……..Prognostic factors and issues for case selection.

Pirsch JD, Kalayoglu M, D'Alessandro AM, Voss BJ, Armbrust MJ, Reed A, Knechtle SJ, Sollinger HW, Belzer FO.

Orthotopic liver transplantation in patients 60 years of age and older.

Transplantation. 1991 Feb;51(2):431-3.

Probably first drew attention to the fact that:……Liver transplant recipients over the age of 60 years have

excellent patient and graft survival and the same postoperative morbidity as recipients who are under 60 years of age. Therefore, advanced age does not appear to be a contraindication to orthotopic liver transplantation.

Transplantation. 66(4):500-506, August 27, 1998.Zetterman, RK.; Belle, SH.; Hoofnagle, JH.; Lawlor, S; Wei, Y; Everhart, J; Wiesner, RH; Lake, JR.

“Age and Liver Transplantation.” (n=735) Conclusions:- Although patient survival was significantly

lower among liver transplant recipients above the age of 60 years, the excess mortality was due to non-hepatic, largely age-related problems. The overall success of liver transplantation and improvement in quality of life for older recipients is excellent.

Patient survival was lower for older than for younger

recipients (81% vs. 90% at 1 year=0.004), whereas graft survival was not different (80% vs. 85% at 1 year; P=0.163).

The excess mortality in older patients was attributable to infections (RR=2.0), cardiac events (RR=2.8), neurological causes (RR=3.5). The incidence of hepatic causes of death in the two groups was similar.

Probablity of death after liver transplantation : young (<60 yrs) vs elderly (>60) at 1 month and at one year. (n=735; age<60 = 600, age > 60 = 135).Higher the age at L Tx : reflected in a lower survival at 1 month as well as at 1 year after L Tx.

Survival after liver transplantation : less than 60 yrs age v/s elderly recipients.(Zettermann et al. 1998.)

Patient survival after liver transplantation was significantly less for older than for younger recipients . The proportion of older and younger recipients surviving was 81% and 90% at 1 year (P = 0.004).

The major differences in survival occurred during the first 6 months after transplantation. After the first 6 months post-transplantation, there was no difference in subsequent patient survival between the 113 older and the 554 younger recipients who had survived for at least 180 days(P = 0.55).

A proportional hazards analysis model that controlled for important factors(diagnosis, CTP score, UNOS score, muscle wasting, and procuring surgeon's assessment of liver quality) revealed recipient age to be significantly associated with mortality at 1 year after transplantation (relative risk=1.96; 95% confidence interval=1.17 to 3.30; P=0.011).

Recipient age was significantly associated with patient mortality at 1 year among patients with hepatitis C (relative risk=3.7; 95% confidence interval=1.3 to 10.5) but not among patients with cholestatic liver disease(relative risk=1.4: 95% confidence interval=0.5 to 3.9).

Similar outcomes, morbidity, and mortality for orthotopic liver transplantation between the very elderly and the young . S. Rudich, and R. Busuttil Transplantation Proceedings Volume 31, Issues 1-2, 3 February 1999, Pages 523-525.

Our study demonstrates that there are no significant differences in morbidity and mortality between very elderly OLT recipients and those more than 25 years younger. The elderly do as well (or as poorly) after complications resulting from OLT as do the much younger.

Median length of follow-up was similar and more than 3 years in both groups. With the exception of cardiac arrhythmias and metabolic encephalopathy, which were more frequent in the elderly, the groups experienced similar complications.

In addition, the elderly spent more time in the intensive care unit post-OLT (14.7 ± 20.9 vs 8.6 ± 14.1 days, elderly and young, respectively).

Firstly, the elderly who survive the ordeal of transplant surgery do not manifest any greater degree of cardiac, vascular, or oncologic disease than the younger recipient. Secondly, physiologic age is much more important, in terms of transplant outcomes, than chronologic age.

Complication Elderly Young

Number

% Number

% P-value

Cardiac arrhythmia 15 43 2 6 0.01

Metabolic encephalopathy

13 37 7 20 0.04

Further surgery 10 29 12 34 NS

Ventilator dependence 10 29 8 23 NS

Renal failure 6 17 10 29 NS

Biliary complication 3 9 1 3 NS

Bone disease 3 9 1 3 NS

New onset diabetes 3 9 0 0 NS

Hepatic artery thrombosis

1 3 0 0 NS

The Elderly Liver Transplant Recipient: A Call for Caution. MF Levy and others. (Texas)Ann Surg. 2001 January; 233(1): 107–113.(n=1446, less than 60=1205, older than 60=241)

Elderly patients with better-preserved hepatic synthetic function or with lower pre-transplant serum bilirubin levels fared as well as younger patients.

Elderly patients who had poor hepatic synthetic function or high bilirubin levels or who were admitted to the hospital had much lower survival rates than the sicker younger patients or the less-ill older patients.

Recipient age 60 years or older, pre-transplant hospital admission, and high bilirubin level were independent risk factors for poorer outcome.

When reviewed alone, recipient age was linked significantly to both patient and graft survival.

Factors evaluating transplant outcome: in terms of ability to predict death after transplant within 3 months (top) and within 1 year (bottom). [age, pre-transplant ICU/ in hospital, liver function]

Herrero JI et al.; Liver transplant recipients older than 60 years have lower survival and higher incidence of malignancy.Am J Transplant. 2003 Nov;3(11):1407-12.

Older age is not considered a contraindication for L Tx, but age-related morbidity may be a cause of mortality.

Two Grps: (patients younger than 60 years, n=54; patients older than 60 years, n=57) and both groups were compared. Older patients were more frequently transplanted for HCV (p= 0.03) and HCC (p= 0.05) and their liver disease was less advanced (CTP and MELD scores were lower; p=0.004 and p=0.05, resp).

After L Tx, older patients had a significantly lower survival (p=0.02).

Higher age was independently associated with mortality (hazard ratio for each 10-year increase: 2.1; 95% CI: 1.1- 4.0; p=0.02).

The incidence of de novo neoplasia and nonskin neoplasia were higher in older patients (p=0.02 and p =0.007, respectively).

In conclusion, older liver transplant recipients have a significantly lower survival than younger patients. Malignancy is responsible for this decreased survival.

The indication for LTx was more frequently hepatitis C virus-related cirrhosis and the prevalence of HCC was higher in Group II than in Group I.

Kaplan-Meier estimate of the development of post-transplantation de novo neoplasia, basal-cell or squamous skin cancer, and non-skin cancer in patients younger than (Group I, n=54) or older than 60 years (Group II, n=57).

Increased cancer risk after liver transplantation: a population-based study.

EB. Haagsma, et al.; Journal of Hepatology

Volume 34, Issue 1, January 2001, Pages 84-91. An increased risk of cancer exists after liver transplantation, for both

for skin/lip cancer, and other solid tumours. Significantly increased RRs were observed for non-melanoma skin cancer (RR 70.0), non-skin solid cancer (RR 2.7), renal cell cancer (RR 30.0), and colon cancer (RR 12.5). Multivariate analysis showed that an age>40 years and pre-transplant use of immuno-suppression were significant risk factors. (sample size=174)

Risk factors for development of de novo neoplasia after liver transplantation.

Xiol X, et al.; Liver Transpl. 2001 Nov;7(11):971-5. Thirty de novo neoplasia appeared in 22 of 137 transplant recipients

between 12 and 104 months after orthotopic liver transplantation. The only associated risk factor for any neoplasia was age. Age and hepatoma were independent risk factors associated with skin cancer. That hepatoma in the explanted liver is an independent risk factor for skin cancer suggests there might be individual susceptibility to both neoplasia.

Collins BH, Pirsch JD, et al..Long-term results of liver transplantation in older patients 60 years of age and older.Transplantation. 2000 Sep 15;70(5):780-3.

N= 478; 387 were <60 yrs of age & 91 were >60yrs of age.The length of hospitalization was the same for both groups, and

there were no significant differences in the incidence of rejection, infection (surgical or opportunistic), repeat operation, readmission, or repeat transplantation between the groups.

The only significant difference identified between the groups was long-term survival. Five-year patient survival was 52% in the older group and 75% in the younger group (P <0.05). Ten-year patient survival was 35% in the older group and 60% in the younger group (P <0.05).

The most common cause of late mortality in elderly liver recipients was malignancy (35.0%), whereas most of the young adult deaths were the result of infectious complications (24.2%).

Acute events after liver transplants in young versus old recipients reveal no statistical difference between the two groups.

Postoperative events occurring in elderly and young adult recipients of primary liver transplants

Outcome of Liver Transplantation in Septuagenarians: A Single-Center Experience. Lipschultz et al.;Archives of Surgery. 142(8):775-784, August 2007.

Group 1 included 62 patients aged 70 years or older (average, 71.9 +/- 2.1 years). Group 2 included 864 patients aged 50 to 59 years (average, 54.3 +/- 2.9 years).

Unadjusted patient survival of group 1 at 1, 3, 5, and 10 years was 73.3%, 65.8%, 47.1%, and 39.7%, respectively.

Unadjusted patient survival of group 2 at 1, 3, 5, and 10 years was 79.4%, 71.5%, 65.3%, and 45.2%, respectively. The difference was not statistically significant (P = .14). Multivariate analysis for factors affecting survival demonstrated preoperative hospitalization, cold ischemia time, and hepatitis C/ethanol as risk factors for death.

Age 70 years or more was not a strong risk factor (mortality ratio, 1.28; P = 0.27).

Volume 73, Number 8; December 2006. Grand Rounds: Update On Liver Transplantation: Indications, Organ Allocation, and Long-Term Care. Lopez PM, Martin P.Peri-operative risk, survival, quality of life, as well as the presence of co-morbidities such as renal, cardiac and overall function, all need to beweighed in the decision to offer a liver transplant. In the elderly, L Tx should be considered with caution, and

with special considerations to relative risks and advantages.Consider medical fitness to tolerate major surgery in terms

of cardiovascular reserve, renal function, respiratory function and neurological status.

Ability to withstand the stresses of surgery, and the delayed post-operative recovery period; and also the reserve to withstand complications, and the treatment of complications after L Tx.

Physiological age more important than chronological age.

Factors that need due consideration include:-

Possible effects of post LTx medications and immunosuppression, …….

Diabetogenic potential of drugs and worsening of diabetes.Other medications and possible drug interactions w.r.t.

immunosuppression ans associated toxicity.Adverse effects on osteogenesis/ bone health. Detail pre-tx

assessment might be very useful for this.Adverse effects on cardiovascular system and post transplant high

incidence of worsening of hypertension, or de-novo new onset of high blood pressure.

Quality of life before transplant and predicted quality of life after transplant…….. Is LDLT going to make a significant improvement?

Predicted life expectancy……. As a result of other co-morbidities, etc.

An increased risk of malignancy in the older age group; esp. lymphoid cancers in those with past or present EBV infection, colo-rectal cancers in those transplanted for PSC/ PBC., and other cancers whose incidence is higher in smokers than in non-smokers.

And last but not the least:………

The risk of recurrence of the liver disease needs to be understood…..

Hepatitis B recurrence is quite rare with current anti-virals and immunotherapy, though recurrence of HBV is associated more frequently with acute hepatitis and flares.

HCV recurrence (Approximately 86% of anti-HCV-positive, 93% of RIBA-positive, and 97% of HCV RNA-positive candidates developed infection after transplantation. (Everhaart and others, Hepatology. 1999 Apr;29(4):1220-6.) with treatment recurrence rates are in the order of 30 – 50%, but recurrent HCV is associated with cirrhosis in 25% patients in 3-5 years.

Recurrence of HCC;… is nearly 40% after LTx for HCC (HEPATOLOGY Vol. 26, No. 2, 1997, MARSH ET AL.) depending on tumour variables (size, grade, margins, etc), sex and NAC. Old age relates to limitations in adjuvant therapy.

The number of both waitlist patients and liver transplant recipients greater than 65 yr of age continues to increase at a steady pace. In 2005, 628 patients who were older than 65 years received a liver transplant.

The question of quality of life…….?

Though an improvement in the quality of life in general has been documented in terms of physical health and health related QOL. (Health-related quality of life after liver transplantation: a meta-analysis. Liver Transpl Surg 1999; 5: 318-331. Bravata DM);

(Assessing health-related quality of life pre- and post-liver transplantation: a prospective multicenter study. Liver Transpl 2002; 8: 263-270; Ratcliffe J).

However this has not been examined in elderly patients undergoing liver transplants.

Whether this is actually the case….. And is it likely to affect the decision to perform a LDLT, since theoretically speaking, we wouldn’t be talking about the scarcity of donors here?

The Ethics of it all:…….The U.S./ world population is aging, and as transplantation

becomes more routine, older people are pushing for the better quality of life it can offer. At the most extreme, a hospital in Pennsylvania recently (2004) put a kidney from a cadaver into a 94-year-old.

Even so, long before their transplanted liver wears out, many older recipients die of the myriad afflictions that come with aging.

From a statistical standpoint, cadaveric livers are being squandered. With living donors, is that the case? Or is it just a question on subjecting the donor (healthy) to a certain risk?

Nearly everybody, (at least amongst the young), lives longer with a transplant than otherwise. But the young gain the most extra years of life. In the mathematics of transplantation, they have the potential for the most "net lifetime survival benefit.”

Maximizing the benefit, in many respects, is a harsh calculation.

And,

How old is ‘too old’?

Thank you!