Sarcopenia in cirrhotic patients waiting for liver transplantation: is diabetes an additional aggravating factor?

doi:10.21203/rs.3.rs-4904783/v1

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Sarcopenia in cirrhotic patients waiting for liver transplantation: is diabetes an additional aggravating factor?

https://doi.org/10.21203/rs.3.rs-4904783/v1

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Diabetes is a well demonstrated risk factor for poor prognosis in people with chronic liver disease. Conversely, the presence of hepatopathy may affect glucose homeostasis. In people with cirrhosis, sarcopenia is related to increased pre- and post-liver transplantation (LT) mortality. Diabetes mellitus and sarcopenia are both known complications of end-stage liver disease but, to date, no studies aimed at assess the clinical impact of their co-presence in LT-candidates are available.

We performed a cross-sectional, single-center, observational study to assess the presence of sarcopenia in 112 people with cirrhosis and waiting for LT to investigate any correlation between this condition and the presence of glucose abnormalities.

In our population, 10 (8.9%) subjects was diagnosed as sarcopenic. Diabetes appears to be strongly associated with sarcopenia in individuals with cirrhosis, affecting 100% of people from the sarcopenic (S) group (vs 59.8% in the non-sarcopenic -NS group).

Subjects from the S group were older and showed lower BMI and fat mass vs subjects from NS group.

Concerning to dietary behaviors, individuals from the S group showed adequate protein intake and achieved the recommended daily intake of fibers, as recommended in the context of nutritional trainings, routinely proposed to this population.

In conclusion, the recognition and metabolic characterization of such frail individuals would allow to target them with structured nutritional and lifestyle educational programs, with the aim to achieve a better metabolic status in view of LT.

Health sciences/Endocrinology/Endocrine system and metabolic diseases/Diabetes/Type 2 diabetes

Health sciences/Diseases/Nutrition disorders/Malnutrition

Sarcopenia

Diabetes

Cirrhosis

Nutrition

Liver transplantation

Actually, cirrhosis is considered a global burden, with metabolic-dysfunction associated fatty liver disease (MAFLD), high alcohol consumption, chronic hepatitis B or C infection, autoimmune diseases, cholestatic diseases, and iron or copper overload being the most frequent etiological factors in United States and Western Europe [1].

Type 2 diabetes mellitus (T2DM) and cirrhosis account for 5 million and 1.2 million deaths worldwide each year, respectively [2]. T2DM and liver disease are linked by a bidirectional relationship, according to which one condition represents a risk factor for the other and vice versa. Diabetes is an independent risk factor for poor prognosis in people with cirrhosis, associated with the occurrence of major complications such as ascites, encephalopathy, and infections [3]. Conversely, the presence of cirrhosis may affect glucose homeostasis.

Sarcopenia is an age-dependent geriatric syndrome characterized by skeletal muscle mass and strength loss and/or decline in physical performance [4]. Sarcopenia is associated with several adverse outcomes, including falls and secondary fractures [5, 6], pulmonary insufficiency [7], sleep disorders [8], cognitive impairment [9], poor quality of life [10] and premature mortality [11], bringing to a significant medical and economic burden.

In people with cirrhosis, sarcopenia is related to increased pre- and post-liver transplantation (LT) complications and it is an important predictor of pre- [12, 13] and post-LT [14] mortality. Moreover, this condition is associated with a higher rate of infection and longer hospitalization [15, 16], hepatic encephalopathy [17], poor quality of life [18], and increased healthcare cost [19]. Again, sarcopenia is associated with poorer survival in patients with hepatocellular carcinoma (HCC) [20]. Finally, it has also been found to be associated with increased risk of post-LT infection and prolonged mechanical ventilation. Sarcopenia is a common finding in cirrhosis, affecting up to 65% of patients with advanced liver disease. Among them, approximately 20% of individuals with mild to moderate liver failure, 80% of individuals with severe liver failure, and up to 80% of LT candidates are sarcopenic [21, 22]. Furthermore, sarcopenia occurs irrespective of liver cirrhosis etiology [23], and a potential gender effect, related to the known differences in adipose and muscle mass distribution in males and females, has been suggested, with male sex at higher risk [23].

The heterogeneity in reported prevalence of sarcopenia and frailty in cirrhosis depend on the potential differences in the populations evaluated, the methods of assessment, and the operational definitions used for diagnosis [24]. Multiple mechanisms have been demonstrated to be involved in sarcopenia development in liver cirrhosis and they include: malnutrition, altered skeletal muscle proteostasis and systemic inflammation [25]. Despite this, the interplay between these factors remains unclear.

Diabetes mellitus and sarcopenia are both known complications of end-stage liver disease. To date, however, no studies aimed at assess the clinical impact of their potential co-presence in LT-candidates are currently available.

For this reason, we performed a cross-sectional, single-center, observational study to assess the presence of sarcopenia in people with cirrhosis and waiting for LT and to investigate any correlation between this condition and nutritional behaviors or glucose abnormalities.

Study population

All participants were recruited at the Endocrinology Unit of Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy. The research protocol was approved by the 129 Ethics Committee of the IRCCS Ca’ Granda – Ospedale Maggiore Policlinico Foundation (Prot. n. 516) and has been registered on ClinicalTrials.gov (Identifier nr: NCT02038571). A written informed consent was provided by each participant. A standardized screening procedure was followed in order to identify eligible participants, who were required to be people with cirrhosis waiting for LT, with age 18–75 years and a body mass index (BMI) of 18.5–40 kg/m². Exclusion criteria were diagnosis of type 1 DM or latent autoimmune diabetes of the adult (LADA).

Nutritional assessment

A 3-day food diary was used to collect information on the dietary intake of micro and macronutrients in the studied population. In particular, all participants were asked to record details on their intake of food and beverages, including information on the total amount, brand and cooking methods of the items listed in the diary. All dietary intake data were analyzed for energy, macro- and micronutrient content using Metadieta® v. Professional 4.0.1.

Anthropometric Measurements

Body weight and standing height were measured with study participants in light clothing and barefoot, using a scale, to the closest 0.1 kg and a wall-mounted stadiometer. Waist circumference (WC) was measured to the nearest 0.1 cm directly over the skin at the umbilicus level, using a flexible steel tape calibrated in cm with mm graduations. Body mass index (BMI) was calculated using Quetelet equation [weight (kg)/height (m)²]. Referring to World Health Organization (WHO) cut-offs for BMI, study participants were classified as underweight (BMI < 18.5 kg/m²), normal weight (BMI 18.5–24.9 kg/m²), overweight (BMI 25.0–29.9 kg/m²) or obese (BMI ≥ 30 kg/m²) [26]. Furthermore, gender-specific waist circumference cut-offs proposed by the WHO were used to categorize study participants for CVD risk: normal (WC < 100 cm in men and 85 cm in women) [27].

Skinfold thickness was determined to the nearest 0.2 mm at the left biceps, triceps, sub-scapular and supra-iliac sites using a skinfold GIMA®.

Screening for sarcopenia

Sarcopenia was diagnosed according to the guidelines proposed by the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) [28], based on indirect measures of muscle function and muscle mass, such as low walking speed (≤ 0.8 m/s walking 4 m), handgrip strength (assessed with dynamometry - <27 kg for men and < 16 kg for women), and loss of lean mass, assessed with bio-impedance analysis (BIA). BIA was performed using a single-frequency analyzer (BIA 101 BIVA, Akern Bioresearch, Firenze, Italy), with application of a 800 µA-50 kHz oscillating current. To perform the analysis, the subject lies in supine position and electrodes are placed on the dorsal surface of the right foot and ankle, as well as on the right wrist and hand. Appendicular Skeletal Muscle mass Index (ASMMI - kg/m2) was predicted by the software BodyGramPro® (≤ 5.5 kg/m2 for women and ≤ 7.0 kg/m2 for men) [29].

Biochemical measurements

Blood samples were taken after a fasting of 10 hours. Alanine transaminase (ALT, UI/L), aspartate transaminase (AST, UI/L), and gamma-glutamyl transferase (GGT, UI/L), alkaline phosphatase (ALP, UI/L), cholinesterase (CHE, UI/L), creatinine (Cr, mg/dl), total cholesterol (TC, mg/dl), high-density lipoprotein cholesterol (HDL, mg/dl), triglycerides (TG, mg/dl) were measured. Low-density lipoprotein cholesterol (LDL, mg/dl) values were calculated using the Friedewald formula [30]. Hemoglobin A1c (HbA1c, %) levels and fasting plasma glucose levels (FPG, mg/dl) were measured to diagnose glucose abnormalities [31].

Statistical Analysis

The general characteristics of the study population were summarized by sarcopenia using percentages (for frequencies) or mean ± standard deviation (SD) (for continuous variables).

Wilcoxon rank sum test or Fisher’s exact test were used to compare No sarcopenia versus sarcopenia. A p-value of < 0.05 was taken as significant. Analyses were done using STATA 16 (StataCorp–College Station, TX, USA) statistical package.

112 subjects (76 male, 36 female) with cirrhosis were consecutively recruited and screened for sarcopenia with EWGSOP2 criteria [28]. We found no correlations between sarcopenia prevalence and liver disease severity, according to Child-Pugh classification.

As shown in Table 1, 10 subjects (70% male) were sarcopenic (S group), with a disease prevalence of 8.9%. Moreover, in the non-sarcopenic group (NS group), 38.2% had “probable sarcopenia”, with handgrip values below the reference cut-offs and ASMMI within the range of normality.

Table 1

Demographic, clinical and metabolic characteristics in subjects waiting for LT according to diagnosis of sarcopenia
	NS group, N = 102¹	S group N = 10 ¹	p-value²
Sex Men Women	69 (67.6%) 33 (32.4%)	7 (70%) 3 (30%)	0.99
Age (years)	60.7 ± 7.5	64.7 ± 6.4	0.10
CP classification Class A Class B Class C Unknown	23 (33.3%) 25 (36.2%) 21 (30.5%) 33	2 (20.0%) 6 (60.0%) 2 (20.0%) 7	0.35
DM (n°/%)	61 (59.8%)	10 (100%)	0.01
FPG (mg/dl)	121.0 ± 51.5	149.1 ± 50.4	0.03
HbA1c (%)	6.6 ± 5.5	6.4 ± 2.5	0.89
AST (U/L)	49.8 ± 29.5	54.9 ± 23.4	0.23
ALT (U/L)	40.6 ± 28.6	36.4 ± 17.7	0.95
GGT (U/L)	99.6 ± 150.5	138.3 ± 120.3	0.61
TC (mg/dL)	148.2 ± 53.8	142.1 ± 39.9	0.64
HDL (mg/dL)	51.5 ± 15.7	55.4 ± 13.5	0.56
LDL (mg/dL)	90.5 ± 40.5	76.8 ± 37.8	0.39
TG (mg/dL)	88.7 ± 39.1	101.9 ± 44.2	0.34
Creatinine (mg/dL)	0.9 ± 0.3	1.6 ± 1.9	0.92
GFR (mL/min/1.73 m²)	84.6 ± 6.4	81.2 ± 29.6	0.86
Sarcopenia category Excluded Probable Confirmed Severe	63 (61.8%) 39 (38.2%) 0 0	0 0 9 (90%) 1 (10%)	0.06
¹ n (%), Mean (SD)
² Wilcoxon rank sum test, Fisher’s exact test
LT: liver transplantation; NS: non sarcopenic; S: sarcopenic; CP: Child_Pugh; DM: diabetes mellitus; FPG: fasting plasma glucose; ALT: Alanine transaminase; AST: aspartate transaminase; GGT: gamma-glutamyl transferase; TC: total cholesterol (TC, mg/dl); HDL: high-density lipoprotein cholesterol; LDL: Low-density lipoprotein cholesterol; TG: triglycerides. (LDL, mg/dl); gfr: glomerular filtration rate.

Subjects from the NS group were younger (60.7 ± 7.5 vs 64.7 ± 6.4 years, p = 0.10).

Regarding to the presence of glucose abnormalities, in the NS group, 61 subjects (58.9%) had diabetes, while all individuals in the S group had diabetes (10 participants, 100%, p = 0.01).

Body weight was higher in the NS group (79.7 ± 16.2 kg vs 64.7 ± 10.6 kg, p < 0.01), as well as the BMI (27.8 ± 4.7 kg/m² vs 22.6 ± 2.3 kg/m², p < 0.01) (Table 2). In the NS group, 28.4% showed a normal weight, 42.2% were overweight, and 29.4% were obese. In contrast, 80% of subjects in S group had a normal weight, 20% were overweight and none was diagnosed with obesity.

Table 2

Anthropometric and functional indicators of nutritional status in subjects waiting for LT according to diagnosis of sarcopenia
	NS group, N = 102 ¹	S group N = 10¹	p-value²
Body weight (kg)	79.7 ± 16.2	64.7 ± 10.6	< 0.01
BMI (kg/m²)	27.9 ± 4.7	22.6 ± 2.3	< 0.01
BMI category Normal weight Overweight Obese	29 (28.4) 43 (42.2) 30 (29.4)	8 (80%) 2 (20%) 0	< 0.01
Waist circumferences (cm)	102.4 ± 12.8	93.1 ± 5.1	0.58
Increased waist circumferences	74 (75.5%)	5 (62.5%)	0.41
FM (% of body weight)	27.1 ± 9.1	25.3 ± 5.4	< 0.01
Hand grip (kg)	25.7 ± 8.6	17.6 ± 6.1	< 0.01
Low grip strength	39 (38.6%)	10 (100%)	< 0.01
ASMMI (kg/m²)	8.0 ± 1.4	6.1 ± 0.6	< 0.01
Low ASMMI	3 (3%)	9 (90%)	< 0.01
Gait speed (m/s)	1.0 ± 0.3	1.0 ± 0.3	0.96
Low gait speed	21 (24.4%)	1 (33.3%)	0.99
¹ n (%), Mean (SD)
² Wilcoxon rank sum test, Fisher’s exact test
LT: liver transplantation; NS: non sarcopenic; S: sarcopenic; BMI: body mass index; FM: fat mass; ASSMI:appendiclual skeletal muscle mass index.

We found no differences in waist circumference between the two groups (102.4 ± 12.8 cm vs 93.1 ± 5.1 cm, p = 0.58), but individuals in the NS group showed a higher fat mass (27.1 ± 9.1% of body weight vs 25.3 ± 5.4% of body weight, p < 0.01).

As reported in Table 3, the energy intake was 1763.7 ± 342.0 Kcal (21.6 ± 7.3 Kcal/kg of body weight in subjects) in the NS group, 1640.0 ± 460.1 Kcal in the S group (23.0 ± 9.6 Kcal/kg of body weight). The proportion of protein, fat and carbohydrate intake was, respectively, 18.3 ± 3.2%, 38.7 ± 6.2% and 43.5 ± 7.1% in individuals from NS group. In the S group, it was 19.2 ± 4.2%, 38.2V3.6% and 42.6 ± 4.6%, respectively. Finally, we found a significative difference in the protein intake, expressed in g/kg of body weight (1.0 ± 0.3 g/kg NS group vs 1.2 g/kg in the S group, p = 0.05).

Table 3

Energy and nutrient intakes in subjects waiting for LT according to diagnosis of sarcopenia
	S group, N = 102¹	NS group, N = 10¹	p-value²
Energy (Kcal)	1763.7 ± 342.0	1640 ± 460.1	0.50
Energy (Kcal/Kg of bw	21.6 ± 7.3	23.0 ± 9.6	0.25
Proteins (% of kcal)	18.3 ± 3.2	19.2 ± 4.2	0.75
Proteins (g/kg of bw)	1.0 ± 0.3	1.2 ± 0.4	0.05
Fats (% of kcal)	38.7 ± 6.2	38.2 ± 3.6	0.76
Carbohydrates (% of kcal)	43.5 ± 7.1	42.6 ± 4.6	0.49
Saturated fatty acids (% of kcal)	10.2 ± 3.1	8.8 ± 2.6	0.87
Fibre (g per 1000 kcal)	11.7 ± 3.8	12.3 ± 4.2	0.21
¹ n (%), Mean (SD)
² Fisher’s exact test
LT: liver transplantation; NS: non sarcopenic; S: sarcopenic

To our knowledge, this is the first cross-sectional, observational study assessing the presence of sarcopenia and correlating this condition to glucose abnormalities in people with cirrhosis waiting for LT, suggesting a potential strong correlation between these two conditions.

In our population, we could diagnose sarcopenia with a prevalence of 8.9%, lower than expected. Indeed, data from literature report a prevalence of sarcopenia of 30–70% in cirrhotic subjects [32], with higher rates in men. A recent meta-analysis by Petermann-Rocha et al. [33] confirmed this data, according to the EWGSOP2 diagnosis criteria.

By definition, people with sarcopenia show lower handgrip and ASMMI values. Hand grip strength is an indicator of health and, in particular, lower levels are related to early mortality from all causes and cardiovascular causes, as well as disability, and correlates with muscle mass and quality. Finally, they have been demonstrated to be a predictor of mortality in individuals waiting for LT [34].

As reported in literature, age is the major risk factor for developing sarcopenia. Data from our population confirmed these evidences. Moreover, our data complied with data from literature concerning body weight and composition. In liver cirrhosis, prevalence and severity of malnutrition are related to disease severity, increasing from 20% in patients with mild to moderate liver failure to more than 60% in patients with advanced disease. Body composition, in subjects with cirrhosis and sarcopenia, is altered and characterized by protein depletion, increased the weight loss and accumulation of total body water accumulation [35]. In our population, people from the S group showed lower BMI and lower FM (%). Conversely, subjects from the NS group were overweight, with 29% of people with obesity.

Patients with cirrhosis and sarcopenia show a significantly lower overall survival rate (RR = 2.64) than patients with cirrhosis and without sarcopenia. A study from Zeng et al. reported a lower five-years survival rate in people with cirrhosis and sarcopenia than people with cirrhosis and without sarcopenia (46.6% vs. 74.2%, P < 0.001) [36].

Furthermore, the interaction between diabetes and sarcopenia has been widely demonstrated in the general population, with people with diabetes having a 3 times greater risk for developing sarcopenia [37]. Prolonged hyperglycemia leads to increased incidence of fatty liver disease, loss of skeletal muscle mass and function and sarcopenia [38]. As mentioned above, no data on the potential contribution of cirrhosis and diabetes in developing sarcopenia are available in subjects with advanced liver disease waiting for LT. In our population, all subjects with sarcopenia were diagnosed with diabetes (100%), while only 58.9% in the NS group had glucose abnormalities, suggesting a synergistic effect between diabetes and cirrhosis in affecting muscle health and developing sarcopenia.

Finally, we performed an analysis on nutritional behaviors in subject from our population. The ESPEN guidelines recommend an energy intake of 25–35 Kcal/kg/die and a protein intake of 1.2–1.5 g/kg of body weight [39]. In our study, subjects from nor NS neither S group reached the goals proposed by the ESPEN guidelines concerning energy intake, whereas individuals from the S group showed adequate protein intake (1.2 g/kg of body weight). Despite this encouraging evidence, we must underly that an adequate dietary protein intake is not sufficient to stimulate muscle mass gain if it is not combined with appropriate resistance exercise [40] in sarcopenic subjects. Moreover, subjects from both groups complied with the recommended intake of saturated fatty acids, expressed in %, according to LARN guidelines (< 10% En), but only people from the S group achieved the recommended daily intake of fibers (12,6–16,7 g/1000 Kcal). This difference could be related to the fact that people from the S group, being in 100% diagnosed with diabetes, received a structured and widespread nutritional education, which includes adequate consumption of vegetables and whole grains [41].

The study presents, as potential limitations, the small sample size of the S group and the observational nature of the study. Further interventional, longitudinal studies on wider populations are needed to better understand the reciprocal interplay between diabetes and sarcopenia in subjects with cirrhosis.

Diabetes appears to be strongly associated with sarcopenia in individuals with liver cirrhosis, who are already prone to the development of this complication due to altered protein turnover, the resulting increased proteolysis of skeletal muscle and decreased protein synthesis. Diabetes, through increased inflammatory state and insulin resistance, could contribute in accelerate muscle depletion in this population.

The recognition and characterization of such frail individuals would allow to target them with structured nutritional and lifestyle educational programs, with the aim to achieve a better metabolic status in view of liver transplantation.

Acknowledgments

A.G., V.G., and I.C. conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript.
E.O.,V.R., F.G and Y.P. collected data, carried out the initial analyses, and reviewed and revised the manuscript.
A.G. and V.G. designed the data collection instruments, coordinated and supervised data collection, and critically reviewed the manuscript

G.A. and A.O. performed the statistical analysis

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

A.G. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This study was (partially) supported by the Italian Ministry of Health (Ricerca Corrente 2023)”

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Sarcopenia in cirrhotic patients waiting for liver transplantation: is diabetes an additional aggravating factor?

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Abstract

INTRODUCTION

MATERIAL AND METHODS

Study population

Nutritional assessment

Anthropometric Measurements

Screening for sarcopenia

Biochemical measurements

Statistical Analysis

RESULTS

DISCUSSION

CONCLUSIONS

Declarations

References

Additional Declarations

Status:

Version 1