Beyond Survival: Targeting Health‐Related Quality of Life Outcomes After Liver Transplantation

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Abbreviations

15D

15‐dimensional generic quality of life instrument

BAI

Beck Anxiety Inventory

BP

bodily pain

CES‐D

Center for Epidemiologic Studies Depression Scale

CLD

chronic liver disease

CLDQ

Chronic Liver Disease Questionnaire

DDLT

deceased donor liver transplantation

EQ‐5D

EuroQol instrument

GH

general health

HRQOL

health‐related quality of life

IPAQ

International Physical Activity Questionnaire

LDLT

living donor liver transplantation

LDQOL

Liver Disease Quality of Life Questionnaire

LT

liver transplantation

MCS

mental component score

MELD

Model for End‐Stage Liver Disease

MH

mental health

N/A

not available

NIDDK

National Institute of Diabetes and Digestive and Kidney Diseases

PCS

physical component score

PF

Physical Functioning

PROMIS

Patient‐Reported Outcomes Measurement Information System

QOL

quality of life

RE

Role–Emotional

RP

Role–Physical

SF

social functioning

SF‐36

Medical Outcomes Study Short‐Form 36

VT

vitality

Liver transplantation (LT) is standard of care for patients with end‐stage liver disease, with patient 1‐ and 5‐year survival rates more than 90% and 70%, respectively. ¹ As posttransplant survival improves, health‐related quality of life (HRQOL) through patient reporting is an important independent measure to contextualize transplant outcomes.

HRQOL Instruments in the Post‐LT Population

HRQOL outcomes are subjective by their nature due to variable patient perceptions of wellness that may be influenced by cultural, social, and economic experiences and personal beliefs, expectations, and perceptions. Meaningful HRQOL assessment relies on translating qualitative perceptions of well‐being into quantitative values for measurement and comparison. Properties of an effective instrument need to demonstrate reliability, validity, responsiveness; be of low burden to the respondent; and adapt to different cultures and languages. ²

A systematic review demonstrated more publications on LT and quality of life (QOL) since 2000 than in the prior two decades, with 128 articles using more than 50 QOL instruments. ³ The generic health instrument, Medical Outcomes Study Short‐Form 36 (SF‐36), is the most widely used instrument (54 of 128 studies), using 36 questions to derive 8 scales in physical (physical functioning, limitations because of physical health, bodily pain [BP], general health [GH]) and mental (vitality [VT], social functioning [SF], limitations because of emotional problems and mental health [MH]) domains. The advantage of the SF‐36 is its widespread use across populations allowing for normative comparisons. By contrast, several disease‐specific, or targeted, instruments have been developed to specifically address the symptoms associated with liver disease. However, the most commonly used tools (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] Transplantation Quality of Life Questionnaire, Liver Disease Quality of Life Questionnaire [LDQOL], and Chronic Liver Disease Questionnaire [CLDQ]) assess QOL in chronic liver disease (CLD) and not specifically in the posttransplant population. The computer adaptive tests, Patient‐Reported Outcomes Measurement Information System (PROMIS), use both generic and disease‐specific components. These are validated in the CLD population and may be the future of posttransplant population assessment as well. ⁴ , ⁵ The absence of uniformity in study designs and the wide variety of instruments have limited the widespread utility of HRQOL outcomes for decision making and long‐term follow‐up.

HRQOL Outcomes After LT

Most LT recipients experience a significant improvement in HRQOL soon after transplant compared with pretransplantation measurement (Table 1). ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ This occurs within the first month by measurement with the SF‐36 in both physical and MH summary scores ⁶ and is supported at 3 months posttransplant, except in BP. ⁷ Adding the CLDQ disease‐specific questionnaire to the SF‐36 generic questionnaire between 2 and 23 months posttransplant (median, 4 months) demonstrates improvement in all aspects of HRQOL after transplant, and MH scores recover to population norms as well. ⁸ Pushing the timeline out to 2 years, all SF‐36 physical measures except GH improve, with the greatest gains occurring in the first 6 months. ⁹ Even up to 20 years after transplant, a systematic review of 23 studies (5402 patients) assessing long‐term HRQOL after LT finds that overall QOL after LT is superior to preoperative status. ¹⁹

TABLE 1.

HRQOL Studies in LT Recipients: Short and Long‐Term Outcomes

Author (year)	Study Design	No. of Patients	Mean Age (years)	Median Follow‐up	HRQOL Tools	Comparison Groups	Main Conclusions
Short‐Term Outcomes
Telles‐Correia et al. (2009) 6	Prospective, cohort study	60	N/A	6 months	SF‐36	Pre‐LT versus 1 month post‐LT versus 6 months post‐LT	QOL improved early after LT (1 month). Between month 1 and 6 post‐LT, only the PCS improved
Ratcliffe et al. (2002) 7	Multicenter prospective	455	46‐60	24 months	SF‐36, EQ‐5D	Pre‐LT versus post‐LT	QOL improved in all domains except BP
Younossi et al. (2000) 8	Prospective	22	50	4 months	SF‐36, CLDQ	Pre‐LT versus post‐LT	All QOL domains improved
Krasnoff et al. (2005) 9	Prospective	50	51	24 months	SF‐36	2, 6, 12, and 24 months post‐LT	All physical health components except GH increased from 2 to 24 months post‐LT with significant increases from 2 to 6 months post‐LT only
Karam et al. (2003) 10	Prospective	67	51	12 months	NIDDK	Pre‐LT versus post‐LT	12‐month post‐LT QOL improved in all 5 domains
Zaydfudim et al. (2012) 11	Retrospective analysis of prospective, longitudinal data	186	54	21 months	SF‐36, BAI, CES‐D	Pre‐LT versus post‐LT (no steroids) versus post‐LT (high‐dose steroids)	All QOL measures improved in post‐LT compared with pre‐LT. Worse physical and mental QOL in high‐dose steroid group compared with the no steroid post‐LT group
McLean et al. (2019) 12	Cross‐sectional	454	56.2	4.3 years	SF‐LDQOL	Pre‐LT versus post‐LT	Overall QOL increased in post‐LT patients compared with pre‐LT cohort
Long‐Term Outcomes
Masala et al. (2012) 13	Retrospective; case‐control	162	55	1‐8 months	SF‐36, IPAQ	Post‐LT versus control	LT recipients QOL improved, but lower than the general population
Ruppert et al. (2010) 14	Prospective	381	48.9	9.7 months	NIDDK	1 and 12 years post‐LT	QOL improves within 1 year post‐LT and remains higher than pre‐LT status
Duffy et al. (2010) 15	Prospective; cross‐sectional	293	28	20 months	SF‐36, LDQOL	20 years post‐LT versus US norms versus CLD norms	Post‐LT QOL better than patients with CLD. Compared with the general US population, 20‐year LT survivors had lower physical scores but comparable mental scores
Kousoulas et al. (2008) 16	Retrospective	104	38	>15 months	SF‐36	15 years post‐LT versus German population	QOL is higher in post‐LT patients compared with patients with CLD, but lower than the general population
Aberg et al. (2012) 17	Retrospective; cross‐sectional	401	42‐55	8 (range 5‐11) months	15D	Various etiologies of CLD	QOL is lower in post‐LT patients compared with population norms but remains relatively high and comparable between etiologies
Sullivan et al. (2014) 18	Prospective; cross‐sectional	161	44.6	20 months	SF‐12	Post‐LT versus US norms	Compared with general US population, 20‐year LT survivors had lower physical health but similar MH

Few studies have examined HRQOL outcomes in recipients of living donor liver transplantation (LDLT). A longitudinal, cross‐sectional study assessing 35 LDLT recipients using the SF‐36 confirmed that, as expected, HRQOL scores are severely impaired in all dimensions preoperatively and improve up to 18 months after transplant, but do not reach those of healthy control subjects. ²⁰ The more ill the patient is prior to transplant, as measured by Model for End‐Stage Liver Disease (MELD) and Child‐Pugh score, the greater the improvement in SF‐36 score after transplant. Another study showed that SF‐36 scores are lowest at 6 months after LDLT but improve and are stable between 1 and 2 years after transplant. ²¹ One study comparing LDLT with deceased donor liver transplantation (DDLT) recipients found DDLT recipients are able to achieve higher HRQOL scores by the SF‐36 in the majority of domains after transplant compared with the LDLT recipients, ²² but this did not take into account severity of liver disease at time of transplant.

Despite significant improvement in QOL after transplantation, transplant recipient HRQOL scores remain lower than the healthy general population (Fig. 1). ¹³ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ²² , ²³ , ²⁴ , ²⁵ In a systematic review of 44 longitudinal studies, with a mean follow‐up of 25 months, Tome et al. ²³ showed that when compared with the general population, the majority of LT recipients still have significant deficiencies in most HRQOL domains. This disparity cannot be predicted by pretransplantation and posttransplantation variables but may be partly a result of psychosocial and physical impairment prior to transplant, medical comorbidities, complications from transplantation, recurrent liver disease, effects from medication, and challenges with reintegration into social and professional networks. ²⁶ , ²⁷

FIG 1.

A comparison of HRQOL outcomes: pretransplant versus posttransplant versus general population. Russell et al. ²⁵ compared 104 pre‐LT and post‐LT adults who reported HRQOL using SF‐36 with that of the general population.

Although the underlying etiology of cirrhosis affects HRQOL in the pretransplant period, the role of the cause of liver disease as an influence on HRQOL after LT has been assessed in a few studies and remains largely inconclusive. ¹⁷ The existing studies have investigated patients who received transplants because of alcoholic cirrhosis, cholestatic diseases, acute liver failure, viral hepatitis, and hepatocellular carcinoma. ¹⁴ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ The general conclusion is that the cause of liver disease does not appear to influence HRQOL scores early after transplant, although recurrent hepatitis C, for example, has been associated with impaired HRQOL in the long‐term outcomes after LT. ³² , ³³ This may be a result of the patient having a negative perception of health, potentially because of ongoing fatigue and stress resulting from the viral infection. When using employment after LT as a marker of functional status and HRQOL, one study finds increased employment in the alcohol‐associated and cholestatic liver disease groups. ¹⁷ , ³⁴ This suggests a greater increase in posttransplantation HRQOL compared with other groups who do not return to employment.

Comparing SF‐36 HRQOL scores between LT recipients and patients with other chronic illnesses demonstrates that the physical component summary scores in 20‐year LT recipients are significantly higher than those for patients with type 2 diabetes mellitus and congestive heart failure, but mental component summary scores were not significantly different. ¹⁵

Role of HRQOL in Transplant Decision Making

The most LTs occurred in the United States in 2019. ³⁵ Although the limited organ supply obligates a system of allocation based on survival benefit (i.e., MELD), we may be able to expand access to transplant with increased donor pools, including those from live donors. This expansion allows for integration of QOL assessments to optimize timing of LT. The European Association for the Study of the Liver recognizes pretransplant QOL as an indication for transplantation itself. ³⁶

The MELD score does not consistently correlate with HRQOL. ³⁷ , ³⁸ , ³⁹ Ascites and hepatic encephalopathy, not captured in MELD, are associated with poor HRQOL, suggesting an ongoing role for the Child‐Pugh score. ³⁷ In the cholestatic liver disease population, classically underrepresented by MELD, pruritus strongly influences HRQOL ⁴⁰ and improves after LT. ⁴¹ Further supporting its importance, HRQOL predicts mortality in cirrhosis independent of MELD. ⁴² It is clear that HRQOL is an adjunctive tool to complement MELD in determining patients who benefit from transplant, especially in those with access to organs outside our standard allocation process.

Conclusion

QOL after LT is improved compared with pretransplant status, but the reasons recipients do not achieve a HRQOL comparable with age‐matched controls is not completely understood. Speculation includes physical and psychological impairment pretransplant, as well as complications from transplant itself or medication side effects. As access to donor organs continues to grow, we will increasingly incorporate QOL assessments into transplant decision making. To make this shift, it is imperative to continue to define our HRQOL outcomes in LT candidates and recipients.

Future direction will include prospective studies with predetermined follow‐up time points that accurately reflect current survival rates and consistently use previously validated QOL instruments and identification of modifiable operative, medical, and psychosocial variables that improve HRQOL after transplantation.