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Title: Gastroenterological View of Late Complications in Liver Transplantation


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 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.

7
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

8
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10
  • 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

11
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

12
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

13
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

14
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

15
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

16
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

17
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
18
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

19
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

20
  • 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.

21
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

22
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

23
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

24
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.

25
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).

26
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

27
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.

28
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.

29
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.

30
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.

31
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

32
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

33
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.
34
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.
35
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

36
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

38
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.

39
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

40
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

41
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

42
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

43
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.

44
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.

45
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).

46
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.

47
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
48
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

49
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

50
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

51
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,

52
Liver Disease Recurrence and De-novo Liver
Disease
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55
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

56
N.A. Terrault Liver Transplantation 14S58-S66,
2008
57
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59
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).

60
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

61
  • 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

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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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