Chronic liver failure Assessment for liver transplantation

Chronic liver failure Assessment for liver transplantation

Liver Transplantation

Dealing with the organ shortage Timing of listing must reflect length on waiting list Ethical issues Justice, equity, utility 50% 5 year rule Arbitrary; quality of life Deceased versus living donors Should indications and contra-indications be similar

Analysis based on adult recipients only 100 90 Paediatrics (0-16) 80 70 % patient survival 60 50 40 Adults 30 20 10 N 585 3600 15 year % survival 86 59 95% CI 76 92 55 64 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

100 Kaplan-Meier estimates by primary liver disease 100 90 90 80 80 70 70 % patient survival 60 50 40 % patient survival 60 50 40 Overall N 15 year 95% CI % survival 30 20 10 Primary biliary cirrhosis Autoimmune cirrhosis Post hepatitis B cirrhosis Sclerosing cholangitis Cryptogenic cirrhosis Alcoholic cirrhosis Post hepatitis C cirrhosis Cancer 30 20 10 3600 59 55 64 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

UK Transplant Kaplan-Meier estimates by year of transplant 100 90 80 70 % patient survival 60 50 40 30 20 1985 1989 1990 1994 1995 1999 2000 2003 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

UK Transplant Kaplan-Meier estimates by year of transplant 100 100 90 80 Restricting dataset to patients who have survived 6 months 90 80 Future patients life expectancy can be predicted from past data 70 70 % patient survival 60 50 40 % patient survival 60 50 40 30 20 1985 1989 1990 1994 1995 1999 2000 2003 30 20 1985 1989 1990 1994 1995 1999 2000 2003 10 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Average life expectancy by primary liver disease K Population - 29.3 years) 60 50 Life expectancy (years) 40 30 20 10 33.9 (27.6-41.6) 26.9 (19.9-36.4) 25.1 (18.0-35.1) 21.6 21.1 (15.1-31.0) (14.4-31.0) 15.4 (12.8-18.6) 12.4 (9.9-15.7) 5.8 (4.4-7.8) 0 Primary biliary cirrhosis Sclerosing cholangitis Cryptogenic cirrhosis Autoimmune cirrhosis Post hepatitis B cirrhosis Primary liver disease Alcoholic cirrhosis Post hepatitis C cirrhosis Cancer

Average life expectancy by sex, age group and primary liver disease Life expectancy (years) 60 17-34 years 35-44 years 45-54 years PBC 55-64 years 50 65-74 years PBC 40 30 20 ALD Hep C ALD Hep C 10 0 Males Females

Average life expectancy by age group 60 50 25.1 lifeyears lost 51.2 13.8 lifeyears lost Adult liver transplant recipients Equivalent UK population Life expectancy (years) 40 30 20 26.1 (18.8-36.2) 24.6 (19.5-31.1) 38.4 6.5 lifeyears lost 29.7 23.2 (19.5-27.6) 1.8 lifeyears lost 20.0 21.8 (17.0-23.6) 4.2 lifeyears lost 12.0 16.2 (9.1-15.8) 10 0 17-34 35-44 45-54 55-64 65-74 Age group

Life-years by sex, age group and primary liver disease 20 PBC PBC 10 17-34 years 35-44 years 45-54 years 55-64 years 65-74 years 0 Life-years -10-20 -30 ALD Hep C ALD -40-50 Males Females Hep C

Assessment Does the patient need a transplant at this time Will the patient survive the peri-operative period Will the patient meet the 50% 5 year criterion Does the patient want a transplant and are they fully informed?

Prognostic models Scoring Systems Child-Turcotte-Pugh MELD Disease specific Limitations Population sensitive Wide confidence intervals

MELD/PELD Equations MELD =(0.957 x LN(creatinine) + 0.378 x LN(bilirubin) +1.12 x LN(INR) +0.643) x 10 Capped at 40 PELD= (0.436 x Age*) *)-(0.687 x log(albumin albumin))+(0.480 x log(bilirubin bilirubin))+ (1.857 x log(inr INR))+(0.667 X growth failure ) x 10 * Age < 1 year gets 1, Age >1year gets 0 growth failure =1, no growth failure =0

Child-Pugh Score Variable components Some are subjective Designed to assess prognosis for patients undergoing oesophageal transection Not really validated Intuitive

60 CTP vs MELD National Wait List 2001 50 MELD Score 40 30 20 10 0 r=0.66; p<0.001 6 8 10 12 14 16 CTP Score

MELD vs. CTP Validation ROC Curve UNOS Waitlist 1 Sensitivity 0.8 0.6 0.4 0.2 MELD CTP MELD AUC = 0.83 CTP AUC = 0.76 0 0 0.2 0.4 0.6 0.8 1 1-Specificity

MELD Validation Hospitalized Cirrhotics Outpatient Cirrhotics PBC Outpatients Historical Cirrhotics n Deaths 3 months 3-Month Mortality (Concordance) 282 59 0.87 (0.82 0.92) 491 34 0.80 (0.69 0.90) 326 5 0.87 (0.71 1.00) 1179 220 0.78 (0.74 0.81) 1-Year Mortality (Concordance) 0.85 (0.80 0.90) 0.78 (0.70 0.85) 0.87 (0.80 0.93) 0.73 (0.69 0.76) Wiesner, et al, Liver Transplantation, 2001; 7:567-580

Survival (%) MELD and PELD Three Month Mortality Risks 1,230 Adult and 649 Pediatric Patients Added to Waiting List between 3/1/01 100% 80% 60% 40% 20% 0% MELD: National Waitlist and 8/15/01 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 reeman Liver Transplantation, 2002, 8:854. Severity Score PELD: SPLIT Patients

Hepatocellular CA MELD Prioritization Original Current Proposed Stage I 1 tumor < 2cm 15% Risk =MELD 24 8% Risk =MELD 20 0 Risk =MELD calculated Stage II 1 tumor 2CM but < 5 cm or 2-3 tumors largest < 3 CM 30% Risk =MELD 29 15%Risk =MELD 24 15% Risk =MELD 24 Centers re-certify every 3 months. Patients continuing to meet stage I or II definition receive additional 10% mortality risk points (~5 MELD points)

Hepatocellular Carcinoma Imaging Study (CT or MRI) Showing Stage I or II Tumor (chest CT and bone scan) AND one of the following APF >200 Angiogram Biopsy Chemoembolization Cryoablation Radiofrequency Ablation Alcohol Ablation

Other Special Cases HPS (hepatopulmonary syndrome =PaO2 < 60 on RA, shunt, no COPD or other lung Dx) RRB will assign MELD points that will give reasonable chance of organ offer within 3 months in that region. FAP (familial amyloidosis) RRB review and assign MELD points Other RRB review, need experience with MELD/PELD to assess proper placement

6-Month Patient Survival 2/27/02-12/31/02 100 M/P percent surviving 80 60 40 Status 1 20 0 0 1 2 3 4 5 6 7 Months

6-Month Patient Survival Calculated MELD, 2/27/02-12/31/02 100 80 Percent Surviving 60 40 20 0 0 1 2 3 4 5 6 7 Months M 7-15 M 16-25 M 26-35 M > 35

6-Month Patient Survival Calculated PELD, 2/27/02-12/31/02 100 80 Percent Surviving 60 40 20 0 0 1 2 3 4 5 6 7 Months P < 6 P 7-15 P 16-25 P 26-35 P > 35

6-Month Patient Survival 02/27/02-12/31/02 100 80 Percent Suriving 60 40 20 0 0 1 2 3 4 5 6 7 Months HCC Non HCC Std M/P

MELD of First Offer (4/1/02-7/31/03)* Offers 450 400 350 300 250 200 150 100 50 0 6 11 16 21 26 31 36 41 46 51 Statu Uncapped Lab MELD 1 *Excludes offers to patients with exception scores

Proportion of Transplants (%) 60 50 40 30 20 10 0 Transplant Distribution by Lab 48 4 MELD/PELD Excludes Status 1 and Exceptions 15 17 18 25 10 20 5 12 10 7 6 2 2 1 <10 10-14 15-19 20-24 25-29 30-34 35-39 40+ MELD/PELD PELD (N=261) MELD (N=4,219) Deceased Donor Transplants from 4/1/2002 7/31/2003

Mortality Rates by MELD 0000 Waitlist Transplant 1482 4168 5990 12841 8852 Rate per 1000 PY 1000 100 10 583 197 176 138 123 129 150 53 62 HR=1.77 P<0.01 HR=0.32 P<0.01 204 HR=0.07 P<0.01 271 262 305 HR=0.03 P<0.01 1 HR=2.19 P=0.01 HR=0.62 P<0.01 HR=0.12 P<0.01 HR=0.06 P<0.01 HR=0.36 P<0.01 <10 10-14 15-19 20-24 25-29 30-34 35-39 40 Status 1 MELD

Lessons from MELD MELD is an objective method of assessing prognosis MELD is relatively objective and since its introduction, deaths on waiting list has been reduced Accuracy may be increased by including serum sodium Those with MELD <22 but hyponatremia (serum Na <128mmol/L) may do badly MELD score <35 does not correlate with post transplant outcome

Indications Unacceptable quality of life (because of the liver) Anticipated survival, in the absence of liver disease, of <1 year

Quality of life Recurrent encephalopathy Recurrent ascites Severe lethargy Exclude treatable causes Does not always improve after transplant Intractable itching Drugs (incl. Rifampicin, naltrexone), plasmaphoresis, MARS

Length of life Clinical End-stage disease Malnutrition, encephalopathy; SBP; progressive hepatic osteodystophy, HCC, developing HPS Serology Falling albumin, rising PT, rising bilirubin

Contra-indications to transplantation Extra-hepatic cancer/metastatic disease Active sepsis Cholangiocarcinoma Advanced cardiac disease Advanced pulmonary disease Widespread vascular thrombosis HIV with AIDS and low CD4

Relative Contra-indications Difficult to assess How many relative contra-indications make an absolute contra-indication?

Age Ethical Issues Equity, justice and utility Good innings argument Age as a continuous variable Chronological age and biological age

Effect of age on transplant outcome 1.0.9.8 Cum Survival.7.6-20 0 20 40 60 80 100 120 >60 < 60 months

Effect of age 4 3 2 1 Survival Period Cum Hazard 0-1 10 20 30 40 50 60 70 180-365 days 30-180 days 0-30 days Age (years)

Nutrition 36 34 32 30 28 26 24 22 MAC 20 18 0 10 20 30 Died Survived TSFT

Nutrition Does malnutrition affect outcome It makes sense to correct nutritional deficiency with oral supplements or nasogastric feeding It makes little sense to defer transplantation for malnutrition

Diabetic patients vs comparison group Diabetic patients vs comparison group matched for age, sex and date of transplant Comparison Diabetics p value matched for age, sex and date of transplant Comparison Diabetics p Num ber 78 78 Sex Number 43 m 7835 f 78 43 m 35 f Sex 43 m f 43 m 35 f Age (m ean) Age (mean) 54 54 53 53 Deaths Deaths 7 7 28 28 0.001 0.001 Child Pugh score 10) 5-14 (median 10) 0.2 Child Pugh scorepatients with Hepatoma 5-156(median 10) 8 5-14 (median 0.8 10) 0.2 P atients w ith H epatom Total previousa 6 34 38 8 ns 0.8 Abdominal surgery T otal previous Median Duration of 34 5 5 38 ns ns (hours) Abdominal surgery Total Units blood 664 711 ns M edian Duration transfused of (all patients) 5 5 ns Time Ventilated postop. (median days) 3 3 ns surgery (hours) T otal U nits bloodmedian ITU stay 664 2 3 711 ns ns Median Hospital stay 14 15 ns transfused (all patients) Median survival 640 469 T im e V entilated postop. 3 3 ns (median days) M edian IT U stay 2 3 ns M edian Hospital stay 14 15 ns M edian survival 640 469 value

Cardiac problems Ischaemic heart disease Role of exercise ECG Stress ECG Angiogram Echocardiogram Assessment of pulmonary hypertension Structural and functional abnormalities

Hepatopulmonary syndrome Resting arterial blood gases If low po 2 Standing and lying po 2 Gases on 100% O 2 Consider bubble echo/muga scan Risk of transplantation increases with degree of orthodeoxia

Pulmonary Hypertension If estimated PA pressure >30mm Hg, or ECG shows RV+, measure PA pressure If PA 25-35mm Hg and PVR 120-250 dynes.s.cm -5 : mild If PA >35 and PVR >250 dynes.s.cm -5 : moderate/severe Consider prostacyclin, Bosentan

Alcohol Controversial Arguments not really based on fact Recidivism Definition Need

Alcohol and substance misuse Alcohol: Abstinence Duration of abstinence does not correlate with posttransplant outcome Markers of recidivism: single, other drug misuse Non-hepatic alcohol damage Cardiomyopathy Cerebral atrophy other

HCC Milan criteria Extended criteria Role of down-sizing Management on the list

HCC Milan criteria Small series, based on examination of explants One lesion <5cm 3 lesions < 3cm Extended criteria Role of down-sizing Management on the list

HCC Milan criteria Extended criteria UCSF Role of down-sizing Management on the list

HCC Milan criteria Extended criteria Role of down-sizing Management on the list Trans Arterial Chemo-embolisation Radio-frequency ablation Cryotherapy/ethanol injection

Conclusions Assessment for transplantation is relatively easy Absolute contra-indications are usually well defined Relative contra-indications are defined but assessment is a matter of clinical judgement

More people die from clinical judgement than from any other cause Nils Tygstrup