Post-OLT Complications and a Focus on Long Term Management

1. Post-OLT Complications and a Focus on Long Term Management Robert G Gish MD Professor Consultant Stanford University TransCaucasus Liver Symposium 2014

2. Disclosures • None

3. Post-OLT Complications and Management • Long-term complications • Recurrence of primary disease • Chronic rejection • Metabolic disorders • Renal failure • Malignancies

4. Acute cellular rejection • Liver biopsy • Histologic findings • Bile duct injury • Mixed inflammatory infiltrate in the portal triad with eosinophils • Endotheliitis A, The portal tract shows a lymphocytic and plasma cell infiltrate that spills over into the periportal hepatocytes and bile duct. B, The central vein shows attachment of lymphocytes to the endothelium (endotheliitis).  (From Cotran RS, Kumar V, Collins T, editors. Robbins' pathologic basis of disease. 6th ed. CD-ROM. Philadelphia: WB Saunders; 1999, with permission.)

5. Acute cellular rejection • Rejection activity index (RAI) • Score 0-3 • Portal inflammation • Bile duct inflammation • Venular inflammation • Three scores added for final RAI score • RAI <= 4, mild acute rejection • RAI score does not correlate with response to steroids or graft survival.

6. Acute cellular rejection • Recurrent HCV and new HEV can mimic ACR • Overlapping histologic features. • Both associated with bile duct injury and portal lymphocytic infiltration. • Endotheliitis more consistent with ACR • Lobular inflammation suggests HCV.

7. Acute cellular rejection • Management • High dose steroids • Methylprednisolone 1000 mg followed by six day taper from 200 mg/day to 20 mg/day. (Volpin, Liver Transpl 2002) • 75% of episodes resolve. • LFTs and histology improve within 3-5 days when steroids are successful. • Caution with HCV pts • Steroids will accelerate HCV progression and increase mortality.

8. Acute cellular rejection • Management • 10% of ACR is steroid-resistant • Sirolimus add-on therapy • Thymoglobulin (polyclonal lymphocyte preparation) 1.5 mg/kg IBW/day x 5 days.

9. Acute cellular rejection • Management • 10% of ACR is steroid-resistant • Basiliximab/daclizumab (anti-IL2 receptor Ab) • MMF check levels • Tacrolimus high dose

10. Immediate Complications • Biliary complications • Incidence of 5-32% • Include biliary strictures, leaks, and stones. Ayoub et al. Dig Dis Sci 2010.

11. Immediate Complications • Biliary strictures • Most common biliary complication after OLT • Incidence of 5-15% after DDLT and 28-32% after LDLT. • Tend to occur in the first 5-8 months post-OLT. Ayoub et al. Dig Dis Sci 2010

12. Biliary Stricture Classification • Anastomotic • Single • Short • Anastomosis site • Tend to occur later • Incidence of 4-9% • Caused by fibrosis, local ischemia, technical issues or bile leak in post-op period. • Non-anastomotic • Multiple • Long • Intrahep and prox to anastomosis • Incidence of 5-15% • Mean time to presentation of 3.3-5.9 mos post OLT.

13. Biliary Stricture Classification • Non-anastomotic

14. Biliary strictures • Diagnostic imaging • Ultrasound • High PPV if bile ducts are dilated • Poor sensitivity (38-68%) for biliary obstruction in absence of biliary dilatation. • MRCP • High sensitivity (93-100%) in detection of biliary strictures. • Helps map out biliary anatomy for planned ERCP. • ERCP

15. Biliary strictures • Management • Endoscopic balloon dilation • Placement of plastic stent • Stent exchanged for larger stent every 3 months for approx 1 yr. • AS successfully treated in 80-90% of cases. • Efficacy of endoscopic intervention limited by • Multiple biliaryanastomosis, peripheral location and strictures of small size.

16. Biliary strictures • Management • Inadequately treated NAS can lead to lobar atrophy, biliary cirrhosis, and recurrent cholangitis. • Up to 50% of pts with NAS will require re-transplantation due to graft loss or die awaiting new liver.

17. Biliary strictures • Management

18. Biliary Complications • Bile leaks • Incidence of 2-25% post-OLT. • Common causes • Anastomotic leak (most common, early) • T-tube related (late) • Ischemia related (early) • R-en-y rupture/dehiscence • Surface leak in LDLT • Treated with ERCP/sphincterotomy and stent placement.

19. Biliary Complications • Prevention • Favor duct-to-duct anastomosis • Allows for preservation of sphincter of Oddi • Less bacterial colonization of biliary tract • Decreased operative time • Lower frequency of bile leak • Fewer biliaryanastomoses • Allows for endoscopic access of biliary tract

20. Biliary Complications • Donation after Cardiac Death • Non-heart beating liver donation • Associated with significant biliary complications. • Up to 60% incidence rate, mostly serious. • Most were NAS, due to ischemic injury occurring prior to organ retrieval. (Maheshwari et al. Liver Transpl 2007)

21. Immediate Complications • Hepatic Artery Thrombosis (HAT) • Occurs in 4-15% of OLTs • More frequent in pediatric transplant recipients (smaller size of vessels). • Leads to graft loss in 53% of cases and mortality in 33% of cases in the immediate post-op period. (Pareja, Transpl Proceed 2010)

22. Immediate Complications • Hepatic Artery Thrombosis (HAT) • Causes biliary tract necrosis and abscess • Risk factors include • Dissection of hepatic arterial wall • Technical problems with anastomosis • Celiac stenosis or compression • Aberrant donor/recipient anatomy • Complex backtable arterial reconstruction of graft • Predisposition to HAT also seen w/ hx of TACE and HCC.

23. Hepatic Artery Thrombosis • Clinical manifestation • Early HAT • Occurring within 1 month of OLT • Causes biliary tract necrosis and subsequent sepsis, death • Late HAT • Occurring > 1 month of OLT • Can be asymptomatic • Causes biliary tract necrosis/abscess and graft ischemia

24. Hepatic Artery Thrombosis • Diagnosis • Gold standard  Doppler US • Also seen on CTA

25. Hepatic Artery Thrombosis • Management Duffy et al. J Am Coll Surg 2008

26. Long-term Complications of OLT

27. Long-term Complications of OLT • Recurrence of primary disease • Congenital and metabolic disease do not recur. • Biliaryatresia, polycystic liver disease, caroli’s disease, congenital hepatic fibrosis, Wilson’s disease, alpha 1 antitrypsin deficiency) • All others can recur • PBC, PSC, AIH, NAFLD, hemochromatosis, HBV, HCV.

28. Long-term Complications of OLT • Recurrence of primary disease El-Masry et al, Liv Internat 2010.

29. Long-term Complications of OLT • Recurrence of primary disease • Hemochromatosis • 74% survival at 5 yrs. • Conflicting data on re-accumulation of iron post-OLT • Most post-OLT deaths due to sepsis and cardiac complications.

30. Long-term Complications of OLT • Recurrence of primary disease • HBV • Without prophylaxis, graft re-infection rates 80-100%, resulting in low pt and graft survival. • Now 75% survival at 5 yrs. • Re-infection rates <10% with HBIG and oral antiviral. • Risk for re-infection • High- cirrhosis with HbeAg+ or eAgneg but with high HBV DNA levels or pts with pre-OLT drug resistance. • Low-fulminant HBV, co-infection with HDV or cirrhotics with Hbe Ag neg with low HBV DNA levels. • Manage re-infection with entecavir/tenofovir/adefovir and reduction of immunosuppression.

31. Long-term Complications of OLT • Recurrence of primary disease • HCV • 95% recurrence after OLT. • Lower 10 yr survival of 60-80% compared to those transplanted for other causes. • 5-8% have graft failure over the first 12-18 mos due to fibrosingcholestatic HCV. • Cirrhosis develops in up to 30% by 5 yrs after OLT. • Risk factors for rapid fibrosis progression include • Older donor age, high pre-OLT and post-OLT VL, episodes of rejection, GT 1b, CMV. • Treatment with PEG-IFN+RBV achieves SVR in up to 30% with high dropout rates.

32. Long-term Complications of OLT • Chronic Cellular Rejection

33. Long-term Complications of OLT • Chronic Cellular Rejection • Uncommon cause of liver dysfunction • Incidence < 5 % • Occurs >1 month to years after OLT • Frequently preceded by episode steroid-unresponsive ACR • Histology shows bile duct atrophy/loss and obliterativevasculopathy of large branches of HA/PV • Risk factors include PSC, PBC, CMV infection.

34. Long-term Complications of OLT • Metabolic Complications • Contribute to cardiovascular complications leading cause of death post-OLT.

35. Metabolic Complications of OLT • Obesity • New Onset DM • HTN • Dyslipidemia • Osteopenia Watt, J of Hepatol 2010.

36. Metabolic Complications of OLT • Obesity • Develops in up to 30% of pts post-OLT • Most wt gain occurs in the first 6 months • Due to improved nutrition + steroids • Management includes prevention, orlistat (limited efficacy), bariatric surgery.

37. Metabolic Complications of OLT • New Onset Diabetes • Incidence up to 25% • Independent predictors include • Recipient age >50 • African American race • BMI>25 • HCV infection • Donor age>60 • Diabetic donor • Use of tacrolimus and steroids at discharge.

38. Metabolic Complications of OLT • New Onset Diabetes • Associated with worse fibrosis in HCV pts • Increased risk of infection, late onset HAT, acute and chronic rejection. • Can be managed with diet, exercise, tapering steroids, oral medications, and insulin. • Consider switching tacrolimus to cyclosporine.

39. Metabolic Complications of OLT • New Onset Diabetes Watt. J of Hepatol 2010.

40. Metabolic Complications of OLT • Hypertension • Can develop in up 70% of OLT pts • Due mostly to calcineurin inhibitors and steroids • Renal and systemic vasocontriction • Impaired GFR and sodium excretion. • Managed with CCB (nifedipine), BB. • Avoid meds that interact with CNI or affect renal function, hyperkalemia.

41. Metabolic Complications of OLT • Dyslipidemia • 45-69% of OLT pts develop hyperlipidemia. • Increased rate of post-OLT cardiovascular events. • Related to steroids, CNI and sirolimus. • Resistant to dietary modification. • Managed with statins, fish oil, decrease CNI dose.

42. Metabolic Complications of OLT • Osteopenia • Due to steroids and possibly CNI. • Rapid bone loss observed in the first 3-6 months after OLT. • Treated with tapering of steroids, Ca/Vit D supplementation, bisphosphonates.

43. Long-Term Complications • Renal Disease

44. Long-Term Complications • Renal failure • Incidence of 20% at 5 yrs post-OLT • Associated with CNI, HTN, DM. • Predictors of ESRD include • Higher pre-OLT Cr • HRS • Requirement of RRT in the first 3 months post-OLT • Elevated Cr at one year post-OLT • HCV • Renal failure associated with decreased post-OLT survival. Ojo. NEJM 2003.

45. Long-Term Complications • Malignancy

46. Long-Term Complications • Malignancy • Incidence of de novo malignancy after OLT is 3-26%. • Second leading cause of death post-OLT. • Attributed to • Life-long immunossupression • Direct carcinogenic effects of medications Chak and Saab. Liver Internat 2010.

47. Long-Term Complications • Increased incidence of malignancy Chak and Saab. Liver Internat 2010.

48. Long-Term Complications • Malignancy risk factors Chak and Saab. Liver Internat 2010.

49. Long-Term Complications • Screening for malignancy Chak and Saab. Liver Internat 2010.

50. Post-OLT Complications and Management • Immediate complications • ACR • Biliary strictures • HAT • Long-term complications • Recurrence of primary disease • Chronic rejection • Metabolic disorders • Renal failure • Malignancies