yr. is 54%(European Liver Transplant Database)

53. Laws for Organ Transplant in India In India the laws for liver transplant surgery are very strict and prohibit any commercial transaction for liver transplant. For organ transplants the government only allows relatives to donate any organ transplant. In case a foreigner wants to donate liver, special permission from government is to be taken once it is established that there is absolutely no commercial transaction for liver between donor and recipient.

54. Cost of Liver Transplant Surgery in India Liver transplant surgery in India is done at few of the best hospitals in India that offer cutting edge technology and highly skilled surgeons who have been performing surgery with great precision. The cost of liver transplant surgery in India varies between 35,000 – 40, 000 USD. The cost of liver transplant is much cheaper in India than the cost of liver transplant surgery in western countries.

55. Advances in antifibrotic agents

56. Artificial detoxification devices currently under clinical evaluation include the Molecular Adsorbent Recirculating System (MARS ) Single Pass Albumin Dialysis (SPAD )

57. Molecular Adsorbents Recirculation System (MARS), developed at the University of  Rostock  in  Germany . MARS is the best known extracorporal liver dialysis system The first circuit consists of  human serum albumin , is in contact with the patient's blood through a semipermeable membrane and has two special filters to clean the albumin after it has absorbed toxins from the patient's blood. second circuit consists of a hemodialysis machine and is used to clean the albumin in the first circuit, before it is recirculated to the semipermeable membrane Remove a number of toxins, including  ammonia ,  bile acids ,  bilirubin ,  copper ,  iron  and  phenols . MARS has approval from the  Food and Drug Administration  (FDA) for drug overdoses and poisoning as of June 2005

58. Single pass albumin dialysis (SPAD) Single pass albumin dialysis (SPAD)  is a simple method of  albumin  dialysis using standard renal replacement therapy machines without an additional perfusion pump system: The patient’s blood flows through a circuit with a high-flux hollow fiber hemodiafilter , identical to that used in the MARS system. The other side of this membrane is cleansed with an albumin solution in counter-directional flow, which is discarded after passing the filter. Hemodialysis can be performed in the first circuit via the same high-flux hollow fibers .

59. References 1.Harrisons principles of internal Medicine 19 th edition 2.Sherlock’s Diseases of the liver & Billiary system 12 th edition 3.Sleisenger & fordtrans Gastrointestinal & liver disease 8 th edition

60. Thank you