Comparison of the Effect of Two Interventions on Liver Frailty Index in Pre-frail and Frail Cirrhotic Patients Enlisted for Liver Transplantation

Comparison of the effect of two interventions on Liver Frailty Index in pre-frail and frail cirrhotic patients enlisted for liver transplantation.

Frailty is a concept derived from geriatrics that translates a reduction in the physiological reserve of various organs and systems (immune, musculoskeletal, endocrine, neurological, etc.) and a greater vulnerability to stressors. It is present in up to one fifth of cirrhotic patients listed for liver transplantation and its determination has been independently related to adverse outcomes. On the other hand, it is closely linked to the concept of sarcopenia, which translates into a reduction of skeletal muscle mass and function. However, there is a proportion of frail patients who are not sarcopenic (patients with sarcopenia) and not all sarcopenic patients are frail so sarcopenia and frailty are not equivalent concepts, although both are related.

In cirrhosis, the presence of frailty and sarcopenia are conditions that may be determined by a multiplicity of factors such as the presence of hepatic encephalopathy, ascites, poor nutrition, sedentary lifestyle, aging, endocrinological factors, hospitalizations, comorbidities, and also socioeconomic and environmental factors. Sarcopenia could be measured employing several methods. One of the most validated is the determination of the skeletal muscle index, which adjusts the area of skeletal muscle at L3 level by height. Thus, a woman is considered sarcopenic if she has an index lower than 39 cm2/m2 and, in men, when it is lower than 50 cm/m2. This index is related to the patient prognosis. Thus, according to this the survival of sarcopenic patients is always lower when adjusted for other variables, especially in women.

Nevertheless, sarcopenia fails to capture spheres that the concept of frailty consider and that influence the prognosis of patients even in the absence of sarcopenia. There is a multiplicity of instruments that allow to establish the diagnosis of frailty, some very simple and quick to perform, such as the Karnofsky scale (although it has a large subjective component) and others more complex and objective, although demanding in time and resources, such as the cardiopulmonary exercise test (CPET). Other tests evaluated are: Clinical Frailty Scale (CFS), Instrumental Activities of Daily Living (IADL), Fried Frailty Phenotype (FFP), 6 Minute Walk Test (6MWT), Dynamometer Prehension Test (handgrip) or gait speed. The choice of the test to be performed should be based on the simplicity of the test, the need for available instruments, the determination of objective variables, reproducibility, cost, time available and the prognostic significance of the test.

A recent study conducted by our group evaluated the prognostic significance of the presence of frailty assessed by FFP. A total of 126 cirrhotic patients were included, 65.1% of whom were diagnosed as frail. The main etiologies were MAFLD (Metabolic dysfunction-associated fatty liver disease), alcohol liver disease and hepatitis C virus infection. The mean age was 64±8.3 years, 47.6% were women, median MELD-Na 15[12-17] and median follow-up was 881 [349-1,277] days. Interestingly, mortality in frail patients was markedly higher than in robust patients i.e., 26.1% versus 5.9% at 12 months, 47.6% versus 12.0% at 24 months, and 68.2% versus 20.6% at 48 months, respectively (p < 0.001). Additionally, patients with reduced gait speed (less than or equal to 0.8 meters/second) also had higher mortality (32.8% versus 13.3% at 12 months, 58.9% versus 26.2% at 24 months, and 79.9% versus 40.8% at 48 months respectively; p < 0.001). Moreover, multivariate analysis showed that the presence of frailty and low gait speed were related to mortality independent of liver function. Thus, the presence of frailty conferred an increased risk of death with any degree of liver dysfunction.

In the study, FFP was used because it meets the requirements and it had a significant experience in other similar studies. Nonetheless, it would be of greater interest to apply a test specifically designed for patients with chronic liver disease and that adjusts to their peculiarities.

The Liver Frailty Index (LFI) is a test developed to be used specifically in patients with cirrhosis, evaluates objective variables, requires simple instruments, is reproducible, widely available and requires few time to be performed. In addition, it predicts the survival of listed patients. The LFI includes the measurement of prehension strength, a squat test (time required to perform 5 squats) and a balance test with parallel, semi-tandem and tandem feet and provides a score (continuous variable). Thus, when the score is less than 3.2 patients are considered robust, if it is 3.2 to 4.4 the participants are considered pre-fragile and if it is 4.5 or more patients are considered fragile.

Recently, the LFI was used in a randomized controlled trial in cirrhotic patients comparing the use of an exercise program versus standard medical care. Although the trial was negative possibly due to low patient adherence, the use of LFI allowed objective assessment of patient progress and the effect of the intervention without using subjective variables and with a test specifically designed for patients with cirrhosis.

It is interesting to note that current studies have attempt to evaluate the effectiveness of interventions to improve frailty in patients with cirrhosis without discriminating those who are frail or pre-frail from those who are robust. Thus, it is not possible to really know what proportion of the patients included were non-robust and if the interventions are effective in the specific subgroup of patients.

Therefore, a trial was designed to evaluate the effectiveness of an intervention consisting of physical and nutritional therapy compared to physical and nutritional counseling over a 12-week period. Unlike the previously described studies, this study will only enroll pre-fragile and frail patients according to the LFI.

This is a randomized trial which will attempt to evaluate if there is a difference between an intervention that corresponds to our standard behavior but intensified in terms of providing very detailed information and periodic reinforcement and another intervention that will consist of personalized physical training associated with nutritional assistance directed to the specific patient and with periodic consultations.

The potential results of this study will be interesting considering that if any of the interventions is superior it should prefer it, but if both are similar, the most cost effective one should be choose.