Long term liver transplant management

Transcription

1 Long term liver transplant management Dr Bill Griffiths Cambridge Liver Unit Royal College of Physicians

2 Success of Liver Transplantation Current survival, 1 st elective transplant: 1 yr survival 93-95% 5 yr survival 80-85% 10 yr survival 60-65%

3 Success of Liver Transplantation Advances in immunosuppression Surgical techniques including preservation Viral hepatitis treatment Patient selection

4 Number of deceased donors, transplants and patients on the active transplant list - livers Figure 8.1 Deceased donor liver programme in the UK, 1 April March 2016, Number of donors, transplants and patients on the active transplant list at 31 March 1000 Donors Transplants 900 Transplant list Num ber Year Source: Organ Donation and Transplantation Activity Report 2015/16

5 Survival after first elective adult whole liver only transplant from DBD donors Year of transplant No. at risk of death on day 0 % Patient survival (95% confidence interval) 15 year 20 year 25 year 30 year 35 year (5-15) 7 (3-12) 5 (2-10) (28-38) 26 (21-30) 19 (15-24) 15 (11-20) (42-48) 35 (32-38) 28 (25-31) (44-49) 35 (32-38) (45-50)

6 Causes of death in LT recipients 4483 liver transplant recipients Main cause of death: Malignancy 30.6% Multisystem failure 10% Infection 9.8% Graft failure 9.8% Cardiovascular disease 8.7% Gelson W et al Transplantation 2011

7 Challenges 7.7 life-years lost even if survive 1 st post op year Maintain stable graft function immunologically Manage technical complications eg biliary Manage recurrent disease Minimise side effects of immunosuppression Psychosocial, alcohol, smoking

8 Immunological stability Prevention or treatment of rejection episodes not particularly problematic unless noncompliant (NB adolescent patients) Approximately 15% have unrecognised tolerance Up to a further 35% have near-tolerance Immunosuppression withdrawal studies in progress but limited cohort at present

9 Question 1 A recipient with normal LFTs presents with diarrhoea and a rash, can request one test: A. Chimerism B. CMV PCR C. Stool culture D. CT scan

10 Question 1 A recipient with normal LFTs presents with diarrhoea and a rash, can request one test: A: Chimerism Detection of donor lymphocytes Indicates graft vs host disease (GVHD)

11 Allograft Rejection Acute cellular rejection 20-30% depending on use of protocol biopsy Late acute cellular rejection (>3/12) Associated with reduction in immunosuppression Difficult to treat can cause graft loss Chronic rejection 2%, decreasing incidence with tacrolimus Typically ductopenia, foamy arteriopathy Role of DSAs?

12 Question 2 2 years out for alcohol; normal LFTs, creat 87 On tac 3/3 and azathioprine 75, tac level 3.9: A. Gradually withdraw azathioprine B. Increase tacrolimus to 4/4 C. Reduce tacrolimus to 2/2 D. Keep status quo

13 Question 2 2 years out for alcohol; normal LFTs, creat 87 On tac 3/3 and azathioprine 75, tac level 3.9: A: Gradually withdraw azathioprine Tacrolimus monotherapy appropriate

14 Incidence of CMV-disease after OLT Incidence depends on donor-recipient status Not uncommon after prophylaxis window CMV-prophylaxis No CMV-prophylaxis D+/ R- D+/ R+ D-/ R+ D-/ R- Total % * 2.7 % 3.9 % 0% 4.8 % % 18.2 % 7.9 % 0 % % ESOT Transplant Hepatology, Padua 9/

15 Technical complications - biliary Up to 20% of patients develop biliary strictures Anastomotic May respond to biliary stenting esp early Late strictures require roux loop Non anastomotic Ischaemic cholangiopathy multiple strictures Medical management until graft failure

16 Anastomotic stricture

17 Ischaemic cholangiopathy eg DCD

18 Technical complications - vascular Caval stenosis Portal vein stenosis/thrombosis Late hepatic artery thrombosis Medical management Abscess presentation do worse consider re OLTx

19 Disease recurrence - PBC PBC recurs in up to 40% Birmingham series of 485 patients Recurrence rate of 23% 2.7 fold increase risk with tacrolimus based immunosuppression as compared with cyclosporine Minimal translation to clinical disease/graft loss

20 Question 3 3 years out for PBC; ALP 187, ALT 51, n US On tac 3/3 and azathioprine 50, tac level 5.6: A. Add ursodeoxycholic acid B. Increase tacrolimus to 4/4 C. Autoimmune screen D. Liver biopsy

21 Question 3 3 years out for PBC; ALP 187, ALT 51, n US On tac 3/3 and azathioprine 50, tac level 5.6: D: Liver biopsy Recurrent PBC vs rejection vs other

22 Recurrent disease - autoimmune AIH recurs in up to 40% Timing often linked to reduction in corticosteroids Normally easily controlled with steroids De novo AIH being increasingly recognised.

23 Recurrent disease - PSC PSC recurs in up to 28% of cases Considerable overlap with ischaemic cholangiopathy and Roux-loop associated cholangitis Only patients with intact colons appear at risk Can cause significant graft dysfunction and graft loss

24 Recurrent disease - HCC HCC recurs in 10% despite tight selection criteria No evidence that any therapy of value except surgical resection in occasional patient Surveillance post transplant for those deemed to be high risk (CT every 6 m for 4 yrs) Surveillance post transplant for graft cirrhosis Sirolimus showed promise but SiLVER study suggests ineffective long term (Geissler et al Transplantation 2016)

25 Disease Recurrence - HCC Early Authors 3 yr Survival 3 yr Recurrence Pittsburgh (85) 25% 75% UCLA (90) 31% 48% Selby (95) 39% 40% Strict criteria Authors Recurrence Survival Mazzaferro % 74% Bismuth % 74% Jonas % 71%

26 Question 4 Which HCC pt cannot undergo a transplant: A. 6 cm HCC stable over 6 m B. AFP 1200 C. Downstaged to inside Duvoux criteria D. 2 cm HCC poorly differentiated on biopsy

27 Question 4 Which HCC pt cannot undergo a transplant: B. AFP 1200 Rest all within current NHSBT criteria AFP must be <1000

28 Threats to health and longevity Malignant disease Renal failure Cardiovascular disease Metabolic disease Obesity Bone disease

29 Malignant disease PTLD Risk correlates with overall intensity of immunosuppression Estimate of 0.5% per year Treatment is immunosuppression minimisation and R-CHOP +/-surgery

30 Question 5 Which virus is associated with PTLD? A. CMV B. HSV C. EBV D. HCV

31 Question 5 Which virus is associated with PTLD? Answer C: EBV Drives B cell proliferation PTLD is a B cell lymphoproliferative disorder

32 Malignant disease 2-3% skin cancers Oro-pharyngeal tumours, especially in patients transplanted for alcohol Increased risk of colonic carcinoma in UC/PSC patients: - 1% risk per year - 21% dysplasia rates by 8 years - annual colonoscopy recommended

33 Question 6 3 years out for NASH; normal LFTs, creat 134 On tac 4/4 and azathioprine 75, tac level 5.8: A. Gradually withdraw azathioprine B. Switch azathioprine to mycophenolate C. Reduce tacrolimus to 3/3 D. Keep status quo

34 Question 6 3 years out for NASH; normal LFTs, creat 134 On tac 4/4 and azathioprine 75, tac level 5.8: C: Reduce tac 3/3 Room for manoeuvre with tac dose Preserve renal function

35 Renal dysfunction and failure Calcineurin inhibitors (cyclosporin and tacrolimus) associated with renal dysfunction Up to 5% in UK of long-term survivors progressed to dialysis or renal transplantation 40% have serum creatinine >120 umol/l or creatinine clearance <60 ml.min NEJM study showed ESRD occurred at 1-1.5% per year

36 Maintaining healthy kidneys CNI exposure in first 3 months very important Avoid NSAIDs and other nephrotoxic drugs if possible Screen for early deterioration with creatinine clearance Decrease or eliminate CNI with mycophenolate or sirolimus

37 Question 7 Patient on tacrolimus requires antibiotic for chest infection, which one to avoid? A. Co-amoxiclav B. Clarithromycin C. Doxycycline D. Ciprofloxacin

38 Question 7 Which antibiotic to avoid on tacrolimus? B: Clarithromycin Cytochrome P450 3A (CYP3A)

39 Abnormal Glucose Metabolism Pretransplant diabetes mellitus Very common early phenomenon Long-term diabetes mellitus - increase in treatment intensity - de novo diabetes mellitus (NODAT) Some cases of improvement in DM 4-20% of patients have significant problem

40 Dyslipidemia Hypercholesterolemia 17-43% Hypertriglyceridemia 40-59% Implicated drugs steroids, cyclosporin, tacrolimus, sirolimus Cyclosporin Vs Tacrolimus 140 to to 164 mg/dl (mean) Steroid withdrawal 223 to 188 mg/dl

41 Question 8 6 years out for NASH, persistent chol 7.2 Tacrolimus monotherapy, consider: A. Atorvastatin B. Pravastatin C. Rosuvastatin D. Simvastatin

42 Question 8 6 years out for NASH, persistent chol 7.2 Tacrolimus monotherapy, consider: B. Pravastatin Non CYP3A metabolised

43 Obesity 21.6% of patients developed de novo obesity after liver transplantation Mean body mass index increased from 24.8 kg/m 2 to 28.1 kg/m 2 at 2 years Corticosteroids and cyclosporine main responsible drugs Tacrolimus may suppress appetite

44 Hypertension Implicated drugs include cyclosporin, tacrolimus and corticosteroids US and European trial showed comparable rates in the range of 36-56% More recent studies 19-23% Calcium antagonist preferred as 1 st line Aim for 130/80

45 Osteopenia 50% of PBC and PSC patients have bone densities below fracture threshold 22-38% have atraumatic fractures Bone density deteriorates in 90% of patients over first 6 months after transplantation Corticosteroids main offending drug Cyclosporine and tacrolimus implicated in animal studies only

46 Modifiable risk factors Non-adherence Underimmunosuppression Adverse effects related to immunosuppression DSAs? Biliary strictures Cardiovascular and metabolic complications Smoking/alcohol COMMIT (Consensus on Managing Modifiable Risk in Transplantation Transplantation 2017)

47 Question 9 Which drug can cause a pneumonitis? A. Cyclosporin B. Mycophenolate C. Basiliximab D. Sirolimus

48 Question 9 Which drug can cause a pneumonitis? D: Sirolimus Common side effects: leg swelling, mouth ulcers, dyslipidaemia, proteinuria Rarely pneumonitis (reverses on drug cessation)

49 Current concepts in nonadherence Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved. 49

50 Tac variability predicts nonadherence Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved. 50

51 Questions?