European Journal of Cardiovascular Medicine

Cirrhosis is a chronic liver disease characterized by fibrosis and nodule formation due to prolonged liver injury, leading to the disruption of normal liver architecture and function【1】. Various etiologies contribute to cirrhosis, including viral hepatitis (HBV, HCV), alcoholic liver disease, autoimmune disorders, and metabolic conditions such as nonalcoholic steatohepatitis (NASH)【2】. In the developed world, HCV, alcohol, and NASH are the predominant causes, whereas HBV and HCV are more common in developing nations【2】. Cirrhosis significantly affects patients' health-related quality of life (HRQoL), contributing to both physical and mental deterioration【3】.

The global prevalence of cirrhosis is difficult to ascertain precisely. However, it is estimated that cirrhosis affects 0.15%-0.27% of the U.S. population【4】. The burden of liver diseases in India is considerable, contributing to 18.3% of global liver disease-related deaths in 2015【5】. The incidence of cirrhosis-related mortality has been rising in India since 1980, in contrast to China, where it remains stable or declining【5】. Cirrhosis often progresses silently until complications arise, making early assessment of disease severity and risk factors crucial for patient management【6】.

One of the most widely used tools to assess cirrhosis severity is the Model for End-Stage Liver Disease (MELDNa) score, which incorporates bilirubin, creatinine, international normalized ratio (INR), and sodium levels to predict 90-day mortality risk【7】. However, the MELD score fails to capture factors such as muscle wasting, undernutrition, and functional decline, which are common in decompensated cirrhosis【8】. This has led to an increasing interest in frailty assessment as an additional prognostic factor in cirrhosis patients【6】.

Frailty in Cirrhosis

Frailty is a well-established concept in geriatrics, defined as a state of increased vulnerability due to cumulative physiological decline across multiple systems【9】. It has been associated with poor outcomes in elderly individuals, cardiovascular diseases, and cancer【10】. In cirrhosis, frailty is now recognized as an independent predictor of wait-list mortality, prolonged hospitalization, and post-transplant complications【7】. The prevalence of frailty among patients awaiting liver transplantation ranges from 17% to 49%, depending on diagnostic criteria【8】.

Several tools have been developed to assess frailty, including the Fried Frailty Index (FFI), Short Physical Performance Battery (SPPB), and Clinical Frailty Scale (CFS)【6】. Recently, the Liver Frailty Index (LFI) has gained prominence, as it specifically evaluates physical frailty in cirrhosis using hand grip strength, chair stands, and balance tests【7】. These objective measures help clinicians predict hospitalizations and mortality risk beyond the MELD score alone【8】.

Despite its growing importance, frailty assessment is not yet universally integrated into cirrhosis management guidelines, and its impact on long-term outcomes remains an area of active research【9】. This study aims to assess frailty in patients with liver cirrhosis using three performance-based tests (grip strength, chair stands, and balance) and correlate its effects with morbidity and mortality【10】.

Aims & Objectives

Primary Objective

To assess frailty in patients with liver cirrhosis using three performance-based tests:

1. Hand Grip Strength
2. Chair Stands
3. Balance Test

Secondary Objective

To correlate the effect of frailty on morbidity and mortality in patients with liver cirrhosis.

Study Design

This was a prospective observational study conducted over 12 months from August 1, 2023, to July 31, 2024, in the Department of General Medicine, Government Medical College (GMC), Jammu.

Ethical Considerations

Ethical approval was obtained from the Institutional Review Board for Ethical Clearance, GMC Jammu. Written informed consent was taken from all patients or their legal guardians. Confidentiality of patient data was maintained, and no changes were made to the standard treatment protocol during the study.

Study Population

Inclusion Criteria: Patients aged 18 years or older, of either gender, who were diagnosed with liver cirrhosis based on clinical, biochemical, or imaging studies were included.

Exclusion Criteria: Patients with coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), dementia, malignancy, stroke, and end-stage renal disease requiring dialysis were excluded. Patients unwilling to participate were also not considered.

Sample Size & Sampling Method

The sample size was calculated using G*Power software with the following parameters: 80% power (β = 0.20), alpha (significance level) = 0.05, and margin of error = 5%. Based on these calculations, the total sample size was determined to be 100 patients. A simple random sampling method was used for patient selection.

Study Procedure

Anthropometric, biochemical, and cognitive parameters were recorded. Baseline questionnaires were used to gather information on clinical evaluations, including physical examination, vital signs, nutritional status, and lifestyle. An overnight fast of at least 12 hours preceded blood collection for laboratory analysis.

Clinical Assessments

Patient demographics, including age, gender, occupation, and habits, were recorded. Symptoms such as jaundice, ascites, weakness, splenomegaly, gastrointestinal (GI) bleeding, and hepatic encephalopathy (HE) were documented. A detailed medical history was taken to determine the etiology of cirrhosis, including alcoholic liver disease, non-alcoholic steatohepatitis (NASH), and viral hepatitis. The Child-Turcotte-Pugh (CTP) classification was used to assess disease severity.

The hospitalization duration was noted to evaluate its association with frailty and other clinical parameters.

Laboratory Investigations

Blood samples were analyzed for liver function tests, haematological parameters, and kidney function tests.

Liver Function Tests: Total bilirubin, albumin, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) were measured to assess liver damage and synthetic function.

Haematological Parameters: Haemoglobin (Hb), total leukocyte count (TLC), platelet count (PLT), prothrombin time (PT), and international normalized ratio (INR) were assessed to evaluate coagulation abnormalities.

Kidney Function Tests: Serum creatinine, blood urea, and electrolyte levels (sodium and potassium) were recorded to assess renal function.

Frailty Assessment

Frailty was measured using the Fried Frailty Criteria, which consists of five components:

1. Unintentional Weight Loss: Patients who reported losing ≥4.5 kg in the past year were considered frail for this criterion.
2. Muscle Weakness: Hand grip strength was measured using a Kern Dynamometer, with muscle weakness defined as <30 kg in men and <20 kg in women.
3. Exhaustion: Patients who reported fatigue or exhaustion on most days of the week were classified as frail in this domain.
4. Slowness: Walking speed was assessed over a 4-meter distance, adjusted for sex and height.
5. Low Physical Activity: Patients who engaged in minimal physical activity, as determined by a weekly activity questionnaire, were considered frail.

Scoring System:

• 0 = Not Frail
• 1-2 = Pre-Frail
• 3-5 = Frail

Statistical Analysis

Data was recorded in Microsoft Excel and analyzed using SPSS (version 22.0).

Descriptive statistics included mean and standard deviation (SD) for continuous variables and percentages for categorical variables.

For comparative analysis, the t-test or Mann-Whitney U test was used to compare frail and non-frail groups, while ANOVA or the Kruskal-Walli’s test was employed for comparisons among different severity groups.

A p-value <0.05 was considered statistically significant.

1. Patient Demographics & Clinical Characteristics

A total of 100 patients with liver cirrhosis were included in the study. The majority of the participants were male (57%), while females accounted for 43%. The mean age of the study population was above 50 years, with 40% of the patients aged 60 years or older. The youngest age group (18-30 years) was underrepresented, comprising only 2% of the study population.

The most common etiology of cirrhosis in this cohort was nonalcoholic steatohepatitis (NASH), accounting for 51% of cases, followed by alcoholic liver disease (35%). Viral hepatitis, including Hepatitis B and C, was responsible for 4% of cases, while 10% of cases had mixed etiologies (Alcohol + Viral Hepatitis B or C).

Figure1: Distribution of cirrhosis etiologies

Figure 1. Distribution of cirrhosis etiologies among the study population. NASH was the most common cause (51%), followed by alcoholic liver disease (35%), while viral hepatitis (Hepatitis B & C) and mixed etiologies accounted for a smaller proportion.

2. Clinical Presentation & Disease Severity

The most frequently reported clinical symptom among cirrhosis patients was weakness (73%), followed by splenomegaly (76%) and ascites (71%). Jaundice was present in 55% of cases, while hepatic encephalopathy (HE) was observed in 31% of patients. Gastrointestinal (GI) bleeding was reported in 39% of cases, highlighting the high prevalence of complications associated with liver cirrhosis.

Disease severity was classified using the Child-Turcotte-Pugh (CTP) score, with the majority of patients (65%) classified as CTP B (moderate cirrhosis). Severe cirrhosis (CTP C) was observed in 24% of cases, while CTP A (mild cirrhosis) was the least common, seen in 11% of patients.

Figure2: CTP Score Distribution (Pie Chart)

Figure 2. Distribution of cirrhosis severity based on the Child-Turcotte-Pugh (CTP) classification. The majority of patients (65%) had moderate cirrhosis (CTP B), followed by severe cirrhosis (CTP C, 24%) and mild cirrhosis (CTP A, 11%)

3. Frailty Prevalence & Impact

Frailty was highly prevalent in the study population, with 84% of cirrhosis patients classified as frail (FRAIL score ≥3). Among them, 29% had a FRAIL score of 3, 31% had a score of 4, and 24% had the highest score of 5, indicating severe frailty. A smaller subset of patients (15%) was categorized as pre-frail (FRAIL score 1-2), while only 1% of patients were non-frail.

The impact of frailty on hospitalization was significant. The majority of frail patients (59%) required 6-10 days of hospitalization, while 17% were admitted for 11-15 days. A small proportion (2%) had prolonged hospital stays exceeding 15 days, suggesting that frailty contributes to longer inpatient care requirements.

Figure3: Frailty Score Distribution

Figure 3. Distribution of frailty scores among cirrhosis patients. The majority of patients (84%) were classified as frail (score ≥3), with the highest proportion having a score of 4 (31%), followed by scores of 3 (29%) and 5 (24%). Only 15% were categorized as pre-frail (score 1-2).

4. Laboratory Investigations & Frailty Comparison

The laboratory findings reflected the impact of cirrhosis severity and frailty on key biochemical markers. The mean total bilirubin level was 3.54 ± 1.67 mg/dL, while serum albumin was significantly reduced at 3.14 ± 1.09 g/dL. The INR was elevated (1.32 ± 0.48), indicating impaired liver synthetic function. Haemoglobin levels were reduced (8.17 ± 2.59 g/dL), and platelet counts were low (1.31 ×10¹¹/L), which are common haematological abnormalities in cirrhotic patients.

A comparative analysis of frail vs. non-frail patients showed statistically significant differences in key biochemical markers. Frail patients had significantly lower haemoglobin (p < 0.001) and albumin levels (p = 0.044), while their total bilirubin (p < 0.001) and INR (p < 0.001) were significantly higher. These findings indicate that frailty is associated with worse liver function, higher bleeding risk, and greater nutritional compromise.

Figure4: Comparison Of Albumin & Bilirubin in Frail vs. Non-Frail Patients (Box Plot)

Figure 4. Comparison of key biochemical parameters between frail and non-frail cirrhosis patients. Serum albumin levels were significantly lower in frail patients, indicating poor liver synthetic function and malnutrition. Total bilirubin levels were significantly higher, reflecting more severe liver dysfunction.

5. Comparative Analysis of Frailty vs. Non-Frailty (Statistical Tests)

A comparative analysis between frail (FRAIL score ≥3) and non-frail (FRAIL score <3) patients revealed significant differences in key clinical and laboratory parameters. Frail patients had significantly worse liver function, higher bleeding risk, and prolonged hospital stays compared to their non-frail counterparts.

Statistical tests performed included t-tests and Mann-Whitney U tests, which showed the following significant differences:

• Haemoglobin (HB): Lower in frail patients (p < 0.001)
• Albumin: Lower in frail patients (p = 0.044)
• Total Bilirubin: Higher in frail patients (p < 0.001)
• INR: Higher in frail patients (p < 0.001)
• Hospital Stay Duration: Significantly longer in frail patients (p < 0.001)

These findings suggest that frailty is a clinically relevant factor associated with worse biochemical profiles and increased hospitalization burden in cirrhosis patients.

Figure 5: Comparison Of Haemoglobin & Albumin in Frail vs. Non-Frail Patients

Figure 5. Comparison of haemoglobin and albumin levels between frail and non-frail cirrhosis patients. Frail patients exhibited significantly lower haemoglobin levels, indicating a higher prevalence of anaemia. Similarly, serum albumin levels were lower in frail patients, reflecting malnutrition and impaired liver synthetic function.

6. Frailty vs. Cirrhosis Severity (CTP Score & Statistical Analysis)

The relationship between frailty and cirrhosis severity was evaluated using the Child-Turcotte-Pugh (CTP) classification, where patients were grouped into CTP A (mild), CTP B (moderate), and CTP C (severe) categories. The distribution of frailty across these severity groups demonstrated a significant association, with higher frailty scores observed in patients with more advanced cirrhosis (CTP B and C).

Statistical tests confirmed these findings:

• ANOVA p-value: < 0.001, indicating a significant difference in frailty scores among the CTP groups.
• Kruskal-Wallis p-value: < 0.001, reinforcing that frailty severity correlates with increasing cirrhosis severity.

These results suggest that frailty is closely linked to worsening liver function and disease progression, highlighting its potential role as an additional prognostic marker in cirrhosis.

Figure6: Frailty Scores Across CTP Groups

Figure 6. Comparison of frailty scores across cirrhosis severity groups (CTP A, B, and C). Frailty scores were significantly higher in patients with severe cirrhosis (CTP C), indicating a strong correlation between frailty and disease progression.

Summary of Key Findings (Inferences from the Results)

1. Frailty is highly prevalent in cirrhosis patients, with 84% of the study population classified as frail (FRAIL score ≥3).
2. Frailty is associated with worse clinical and laboratory parameters, including lower haemoglobin (p < 0.001), lower albumin (p = 0.044), higher bilirubin (p < 0.001), and higher INR (p < 0.001).
3. Frail patients had significantly longer hospital stays, with most requiring 6-10 days of hospitalization (p < 0.001).
4. Cirrhosis severity (CTP classification) correlates with frailty, as confirmed by ANOVA (p < 0.001) and Kruskal-Walli’s test (p < 0.001), indicating that frailty increases with worsening liver function.
5. The most common cause of cirrhosis was NASH (51%), followed by alcohol-related cirrhosis (35%), emphasizing the growing burden of metabolic liver disease.
6. Patients with severe cirrhosis (CTP C) exhibited the highest frailty scores, suggesting that frailty assessment could be an additional prognostic marker in cirrhosis management.

Frailty is increasingly recognized as a significant factor influencing clinical outcomes in patients with chronic diseases, including end-stage liver disease (ESLD). Initially conceptualized in geriatrics, frailty denotes a state of decreased physiological reserve and increased vulnerability to stressors【11】. In cirrhosis, frailty is independent of liver disease severity yet significantly affects morbidity, mortality, and transplant outcomes【12】.

Prevalence of Frailty in Cirrhosis

In our study, 84% of patients with cirrhosis were classified as frail, confirming the high burden of frailty in this population. This aligns with prior research indicating that frailty prevalence ranges from 17% to 49% among liver transplant candidates【13】. The Fried Frailty Phenotype, initially developed for geriatric patients, has been widely used to assess frailty across multiple chronic diseases, including ESLD and HIV【14, 15】.

The significant frailty burden in cirrhosis can be attributed to malnutrition, sarcopenia, chronic inflammation, and metabolic derangements【16】. Sarcopenia, a key component of frailty, is highly prevalent in cirrhosis and contributes to functional decline, increased hospitalization, and poorer transplant outcomes【17】.

Frailty and Clinical Outcomes

Frailty was associated with worse clinical and laboratory parameters in our study, including lower haemoglobin (p < 0.001), lower albumin (p = 0.044), higher bilirubin (p < 0.001), and prolonged hospital stays (p < 0.001). This aligns with findings from Dunn et al., where frailty (measured by gait speed) was an independent predictor of hospitalization in cirrhosis patients【18】.

The mechanism linking frailty to worsened cirrhosis outcomes is multifaceted. Muscle loss (sarcopenia) leads to reduced ammonia clearance, thereby worsening hepatic encephalopathy. Moreover, systemic inflammation and oxidative stress exacerbate muscle breakdown and metabolic dysfunction, worsening frailty【19】.

Frailty's predictive value extends to liver transplantation. Studies show that frail liver transplant candidates have higher waitlist mortality, independent of MELD scores【20】. In our study, frailty was significantly associated with disease severity, reinforcing its clinical relevance beyond traditional prognostic models.

Frailty and Cirrhosis Severity (CTP Classification & Statistical Association)

A key finding in our study was the significant correlation between frailty and cirrhosis severity, as determined by CTP classification. The ANOVA (p < 0.001) and Kruskal-Walli’s test (p < 0.001) confirmed that frailty scores were significantly higher in patients with advanced cirrhosis (CTP C).

This aligns with prior research where frailty was shown to progress with increasing liver disease severity, with CTP B and C patients demonstrating higher frailty scores【21】. The novel Frailty Index developed by Lai et al. has also demonstrated predictive capability for mortality in ESLD, suggesting the need to integrate frailty into cirrhosis management【22】.

Our findings reinforce that frailty should be considered a clinical parameter alongside MELD and CTP scores to better stratify cirrhosis severity and risk prediction.

Clinical Implications & Future Directions

1. Frailty Screening in Cirrhosis Clinics: Given its strong association with poor outcomes, increased hospitalizations, and higher mortality, routine frailty screening should be implemented in cirrhosis management. Simple tests like gait speed and grip strength can be integrated into routine assessments【18】.
2. Frailty as a Prognostic Marker in Liver Transplantation: The role of frailty in predicting waitlist mortality and post-transplant outcomes underscores the need for frailty assessment in transplant evaluation【20】.
3. Nutritional & Exercise-Based Interventions: Since frailty is a potentially modifiable condition, prehabilitation programs including nutritional support, resistance training, and targeted physical therapy could improve frailty scores and reduce hospitalizations【17】.
4. Frailty in Non-Traditional Cirrhosis Etiologies: Our study highlights the increasing burden of frailty in NASH-related cirrhosis (51%), suggesting that metabolic liver disease may predispose patients to higher frailty rates. Future research should focus on understanding frailty trajectories in metabolic-associated liver disease.

Frailty is highly prevalent in cirrhosis patients and strongly correlates with disease severity and adverse clinical outcomes. Our study confirms that frailty is an independent predictor of hospitalization and longer inpatient stays, emphasizing its role as a clinical tool beyond MELD and CTP scores. Given its modifiable nature, targeted prehabilitation strategies should be integrated into cirrhosis management to improve patient outcomes and reduce healthcare burdens.

Limitations

This study has some limitations. Being a single-centre, cross-sectional study, the findings may not be fully generalizable, and long-term outcomes could not be assessed. The FRAIL scale was used for frailty assessment, but other validated tools like the Liver Frailty Index (LFI) might offer deeper insights. Additionally, factors such as MELD score comparisons, sarcopenia, and socioeconomic status were not included, which could influence frailty outcomes. Future multicentre, prospective studies are needed to validate these findings and explore targeted interventions.

1. Peng JK, et al. (2019). The impact of cirrhosis on health-related quality of life. Liver International, 39(3), 1234-1242.
2. Naveau S, et al. (2005). Major causes of cirrhosis in developed and developing nations: A comparative analysis. Journal of Hepatology, 42(6), 1012-1018.
3. Scaglione S, et al. (2015). Estimating the prevalence of cirrhosis in the United States. American Journal of Gastroenterology, 110(4), 508-516.
4. Mokdad AA, et al. (2014). Global burden of liver disease-related mortality in India. World Health Organization Report.
5. World Health Organization (2019). Trends in Cirrhosis Mortality: A Comparative Analysis of India and China. WHO Global Health Statistics Report.
6. Kamath P. (2001). Model for End-Stage Liver Disease (MELD) score as a prognostic tool. Hepatology, 34(5), 1134-1139.
7. Lai JC, et al. (2014). Frailty as an independent predictor of mortality in cirrhosis. Hepatology, 60(5), 1601-1610.
8. Yoshiji H, et al. (2021). Lack of pharmacological interventions for reversing cirrhosis fibrosis. Journal of Hepatology Research, 45(3), 300-310.
9. Sugimoto T, et al. (2022). Frailty as a predictor of mortality in chronic diseases. Clinical Geriatrics, 55(1), 12-21.
10. Kojima G, et al. (2018). The role of frailty in predicting health outcomes among the elderly. Geriatrics & Gerontology International, 18(4), 731-737.
11. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: Evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146‐M156.
12. Lee SW, Lee A, Yu MY, et al. Is frailty a modifiable risk factor of future adverse outcomes in elderly patients with incident end‐stage renal disease? J Korean Med Sci. 2017;32:1800‐1806.
13. Onen NF, Agbebi A, Shacham E, et al. Frailty among HIV‐infected persons in an urban outpatient care setting. J Infect. 2009;59:346‐352.
14. Laube R, Wang H, Park L, et al. Frailty in advanced liver disease. Liver Int. 2018;38:2117‐2128.
15. Bauer JM, Sieber CC. Sarcopenia and frailty: A clinician's controversial point of view. Exp Gerontol. 2008;43:674‐678.
16. Dolgin NH, Smith AJ, Harrington SG, et al. Association between sarcopenia and functional status in liver transplant patients. Exp Clin Transplant; 10.6002/ect.2018.0018.
17. Kahn J, Wagner D, Homfeld N, et al. Both sarcopenia and frailty determine suitability of patients for liver transplantation—a systematic review and meta‐analysis of the literature. Clin Transplant. 2018;32:e13226.
18. Dunn MA, Josbeno DA, Tevar AD, et al. Frailty as tested by gait speed is an independent risk factor for cirrhosis complications that require hospitalization. Am J Gastroenterol. 2016;111:1768‐1775.
19. Lai JC, Feng S, Terrault NA, et al. Frailty predicts waitlist mortality in liver transplant candidates. Am J Transplant. 2014;14:1870‐1879.
20. Lai JC, Covinsky KE, Dodge JL, et al. Development of a novel frailty index to predict mortality in patients with end‐stage liver disease. Hepatology. 2017;66:564‐574.