Total Body Potassium, Body Cell Mass, and Their Relation to Frailty and Bedside Tools: A Pilot Study in Adults with Cirrhosis

doi:10.21203/rs.3.rs-4784761/v1

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Total Body Potassium, Body Cell Mass, and Their Relation to Frailty and Bedside Tools: A Pilot Study in Adults with Cirrhosis

https://doi.org/10.21203/rs.3.rs-4784761/v1

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Accurately assessing body composition in cirrhosis is challenging as fluid shifts affect most techniques. The whole-body counter is a state-of-the-art method that measures total body potassium (TBK) unbiased by fluid, from which body cell mass (BCM) is derived. This pilot study in 20 patients with cirrhosis characterized TBK and BCM, and explored their association with frailty; evaluated BCM relationship with the liver frailty index (LFI), bioimpedance analysis-based phase angle, calf circumference (CC), and BMI (body mass index)/edema-adjusted CC. Stepwise multiple linear regression analysis and Pearson’s correlation tests were conducted. Adjusted for sex, BCM and TBK were inversely associated with frailty (p<0.0001). LFI r=-0.568 (p=0.009), CC r=0.484 (p=0.031), and edema-adjusted CC r=0.467 (p=0.038), demonstrated moderate correlations with BCM. Further research involving a larger sample of participants with cirrhosis is needed to confirm these findings and enhance our understanding of the association between these advanced body composition measures and frailty.

Health sciences/Health care/Nutrition

Health sciences/Diseases/Gastrointestinal diseases/Liver diseases/Liver cirrhosis

whole body counter

body composition

liver frailty index

calf circumference

phase angle

sarcopenia

Low muscle mass and impaired muscle contractile function are prevalent prognostic factors in cirrhosis, known as ‘sarcopenia’ and frailty (1). Optimal care requires prompt and routine screening and assessment of these conditions (1–3).

The liver frailty index (LFI) is a sensitive tool for detecting frailty in cirrhosis across various disease stages and demographics (4). Body composition (BC) analysis of low muscle mass in cirrhosis is challenging due to limited bedside tools and fluid shifts affecting most techniques (1). Bioimpedance analysis-based phase angle (PhA), and calf circumference (CC), including body mass index (BMI)- and edema-adjusted CC, are promising bedside tools with prognostic significance (1, 4–6). However, data on these tools and their association with the state-of-the-art BC technique, whole-body counter (WBC), are limited (7, 8).

The WBC provides accurate BC analysis regardless of hydration status (9) by detecting gamma rays from radioactive potassium (⁴⁰K) in the body, giving total body potassium (TBK) measurements (10). Since 98% of TBK is within body cell mass (BCM), TBK accurately reflects BCM, which includes oxygen-exchanging, potassium-rich, glucose-oxidizing tissues (Supplementary Information (SI)-A1).

In cirrhosis, evidence on TBK and BCM is limited to 5 studies published 20 years ago, with mixed results regarding BCM differences by disease severity or after procedures (7, SI-A2-5). We lack data on the association of TBK and BCM with frailty and other bedside BC assessment tools in cirrhosis (8). Identifying these associations could enhance patient care and treatment outcomes by broadening the accessibility of essential assessments in diverse clinical settings.

This pilot study aimed to explore BC through TBK and BCM and determine their association with frailty in patients with cirrhosis. It also examined the correlation between BCM and bedside approaches, including CC, BMI- and edema-adjusted CC, and PhA.

Adult patients with confirmed cirrhosis were recruited from the University of Alberta Cirrhosis Care Clinic, and screened using a customized ruler, to ensure they fit the WBC dimensions. Medical charts were reviewed to obtain specific data (e.g., age, sex, etiology, and disease severity). Exclusion included inpatients, hepatocellular carcinoma outside local transplant criteria (SI-A6), other active malignancies, HIV, prior solid organ transplant, or end-stage disease.

Participants fasted (≥ 8 h), emptied their bladder, wore a hospital gown, and followed remaining protocols (SI-A2). Weight, height, and CC were measured to the nearest 0.1 kg and 0.1 cm, respectively. Adjustment factors were applied to CC (2, SI-A7), and in presence of lower limb edema (6). PhA was obtained at 50 KHz using an 8-point device (SECA 525, Seca GmbH & Co. KG., Hamburg, Germany) after 5 min of supine rest. Performance measures (handgrip strength, sit-to-stand test, and balance tests) were used for LFI calculation (4). Patients were scanned (45 min) in an Accuscan Horizontal Bed WBC 2260 Mirion Technologies (Canberra), Inc™ Meriden, Connecticut, USA, and counting data was analyzed using the Mirion Apex-Invivo™ software to obtain TBK. BCM was assessed using the Cohn equation (SI-A8). TBK values were reported in mmol and grams, while BCM in kilograms and % of body weight; abnormal values were compared to previous literature (SI-A1, SI-A9-10).

Descriptive characteristics are presented as appropriate. Mann-Whitney U and Chi-Square tests were performed. The Shapiro-Wilk test assessed normality of the dependent variables. Pearson’s correlation and stepwise multiple regression analyses were performed considering p < 0.05 significant. IBM SPSS software (Mac. Version 28.0, USA).

Demographic, BC characteristics, and frailty prevalences are shown in Table 1. TBK and BCM were lower in females (p < 0.0001, for both) (Table 1). CC and edema-adjusted CC identified and classified as low CC the same individuals, as BMI-CC and BMI/edema-CC, respectively. Outside of these combinations, CC adjustments and corresponding prevalences differed significantly (χ²(1) = 1.513, p = 0.219).

Table 1

Characteristics of participants and prevalence of body composition abnormalities and frailty
Characteristics	Males n = 10 Median (IQR) n [%]	Females n = 10 Median (IQR) n [%]	Total n = 20 Median (IQR) n [%]
Age, years	55.5 (20.3)	60.5 (30.9)	58.5 (20.5)
Ethnicity, %
Non-White	2 [20]	3 [30]	5 [25]
White	8 [80]	7 [70]	15 [75]
Cirrhosis etiology, %
AIH	0 [0]	1 [10]	1 [5]
Hepatitis B	1 [10]	0 [0]	1 [5]
HCV only	1 [10]	0 [0]	1 [5]
MAFLD	2 [20]	1 [10]	3 [15]
NASH/Cryptogenic	1 [10]	2 [20]	3 [15]
Alcohol only	5 [50]	6 [60]	11 [55]
Child-Pugh^a
Score	6 (2)	6 (2)	6 (2)
Class A/B/C	6/4/0 [60/40/0]	5/4/1 [50/40/10]	11/8/1[55/40/10]
Edema	3 [30]	2 [20]	5 [25]
Weight (kg)	92.5 (16.7)	79.2 (42.8)	90.6 (32.0)
Height (m)	1.757 (0.1)	1.644 (0.1)	1.740 (0.2)
Body Mass Index (kg/m²)	30.2 (8.7)	28.7 (13.9)	30.3 (9.6)
CC (cm)	39.3 (6.0)	38.1 (7.8)	38.7 (7.8)
BMI-adjusted CC (cm)	33.9 (7.2)	32.4 (2.9)	33.4 (4.4)
Edema-adjusted CC (cm)	39.0 (6.9)	36.6 (8.3)	39.1 (8.0)
BMI and edema-adjusted CC (cm)	33.4 (7.2)	31.9 (3.7)	33.0 (4.8)
Phase angle (°)^b	5.9 (1)	5.8 (2)	5.9 (1.1)
TBK (g)	124.1 (28.7)	80.3 (18.3)	95.4 (46.6)
TBK(mmol)	3175 (732.8)	2054 (468.2)	2439 (1192)
BCM (kg)	29.2 (6.8)	18.9 (4.3)	22.4 (11.0)
Liver Frailty Index score	3.5 (0.7)	3.6 (1.2)	3.5 (0.7)
Prevalences
Low CC^c	10%	20%	15%
Low BMI-adjusted CC^c	60%	80%	70%
Low edema-adjusted CC^c	10%	20%	15%
Low BMI/edema-adjusted CC^c	60%	80%	70%
Low phase angle^b,d	20%	38%	28%
Low TBK^e	60%	50%	55%
Low TBK^f	40%	50%	45%
Low BCM^g	80%	90%	85%
Prefrailty^h	70%	70%	70%
Frailty^h	0%	20%	10%
Abbreviations: autoimmune hepatitis (AIH), body mass index (BMI), body cell mass (BCM), calf circumference (CC), hepatitis C virus (HCV), interquartile range (IQR), metabolic dysfunction-associated fatty liver disease (MAFLD), non-alcoholic steatohepatitis (NASH), total body potassium (TBK). ^aA: 5 to 6 points (good hepatic function); B: 7 to 9 points (moderately impaired hepatic function); C:10 to 15 points (advanced hepatic dysfunction);^b n = 18; ^clow CC males ≤ 34 cm and females ≤ 33 cm; ^dlow phase angle ≤ 5.4°; ^eWang et al. (19); ^fKehayias et al. (20); ^gMoore et al. (11); ^hPrefrailty LFI score 3.2–4.4 and Frailty LFI ≥ 4.5.

BCM was strongly associated with male sex (r = 0.802, p < 0.0001). LFI (r=-0.568, p = 0.009), CC (r = 0.484, p = 0.031), and edema-adjusted CC (r = 0.467, p = 0.038) were moderately correlated with BCM. Other tools presented weak (PhA r = 0.031, p = 0.904) or moderate (BMI-adjusted CC r = 0.406, p = 0.075 and BMI/edema-adjusted r = 0.389 (p = 0.090) non-significant correlations with BCM.

Regression models (Table 2) highlight sex-adjusted LFI was predictive of BCM and TBK. LFI was predictive of TBK and BCM while controlling for sex and ethnicity (SI-B).

Table 2

Stepwise multiple linear regression models for predicting total body potassium and body cell mass in patients with cirrhosis
		Unstandardized coefficients		Standardized coefficient			95% Confidence Interval for Beta
Dependent variable (model)	Independent variables	Beta	Standard Error	Beta	t	p	Lower bound	Upper bound
Total body	(Constant)	204.891	17.683		11.587	< 0.0001	167.201	242.580
potassium (g)^a	Sex	-35.019	7.057	-0.666	-4.962	< 0.0001	-50.060	-19.977
	LFI score	-14.150	4.921	-0.386	-2.875	0.012	-24.640	-3.660
Body cell mass (kg)^b	(Constant)	48.214	4.162		11.585	< 0.0001	39.343	57.085
	Sex	-8.240	1.661	-0.666	-4.961	< 0.0001	-11.781	-4.700
	LFI score	-3.330	1.158	-0.386	-2.875	0.012	-5.799	-0.861
n = 20; Abbreviation: liver frailty index (LFI); ^a R² = 0.758, F(2,15) = 23.508, p < 0.0001; ^b R² = 0.758, F(2,15) = 23.500, p < 0.0001.

To our knowledge, this pilot study is the first to assess BC using TBK and BCM, and explore their association with frailty in patients with cirrhosis. It also evaluates practical prognostic tools as potential BCM assessment alternatives. These preliminary findings support the inverse associations between reduced TBK and BCM with LFI, adjusted for sex.

Five studies have evaluated BC using WBC in individuals with cirrhosis; however, none explored the association of TBK or BCM with frailty (7, SI-A2-5). In 225 patients (all stages), while a correlation between anthropometric muscle mass and TBK was observed, there was no significant association between BC and disease severity (Child–Pugh score) (7). Müller et al. also did not find differences in TBK values across disease severity in 473 patients with cirrhosis. Similar to our findings, they reported sex differences in TBK values, observing higher values in males (SI-A4). In 57 patients with severe liver cirrhosis (Child-Pugh C), lower mean TBK index and BCM were observed when compared to compensated patients (Child-Pugh A) (SI-A3).

This study extends existing findings by adding data on the association of TBK and BCM, with bedside BC tools and frailty status. In 631 patients with chronic liver disease (n = 226 with cirrhosis) identified unadjusted CC and handgrip strength were independent predictors of survival. The AIC values of a combined CC-grip strength variable were similar to a CC-skeletal muscle index variable, endorsing CC as a valuable bedside tool (SI-A11). In our cohort, unadjusted CC and edema-adjusted, correlated with BCM, but combined BMI/edema-adjusted CC and BMI-adjusted CC did not. In hospitalized patients, CC was associated with length of hospital stay and mortality, while BMI-adjusted low CC was not (5). The association of the different CC adjustments with clinical outcome deserves further investigation.

Study strengths include the evaluation of novel bedside tools, appropriate adjustments, and use of state-of-the-art techniques. Limitations include device-related constraints, small sample size, and single-center data. Future large-scale research with a diverse sample is essential for validation.

Ethical approval:

This study was approved by the Health Ethics Research Board at the University of Alberta (Pro00099333). Informed consent was obtained from all participants.

Competing Interests:
CMP reports honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, Nestlé Health Science, Pfizer, and AMRA medical. PT received grants from Lupin Pharma Canada and the Nestlé Nutrition Institute. The remaining authors have no conflicts to report.

Supplementary Information:

Supplementary Information A. Additional references unable to fit within the reference limit but of potential interest to the reader

Supplementary Information B. Models for predicting total body potassium and body cell mass in which ethnicity was not dichotomized

Funding:

This study is funded through a grant by the University Hospital Foundation and Alberta Collaboration of Nutrition in Digestive Disease (Ascend) grant awarded to Dr. Puneeta Tandon. CMP is partially funded through the Canada Research Chairs Program.

Acknowledgements:

The University of Alberta Human Nutrition Research Unit (HNRU) staff and facilities that helped us to carry out the study visits and assessments, particularly Stephanie Ramage and Susan Finch. Ben Vandermeer – Alberta Research Centre for Health Evidence, University of Alberta, Edmonton, AB Canada for providing guidance on the statistical analyses for the manuscript. Dr. Richard Mackenzie for supporting researcher KS during the course of this research. Researcher ATLM was supported by the Canadian Institutes of Health Research (CIHR) Postdoctoral Research Fellow, TRIANGLE Canada Research fellow in the ENRICH stream program, ASPEN Rhoads Research Foundation, and the Nutricia Research Foundation International Training Fellow.

Contribution statement

Conceptualization: ATLM, KS, CP, PT; Methodology: ATLM, KS, SI, CP, PT; Software: ATLM, KS, SI; Formal analysis: ATLM, KS; Data curation: ATLM, KS; Investigation: ATLM, KS, SI; Writing – Original draft preparation; ATLM, KS, Writing –Reviewing and Editing: ATLM, KS, SI, CP, PT; Supervision: CP, PT.; Project administration: CP, PT.; Funding Acquisition: ATLM, CP, PT.

Data availability statement:

Within the published article and its supplementary files; additional data are available from the corresponding authors on reasonable request.

Lai JC, Tandon P, Bernal W, Tapper EB, Ekong U, Dasarathy S, et al. Malnutrition, Frailty, and Sarcopenia in Patients With Cirrhosis: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021;74(3):1611–44.
Prado CM, Landi F, Chew STH, Atherton PJ, Molinger J, Ruck T, et al. Advances in muscle health and nutrition: A toolkit for healthcare professionals. Clin Nutr. 2022;41(10):2244–63.
Tandon P, Montano-Loza AJ, Lai JC, Dasarathy S, Merli M. Sarcopenia and frailty in decompensated cirrhosis. J Hepatol. 2021;75 Suppl 1(Suppl 1):S147-s62.
Wang CW, Lebsack A, Chau S, Lai JC. The Range and Reproducibility of the Liver Frailty Index. Liver Transpl. 2019;25(6):841–7.
Sousa IM, Fayh APT, Lima J, Gonzalez MC, Prado CM, Silva FM. Low calf circumference adjusted for body mass index is associated with prolonged hospital stay. Am J Clin Nutr. 2023;117(2):402–7.
Ishida Y, Maeda K, Nonogaki T, Shimizu A, Yamanaka Y, Matsuyama R, et al. Impact of edema on length of calf circumference in older adults. Geriatr Gerontol Int. 2019;19(10):993–8.
Selberg O, Böttcher J, Pirlich M, Henkel E, Manns MP, Müller MJ. Clinical significance and correlates of whole body potassium status in patients with liver cirrhosis. Hepatology Research. 1999;16(1):36–48.
Lautz HU, Selberg O, Korber J, Burger M, Muller MJ. Protein-calorie malnutrition in liver cirrhosis. Clin Investig. 1992;70(6):478–86.
Murphy AJ, Ellis KJ, Kurpad AV, Preston T, Slater C. Total body potassium revisited. European Journal of Clinical Nutrition. 2014;68(2):153–4.
Naqvi S, Bhat KG, Preston T, Devi S, Joseph J, Sachdev HS, et al. The development of a whole-body potassium counter for the measurement of body cell mass in adult humans. Asia Pac J Clin Nutr. 2018;27(6):1190–7.

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SupplementaryInfoA.docx
Supplementary Information A. Additional references unable to fit within the reference limit but of potential interest to the reader
SupplementaryInfoB.docx
Supplementary Information B. Models for predicting total body potassium and body cell mass in which ethnicity was not dichotomized

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You are reading this latest preprint version

Total Body Potassium, Body Cell Mass, and Their Relation to Frailty and Bedside Tools: A Pilot Study in Adults with Cirrhosis

Status:

Version 1

Abstract

INTRODUCTION

METHODS

RESULTS

DISCUSSION

Declarations

Ethical approval:

Competing Interests:
CMP reports honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, Nestlé Health Science, Pfizer, and AMRA medical. PT received grants from Lupin Pharma Canada and the Nestlé Nutrition Institute. The remaining authors have no conflicts to report.

Supplementary Information:

Funding:

Acknowledgements:

Contribution statement

Data availability statement:

References

Additional Declarations

Supplementary Files

Status:

Version 1

Total Body Potassium, Body Cell Mass, and Their Relation to Frailty and Bedside Tools: A Pilot Study in Adults with Cirrhosis

Status:

Version 1

Abstract

INTRODUCTION

METHODS

RESULTS

DISCUSSION

Declarations

Ethical approval:

Competing Interests: CMP reports honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, Nestlé Health Science, Pfizer, and AMRA medical. PT received grants from Lupin Pharma Canada and the Nestlé Nutrition Institute. The remaining authors have no conflicts to report.

Supplementary Information:

Funding:

Acknowledgements:

Contribution statement

Data availability statement:

References

Additional Declarations

Supplementary Files

Status:

Version 1

Competing Interests:
CMP reports honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, Nestlé Health Science, Pfizer, and AMRA medical. PT received grants from Lupin Pharma Canada and the Nestlé Nutrition Institute. The remaining authors have no conflicts to report.