Comprehensive assessment of frail phenotype determinants in cirrhotic patients evaluated for liver transplantation

BACKGROUND. Frailty is defined as a distinct biologic syndrome of decreasing physiologic reserve and increasing vulnerability to health stressors that predispose affected individuals to health adverse outcomes. So far, frail phenotype in cirrhotic patients has been regarded to a large extent as a manifestation of a wasting disorder, with sarcopenia as the major pathogenic mechanism. However, specific investigations on the pathogeneis of cirrhosis-related frailty are lacking. Therefore, the aim of this study was to perform a comprehensive assessment of potential determinants of frail phenotype, testing known risk factors for cirrhosis-related sarcopenia and exploring other pathogenic mechanisms derived from aging-related frailty METHODS. Observational prospective study on a cohort of cirrhotic patients, aged 50-70 years, who underwent the clinical workup for deceased-donor LT listing at the Hepatology and Liver-Kidney Transplant Unit of the Udine Academic Hospital, from June 2019 to November 2021. Patient physical performance was assessed using the Liver Frail index (LFI) and a LFI≥4.5 was used as diagnostic criteria for frailty. Body mass composition was assessed on cross-sectional computer tomography images at the third lumbar spine level, as follows: skeletal muscle mass index (SMI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (TATI); total adipose tissue index (VATI+TATI), visceral-to-subcutaneous adipose tissue ratio (VSR) and skeletal muscle radiodensity (SMRD). Osteoporosis was diagnosed based on T score<-2.5 on dual-energy X-ray absorptiometry. For endocrine, inflammatory and metabolic assessment, the following parameters were evaluated on blood samples: thyroid stimulating hormone, freeT4, 17-beta estradiol, testosterone, dehydroepiandrosterone solphate, cortisol and IGF-1 [endocrine profile], neutrophil-to-lymphocyte ratio, C-reactive protein (CRP) and erythrocyte sedimentation rate [inflammatory profile], 25(OH) Vitamin D, prognostic nutritional index, triglyceride, cholesterol HDL, cholesterol LDL, total proteins, albumin, cholinesterase, ammonia, uric acid, creatinine and percent glycated hemoglobin [metabolic profile] RESULTS. One hundred ten patients were assessed. The median LFI was 3.9 [IQR 3.6-4.4], with a frail status prevalence of 23.6% (n=26). Frail patients were not significantly older than non-frail ones but showed a tendency toward an higher prevalence of female sex (46.1% vs 26.2%, p 0.054). Frailty was associated with higher MELD-Na score (median,19 vs 13, p <0.001). Moreover, it was associated with higher NASH prevalence (15.4% vs 0.24%, p 0.027), higher TATI (124.8 cm2/m2 vs 69.7 cm2/m2, p 0.001) and higher metabolic syndrome prevalence (23.1% vs 1.4%, p<0.001). Vitamin D levels were significantly lower, irrespective of pre-existing vitamin D oral supplementation, but frailty was not associated with osteoporosis. Cortisol (431 nMol/L vs 332 nMol/L, p 0.041) as well as CRP (6.5 mg/L vs 3.5 mg/L, p 0.032) levels were significantly higher, while and IGF-1 levels were significantly lower (37 pg/mL vs 45 pg/mL, p 0.032). Frail women specifically showed higher VATI and VSR (0.80 vs 0.41, p 0.27), but comparable SMI and SMRD, as well as significantly lower testosterone (0.7 nMol/L vs 1.4 nMol/L, p<0.001) and estrogen levels (40 pMol/L vs 69 pMol/L, p 0.017). Conversely, frail men showed significantly lower SMI (47.8 cm2/m2 vs 50.9 cm2/m2, p 0.012) and lower SMRD, higher SATI but comparable VSR, with significantly lower testosterone levels (4.5 nMol/L vs 8.7 nMol/L, p<0.001). CONCLUSIONS. Frailty in cirrhotic patients should not be primarily considered as a wasting disorder and the pathogenic role of adipose tissue may be at least as important as that of skeletal muscle. Therefore, beyond sarcopenia and malnutrition, diagnostic and therapeutic interventions should also possibly target obesity, chronic inflammation, hypogonadism, IGF-1 deficiency and vitamin D deficiency.