High Prevalence of Hormonal Changes and Hepatic Osteodystrophy in Frail Patients with Cirrhosis—An Observational Study

Abstract

Background/Aim

Hormonal changes and hepatic osteodystrophy are less often studied complications of cirrhosis. This study describes the variance in hormones and osteodystrophy between Frail and Not frail patients with cirrhosis.

Methods

116 outpatients with cirrhosis were prospectively enrolled in this study. Frailty assessment was done using Liver Frailty Index (LFI). Sociodemographic assessment, anthropometry, nutritional assessment, hormone profile, and dual-energy X-ray absorptiometry scan were done in all patients.

Results

116 patients, predominantly males (100 (86.2%) with mean age of 50.16 years (95% CI, 48.43–51.89) were included. Malnutrition was more common in Frail group as compared to Not frail group. Subjective global assessment (SGA) class-B patients were significantly more in Frail group (37 (74%) vs 3 (4.5%), P = 0.001). The prevalence of lower parathyroid hormone (PTH) (14 (28%) vs 2 (3%)), testosterone (33 (66%) vs 15 (22.7%)), vitamin D3 (44 (88%) vs 39 (59.1%)), and cortisol (37 (74%) vs 37 (56.1) levels was higher in Frail group (P < 0.05). The number of patients diagnosed with osteodystrophy (34 (68%) vs 21 (31.8%), P = 0.001) was significantly higher in Frail group. The marker of osteoclastic activity, β-cross laps, was significantly elevated in the Frail group both in males (736 (655–818) vs 380 (329–432), P = 0.001) and (females 619 (479–758) vs 313 (83–543), P = 0.02). Bone mineral density (BMD) at lumbar spine (LS) and neck of femur (NF) had significant correlation with LFI (ρ = 0.60, P = 0.001 for LS and ρ = 0.59, P = 0.001 for NF), serum testosterone (ρ = 0.58, P = 0.001 for LS and ρ = 0.53, P = 0.001 for NF), β-cross laps (ρ = 0.38, P = 0.001for LS and ρ = 0.35, P = 0.000 for NF), vitamin D3 (ρ = 0.23, P = 0.04 for LS and ρ = 0.25, P = 0.01 for NF), PTH (ρ = 0.52, P = 0.001 for LS and ρ = 0.48. P = 0.001 for NF), and cortisol (ρ = 0.50, P = 0.001 for LS and ρ = 0.45, P = 0.001 for NF) levels.

Conclusion

This is the first study that highlights the high prevalence of hormonal changes and hepatic osteodystrophy in frail patients with cirrhosis and opens a new dimension for research and target of therapy in this field.

Cirrhosis is a chronic debilitating disease associated with multisystem involvement. Hormonal changes and hepatic osteodystrophy are less often studied complications of cirrhosis.¹ Endocrine function is complex and involves many biological processes, and as the liver is involved in multiple physiological functions, dysfunction is expected in patients with cirrhosis. The prevalence of hormonal changes in cirrhosis varies from 13% to 58% across various studies.² It consists of low levels of serum cortisol, testosterone, vitamin D, growth hormone, parathyroid hormone (PTH), and raised levels of estradiol and thyroid-stimulating hormone (TSH).^{3, 4, 5, 6, 7, 8} These alterations can be associated with poor health-related quality of life and can adversely affect patient outcomes leading to increased morbidity and mortality.^{9, 10, 11} As the liver plays a critical role in the metabolism of calcium, vitamin D, and parathyroid hormone,¹² hepatic osteodystrophy is common in patients with cirrhosis with a reported prevalence of 12–45% across various studies.^13,14

Frailty is now considered an important predictor of morbidity and mortality in patients with cirrhosis and involves multiple physiological systems including skeletal, neuromuscular, and endocrinal system.^{15,16, 17, 18, 19, 20, 21, 22, 23, 24} As there is scant literature on hormonal changes and hepatic osteodystrophy in Frail patients with cirrhosis, this study was planned to address the knowledge gaps.^{3,4,8,13,14,25, 26, 27, 28, 29}

Patients and methods

This was a prospective observational cohort study done at a tertiary hospital. The study protocol was approved by the ethics committee of the institute (NK/4739/DM/515). Written informed consent was taken from each patient before inclusion in the study. The study was conducted as per the guidelines laid down by the Helsinki declarations (modified 1989).

Patient Selection

116 consecutive patients who visited the Liver Clinic of the Department of Hepatology between July 2018 and June 2019 were enrolled in the study.

Inclusion Criteria

All patients with cirrhosis aged ≥18 years, who attended the liver clinic and were willing to participate in the study, were eligible for inclusion in the study. The diagnosis of cirrhosis was based on clinical, biochemical, and ultrasonography, and/or liver histological data.

Exclusion Criteria

All the patients with hepatocellular carcinoma (HCC) or any other active malignancy, end-stage renal disease, pregnant females, history of recent (<6 weeks) use of drugs that can affect the metabolic bone and endocrinal profile, prior enrolment in another conflicting study, and those who refused to give informed written consent were excluded from the study.

Assessment for Frailty

Liver Frailty Index

The Liver Frailty Index (LFI) was used to diagnose frailty in patients with cirrhosis. It takes into account the handgrip strength, chair stand test, and balance testing.¹⁹ A patient is said to be frail if LFI >4.5, pre-frail if 3.2–4.5, and robust if LFI <3.2. The LFI was calculated in all the patients at the beginning of the study using an online calculator available at http://liverfrailtyindex.ucsf.edu.³⁰

Other Assessments

Sociodemographic assessment, anthropometric measurements, and nutritional assessment of the patients were done in all patients. All the patients at the time of enrolment underwent a battery of laboratory tests including a complete blood count, liver function tests, renal function tests, coagulation profile, serum electrolytes, serum vitamin D3 levels, thyroid profile, iron profile, HbA1c, fasting blood levels of estradiol, testosterone, cortisol, PTH, β-cross laps, procollagen type 1 N-terminal propeptide (P1-NP), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). The assays for vitamin D3, T3/T4/TSH, serum iron, ferritin, total iron-binding capacity, transferrin saturation, estradiol, testosterone, cortisol, PTH, β-cross laps, and P1-NP were done using the chemiluminescence method in cobas® 801 modules (manufactured by Roche Diagnostics, Switzerland). The reference values used to define endocrine dysfunction are mentioned in Supplementary Table 1. A dual-energy X-ray absorptiometry scan (HOLOGIC® QDR 4500, Bedford, MA) was done to assess the bone mineral density (BMD) in g/cm² at the femoral neck and lumbar spine. T-score was calculated for all the patients. Osteopenia was defined as a T-score between −1 and −2.5 standard deviation below the reference value and osteoporosis as T-score > −2.5 standard deviations below the reference value (WHO criteria).³¹

Anthropometry and Nutritional Assessment

Height (cm), dry weight (kg), BMI (kg/m²), mid-arm circumference (MAC), mid-arm muscle circumference (MAMC), and triceps skin-fold thickness (TSF) were measured in all the patients by the research scholar well trained in taking these measurements. Height was measured to the nearest cm using a wall-mounted or freestanding measure. Weight was measured to the nearest 1 kg on a standard weighing scale. The corrected weight was calculated by subtracting a correction for the grade of ascites and/or edema from the weight that was depicted on the weighing machine.³²

The dry weight was used to calculate BMI. The MAC was measured at the mid-point between the acromion and olecranon process in the left arm using a plastic-coated non-stretchable measuring tape to the nearest 0.1 cm. The TSF was measured in the left arm to the nearest 0.2 mm using Harpenden skinfold caliper (Baty International, United Kingdom) calibrated to a pressure of 10 g/mm². The MAMC was calculated using the following formula³³: MAMC = MAC – (TSF X 0.3142).

A nutritional assessment of all the patients was done using the Subjective Global Assessment (SGA).³⁴ All the patients were asked about the history of weight loss in the past 6 months, dietary changes, and their duration, frequency, and duration of gastrointestinal symptoms, and changes in the functional capacity of the patients. Physical examination was done to look for loss of subcutaneous fat, muscle wasting, edema, and ascites. All the patients were classified into SGA class A/B or C depending on the assessment.

Statistical Analysis

The statistical analysis was carried out using IBM® SPSS® Statistics version 23 for Mac. Data were expressed as mean with 95% confidence interval (CI) and proportions with 95% CI where appropriate. Statistical analyses for the categorical data were performed using the Chi-square test or Fisher's exact test, and continuous data were checked for normalcy. For normally distributed data, ANOVA was used, and for skewed data, the Kruskal–Wallis test followed by the Mann–Whitney test was used. All the patients were divided into two groups—Frail and Not frail based on LFI >4.5. The clinical characteristics, hematological and biochemical parameters, anthropometric measurements, and frailty-related parameters were compared between the Frail and Not frail group, and P-values were calculated. Spearman's correlation coefficient was used to study the correlation between two variables. The probability level of P < 0.05 was set for statistical significance.

Results

Out of the 116 patients included in the study, 100 (86.2%) were males. The mean age of the patients enrolled was 50.16 years (95% CI, 48.43–51.89). The most common etiology of liver cirrhosis was alcoholic liver disease in 55 (47.4%) patients, followed by hepatitis C in 15 (12.9%) and NASH in 12 (10.3%) patients. The clinical and demographic profile of the study population is shown in Table 1.

Table 1.

Clinical and Demographic Characteristics of Patients Included in the Study.

Parameters	Patients (n = 116)
Age (years)a	50.16 (48.43–51.89)
Sex (male:female)	6.25:1
Males	100 (86.2%)
Females	16 (13.8%)
Education
Professional	2 (1.7%)
Graduate	37 (31.9%)
Intermediate/Diploma	10 (8.6%)
High school	38 (32.8%)
Middle school	5 (4.3%)
Primary	13 (11.2%)
Illiterate	11 (9.5%)
Socioeconomic status
Upper class	1 (0.9%)
Upper middle class	25 (21.6%)
Lower middle class	63 (54.3%)
Upper lower class	25 (21.6%)
Lower class	2 (1.7%)
Etiology of cirrhosis
Alcohol	55 (47.4%)
Hepatitis C	15 (12.9%)
Hepatitis B	7 (6%)
NASH	12 (10.3%)
Cryptogenic	8 (6.9%)
Others	19 (16.4%)
CTP class
A	30 (25.9%)
B	52 (44.8%)
C	34 (29.3%)
CTP scorea	8.15 (7.75–8.54)
MELD Naa	16.01 (14.9–17.12)

Abbreviations: NASH, non-alcoholic steatohepatitis; CTP, Child–Turcotte–Pugh; MELD Na, model of end-stage liver disease—sodium.

^aValues expressed as mean (95% confidence interval, CI).

Baseline Characteristics

The patients were divided into two groups, Frail (n = 50) and Not frail (n = 66) based on the LFI > 4.5. There was no significant difference between the two groups based on age, etiology of cirrhosis, and the prevalence of diabetes mellitus (Supplementary Table 2). The mean Child–Turcotte–Pugh (CTP) score was 9.48 (8.93–10.03) in the Frail group versus 7.14 (6.72–7.55) in the Not frail group suggestive of severe liver disease in the Frail group (P = 0.001).

Prevalence of Frailty

Frailty in cirrhosis using LFI was diagnosed in 50 (43.1%) patients. The prevalence of frailty was higher in patients with alcoholic cirrhosis 25 (50%) followed by Hepatitis C, 7 (14%), and NASH, 5 (10%). The prevalence of frailty was significantly high in CTP class C patients as compared to the CTP Class B and A patients (Supplementary Table 3). Frailty assessment results for each of the frailty tools are shown in Supplementary Table 4.

Anthropometry and Nutritional Assessment

Malnutrition was more common in the Frail group as compared to the Not frail group. SGA Class-B patients were significantly more in the Frail group (37 (74%) vs 3 (4.5%), P = 0.001) and Class-A patients were significantly more in the Not frail group (63 (95.5%) vs 11 (22%), P = 0.001). All anthropometric parameters including BMI, MAMC, and TSF were significantly lower in the Frail group as compared to the Not frail group. The anthropometric and nutritional assessment of the study population is shown in Table 2.

Table 2.

Anthropometry and Nutritional Assessment.

Parameters	Frail (n = 50) Mean (95% CI)	Not frail (n = 66) Mean (95% CI)	P-value
Body mass index (kg/m2)	19.72 (18.43–21.03)	26.46 (25.12–27.79)	0.001
Mid-arm muscle circumference (cm)
Females	17.12 (15.29–18.95)	21.65 (10.44–32.87)	0.049
Males	18.26 (16.92–19.6)	24.38 (23.55–25.21)	0.001
Triceps skinfold thickness (mm)
Females	7.19 (5.7–8.6)	11.66 (5.4–17.9)	0.019
Males	6.75 (5.74–7.77)	12.67 (11.6–13.74)	0.001
Subjective global assessment (class)
A	11 (22%)	63 (95.5%)	0.001
B	37 (74%)	3 (4.5%)	0.001
C	2 (4%)	0	0.183

Abbreviations: LFI, Liver Frailty Index; CI, confidence interval.

Hormonal Changes

The prevalence of low PTH (14 (28%) vs 2 (3%)), testosterone (33 (66%) vs 15 (22.7%)), vitamin D3 (44 (88%) vs 39 (59.1%)), and cortisol (37 (74%) vs 37 (56.1) was higher in the Frail group (P < 0.05). However, the prevalence of elevated TSH levels (8 (16%) vs 11 (16.7%)) and estradiol levels (35 (70%) vs 46 (69.7%) was similar in both the groups (P > 0.05) as shown in Table 3.

Table 3.

The Prevalence of Hormonal Changes in Frail and Not Frail.

Parameter	Frail (n = 50)	Not frail (n = 66)	P-value
Low PTH	14 (28%)	2 (3%)	0.001
Low testosterone	33 (66%)	15 (22.7%)	0.001
Low vitamin D3	44 (88%)	39 (59.1%)	0.004
Low cortisol	37 (74%)	37 (56.1%)	0.003
Elevated TSH	8 (16%)	11 (16.7%)	0.987
Elevated estradiol	35 (70%)	46 (69.7%)	0.934

TSH, thyroid-stimulating hormone; PTH, parathyroid hormone.

The mean levels of cortisol and PTH were significantly lower in the Frail patients as compared to those Not frail (P = 0.001). The mean testosterone levels were significantly lower in the male Frail patients (P = 0.001), and the mean level of estradiol was significantly higher in the male Frail patients (P = 0.001). There was no difference in the mean TSH, testosterone, and estradiol levels in the females between the Frail and Not frail groups. Table 4 shows the differences in the level of hormones in patients included in the study.

Table 4.

The Difference in the Mean Level of Hormones Between Frail and Not Frail.

Parameters	Frail (n = 50) Mean (95% CI)	Not frail (n = 66) Mean (95% CI)	P-value
TSHa (μIU/ml)	3.02 (2.3–3.74)	2.99 (2.48–3.5)	0.559
Estradiola (pg/ml)
Females	56.12 (35.89–76.34)	54.08 (22.25–130.42)	0.736
Males	66.88 (60.77–73)	52.53 (47.22–57.85)	0.001
Testosteronea (nmol/l)
Females	1.15 (0.79–1.52)	1.74 (0.39–3.9)	0.092
Males	4.28 (2.41–6.15)	19.26 (16.76–21.75)	0.001
Cortisola (nmol/l)	134.85 (109.4–160.29)	218.28 (192.53–244.04)	0.001
PTHa (pg/ml)	28.38 (16.86–39.9)	38.59 (34.07–43.1)	0.001

Abbreviations: LFI, Liver Frailty Index; CI, confidence interval; TSH, thyroid-stimulating hormone; PTH, parathyroid hormone.

^aReference range as mentioned in Supplementary Table 1.

Hepatic Osteodystrophy

The prevalence of hepatic osteodystrophy was significantly higher in the Frail group as compared to the Not frail group (34 (68%) vs 21 (31.8%), P = 0.001). Osteoporosis at the femoral neck (16 vs 0, P = 0.000), as well as the lumbar spine (15 vs 4, P = 0.001), was significantly higher in the Frail group compared to the Not frail group; however, there was no significant difference in the prevalence of osteopenia between the two groups as shown in Table 5. There was a significant difference in the levels of serum calcium (8.26 (8.12–8.4) vs 8.84 (8.71–8.97), P = 0.001), phosphate (2.83 (2.71–2.96) vs 3.42 (3.28–3.56), P = 0.001), and vitamin D3 (20.49 (17.76–23.21) vs 28.22 (24.79–31.64), P = 0.001) between the Frail and Not frail patients. The marker of osteoclastic activity, β-cross laps was significantly elevated in the Frail group as compared to the Not frail group both in the males (736 (655–818) vs 380 (329–432), P = 0.001) and the females (619 (479–758) vs 313 (83–543), P = 0.02). However, the marker of the osteoblastic activity P1-NP was similar between the two groups both in males (100.15 (75.7–124.61) vs 74.80 (59.21–90.4), P = 0.163) and in females (54.98 (36.51–73.44) vs 51.74 (24–79.47), P = 0.946). Table 6 shows the parameters related to hepatic osteodystrophy.

Table 5.

Bone Mineral Density (BMD) at the Neck of Femur and Lumbar Spine.

Group	BMD Normal		Osteopenia		Osteoporosis		Osteodystrophy
	Frail	Not frail	Frail	Not frail	Frail	Not frail	Frail	Not frail
Neck of femur	16 (32%)	45 (68.2%)	18 (36%)	21 (31.8%)	16 (32%)	0	34 (68%)	21 (31.8%)
Lumbar spine	18 (36%)	44 (66.6%)	17 (34%)	18 (27.3%)	15 (30%)	4 (6.1%)	32 (64%)	22 (33.3%)

P = 0.000 for osteoporosis at the neck of femur, P = 0.001 for osteoporosis at the lumbar spine.

P = 0.69 for osteopenia at the neck of femur, P = 0.541 for osteopenia at the lumbar spine.

Table 6.

The Comparison of Parameters Related to Hepatic Osteodystrophy.

Parameters	Frail (n = 50) Mean (95% CI)	Not frail (n = 66) Mean (95% CI)	P-value
Calcium (mg/dl)	8.26 (8.12–8.4)	8.84 (8.71–8.97)	0.001
Phosphate (mg/dl)	2.83 (2.71–2.96)	3.42 (3.28–3.56)	0.001
Vitamin D3a (ng/ml)	20.49 (17.76–23.21)	28.22 (24.79–31.64)	0.001
β-cross lapsa (pg/ml)
Females	619 (479–758)	313 (83–543)	0.026
Males	736 (655–818)	380 (329–432)	0.001
P1-NPa (ng/ml)
Females	54.98 (36.51–73.44)	51.74 (24–79.47)	0.946
Males	100.15 (75.7–124.61)	74.80 (59.21–90.4)	0.163

Abbreviations: LFI, Liver Frailty Index; CI, confidence interval; P1-NP, procollagen type 1 N-terminal propeptide.

^aReference range as mentioned in Supplementary Table 1.

Correlation of BMD with Various Parameters

BMD at lumbar spine had a significant correlation with vitamin D3 (ρ = 0.23, P = 0.04), serum PTH (ρ = 0.52. P = 0.001), LFI (ρ = 0.60, P = 0.001), testosterone (ρ = 0.58, P = 0.001), β-cross laps (ρ = 0.38, P = 0.001), and cortisol levels (ρ = 0.50, P = 0.001) (Supplementary Figures 1 and 2). BMD at neck of femur showed a significant correlation with vitamin D3 (ρ = 0.25, P = 0.01), serum PTH (ρ = 0.48. P = 0.001), LFI (ρ = 0.59, P = 0.001), testosterone (ρ = 0.53, P = 0.001), β-cross laps (ρ = 0.35, P = 0.000), and cortisol levels (ρ = 0.45, P = 0.001).

Other Laboratory Investigations between Frail and Not Frail Group

There was a significant difference in the hemoglobin, serum albumin, bilirubin, INR, creatinine, urea, and sodium levels between the Frail and Not frail groups. The surrogate markers of inflammation including ESR, CRP, and ferritin were also significantly higher in the Frail group as compared to the Not frail group. The laboratory investigations are summarized in Table 7.

Table 7.

Hematological and Biochemical Investigations.

Parameter	Frail (n = 50) Mean (95% CI)	Not frail (n = 66) Mean (95% CI)	P-value
Hemoglobin (gm/dl)	9.96 (9.48–10.44)	11.8 (11.17–12.42)	0.001
Platelets (/mm3)	104,607 (89,188–120,026)	102,573 (92,804–112,343)	0.470
WBC (/mm3)	6018.6(5289.27–6747.93)	6200.11 (5721.13–6679.08)	0.392
Protein (g/dl)	6.85 (6.55–7.15)	7.197 (7.01–7.37)	0.052
Albumin (g/dl)	3.09 (2.94–3.25)	3.63 (3.47–3.79)	0.001
Bilirubin (mg/dl)	3.05 (2.36–3.74)	1.95 (1.63–2.27)	0.002
AST (IU/ml)	63.82 (54.21–73.43)	59.94 (50.8–69.02)	0.273
ALT (IU/ml)	48.86 (40.56–57.16)	45.53 (38.29–52.77)	0.285
ALP(IU/ml)	159.94 (137.44–182.44)	132.02 (119.72–144.31)	0.061
INR	1.59 (1.49–1.69)	1.38 (1.3–1.46)	0.001
Creatinine (mg/dl)	1.12 (1.01–1.23)	0.96 (0.88–1.03)	0.031
Urea (mg/dl)	41.52 (35.58–47.47)	31.94 (27.9–35.99)	0.002
Sodium (mmol/l)	132.9 (131.57–134.23)	137.67 (136.74–138.59)	0.001
Potassium (mmol/l)	3.99 (3.83–4.14)	4.13 (4.02–4.23)	0.039
Chloride(mmol/l)	100.77 (96.51–105.02)	102.53 (101.7–103.35)	0.726
ESR (mm/hour)	30.71 (26.89–34.54)	13.54 (10.89–16.19)	0.001
CRP (mg/dl)	71.44 (63.5–79.38)	32.04 (24.72–39.37)	0.001
Iron (μg/dl)	57.65 (36.91–78.39)	86.9 (72.1–101.7)	0.002
TIBC (μg/dl)	309.54 (236.26–382.82)	304.12 (272.67–335.58)	0.797
Ferritin (ng/ml)	264.17 (208–320.31)	164.53 (129.5–199.57)	0.004
Transferrin saturation (%)	30.58 (13.75–47.4)	34.36 (27.94–40.78)	0.330
FBS (mg/dl)	109.16 (102.1–116.22)	100.05 (96.84–103.25)	0.078

Abbreviations: CI, confidence interval; WBC, white blood cells; AST, aspartate transaminase; ALT, alanine transaminase; INR, international normalization ratio; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; TIBC, total iron-binding capacity; FBS, fasting blood sugar.

Discussion

This study highlights the high prevalence of hormonal changes and hepatic osteodystrophy in frail patients with cirrhosis. Although previous studies have reported similar findings of decreased levels of cortisol,^3,4,25 testosterone,^7,35,36 PTH,³⁷ and vitamin D3^8,38,39 in patients with cirrhosis, there are no studies available that have looked at the differences between Frail and Not frail patients. Frail patients tend to have advanced disease and impairment of regulatory hormonal pathways contributing to endocrine and metabolic dysfunction. Future studies that gauge these changes periodically and assess their correlation can help to establish the cause and the effect relationship.

Hepatic osteodystrophy being more common in Frail patients is multifactorial contributed by malnutrition as evident by lower SGA class, impaired absorption of minerals from intestines, and higher osteoclastic activity as evidenced by low calcium, phosphate, and vitamin D3 levels and elevated β-cross laps. A higher prevalence of osteodystrophy has been reported in multiple studies in patients with cirrhosis^14,40,41; however, none have been reported in frail patients.

Another interesting finding was the significant correlation of BMD with serum testosterone and cortisol levels. Whether supplementing with these hormones early in frail patients can help in decelerating the development of osteodystrophy is an exciting research question that merits further studies. In a previous study by Sinclair et al in patients with cirrhosis, testosterone therapy has shown improvement in muscle mass, bone mass, and reduced fat mass suggesting that hormone therapy may also benefit frail patients.⁴²

Our study also showed significantly higher levels of inflammatory markers such as ESR, CRP, and ferritin in the Frail group. Although previously reported studies have shown CRP,^{28,43, 44, 45} ESR,⁴⁶ and ferritin levels^47,48 to be higher in the patients of cirrhosis and geriatric non-cirrhotic frail patients, to the best of our knowledge no studies have reported an increase in inflammatory markers in the Frail patients with cirrhosis. The possible explanation of these elevated inflammatory markers could be ongoing smoldering chronic inflammation and gut dysbiosis.⁴³

The most common etiology of cirrhosis in this study was alcohol. Alcohol use and alcohol-related cirrhosis have been associated with poor outcomes including deaths that could be explained due to malnutrition, lack of social support, self-neglect, and seeking medical help at an advanced stage of disease.^49,50

Frailty is also an independent predictor of patient outcomes in patients with HCC. Early diagnosis of frailty and hormonal changes and corrective measures such as exercise, dietary modifications, and hormonal supplementation^{51, 52, 53} may improve the quality of life and outcome in patients with HCC.

There are a few limitations of the study. Only outpatients with cirrhosis were recruited in the study which excluded the sick decompensated group and acute on chronic liver failure patients where these changes can be more pronounced and have profound effects on the short-term outcome. A small number of female patients were included in the study; hence, results cannot be generalized. The contribution of age-related changes to hormone and metabolic profiles were not assessed in this study.

This study highlights the high prevalence of hormonal changes and hepatic osteodystrophy in frail patients with cirrhosis and opens a new dimension for research and target of therapy in this field. Future studies focusing on measures to reverse these changes can have a paradigm shift in improving the quality of life and reducing morbidity and mortality in this difficult-to-treat group.

Credit authorship contribution statement

ST—conceptualized study design, interpreted data, drafted manuscript, critical revisions, PT—conceptualized study design, interpreted data, drafted manuscript, critical revisions, SS—acquisition, analysis, and interpretation of data, drafted manuscript, critical revisions, ADe—acquisition of data and critical revisions, NV—acquisition of data and critical revisions, MPK—acquisition of data and critical revisions, AD—acquisition of data and critical revisions, RKD—acquisition of data and critical revisions, VS—acquisition of data, critical revisions, and administrative support.

Conflicts of interest

The authors have none to declare.

Acknowledgments

None.

Funding

None.

Patient consent statement

Consent taken.

Appendix A. Supplementary data

The following is the Supplementary data to this article: