Predictors of Frailty in Patients With Liver Cirrhosis

Introduction Frailty is noticed in a large number of cirrhotic patients with advanced liver disease. Frailty not only disposes cirrhotic patients to increased rates of decompensation and hospitalization but also leads to prolonged hospital stay and increased psychological and social impact, resulting in the delisting of these patients from the transplant list. Therefore, our aim was to identify the factors that are independent predictors of frailty in patients with liver cirrhosis. Methods This cross-sectional study was carried out at the Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan, from March 1, 2022, to August 31, 2022. All the patients diagnosed with liver cirrhosis and aged 18-70 years were included in the study. The excluded patients comprised those with disorders that over-estimate frailty such as cardiopulmonary disease and hepatocellular carcinoma. The measurement of the Liver Frailty Index (LFI) was done using the hand grip strength method, timed chair stands, and balance testing. Patients with LFI >4.5 were considered frail. All data was entered and analyzed using IBM SPSS Statistics for Windows, Version 22.0 (Released 2013; IBM Corp., Armonk, New York, United States). Continuous variables were analyzed using the student-t test while categorical variables were analyzed using the chi-square test. Variables with significance on univariate analysis then underwent multivariate analysis to identify the independent predictors of frailty in cirrhotic patients. A p-value < 0.05 was considered statistically significant. Results A total of 132 patients were included in the study. Out of them, 89 (67.4%) were males. On assessment, 51 (38.6%) patients were frail on presentation. On univariate analysis, female gender, advanced age, raised total leucocyte count, increased percentage of neutrophils on peripheral smear, raised serum creatinine, raised total bilirubin, raised prothrombin time, high Child Turcotte Pugh (CTP) score, and high model for end-stage liver disease along with low hemoglobin and low serum albumin levels were statistically significantly associated with frailty in cirrhosis. On multivariate analysis, female gender, age >40 years, CTP>B7, Hemoglobin <10g/dl, and neutrophils >60% on peripheral smear were independent predictors of liver frailty in cirrhotic patients. Conclusion Female gender, advanced age, increased neutrophils on peripheral smear, decreased hemoglobin along with increased degree of liver dysfunction were independent predictors of increased frailty in patients with chronic liver disease.


Introduction
Cirrhosis is the ultimate result of sustained liver damage as a result of viral infections, autoimmune disorders, metabolic diseases, alcoholic steatohepatitis, non-alcoholic steatohepatitis, and cholestasis [1].Cirrhosis is characterized by fibrous bands and nodule formation on analysis of liver tissue [2].Ascites, portosystemic encephalopathy, variceal bleeding, hepatocellular carcinoma, and various other complications can develop as a result of cirrhosis [3].
Frailty is defined as a decreased physiological reserve and increased susceptibility to adverse outcomes due to various stressors like infections and ischemic events [4].Frailty is a common feature of the cirrhotic

Statistical analysis
For the data analysis, IBM SPSS Statistics for Windows, Version 22.0 (Released 2013; IBM Corp., Armonk, New York, United States) was utilized.Mean±SD was used to express continuous variables while frequencies and percentages were used for the expression of categorical variables.Outcomes were measured in terms of frailty (LFI>4.5).Student T-test was used for the comparison of variables between frail and non-frail groups while Chi-square test was used for categorical variables.Statistically significant variables on univariate analysis then underwent multivariate Cox-regression analysis to identify the independent predictors of frailty in cirrhotic patients.A p-value < 0.05 was considered statistically significant.

Results
A total of 132 patients were included in the study and the baseline characteristics are given in Table 1.The mean age was 47±12.3years.Out of them, 89 (67.4%) were males while 43 (32.6%) were females.Hepatitis C was the most common etiology of chronic liver disease observed in 69 (52.3%) patients followed by hepatitis B in 43 (33.5%)patients, autoimmune hepatitis in seven (5.3%), and non-alcoholic fatty liver disease in four (3%), respectively.Twenty-one (15.9%) patients had a history of one or more episodes of hepatic encephalopathy while a previous history of secondary bacterial peritonitis was noted in eight (6.1%) patients.A history of esophageal varices was noted in 54 (40.9%) patients while there was a history of variceal band ligation previously in 16 (12%) patients.A history of hepato-renal syndrome was also observed in 12 (9%) patients.On assessment, 51 (38.6%) patients were frail at the time of presentation.Hospital admission was required in 56 (42.4%) patients due to liver-related complications.1).Mean hand grip strength was 20.4+14 kg, balance testing was 9.9+0.87seconds and timed chair stand was 14.7+10.3seconds.Using these variables, frailty was measured using the LFI, and the mean LFI was 4.1+0.83.
On comparative analysis, female gender, advanced age, increased total leucocyte count (TLC), percentage of neutrophils on peripheral smear, serum creatinine, total bilirubin, prothrombin time, Child Turcotte-Pugh (CTP) score, and MELD-Na score while decreased hemoglobin and serum albumin were associated with increased frailty in patients with cirrhosis (Table 2).However, no significant difference was observed in terms of peripheral lymphocyte count between the frail and non-frail population.

Discussion
Frailty is a dynamic process and quality of life can be improved by impeding further decline in frailty [11].
Frail patients have an increased risk of disease progression, unplanned hospitalization, and death in both compensated and decompensated cirrhosis as compared to non-frail patients [12].The main purpose of this study was to evaluate the factors that can have an impact on frailty.So, in this study, we came to know that higher CTP scores, advanced age, low hemoglobin (< 10g/dl), and higher neutrophil percentage on different counts of leucocytes are the factors that have an effect on frailty.
Previously, it was known that only age had an impact on frailty and was linked with adverse outcomes in the general population [13].However, in our study we have also identified reversible factors like higher CTP score, low hemoglobin, and raised neutrophil percentage, to be directly related to an increase in frailty.
Correcting the modifiable factors like anemia and increased neutrophil percentage (mostly seen in infectious states) will ensure improvement in overall quality of life, increase life expectancy, and decrease the risk of disease progression and prolonged hospitalization in the cirrhotic population.Cirrhotic patients are very vulnerable and recurrent infections as depicted by raised neutrophils and low exercise capacity due to underlying disease reinforced by anemia can further lead to a decline in physiological reserve and result in frailty.Similarly, elder patients are at risk of frailty, and targeting this group of the cirrhotic population and taking measures to slow down the further decline of performance status may also increase their survival and improve their quality of life.
Moreover, frailty in this study was assessed by the LFI.LFI is an objective tool, more specific to liver-related diseases as compared to other frailty parameters i.e.Fried Frailty Index (FFI), clinical frailty scale, short physical performance battery (SPPB), easy to perform, and time-saving with good inter-observer reproducibility [6].LFI captures the impact of declining liver status on extrahepatic organs as manifested by malnutrition, wasting, and functional impairment [14].Studies have shown that LFI is correlated to MELD-Na and it not only improves the efficiency of MELD-Na while predicting short-term mortality in cirrhosis but also enhances subjective analysis of patient overall health status [9,15].
Our study will help to target a specific group of the cirrhosis population and take measures in order to save them from developing frailty in the future and improve their survival and quality of life.
Frailty is a well-known phenomenon and has many ramifications in cirrhosis [16,17].However, little work has been done to identify predictors of frailty.Without knowing the real culprits leading to frailty, this lethal process cannot be managed.Thus, this study will open gates for further research regarding this topic and may lead to better and prolonged life for patients with cirrhosis.
We acknowledge some limitations in our study.Firstly, this was a single-center study.Secondly, we did not segregate the patients into compensated and decompensated groups.As we all know, frailty is a dynamic process and should be followed with time.In our study, we did not follow our patients and hence we consider it as one of the shortcomings of our study.However, one of the major strengths of our study was that it was a pioneer study revealing the predictors of frailty in cirrhosis and such a study has not been carried out previously, to the best of our knowledge, especially in this part of the world.

Conclusions
Frailty has an impact in cirrhosis and is associated with increased morbidity and prolonged hospitalization in this population.Factors predicting increase risk of frailty were studied and female gender, advanced age, increased neutrophils on peripheral smear along with decreased hemoglobin and increased degree of liver dysfunction were the factors that were independent predictors of frailty in cirrhotic patients.Managing these reversible factors of frailty, i.e. raised total leucocyte count and neutrophil percentage, will not only improve the prognosis in these patients but will also result in improved overall quality of life in this population.For the validation of our results and in order to make these results widely acceptable, multicentered studies with large sample sizes are required.

TABLE 3 : Multivariate cox-regression analysis showing independent predictors of frailty in patients with liver cirrhosis
CTP: Child Turcotte-Pugh