Gastroenterological View of Late Complications in Liver Transplantation

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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

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

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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 7080 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 200410 886897
• 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.

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Introduction-2

• Outcome after orthotopic liver transplantation
  has improved continuously over the past 15 years
• The recognition and prevention of long-term
  complications after transplantation have become
  ever more important
• Physicians should be aware of the risk of late
  and chronic rejection episodes and of recurrence
  of the underlying liver disease after LT

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• The major challenge of posttransplant care is
• To prevent and manage the long-term adverse
  effects of the immunosuppressive medications.
• Screening investigations for early diagnosis of
  malignancy
• strict control of cardiovascular risk factors,
• preservation of renal function
• prevention of infections

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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

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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 lt30
  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 931940

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Risk Factors For Renal Dysfunction

• 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

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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

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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

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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

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Risk factors for cardiovascular complications
Cardiovascular complication Incidence () Risk factors
Hypertension 3182 Cyclosporinegttacrolimus, Glucocorticoids
Hyperlipidaemia 2950 Sirolimus and glucocorticoidsgtCyc gtTAC
Diabetes mellitus 1064 Glucocorticoids, Tacrolimusgtcyclosporine. Hepatitis C, cytomegalovirus,male gender
Obesity 2264 Glucocorticoids, greater recipient BMI, greater donor BMI, being married, absence of acute cellular rejection, Family history of diabetes/arteriosclerotic heart disease//hypertension
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Arterial hypertension-1

• Definition
• Sistolic BPgt140 and/or diastolic BPgt90
• Prehypertension
• sistolic BP 120-129 mmHg or diastolic BP 80-89
• The incidence was ranges from 50 to 70.
• with cyclosporine, can occur in 5882 of
  patients
• with tacrolimus, in 3138 of patients.
• Risk factors for development of hypertension
• Calcineurin inhibitor immunosuppressive therapy
• pre-existing or worsening renal disease
• obesity

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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

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• Glucocorticoid leads to hypertension via multiple
  pathways
• activate the reninangiotensin 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.

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Arterial hypertension-3

• Targets for treatment of patients
• DM or renal disease absent lt140/90
• DM or renal disease present lt130/80
• Target blood pressure levels should be
  lt130/80mmHg in order to minimize the risk for
  cardiovascular events

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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

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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

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Arterial Hypertension-5

• Long-acting calcium channel blockers that are not
  metabolized through CYP3A4such as amlodipine,but
  not diltiazem or verapamilare 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
• ß-Blockers that are selective for the ß1
  adrenoceptor can also be given, but their effect
  can be less marked.

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Dyslipidemia-1

• Hypercholesterolaemia and hypertriglyceridaemia
  both commonly occur in liver allograft
  recipients.
• Hypercholesterolaemia is prevalent in 5166 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 4455 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).

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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

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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.

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Dyslipidemia-4

• Treatment with statins is indicated in patients
  who have an LDL cholesterol level greater than
  100130 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 since 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.

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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.

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Diabetes Mellitus

• The general prevalence of diabetes is as high as
  3138 in the post-transplant population
• New onset diabetes is found in 1328 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.

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Diabetes Mellitus

• Risk factors for DM
• Male gender
• CMV infection in the first year of
  transplantation
• Obesity
• HCV
• CNI (TACgtCyc, (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

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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
• Immunosupressive modifications
• steroid withdrawal
• reducing the CNI dose,
• switching from tacrolimus to the less
  diabetogenic agent cyclosporin

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Obesity

• Obesity is defined as a body mass index (BMI) gt30
  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 1059.
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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 gt40 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 3540 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 1059.
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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

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LTx at the extremes of BMI( 73538 patients from
UNOS Database )
Patient survival according to BMI
37
LTx at the extremes of BMI cont.

• BMI lt 18.5 more likely to die from hemorrhagic
  complications ( Plt0.002) and CVA (Plt0.004)
• BMI gt 40 died of infectious complications and
  cancer events ( P0.02)
• Liver Transplantation 15 968-977, 2009

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Obesity

• Recommendations for obesity
• Weight loss should be recommended for all
  patients before undergoing liver transplantation,
  especially patients with a BMI gt35 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.

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Metabolic Bone Disease

• The cumulative incidence of fracture is
• 14-50 at 1 year
• 24-55 at 2 years after 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 smoking cessation and weight-bearing
  exercise should be encouraged
• Vit D 800 IU/day and calcium 1000 mg/day in low
  vit D levels

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Risk Factors for Fracture After LT

• 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

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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 possible
• Studied pharmacologic treatments include
• Testosterone replacement in male patients with
  low serum testosterone levels,
• replacement of additional vitamin D (25 00050
  000 IU orally two to three times per week) 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

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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

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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.

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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.

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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 patients
  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).

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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.

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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 82111-2118 Kotton CN,
et al. Transplantation 2010 89 779-795
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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
  1.526.5.
• 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

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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
  35 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

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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 EpsteinBarr 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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De novo malignancies-4

• Be aware of the risk of
• high incidence of colon cancer in OLT patients
  who have ulcerative colitis or PSC
• annual colonoscopies are necessary
• high incidence of esophageal and oropharyngeal
  cancer in patients who undergo transplantation
  for alcoholic cirrhosis
• Whether other common types of cancer such as
  vulva, cervix, breast, renal and prostate cancer
  also occur more frequently in OLT recipients than
  in the general population is still not clear,

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Liver Disease Recurrence and De-novo Liver
Disease
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Natural History of Recurrent Hep C

• Recurrence is universal with 20-40 progression
  to cirrhosis in 5 years
• Annual liver biopsy to be considered due to lack
  of sensitivity and specificity of ALT. More risk
  of fibrosis after 5 years
• More than F1 fibrosis should be considered for
  Peg-IFNRibavirin treatment.
• Immunosuppression is the only modifiable factor
  and awaits better clinical trials for appropriate
  power and duration (? antiviral effect of CYA in
  HCV replicon models)
• Said A Lucey MR, Current Opinion in Gastro
  2008, 24339-345

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N.A. Terrault Liver Transplantation 14S58-S66,
2008
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De-novo Liver Disease

• Patients who are transplanted for one type of
  primary liver disease and subsequently develop
  features suggesting a different primary liver
  disease.
• viral infection hepatitis B and C
• AIH
• non-alcoholic fatty liver disease (NAFLD).

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De-novo AIH

• A higher frequency has been reported in children
  (510) compared with adults (12),
• Most cases present gt1 year post-LT and respond
  well to increased immunosuppression, but some
  have progressed to cirrhosis or graft failure
• Autoantibodies are frequently present without
  signs of graft dysfunction, particularly in the
  paediatric population and liver biopsy is,
  therefore, required to determine the nature of
  any damage present.
• anti-GSST1 antibodies
• antibodies to cytokeratin 8/18
• atypical LKM antibodies to carbonic anhydrase III
  or subunit beta1 of proteasome
• the de novo development of antibodies to the bile
  salt export pump (BSEP) protein, in children who
  became cholestatic following transplantation

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• Histological features closely resemble those
  occurring with AIH in the native liver and
  recurrent AIH in the liver allograft.
• They include a plasma-cell rich mononuclear
  portal inflammatory infiltrate associated with
  varying degrees of interface hepatitis
• Lobular inflammation and necrosis tend to be more
  prominent than in the native liver and can
  include features of central perivenulitis

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De novo non-alcoholic fatty liver disease (NAFLD)

• The distinction between recurrent and de novo
  NAFLD is often difficult.
• Risk factors
• diabetes mellitus and insulin resistance
• weight gain,
• hypertension, and hyperlipidaemia
• steatosis in the donor liver
• HCV
• Patients who were transplanted for cryptogenic
  cirrhosis and/or had risk factors for the
  metabolic syndrome prior to transplantation and
  could thus be regarded as having recurrent rather
  than de novo disease

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De novo non-alcoholic fatty liver disease (NAFLD)

• Interactions between hepatitis C infection,
  insulin resistance and NAFLD also appear to be
  important in the pathogenesis of recurrent HCV
  and de novo NAFLD
• Histologic features
• Fatty change, apparently unrelated to recurrent
  disease, is present in 1840 of post-transplant
  biopsies and a common finding in protocol
  biopsies obtained from patients with normal liver
  function tests
• Steatosis is mainly macrovesicular and usually
  mild in severity.
• Features of steatohepatitis, also typically mild
  in severity, are present in 113 of cases.
• Perisinusoidal fibrosis was present in 29 of
  patients with de novo NAFLD in one study

64
Summary

• Long-term mortality after liver transplantation
  mainly results from
• complications associated with the use of
  immunosuppressive drugs
• the recurrence of the underlying liver disease
• Management of the metabolic adverse effects of IS
  drugs after LT is essential for a good long-term
  outcome
• Patients should undergo regular tumor screening
  since the increased risk of malignancies in LT
  recipients
• Multidisiplinary approach is mandatory

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