Pre Liver Transplant Evaluation 24/4/15. “A treatment modality that would be without risk and available to all who would benefit from it” “ a terminal.

Pre Liver Transplant Evaluation

24/4/15

“A treatment modality that would be without risk and available to all who would benefit from it”

“ a terminal illness is being replaced by a new and different chronic condition”

Liver Transplantation

Issues• Whether patient needs LT?• When to refer or consider for LT?• Is patient suitable for LT?• Specific issues regarding recipient

Liver Transplantation

Proportion of liver transplants for specific etiologies, 1992–2007O’Leary et al Gastroenterology 2008

Indications and Contraindications

Indications Of Liver Transplantation: ESLD

1. Gastro esophageal variceal bleed-

each episode of bleeding carries a 20% mortaliity

rate. LT is the best way to decompress the portal

system if other therapies have failed. – De Francis et al, Baveno V, J Hepatology, 2010]

2. Hepatic encephalopathy

LT remains the only permanent Rx

Indications Of Liver Transplantation: ESLD

3. Refractory ascites-

- carries a mortality of >50% at 2 yrs.

- More prone for variceal bleed, HRS, SBP.

- Annual incidence of HRS in cirrhotics with ascites is 8% with

median survival of 2 wks in Type I and 6 months in Type II.

- LT should be considered as soon as HRS is diagnosed.

Planas et al, Clini gastro hepatology 2006;4:1385-94Gines A et al, Gastroenterology 1993;105:229-36

Indications Of Liver Transplantation: ESLD

4. Hepatopulmonary syndrome

-4-47%

- LT is the only curative Rx for HPS

5. Portopulmonary Hypertension

-2-8%,

- associated with higher post transplantation mortality

Need For Liver Transplantation

• CTP and MELD most commonly used• 5-year survival (CTP 7-15) with (ascites,

bleeding, HE, SBP, HRS) : 20% to 50%• Survival rates 1, 3, and 5 years after LT 88%,

80%, and 75%-Shetty K et al Hepatology 1997

-Kamath PS et al Hepatology 2001

-Freeman RB et al Liver Transpl 2004-H-C Huang et al. Journal of Gastroenterology and Hepatology 24 (2009) 1716–1724

• Comparison of mortality risk expressed as hazard ratio by MELD score for recipients of liver transplants compared to candidates on the liver transplant waiting list

– Merion et al, Am J transplantation 2005;5:307-13

In pts with MELD<14, the mortality with LTx > not undergoing LTx

When to refer patient for Liver Transplantation

• Refer for liver transplantation when (CTP > 7 and MELD > 10) or they experience their first major complication (ascites, bleeding, or HE)

AASLD:Karen F et al Hepatology 2005 Berg CL et al Gastroenterology 2007

Upper Limit Of MELD

• The estimated survival for patients with MELD score > 25 was lower at 12 months (68.86% vs 39.13%).

– Ilka Fatima Ferreira Santana Boin et al, Arc Gastroenterol 2008

• In 11 studies (19,311 patients), high MELD score indicated poor post-LT mortality for cut off values of 24-40 points

– Cholongital et al, Liver transplantation 2006

Process of Liver Transplant Evaluation

Referral To transplant center or hepatologist

Financial screeningSecure approval for evaluation

Medical evaluation

Hepatology assessment Confirm diagnosis and optimizemanagement

Laboratory testing

Assess hepatic synthetic function, renal function, viral serologies, markers of othercauses of liver disease, tumor markers, ABO-Rh blood typing; inulin clearance or 24-hour urine for creatinine clearance; urinalysisand urine drug screen

Investigations

• HBsAg, Total anti HBc, HBV DNA• Anti HCV, HCV RNA• CMV IgG and IgM, VDRL, HIV• ANA, ASMA, p-ANCA, Anti LKM• Doppler USG( SPA), TPCT , MRCP• S.AFP, CEA, CA19.9• Iron studies, copper studies• Thyroid profile

Investigations

• Lipid profile• 24 hr urine studies- Na, K, Creatinine, albumin• Pap smear in females• Blood c/s, urine c/s• Throat swab, b/l axilla c/s, groin c/s• PFT, CXR, ABG• ECG, 2D ECHO

Transplant surgeryevaluation

Assess technical issues anddiscuss risks of procedure

Anesthesia evaluation Required if unusually high operativerisk, eg, portopulmonary hypertension, hypertrophic obstructive cardiomyopathy,previous anesthesia complications

Psychiatry or psychologyIf prior history of substance abuse,psychiatric illness, or adjustmentdifficulties

Cardiao-pulmonary evaluation Electrocardiography,stress testing and cardiologyconsult if risk factors are present and/or age 40 years or older, pulmonologist opinion

Hepatic imaging USG with Doppler for portal vein patency,triple-phase CT/ gadolinium MRI for tumor screening

General healthassessment

Chest x-ray, prostate-specific antigen level (males), Pap smear and mammogram (females), colonoscopy if age 50 years orolder or PSC

Social work Address potential psychosocial issues and possible impact of transplantation on patient’s personal and social system

Financial counseling Itemize costs of transplant and post transplant care, help develop financial management plans

Nutritional support Assess nutritional status and patient education

Issues Regarding Recipient

• Does age matter?• HLA matching and ABO incompatibility• HIV status• Underlying cardiac status• Pulmonary status• Obesity and smoking• Diabetes Mellitus and Hypertension• Alcohol• Combined transplantation

Age > 60 years

Age > 60 yrs and Liver Transplantation

Gray bars equals Age<60; dark gray bars equal Elderly-Age > 60

Problems: more comobidities, increased chance of mortality due to malignancy, CAD

Benefits; low acute rejection rate, better graft survivalKeswani et al Liver Transplantation,2004

HLA Matching : is it required?

• Not applied Patient pool is too small for matchingCold ischemia time is too shortMost liver transplants are performed for

reasons of urgency that overrides matching• ? Does that mean it does not have any effects

HLA Matching

• The differences in the 6-month graft survival rates between the best and worst matched transplants were 6.6% for the A locus, 10.4% for the B locus, and 10.9% for the A, B loci

Transplant Proc. 1992

ABO Incompatibilty

• Have become a viable option with development of newer immunosuppressant's and strategy

ABO Incompatibility

• ABO incompatibility is associated with high risk of graft failure

• BW Kim et al showed use of Rituximab 375mg/m2 preoperatively on 15 and 8, as well as preoperative plasma exchange reduced humoral rejection in 3 ABO incompatible liver transplant.

BW Kim et al J.transproceed.2008

ABO Incompatibility

• 1 year and 2 year survival 90%(in 10 cases) - Song GW et al, Transplant Proc.2013

• In a single centre experience, in 22 cases, Rituximab and plasmapheresis were used prior to LDLT and plasmapheresis was continued for upto 2 weeks after LDLT to maintain anti ABO titres below 1:32.

• Graft survival was 100 % at 10 months and no acute humoral rejection was noted

- Kim JM et al, J Hepatol 2013

ABO Incompatibilty

• In a retrospective analysis of ABO incompatible liver transplants( n =22), rate of infections were higher in ABO – I transplants but rate of rejection , complications, cumulative survival was similar( 72.5.3 vs 72.9% at 1year, 69.1 vs 65.6 % at 3 years and 61.8 % vs 56.2% at 5 years.)

Shen Z et al. cma.j.issn.2014

ABO Incompattibility

HIV and Liver TransplantCriteria:• Absolute CD4 count >200 cells/mL and controllable HIV

viremia on HAART therapy.

Contraindication:• CD4+ counts <100/mL and multi-drug resistant HIV

• Short-term survival with HIV infection controlled with HAART comparable with HIV-negative recipients

• Requires well-coordinated, multidisciplinary team

HIV +ve status is not a contraindication for LT

Fung et al Liver transplantation 2004

Evaluation of cardiac status

• High risk factorsDiabetesHypertensionNASHPeripheral vascular diseasePrevious CADAge > 50 yearsDyslipidemia Obesity

Evaluation of cardiac status in LT recipients

Mandell et al World J gastro 2008, Shaw et al Radiology 2003

Asymptomatic Liver transplant candidate

No high risk factors High risk factors

Stress testing

Calcium Score

PositiveNegative

No further testing

Coronary angiography

0-1 risk factors 2 or more risk factors 3 or more risk factors

Negative Positive

Coronary Artery Disease

Murray et al Hepatology 2005

• Dobutamine stress ECHO

• Confirmed by cardiac catheterization

Portopulmonary Hypertension

• Portopulmonary(PoPH) hypertension is associated

with reduced survival: 1-year survival of

approximately 35 to 46% without treatment

• Risk of perioperative mortality after LT is increased in

patients with PoPH ( 35%)

• Right ventricular failure in susceptible patients with

PoPH(MPAP > 50 mm Hg) Krowka M J , Liver Transpl 2004

Portopulmonary Hypertension

• Doppler ECHO : sensitive method• Positive test: confirmed with right heart

catheterization• Severe pulmonary HT >60 mmHg: post LT 70%

mortality by 3 yr• LT if effectively controlled(<45mmHg) with

medical therapy Ramsay MA et al Liver Transpl Surg 1997 Starkel P et al Liver Transpl 2002 Kim WR et al Liver Transpl 2000

MAYO clinic algorithm

American Journal of Transplantation 2008; 8: 2445–2453

Screening Transthoracic Echocardiogram

RVSP >50 mm Hg? Re-Echo in 12 mo

Right Heart Catheterization ( with SvO2 full saturation run)

MPAP < 35 35 <= MPAP <= 50 50 < MPAP

> 240< 240 > 240< 240 > 240< 240

PVR

LT

OKOK OK NRRX

Yes

No

Contraindicated

Hepatopulmonary Syndrome

• Every patient being evaluated for LT should be screened for HPS

• ABG, contrast echo, response to 100% oxygen, and quantification of shunting using MAA scan.

• Median survival of patients with severe HPS <12 months• PaO2 < 50 mmHg with a MAA shunt fraction >20%

predictors of postoperative mortality

AASLD• Expedited referral and evaluation for liver transplantation

Arguedas MR et al Hepatology 2003Collisson EA et al Liver transplantation 2002

Prognosis of HPS: MAYO experience

Eur Respir Mon 2011; 54: 246–264

Arterial blood gases

OLT candidatesHepatic disease patients with dyspnoea

No HPS

Pa,o2 < 80 mmHg(and/or)

PA-a,o2 >= 15 mmHg

CEE

Pa,o2 >= 80 mmHg

Negative CEE Positive CEE + PFTs

No HPS

Pa,o2 >=60 - < 80 mmHg(and/or)

PA-a,o2 >= 15 mmHgPa,o2 >=50 - <60 mmHg

Pa,o2 < 50 mmHg;MAA >=20%

Follow-up OLT OLT

HPS:MELD exception

• HPS: PaO2 < 60 mmHg on room air will be listed at a MELD

score of 22 with a 10% mortality equivalent increase in points

every three months if the candidate’s PaO2 stays below 60

mmHg

• Preoperative PaO2 of 50 mmHg or less alone or in combination

with a MAA shunt fraction of 20% or more are the strongest

predictors of postoperative mortality AASLD Practice Guidelines 2005

Organ Procurement and Transplantation Network (OPTN) Policies

HEPATOLOGY 2003;37:192-197.

Kidney-Liver Transplant if:

• Primary renal disease expected to cause renal failure within 3 years of transplant

• HRS with dialysis dependent renal failure lasting over 8 weeks

• Renal biopsy shows over 30% tubulointerstitial fibrosis or 40% glomerulosclerosis or moderate to severe arteriosclerosis

Grewal HP et al Transplantation 2000Rogers J et al Transplantation 2001

Obesity

• Obesity is thought to affect prognosis of post liver transplant patients adversely.

• Difficult to determine in part due to confounding effect of ascites

• In a meta-analysis, no difference in mortality in patients with different BMI, however obese patients had worse prognosis than non obese patients in pooled analysis of studies which had similar causes of liver disease among obese and non obese patients

-Saab et al, liver int.2015

Obesity

• Corrected BMI is not an independent predictive of patient or graft survival

- Leonard J et al, Am Transplant,2008

ObesityNormal weight(n=643)

Overweight(n=417)

Obese(n=145)

Morbidly obese(n=73)

p value

Postoperative infectivecomplications

50.4% 60.7% 65.5% <.01

ICU stay 3.2 days 4.7 days <.01

Mean hospital stay 18days 22.4 days 21.3 days 22.4 days <.0001<.04<.05

Abdul R. Hakeem et al. Liver Transpl 2013

Smoking

• Those who quit smoking for more than six months had

complications rates similar to those who had never smoked (11%

vs. 11.9%)

• Smoking history of 40 pack years or more was strongly associated

with increased risk of pulmonary complications

• Risk of hepatic artery thrombosis appears to be significantly

increased among chronic smokers

Anaestheseology 1984;60:380-3

Am J Respir Crit Care Med 2003;167:741-4

Liver Transpl 2002;8:582-587.

Diabetes In Recipients

Diabetes in Recipients

• Type 1 diabetes mellitus have 40 % lower 5 year survival as compared to those without it

• Type 2 diabetes mellitus was not an independent predictor of survival but had 27 % more risk of having postoperative infective complication

Yoo et al, Transplantation.2002

Liver Transplantation in patients with Tuberculosis

• Active tuberculosis is a contraindication• But no option if indication is fulminant hepatic

failure• In a series of 9 patients with such scenario, patients

were treated with modified ATT after LDLT.• All patients were treated successfully and followed

for median of 926 days without relapse Lee YT et al, Int J Tuberc Lung Dis.2010

Tuberculosis screening for LT

• Prevalence of TB infection in liver transplant

recipients :1% to 6%

• The mortality rate : 40% despite treatment;

without treatment it is 100%

• Positivity (TT ≥ 5 mm) occurs among up to 25%:

4-fold risk for tuberculosis after LTTransplantation 83:1536, 2007

Liver transplant in Alcoholics

• 6 month period of abstinence ? • 50 % of patients go back to some form of

alcoholism after transplant• NHS first allowed listing of alcoholics with

severe liver disease for transplant listing in 2014 in UK

• This major shift in policy was inspired by landmark study published in NEJM in 2011

The ideal LDLT recipient profileListing Must first be listed on DD waiting list (Meets UNOS)

MELD score <25

Recipient risk factors No thrombosis of multiple visceral veins/ multiple medical problems/ multiple significant abdominal surgeries; advanced age

Specific recipient subgroups

HCC Benefit substantially from rapid LDLT as DDLT may allow for metastasis

Severity of illness not reflected by MELD score

Complicated cholestatic liver disease, patients with ascites, uncontrolled HE and/ or severe cachexia, HPS,PP hypertension

Donor Evaluation

Objectives of the Evaluation

• Provide all relevant information to donor to facilitate the right decision in order to make a voluntary donation without any pressure

• Donor’s interest should be protected

• Advocates of donor safety

The Ideal Living Liver Donor

• Between the ages of 18 and 50• A family member such as a spouse, parent,

sibling, child, nephew or niece or a friend • The same or compatible blood type as the

recipient• BMI <28 • In excellent medical and psychological health• Highly motivated

Swap/Domino Liver Transplant• Swap liver transplant- method to match the blood

group incompatible donor and recipient couples with the couples having same problems

• Domino Liver transplant- in patients with familial amyloidosis(FAP)

• Patient receives liver and his own liver( physiologically normal but with defective gene) is transplanted to another patient

• The recipient will take decades(2-3) to develop amyloidosis

• Only 2 out of 500 patients developed amyloidosis Ericzon et al, Transplant

Proc.2008

Contraindications

• Previous liver surgery• HIV infection• Viral hepatitis• History of cancer• Heart and lung disease• Diabetes• Active alcoholism• Psychiatric problems

Extended Donors

• ABO incompatible• Anti HBc antibody positive but HBsAg -• Chronic hepatitis C?• Marginal donors- Donors with steatosis 10- 40%- Donors with significant alcohol consumption- Cadaveric donors with possible sepsis, transient

hypotension and transient abnormal liver function test

Approach to Donor with fatty liver

• 78 % of potential donors with a BMI > 28 had hepatic steatosis (>10% steatosis) on liver biopsy-

Rinella et al.Liver Transpl 2001

• Most centers exclude donors who have > 10% of steatosis as hepatic steatosis is associated with poor posttransplantation graft function

• Obesity also increases risk of complications with donor surgery

• Also, obese people are more likely to have comorbid conditions

Approach to donor with fatty liverDonor with no fatty change

10-30% steatosis

30-60% steatosis

P value

3 month survival in recipient

68% 72% 76% >.05

Hospital stay 30.89 days 29.93 days 23.62 days >.05

ICU stay 5.06 days 5.89 days 4.39 days >.05

Nikeghbalian S, Transplant Proc. 2007

Liver biopsy in potential Donor

• Some centers do liver biopsy in all• Others do when 1) BMI > 28 kg/m22)significant alcohol intake3) elevated serum ferritin levels4) presence of steatosis on imaging5) HBV core positive serology• Liver biopsy determines presence and extent of

hepatic steatosis

Liver biopsy in potential Donor

• Protocol liver biopsy in all detects abnormal liver biopsy in upto 73% donors but most of them were non specific/not significant e.g steatosis < 10%.

Tran T et al. Gastroenterology 2003

Donor suitability

• Are the intentions authentic?

– No evidence of gross financial disparity between donor and recipient especially in unrelated donation

• Are the implications of LDLT in terms of risks and benefits clearly understood?

– Mortality of one in 250-300 cases– Morbidity of up to 10% including bleeding,

biliary, wound complications– Clear discussion of risk, benefit, ethical

issues involved

Donor Evaluation – Step Wise

• Step 1 – Consultation and Clinical Examination– With donor alone and – With close relative

• Donor willingness• Motivation• Offer for walk out on clinical reason – to protect relationship

• Step 2 – After work up – if donor is suitable match– Psychiatric evaluation

• Step 3 – Days prior to operation – with donor alone

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