Liver transplant

Liver transplant, indications & complications

1. Liver Transplant Presenter: Dr. Dhileeban Maharajan Moderator: Dr. Romeo Singh

2. Introduction Thomas Starzl 1960 Orthotopic (rarely heterotopic ) One year survival from 30% to >90% Improved operative technique, immunosuppressive therapy Cadaver organ transplantation

3. Trend of liver transplant in India

4. Orthotopic graft : Graft placed in its normal anatomical site Heterotopic graft : Graft placed in a site different from normal location Allograft : From one individual to another Xenograft : Between different species

5. Major indications Decompensated cirrhosis Acute liver failure Unresectable primary hepatic malignancy

6. Indications CHILDREN Biliary atresia Neonatal Hepatitis Congenital hepatic fibrosis α 1 Antitrypsin deficiency Inherited disorder Glycogen storage disorder Lysosomal storage disorder Wilson’s disease Tyrosinemia Protoporphyria Crigler - Najjar disease Type I Primary hyperoxaluria Type I Hemophilia ADULTS 1 & 2 biliary cirrhosis Primary sclerosing cholangitis Autoimmune hepatitis Caroli’s disease Cryptogenic cirrhosis Chronic hepatitis with cirrhosis Hepatic vein thrombosis Fulminant hepatitis Alcoholic cirrhosis Chronic viral hepatitis Primary hepatocellular malignancies Hepatic adenomas NASH Familial amyloid polyneuropathy

7. Proportion of liver transplants performed for specific indications

8. Contraindications ABSOLUTE Uncontrolled extrahepatobiliary infection Active sepsis Uncorrectable life limiting congenital anomalies Active alcohol abuse Advanced cardiopulmonary disease Extrahepatobiliary malignancy Liver metastasis Cholangiocarcinoma AIDS Life threatening systemic diseases RELATIVE Age> 70 Prior extensive hepatobiliary surgery Portal vein thrombosis Renal failure (not related to liver) Previous extrahepatic malignancy Severe obesity Severe malnutrition Medical noncompliance HIV with CD 4 <100/µL Intrahepatic sepsis

9. Selection Criteria MELD Score: 0.957* log e ( creatinine ) + log e (total bilirubin) +1.120* log e (INR) + 0.643 Child Pugh score Utility Models Transplant benefit models

10. Meld score The MELD score assigns points that reflect the severity of liver disease A patient’s priority on the waiting list is based on the medical status as determined by MELD score The score is based on a formula that considers bilirubin, INR, Creatinine

11. Score : 6 in healthy person to 40 in severe ESLD Score < 15 should not undergo liver transplantation Preference – Sickest patient as per MELD score Significant decrease in the rate of death of potential recipients on the waiting list because it allows livers to be directed to the sickest patients. The scoring used in pediatric patients is referred to as the pediatric end-stage liver disease (PELD) score. Pediatric donors are distributed to pediatric patients preferentially.

12. Fulminant hepatic failure Primary graft nonfunction Portopulmonary hypertension Hepatopulmonary syndrome Familial amyloid polyneuropathy Primary hyperoxaluria Cytic Fibrosis liver disease HCC Disease specific MELD exceptions:

13. King’s college criteria Acetaminophen induced ALF o Ph- <7.3 or o INR- >6.5 and o S. creat - >3.4mg/dl Non- acetaminophen induced ALF o INR> 6.5 or Any three of the following o Age- <10 or >40 o Time of onset of jaundice to development of coma of >7 days o INR- >3.5 o S.Bilirubin - >17mg/dl

14. Cadaver donor selection Acceptable Criteria Brain dead Hemodynamic stability Adequate oxygenation Absence of infections No abdominal trauma No hepatic dysfunction HBV, HCV HIV sero -negative Most important factors Organ size ABO compatibility * HLA matching not mandatory*

15. Living donor transplantation Requirements: 18 – 60 years old Compatible blood type No chronic diseases No major abdominal surgery Related genetically or emotionally

16.  Aim - Preserve the functional integrity of the organs - Careful monitoring and management of fluid balance.  Warm ischaemia - Time between the diagnosis of death ( cardiorespiratory arrest) and cold perfusion of the organ(up to 45 minutes is acceptable)  Storage time- Liver - <12hrs(Optimal) , 18hrs(Max. time Organ recovery from deceased donors

17. Surgical technique Removal of native liver complicated by Coagulopathy and portal hypertension Lead to large blood product transfusion Portal vein  Intra & suprahepatic IVC  Hepatic artery  Bile duct Anhepatic phase ( coagulopathy , hypoglycemia, hypocalcemia , hypothermia) Donor liver inserted Caval  Portal Vein  Hepatic artery  Bile duct

18. Post operative monitoring -- Invasive monitoring (arterial and venous) -- T tube  Dark copious bile -- Routine antimicrobials Bowel decontamination Systemic Broad spec. antibiotics Antifungal Antiviral

19. Good signs : -- Aminotransferase downward trend -- Improvement in coagulopathy -- Falling serum bilirubin level Bad Signs -- Scanty pale bile -- Metabolic acidosis -- Depressed mentation -- Continued vasopressor support -- Worsening liver parameters

20. iMmunosuppressive therapy Cyclosporin Tacrolimus Prednisone Mycophenolic acid Antithymocyte globulin OKT 3 ( Muromonab ) Sirolimus or Everolimus Basiliximab , Alemtuzumab Azathioprine

21. Initial Maintenance Immunosuppression To prevent graft rejection while avoiding morbidity due to its side effects AIM

22. Cyclosporin 1980 Calcineurin inhibitor Blocks early activation of T cells Nephro -toxicity ( dose dependent) Reversible other adverse effects Hypertension Tremor Hirsutism Glucose intolerance Gingival hyperplasia

23. tacrolimus Macrolide lactone antibiotic Streptomyces tsukubaensis 10- 100 time more potent Rescue therapy Reducing the likelihood of bacterial and CMV infections Good oral absorption Metabolized by cyt P450 Adverse effects: Nephrotoxicity and neurotoxicity Diabetes mellitus

24. Mycophenolic acid Non-nucleoside purine metabolism inhibitor Penicillium species Bone marrow suppression

25. OKT 3 ( Muromonab ) Monoclonal antibodies to T cells Mainly in renal dysfunction patients Reversing acute rejection Adverse effects: Fever and chills Diarrhea pulmonary edema opportunistic infections

26. Sirolimus & everolimus mTOR inhibitor (blocks later events in T cell activaton ) Complication - Hepatic artery thrombosis Everolimus – hydroxyethyl derivative of sirolimus Used in kidney transplantation Not accepted for liver transplantation

27. Non-hepatic complications Cardiovascular instability Arrhythmias CCF Cardiomyopathy Pulmonary compromise Pneumonia Fluid overload Renal Dysfunction Prerenal azotemia ATN Drug nephrotoxicity Malignancy: B-cell lymphoma De nova neoplasm Hematologic: Anemia Thrombocytopenia Infection: Bacterial Fungal/Parasitic Viral Neuro -psychiatric: Seizures Metabolic encephalopathy Depression Diseases of donor: Infection Malignancy

28. Hepatic complications Prehepatic : Pigment load Hemolysis Blood Collections Intra-hepatic: Hepato -toxic drugs Hypoperfusion Benign postoperative cholestasis Intra-hepatic: Transfusion associated hepatitis Exacerbation of primary hepatic disease Posthepatic : Biliary obstruction renal dysfuction

29. Hepatic dysfunction cont.. Primary graft non dysfunction Rejection Recurrent primary hepatic disease Vascular compromise Portal vein obstruction Hepatic artery thrombosis Anastamotic leak Bile duct disorder: Stenosis Obstruction leak

30. Acute cellular rejection -- one week after surgery -- impaired LFT -- LIVER BIOPSY 1. Bile duct injury 2. Partial inflammation with eosinophils 3. Endothelitis -- High dose steroids -- if not improved add OKT-3 Mimic Acute rejection: Slowly resolving reperfusion injury Biliary tract obstruction 3. Cholestasis related to sepsis

31. ACUTE REJECTION HISTOPATHOLOGY

32. CMV HEPATITIS

33. Chronic rejection Due to repeated bouts of acute rejection Liver Biopsy: 1. Progressive cholestasis 2. Focal parenchymal necrosis 3. Mononuclear infiltration 4. Vascular lesion 5. Ductopenia Treatment : Retransplantation

34. • Previous episodes of acute rejection • Long warm ischaemia time • Cytomegalovirus (CMV) infection • Raised blood lipids • Inadequate immunosuppression (including poor compliance) Risk factors for chronic rejection

35. Post-transplantation immunoproliferative disorder -- Low grade to aggressive neoplasm -- Uncontrolled proliferation of B cell after LT -- Typically in primary EBV infection -- Monoclonal or polyclonal -- More in pediatric LT -- Mostly due to immunosuppressive therapy Clinical features: 1. Lymphadenopathy 2. unexplained fever 3. Extranodal masses

36. WHO GRADING I. Benign polyclonal lympho -proliferative disorder II. Polymorphic PTLD III. Monomorphic PTLD iv. Classic non- Hodgkins like PTLD Treatment includes  Reduction in immunosuppressive therapy  Antiviral against EBV  Systemic chemotherapy ( Rituximab )

37. Major challenges Shortage of donor organ Threat of recurrence Morbidity due to immunosuppressives

38. Recent research Using expanded criteria graft Good graft flow by segmental hepatic veins Limiting antibiotic usage Optimizing immunosuppression Minimizing donor morbidity

39. THANK YOU