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Gastroenterological View of Late Complications in Liver Transplantation

Gastroenterological View of Late Complications in Liver Transplantation. Dr.Murat AKYILDIZ, MD Assoc. Prof of Gastroenterology Istanbul Bilim University, Department of Gastroenterology Sisli Florence Nightingale Hospital, Organ Transplantation Center, Istanbul. POSTGRADUATE COURSE ISTANBUL.

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Gastroenterological View of Late Complications in Liver Transplantation

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  1. Gastroenterological View of Late Complications in Liver Transplantation Dr.Murat AKYILDIZ, MD Assoc. Prof of Gastroenterology Istanbul Bilim University, Department of Gastroenterology Sisli Florence Nightingale Hospital, Organ Transplantation Center, Istanbul POSTGRADUATE COURSE ISTANBUL

  2. Case-1 • 67 years-old woman was admitted to hospital with acute coronary syndrome • She was hospitalised in intensive care unit and coronary angiography revealed LAD and main coronary artery disease • Cardiovascular surgery unit decided to perform CABG operation and preoperative consultation from hepatology unit performed since she was liver transplant recipient.

  3. Medical History • She had decompansated liver cirrhosis because of HCV and living donor liver transplantation was performed in 2007. • She had CNI nephrotoxicity after the first year and switched to sirolimus monotherapy • PEG-INF plus ribavirin was given since HCV RNA was positive and stage 2 fibrosis at 1 year • There was no response to treatment and PEG-INF was discontiniued at 6 moth of therapy • Aleondrate plus calcium and vit D for osteoporosis were given for 3 years • Amlodipine plus ramipril was given for hypertension and using insulin during last 2 years.

  4. Physical Examination There was 1 cm splenomegaly, pretibial eodema (+), no icter, no ascites Blood pressure 150/90 mmHg, HR 90/R Lab Glucose fasting 140 mg/dl, HbA1C 7.8 Tryglycerid 280 mg/dl Cholesterol 320 mg/dl HDL 40 mg/dl LDL 180 mg/dl BUN 40 mg/dl Cr 2 mg/dl AST 80 IU/ml ALT 90 IU/ml T. Bil 1 mg/dl Albumin 4 g/dl PLT 120 000/mm3 Hb 10 g/dl WBC 3500/mm3

  5. Diagnosis • Liver Transplant Recipient (2007, LDLT) • Recurrent HCV infection • Hypertension • Tip 2 diabetes mellitus • Coronary artery disease • Chronic renal failure, CNI nephrotoxicity

  6. Introduction-1 • Orthotopic liver transplantation (OLT), is now the best treatment for selected patients with end-stage liver disease, hepatocellular carcinoma or acute liver failure. • OLT currently has a 5-year survival of 70–80% and generally provides a good quality of life. • Roberts MS et al. Survival after liver transplantation in the United States: a diseasespecific analysis of the UNOS database. Liver Transpl 2004:10; 886–897 • Most life-threatening complications associated with OLT occur within the perioperative period • primary graft dysfunction, • acute rejection episodes, • severe infections • technical complications such as hepatic artery thrombosis or biliary leaks.

  7. Introduction-2 • Outcome after orthotopic livertransplantation has improved continuously over the past 15 years • The recognition andprevention of long-term complications after transplantation have becomeever more important • Physiciansshould beaware of the risk of late and chronic rejection episodes and ofrecurrence of the underlying liver disease after LT

  8. The major challenge of posttransplantcare is • To prevent and manage the long-termadverse effects of the immunosuppressive medications. • Screening investigations for early diagnosis of malignancy • strict control ofcardiovascular risk factors, • preservation of renal function • preventionof infections

  9. Objectives • Describe the cumulative incidence of renal failure after LT. • Describe the incidence of cardiovascular risk factors and metabolic bone disease after LT. • Describe the most common nonhepatic malignancies occurring after LT • Describe the primary disease recurrence and de-novo liver disease after LT

  10. Renal Dysfunction • One of the most common complications after LT. • Chronic CNI toxicity, which causes structural changes to the renal parenchyma, is the main cause of renal failure, but other causes have to be ruled out. • The cumulative incidence of renal impairment in more than 69,000 nonrenal transplant recipients, (defined as a glomerular filtration rate of <30 ml/min/1.73m2) • 8.0% at 1-years • 13.9% at 3-years • 18.1% at 5 years after transplantation • Ojo AO et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003; 349: 931–940

  11. Pretransplant renal dysfunction Pretransplant hepatorenal syndrome Duration of renal dysfunction prior to liver transplantation Calcineurin induced nephrotoxicity Hypertension Diabetes mellitus (preexisting or new onset DM after liver transplantation) Nephrotoxic drugs Postoperative acute renal failure Renal replacement therapy requirement in the pretransplant or posttransplant period HCV infection Older age Risk Factors For Renal Dysfunction

  12. Recommendations for CNI Nephrotoxicity • Reduction or withdrawal of CNI • Conversion to MMF or sirolimus based protocols • Aggressive management of diabetes mellitus • Control blood pressure • Avoid toxic drugs and contrasts

  13. Objectives • Describe the cumulative incidence of renal failure after LT. • Describe the incidence of cardiovascular risk factors and metabolic bone disease after LT. • Describe the most common nonhepatic malignancies occurring after LT • Describe the primary disease recurrence and de-novo liver disease after LT

  14. Cardiovascular Risk Factors • Liver transplant recipients have a higher risk of cardiovascular death and ischaemic events as compared with an age- and sex-matched population without liver transplant • 9% at 5 years post-transplant • 25% at 10 years post-transplant • Cardiovascular disease causes 21% of deaths among liver transplant patients with functioning grafts surviving more than 3 years

  15. Risk factors for cardiovascular complications

  16. Arterial hypertension-1 • Definition • Sistolic BP>140 and/or diastolic BP>90 • Prehypertension • sistolic BP 120-129 mmHg or diastolic BP 80-89 • The incidence was ranges from 50% to 70%. • with cyclosporine, can occur in 58–82% of patients • with tacrolimus, in 31–38% of patients. • Risk factors for development of hypertension • Calcineurin inhibitor immunosuppressive therapy • pre-existing or worsening renal disease • obesity

  17. Arterial Hypertension-2 • The mechanism underlying CNI-induced hypertension is vasoconstriction of systemic and renal vessels by various mechanisms • cyclosporine stimulates renin release and causes upregulation of angiotensin II receptors in vascular smooth muscle • leading to a decrease in glomerular filtration and enhanced sodium re-absorption in the renal tubules • calcineurin inhibitors, especially cyclosporine, may also directly impair normal vasodilating systems by reducing prostacyclin and nitric oxide production • mediate systemic vasoconstriction directly by leading to increased thromboxane and endothelin release • prolonged therapy with cyclosporine has also been shown to lead to chronic sympathetic overactivity

  18. Glucocorticoid leads to hypertension via multiple pathways • activate the renin–angiotensin system, • reduce activity of depressor systems such as nitric oxide and prostaglandins, • increase pressor responses to angiotensin II and norepinephrine, • increase the number of angiotensin II receptors on vascular smooth muscle cells. • So, the net effect of these changes promotes systemic vasoconstriction leading to the development of hypertension.

  19. Arterial hypertension-3 • Targets for treatment of patients • DM or renal disease absent <140/90 • DM or renal disease present <130/80 • Target blood pressure levels should be <130/80mmHg in order to minimize the risk for cardiovascular events

  20. Arterial hypertension-4 • First of all standard advice should be given to all patients highlighting the importance of adequate exercise and the avoidance of smoking and alcohol. • Additionally, lifestyle modifications such as weight loss in overweight individuals and restricting sodium intake reduce blood pressure

  21. Arterial Hypertension-4 • Modifications of immunosuppressive therapy can help control hypertension • Conversion from cyclosporine to tacrolimus • Switching from a calcineurin based regimen consisting of either cyclosporine or tacrolimus to a regimen consisting of mycophenolate mofetil or sirolimus decreases hypertension • Mycophenolate mofetil may be combined with low-dose calcineurin inhibitors to improve hypertension while providing adequate immunosuppression and decreasing the risk of rejection • Steroid medication should be minimized and withdrawn as soon as possible after liver transplant

  22. Arterial Hypertension-5 • Long-acting calcium channel blockers that are not metabolized through CYP3A4—such as amlodipine,but not diltiazem or verapamil—are often used as first-line agents in OLT recipients • Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are also very effective, especially in patients who have diabetes mellitus and/or proteinuria, but should be aware of the possibility of hyperkalemia • In patients nonresponsive to single agent therapy, calcium channel blockers can be combined with ACE inhibitors or ARBs • Studies comparing ACE inhibitors, calcium channel blockers, and beta blockers, specifically lisinopril, amlodipine and bisoprolol, in liver transplant recipients showed that • lisinopril and amlodipine were more effective than bisoprolol • β‑Blockers that are selective for the β1 adrenoceptor can also be given, but their effect can be less marked.

  23. Dyslipidemia-1 • Hypercholesterolaemia and hypertriglyceridaemia both commonly occur in liver allograft recipients. • Hypercholesterolaemia is prevalent in 51–66% of liver transplant patients • hypertriglyceridaemia occurring in up to 50% of patients • Lipid profiles should be check at least biannuly • Sirolimus and glucocorticoids are associated with higher rates of dyslipidaemia as compared with cyclosporine and tacrolimus. • Sirolimus is heavily associated with hyperlipidaemia and has been reported to cause hypercholesterolaemia in 44–55% of patients • alters the insulin signalling pathway to increase adipose tissue lipase activity and decrease lipoprotein lipase activity, thereby resulting in increased hepatic synthesis of triglycerides and increased secretion of very low-density lipoprotein (VLDL).

  24. Dyslipidemia-2 • Glucocorticoids • increase activity of acetyl-CoA carboxylase, free fatty acid synthetase and HMG CoA reductase, leading to elevated VLDL, total cholesterol, and triglycerides and reduced high-density lipoprotein (HDL) • Cyclosporine is associated with moderate rates of dyslipidaemia, with hypercholesterolemia found in 30% of patients and hypertriglyceridaemia found in 33% of patients. • reduces the conversion of cholesterol to bile salts and decreases activity of lipoprotein lipase, thereby resulting in increased VLDL and lowdensity lipoprotein (LDL) levels • Tacrolimus has similar effects to cyclosporine but is associated with a lower prevalence of hyperlipidaemia

  25. Dyslipidemia-3 • Risk factors for the development of dyslipidemia • Steroids, • CNIs, • mTOR inhibitors, • post-transplant diabetes mellitus, • Dietetian consultation and lifestyle modifications help the normalization of lipid profiles • Immunosuppressive therapy modifications such as • conversion from cyclosporine to tacrolimus, • decreased prednisone usage, • minimization of sirolimus usage all assist in the normalization of cholesterol levels.

  26. Dyslipidemia-4 • Treatment with statins is indicated in patients who have an LDL cholesterol level greater than 100–130 mg/dl despite taking dietary measures and implementing lifestyle changes. • Pravastatin or fluvastatin do not undergo metabolism by CYP3A4 and select those as first line treatment for hyperlipidemia. On the other hand, atorvastatin and simvastatin are the other lipid lowering agents which should be used lower dosage and titrated up slowly sınce the toxicity risk • When comparing statins with fibrates, it appears that lovastatin more effectively reduces total cholesterol and LDL levels, while gemfibrozil more effectively lowers triglyceride levels.

  27. Dyslipidemia-5 • In patients who remain dyslipidaemic on statin therapy alone, a fibrate medication should be added to improve control of hyperlipidaemia. • Fibrates should be used with caution and are contraindicated in patients with renal failure • Monitoring levels of the muscle enzyme creatine kinase and liver tests for side effects • In order to avoid statin toxicities in patients on immunosuppressive therapy, statins should be started at the lowest possible dosage and titrated up slowly, with close monitoring of the patient for side effects. • Combination therapy comprising statins and the cholesterol absorption inhibitor ezetimibe ban be used safely.

  28. Diabetes Mellitus • The general prevalence of diabetes is as high as 31–38% in the post-transplant population • New onset diabetes is found in 13–28% of liver transplant recipients more than 1 year after transplantation • Before liver transplantation, patients should be screened for diabetes for proper risk stratification of cardiovascular morbidity. • After liver transplantation, patients should undergo diabetes screening on a regular basis, at weekly intervals for the first month after transplant, at 3, 6 and 12 months after transplant, and on an annual basis thereafter • Patients diagnosed with diabetes should hae HbA1c levels measured every 3 months, with a goal HbA1c level of o7%.

  29. Diabetes Mellitus • Risk factors for DM • Male gender • CMV infection in the first year of transplantation • Obesity • HCV • CNI (TAC>Cyc, (17 vs 10% ) • Steroid therapy • Pre-existing and new-onset diabetes mellitus is associated with • increased cardiovascular morbidity and mortality, • the development of renal dysfunction, • a higher incidence of fatal infections, • more rejections, • impaired graft survival, an increased risk of graft failure and death • microvascular complications, retinopathy and nephropathy, • an increased risk of developing hypertension and coronary artery disease and neurologic complications

  30. Diabetes Mellitus • Strict glycaemic control is important in order to reduce the long-term complications of diabetes. • Treatment of post-transplant diabetes includes • limiting caloric intake, • a low carbohydrate diet, • appropriate exercise, • pharmacological therapy with oral hypoglycaemic agents and insulin as needed • Immunosupressıve modifications • steroid withdrawal • reducing the CNI dose, • switching from tacrolimus to the less diabetogenic agent cyclosporin

  31. Obesity • Obesity is defined as a body mass index (BMI) >30 kg/m2, • UNOS database has shown that 54% of liver transplant recipients were considered overweight or obese • After liver transplant, the incidence of obesity ranges from 18 to 64% of patients • Post-transplant weight gain is significantly greater in patients over 50 years old and those transplanted for chronic liver disease as compared with fulminant hepatic failure. Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002; 35: 105–9.

  32. Obesity • Many transplant centers will encourage weight loss before transplantation. • Elevated preoperative BMI in liver transplant recipients predisposes to increased surgical complications • Wound infections • Respiratory failure • Sytemic vascular problems • UNOS database have shown that morbidly obese patients (BMI >40 kg/m2) • have significantly higher rates of primary graft nonfunction, • higher rates of immediate, 1-year, and 2-year mortality • 5-year mortality was significantly higher both in severely obese (BMI 35–40 kg/m2) and morbidly obese patients. Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002; 35: 105–9.

  33. Obesity • Pre-transplant predictors of the post-transplant obesity • higher recipient BMI, • higher donor BMI • being married • absence of acute cellular rejection (unknown mecanism, probably having improved overall appetite with increased oral intake) • Higher cumulative prednisone dose • Patients who are overweight after liver transplant also more commonly have a • family history of diabetes mellitus, • family history of arteriosclerotic heart disease, • family history of hypertension

  34. LTx at the extremes of BMI( 73538 patients from UNOS Database ) Patient survival according to BMI

  35. LTx at the extremes of BMI cont. • BMI < 18.5 more likely to die from hemorrhagic complications ( P<0.002) and CVA (P<0.004) • BMI > 40 died of infectious complications and cancer events ( P=0.02) • Liver Transplantation 15: 968-977, 2009

  36. Obesity • Recommendations for obesity • Weight loss should be recommended for all patients before undergoing liver transplantation, especially patients with a BMI >35 kg/m2. • obese patients should be encouraged to limit caloric intake and engage in regular physical activity. • glucocorticoid should be withdrawn as soon as possible after LT • Orlistat, (pancreatic and gastric lipase inh) can be used safely, decreases waist circumference, but not in weight or body mass index in obese liver transplant recipients.

  37. Metabolic Bone Disease • Thecumulativeincidence of fracture is • 14-50% at 1 year • 24-55% at 2 yearsafter LT • Before LT • Decreased bone density is common ( 68%) in cirrhotic patients • Vitamin D level deficiency (92%) hypogonadism 41% of patients • Lifestyle modifications • such as smokingcessation and weight-bearing exercise should be encouraged • Vit D 800 IU/dayandcalcium 1000 mg/day in lowvit D levels

  38. Pre-TX factors Older age Female sex Poor nutritional status Low pre-TX BMD Osteoporotic fractures Cholestatic liver disease Post-TX factors Dose of steroid Cyclosporin Low pre-TX BMD Rejection episodes Independent Risk factors Pre-TX Low BMD Cholestatic liver disease Osteoporotic fractures in pre-transplant Post-TX Cumulative dose of steroid Low BMD after LT Fall in BMD after LT Risk Factors for Fracture After LT

  39. Management of Osteoporosis-1 • Nonpharmacologic therapies include • ETOH and smoking cessation, • increased physical activity • a balanced diet with 1500 mg of calcium and 800 IU of vitamin D daily. • Steroid should be stopped as soon as possıble • Studied pharmacologic treatments include • Testosterone replacement in male patients with low serum testosterone levels, • replacement of additional vitamin D (25 000–50 000 IU orally two to three times perweek) if a deficiency is present • Bisphosphonates • Check BMD after 2 year of treatment • If no response to treatment • add bisphosphonates in patients receiving HRT • in patients already receiving bisphonates switch to strontium

  40. Management of Osteoporosis-1 • Pain control with transdermal fentanyl and oral metamizole is important for the fast rehabilitation • Avoid administration of selective and nonselective NSAIDs due to their nephrotoxicity and association with acute renal failure

  41. Metabolic Bone Disease • Osteonecrosis of the Femoral Neck • Another important metabolic bone disease after LT • presents as hip pain due to corticosteroid use. • diagnosed by magnetic resonance imaging (MRI) • require hip replacement.

  42. Infections • The frequency and localization of infections in the long term generally resemble in the general population, • with upper respiratory tract infections and urinary tract infections being most common after the first 6 months of LT • Cholangitis should be considered in LT recipients who have a fever of unknown origin, • The risk for recurrent cholangitis is particularly high in patients with biliodigestive anastomosis • biliary strictures following transplantation • The initial diagnostic algorithm for fever of unknown origin in OLT recipients in the long term is similar to that used for nontransplant patients, but should be performed early and thoroughly.

  43. Infections-2 • Empiric treatment with antibiotics is recommended if patients show clinical signs of infection and levels of inflammatory parameters are elevated. • Attention should be paid to potential interactions between the antimicrobial agent and the CNI • macrolide antibiotics should be used with great caution as they considerably increase a patient’s exposure to the CNI and can cause renal failure. • Hepatotoxicity potential should be kept in mind • Nephrotoxicity potential should be kept in mind • Quinolones are usually a good choice because they do not interfere with the effects of CNIs and are effective against cholangitis, most bacterial respiratory infections,and urinary tract infections. • When patients do not respond to antibiotic treatment, a thorough work-up is mandatory,since the possibility of • tuberculosis, • opportunistic infections • post-transplant lymphoproliferative disorders (PTLDs).

  44. CMV • Liver recipients at highest risk of CMV infection and disease are those who have never had CMV infection until they receive a latently infected organ from a CMV-seropositive donor (CMV D+/R- mismatch). • The risk of progression into CMV disease is increased by the intense immunosuppression required to avoid or to treat allograft rejection. • CMV pp65 antigenemia or CMV DNA by polymerase chain reaction) as the earliest indicators of infection. • Intravenous ganciclovir (5 mg/kg every 12 h) or oral valganciclovir (900 mg orally twice daily), combined with reduction in immunosuppression.

  45. Treatment of CMV Disease • serial weekly monitoring of viral load or antigenemia levels. • The vast majority of CMV disease cases after liver transplantation remain susceptible to ganciclovir. • Non-responders should be tested for drug resistant virus, with UL97 and UL54 gene sequencing. • Foscarnet and cidofovir are often used for treatment of ganciclovir-resistant UL97-mutant CMV strains, but they have a high risk of nephrotoxicity Eid AJ, Razonable RR. Drugs 2010; 70: 965-981 Sun HY, Am J Transplant 2008; 8:2111-2118 Kotton CN, et al. Transplantation 2010; 89: 779-795

  46. De novo malignancies-1 • Transplant recipients are generally at higher risk than the general population for the development of de novo malignancies or the recurrence of previous cancers. • The incidence has been reported to be as 1.5–26.5%. • Nonmelanoma skin cancer and PTLD are by far the most common malignancies in OLT recipients. • Human herpes virus 8 is a central etiological factor in the development of Kaposi sarcoma

  47. De-novo malignancies-2 • Cutaneous malignancies, especially SCC, develop at a younger age, are more aggressive, metastasize and tend to be multiple in transplant recipients than those in the general population. • The peak incidence of cutaneous malignancies is 3–5 years after organ transplantation • Risk factors for SCC after organ transplantation • a history of skin cancer and/or actinic keratosis, • fair skin, • chronic sun exposure and/or sunburn, • older age, duration and intensity of immunosuppression, • history of HPV infection, and CD4 lymphopenia. • Patients at high risk for SCC require close monitoring before and after LT • Effective sun protection and annual examination of the skin by an expert dermatologist is, therefore, highly recommended

  48. De-novo malignancies-3 • PTLDs mainly result from primary or reactivated EBV. • The cumulative 5-year incidence of PTLD in OLT recipients was 1.5%. • Risk factors for the development of PTLD include • negative pretransplant Epstein–Barr virus serology, which is common in children, • over immunosuppressive therapy using polyclonal or monoclonal T‑cell antibodies. • Most cases of PTLD develop during the first year after transplantation • Diagnosis is established according to the results of biopsy of lymph nodes or affected organs. • Treatment of PTLD involves, • withdrawal of CNIs. • In vitro studies and case reports suggest that the use of mTOR inhibitors can lead to regression of lymphoma and, in addition, offers safe prevention of graft rejection. • monoclonal B-cell antibodies (e.g. rituximab), • radiation or chemotherapy

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