Introduction: There are a number of causes for Vitamin D deficiency in chronic liver disease, including insufficient sun exposure, inadequate dietary intake, steroid use, deterioration of vitamin synthesis in the skin caused by jaundice, and decreased Vitamin D absorption brought on by intestinal edema secondary to portal hypertension. Present study was aimed to study vitamin D deficiency and its relationship with Child Pugh score in patients with chronic liver disease. Material and Methods: The present study was carried out in the patients who were clinically diagnosed with chronic liver disease. All necessary investigations were performed, and the severity of chronic liver disease (CLD) was defined as per Child Pugh Criteria and MELD scoring system. Results: In the study, the mean age of the subjects was 47.36 ± 10.56 years. Majority were males(80.7%), normal BMI (53.5%). The prevalence of Vitamin D deficiency among the subjects with chronic liver disease was 60.5%. About 28.9% of the subjects were deficient of Vitamin-D, while remaining 10.5% cases showed normal levels of Vitamin D. The mean Vitamin D levels among the subjects was 22.15 ± 5.72 ng/mL. On cross-analysis, the Vitamin D status found to deteriorate significantly with increase in the age group and BMI, more among males and increase in the severity of hepatic encephalopathy. The mortality rate was 2.9% and 30.3% among the subjects with insufficient and deficient levels of Vitamin D respectively. The study also found statistically significant difference in the levels of Vitamin D with respect to severity of liver disease, thereby suggesting that Vitamin D levels reduce significantly among the subjects with severe liver disease. Conclusion: Statistically significant difference was observed in the levels of Vitamin D with respect to the severity of chronic liver disease based on Child Pugh Score.
As an advanced form of liver disease, liver cirrhosis leads in high mortality rates and frequent complications that significantly reduce the quality of life. Patients with decompensated cirrhosis have mortality rates at 1 and 2 years that were estimated to be 40% and 55%, respectively. They made up around 2% of all fatalities worldwide.1 There is need for biochemical prognostic marker. The Child-Pugh Score and Model for End-stage Liver Disease (MELD) scoring systems are now commonly utilized for clinical decision-making in patients with decompensated cirrhosis.2,3
Since the liver is the primary organ responsible for 25-hydroxylation of Vitamin D and generation of 25(OH)D3 carrier proteins. Any dysfunction of the liver might impact serum levels of 25(OH)D3. In fact, 25(OH)D3 slow the development of chronic liver disease and may modulate immune system. The fact that Vitamin D deficiency is quite common in non-cirrhotic individuals proves that the Vitamin D deficiency in CLD is only partially the product of a hepatic synthesis malfunction. Following Vitamin D therapy, 25(OH)D levels in cirrhotic patients return to normal.4,5
There are a number of causes for Vitamin D deficiency in CLD, including insufficient sun exposure, inadequate dietary intake, steroid use, deterioration of vitamin synthesis on the skin caused by jaundice, and decreased Vitamin D absorption brought on by intestinal edema secondary to portal hypertension or to cholestasis-induced bile salt disruption.6,7 Present study was aimed to study vitamin D deficiency and its relationship with Child Pugh score in patients with chronic liver disease.
Present study was single-center, prospective, observational study, conducted in department of General Medicine, Karnataka Institute of Medical Sciences, Hubballi, India. Study duration was of 2 years (December 2020 to November 2022). Study was approved by institutional ethical committee.
Inclusion criteria
Exclusion criteria
Study was explained to participants in local language & written informed consent was taken. Patients who were clinically diagnosed with chronic liver disease, and were eligible for the study according to the above mentioned eligibility criteria were included in the study after informed consent from the patient. All patients were subjected to clinical and laboratory evaluation as per proforma.
The following investigations will be done such as CBC, Liver function test, PT, INR, Renal function tests, Serum electrolytes, HCV, HBsAg serology, Serum Vitamin D level, Ascitic fluid analysis, ECG, Chest X Ray, USG abdomen and pelvis were done in the selected patient. Severity of CLD was defined as per Child Pugh criteria and MELD system. Serum level of Vitamin D was measured by venous sampling.
Data was entered into Microsoft excel data sheet and was analyzed using SPSS 22 version software. Normality of the continuous data, was tested by Kolmogorov–Smirnov test and the Shapiro–Wilk test. Continuous data was represented as mean and standard deviation. Independent t test was used as test of significance to identify the mean difference between two quantitative variables. Categorical data was represented in the form of Frequencies and proportions. Chi-square test was used as test of significance for qualitative data. Fischer’s exact test was used as test of significance for qualitative data which does not fulfill the criteria for Chi-square test (2x2 tables only). Yates correction was applied were ever chi-square rules were not fulfilled (for 2x2 tables only).
In the study, majority of the subjects belonged to the age group of 46 to 60 years (54.4%).followed by age group was 31 to 45 years (28.9%). The mean age of the subjects was 47.36 ± 10.56 years. In the study, majority of the subjects were males (80.7%), and the remaining were females(19.3%). Based on body mass index (BMI) in the study, majority of the subjects were normal (53.5%). The next common group was overweight (28.9%), followed by underweight (12.3%) and obese (5.3%). The mean BMI of the was 22.93 ± 4.81 kg/m2.
Table 1: General characteristics
Characteristics |
No. of subjects |
Percentage |
Age group (in years) |
|
|
18 to 30 years |
10 |
8.8% |
31 to 45 years |
33 |
28.9% |
46 to 60 years |
62 |
54.4% |
>60 years |
9 |
7.9% |
Mean Age (in years) |
47.36 ± 10.56 |
|
Gender |
|
|
Male |
92 |
80.7% |
Female |
22 |
19.3% |
Body Mass Index (BMI) |
|
|
Underweight |
14 |
12.3% |
Normal |
61 |
53.5% |
Overweight |
33 |
28.9% |
Obese |
6 |
5.3% |
Mean BMI (in kg/m2) |
22.93 ± 4.81 |
|
In the study, majority of the subjects had insufficient levels of Vitamin-D (60.5%), followed by deficient levels (28.9%). Remaining 10.5% cases showed normal levels of Vitamin-D. The mean Vitamin-D levels among the subjects was 22.15 ± 5.72 ng/mL.
Table 2: Distribution of the study subjects based on Vitamin D levels
Vitamin D levels |
Frequency (N) |
Percentage (%) |
Optimal |
12 |
10.5% |
Insufficient |
69 |
60.5% |
Deficient |
33 |
28.9% |
Mean Vitamin D (in ng/mL) |
22.15 ± 5.72 |
|
In the study, the mean hemoglobin, total protein and bilirubin, and serum albumin were 10.76 ± 2.60 g/dL, 6.28 ± 4.63 g/dL, 5.96 ± 3.02 g/dL and 3.15 ± 0.57 g/dL respectively. The mean serum creatinine was 1.89 ± 1.81 mg/dL. The mean INR was 1.92 ± 1.31 and mean prothrombin time was 4.30 ± 3.86 seconds.
Table 3: Laboratory investigation findings among the study subjects
Parameters |
Mean |
SD |
Median |
Min |
Max |
Hemoglobin (in g/dl) |
10.76 |
2.60 |
11.00 |
1.20 |
15.00 |
Total Protein (in g/dl) |
6.28 |
4.63 |
5.90 |
2.60 |
40.00 |
Total Bilirubin (in mg/dl) |
5.96 |
3.02 |
5.00 |
2.00 |
12.00 |
Serum Albumin (in g/dl) |
3.15 |
0.57 |
3.20 |
2.00 |
4.70 |
Serum Creatinine (in mg/dl) |
1.89 |
1.81 |
0.90 |
0.40 |
7.70 |
International Normalized Ratio |
1.92 |
1.31 |
1.50 |
0.80 |
6.50 |
Prothrombin Time (in seconds) |
4.30 |
3.86 |
2.90 |
0.90 |
18.00 |
In the study, the most common etiology of the liver disease was found to be alcohol (79.8%). The other causes were viral infection (8.8%) and autoimmune condition (1.8%).
Table 4: Etiology of the liver disease among the study subjects
Etiology |
Frequency (N) |
Percentage (%) |
Alcohol |
91 |
79.8% |
Autoimmune |
2 |
1.8% |
Viral Infection |
10 |
8.8% |
Cryptogenic |
11 |
9.6% |
In the study, most common grade of hepatic encephalopathy was Grade I (14.0%), followed by Grade II (12.3%) and Grade III (9.6%). Remaining 7.0% cases were diagnosed with Grade IV hepatic encephalopathy.
Table 5: Severity of hepatic encephalopathy
Encephalopathy |
Frequency (N) |
Percentage (%) |
No |
65 |
57.0% |
Grade I |
16 |
14.0% |
Grade II |
14 |
12.3% |
Grade III |
11 |
9.6% |
Grade IV |
8 |
7.0% |
In the study, mean Child Pugh score among the subjects was 9.61 ± 2.74. Majority of the subjects belonged to Class B(43.9%) with significant compromise of liver functions. The next common group was Class C (35.1%) where decompensated disease was evident. Remaining 21.1% cases were regarded as Class A with compensated disease.
Table 6: Distribution of the study subjects based on Child Pugh classification
Child Pugh Classification |
Frequency (N) |
Percentage (%) |
Class A (5 to 6) |
24 |
21.1% |
Class B (7 to 9) |
50 |
43.9 % |
Class C (10 to 15) |
40 |
35.1% |
Mean Child Pugh Score |
9.61 ± 2.74 |
|
In the study, Model for End-Stage Liver Disease (MELD score) was used, mean score among the subjects was 20.00 ± 9.33. Majority of the subjects scored between 10 and 19 (67.5%), where the mortality was less than 6.0%. The next common majority was observed between the scores of 20 and 29 (15.8%), followed by 30 to 39 (8.8%), where the mortality chances increase respectively. The chances of mortality among the remaining 7.9% cases were more than 71.3% as the score was 40.
Table 7: Distribution of the study subjects based on MELD Score
MELD Score |
Frequency (N) |
Percentage (%) |
10 to 19 (6.0%) |
77 |
67.5% |
20 to 29 (19.6%) |
18 |
15.8% |
30 to 39 (52.6%) |
10 |
8.8% |
40 (71.3%) |
9 |
7.9% |
Mean MELD Score |
20 ± 9.33 |
|
Present study found statistically significant association of age of the subjects with respect to the status of Vitamin D, thereby suggesting that Vitamin D status deteriorates significantly with increase in the age group.
Present study found statistically significant association of gender of the subjects with respect to the status of Vitamin D, thereby suggesting that Vitamin D status is significantly poorer among males in comparison with females.
Present study found statistically significant association of BMI of the study subjects with respect to the status of Vitamin D, thereby suggesting that Vitamin D status deteriorates significantly with variation in BMI.
Table 8: Comparison of Vitamin D status with respect to age of the study subjects
|
Vitamin D Status |
p-value # |
|||||
Optimal (N=12) |
Insufficient (N=69) |
Deficient (N=33) |
|||||
N |
% |
N |
% |
N |
% |
||
Age |
|
|
|
|
|
|
|
18 to 30 years |
6 |
50.0% |
4 |
5.8% |
0 |
0.0% |
<0.001* |
31 to 45 years |
3 |
25.0% |
21 |
30.4% |
9 |
27.3% |
|
46 to 60 years |
2 |
16.7% |
40 |
58.0% |
20 |
60.6% |
|
>60 years |
1 |
8.3% |
4 |
5.8% |
4 |
12.1% |
|
Gender |
|
|
|
|
|
|
|
Male |
5 |
41.7% |
59 |
85.5% |
28 |
84.8% |
0.001* |
Female |
7 |
58.3% |
10 |
14.5% |
5 |
15.2% |
|
BMI |
|
|
|
|
|
|
|
Underweight |
0 |
0.0% |
6 |
8.7% |
8 |
24.2% |
0.049* |
Normal |
7 |
58.3% |
42 |
60.9% |
12 |
36.4% |
|
Overweight |
3 |
25.0% |
19 |
27.5% |
11 |
33.3% |
|
Obese |
2 |
16.7% |
2 |
2.9% |
2 |
6.1% |
In the study, most common etiology is alcohol, irrespective of the status of Vitamin D. However, the study found statistically significant association of etiology of the CLD with respect to the levels of Vitamin D, thereby suggesting that Vitamin D status deteriorates significantly with variation in etiological factors.
In the study, the Vitamin D levels were either insufficient or deficient in majority of the subjects with hepatic encephalopathy. Also the study found statistically significant association of severity of hepatic encephalopathy with respect to the status of Vitamin D, there by suggesting that Vitamin D status deteriorates significantly with increase in the severity of hepatic encephalopathy.
Table 9: Comparison of Vitamin D status with respect to the etiology of chronic liver disease & severity of hepatic encephalopathy
|
Vitamin D Status |
p-value # |
||||||||
Optimal (N=12) |
Insufficient (N=69) |
Deficient (N=33) |
||||||||
N |
% |
N |
% |
N |
% |
|||||
Etiology |
|
|
|
|
|
|
|
|||
Alcohol |
5 |
41.7% |
56 |
81.2% |
30 |
90.9% |
<0.001* |
|||
Autoimmune |
2 |
16.7% |
0 |
0.0% |
0 |
0.0% |
||||
Viral |
2 |
16.7% |
6 |
8.7% |
2 |
6.1% |
||||
Cryptogenic |
3 |
25.0% |
7 |
10.1% |
1 |
3.0% |
||||
Gender |
|
|
|
|
|
|
|
|||
No |
12 |
100.0% |
51 |
73.9% |
2 |
6.1% |
<0.001* |
|||
Grade I |
0 |
0.0% |
15 |
21.7% |
1 |
3.0% |
||||
Grade II |
0 |
0.0% |
0 |
0.0% |
14 |
42.4% |
||||
Grade III |
0 |
0.0% |
0 |
0.0% |
11 |
33.3% |
||||
Grade IV |
0 |
0.0% |
3 |
4.3% |
5 |
15.2% |
||||
In the study, the mean Vitamin D levels in Class C were 16.93 ± 3.41 ng/mL, which was lower compared to that of 23.08 ± 2.88 ng/mL among subjects in Class B, and that of 28.92 ± 5.10 ng/mL among Class C. The study also found statistically significant difference in the levels of Vitamin D with respect to severity of liver disease, thereby suggesting that Vitamin D levels reduce significantly among the subjects with severe liver disease.
Table 10: Comparison of Vitamin D levels with respect to Child Pugh Classification
|
Child Pugh Classification |
p-value # |
|||||
Class A (N=23) |
Class B (N=54) |
Class C (N=43) |
|||||
Mean |
SD |
Mean |
SD |
Mean |
SD |
||
Vitamin D (in ng/mL) |
28.92 |
5.10 |
23.08 |
2.88 |
16.93 |
3.41 |
<0.001* |
In the study, majority of the subjects got discharged alive (89.5%). The mortality rate in the study was 10.5%. Study found statistically significant association of final outcome with respect to the status of Vitamin D, there by suggesting that decrease in Vitamin D levels increases the risk of mortality. Also the mortality rate was 2.9% and 30.3% among the subjects with insufficient and deficient levels of Vitamin D respectively.
Table 11: Comparison of Vitamin D status with respect to the final outcome
Outcome |
Vitamin D Status |
p-value # |
|||||||||
Optimal (N=12) |
Insufficient (N=69) |
Deficient (N=33) |
|||||||||
N |
% |
N |
% |
N |
% |
||||||
Alive |
12 |
100.0% |
67 |
97.1% |
23 |
69.7% |
<0.001* |
||||
Dead |
0 |
0.0% |
2 |
2.9% |
10 |
30.3% |
Recently Vitamin D has attracted attention as pro-survival molecule. Many researches have revealed that this molecule has pleiotropic effects in relation to cell differentiation, proliferation. And anti-inflammatory processes. Several studies have focused on the association of serum Vitamin D levels and prognosis of patients with chronic liver disease. In most studies Vitamin D levels were significantly correlated with conventional liver function scoring systems, such as Child Pugh and MELD scores.
In the present study, majority of the subjects belonged to the age group of 46 to 60 years (54.4%). Mean age in present study is 47.36 ± 10.56 years, which is comparable with study done by Kumar R et al.,8 47.98 ± 12.13 years and Khan MA et al.,9 48.85 ± 13.60 years. Mean age group in Putz Bankuti C et al.,10 study was 58.00 ± 11.00 years, which is slightly higher compared to our study because it had more patients in older age group
Majority of the subjects in the present study were males (80.7%), and the remaining were females (19.3%), because alcohol abuse is major cause of CLD, which is more common in males. Fernandez NF et al.,11 Kumar R et al.,8 and Putz Bankuti et al.,10 study had comparable M:F ratio and 65.0 : 34.0 , 65.0 : 35.0 and 68.0 : 32.0 respectively. Khan MA et al.,8 study has lower males group (53.3 : 46.7) compared to other studies because majority of study subjects belongs to NAFLD and viral etiology.
Since Vitamin D deficiency is common in majority of overall population in Indian and many Asian countries as compared to studies based on Western population. Various Asian country studies have shown high prevalence of Vitamin D deficiency, this can be observed from the below figure number 26. Gupta BK et al.,12 had 85.0%, Fernandez NF et al.,11 87.0% & Kumar et al.,8 79.0% Vitamin D deficiency. These values are comparable with our present study and majority of subjects belongs Child Pugh Class B and C.
Putz Bankuti et al.,10 study which was conducted in European population has lower prevalence of Vitamin D compared to other studies, because it included few patients with advanced stages of liver dysfunction i.e. Child Pugh Class C. This further tells us that Vitamin D deficiency increases with advanced stages of chronic liver disease.
Due to high prevalence of alcohol abuse in community, most common etiology of the chronic liver disease in our present study was found to be alcohol (79.8%). The other causes were viral infection (8.8%) and autoimmune condition (1.8%). Remaining 9.6% cases were observed to have uncertain origin. This has been universal as the alcohol was found to be the commonest etiology of CLD in all the previous studies such as Kim TH et al.,13 Gupta BK et al.,12 Putz-Bankuti C et al.,10 etc.
Various studies have majority of subjects in Class B and C group like Kim TH et al.,13 Class B (32.9%) and Class C (46.4%) , Gupta BK et al.,12 Class B (49%) and Class C 33.7%) which was comparable with our present study.
In the present study, the mean MELD score among the subjects was 20.00 ± 9.33. This is quite higher than the mean scores of 14.42 ± 4.32 , 18.85 ± 5.21, 16.12 ± 3.96, in the studies by Kumar R et al.,8 Jamil Z et al.,14 and Kim TH et al.,13 respectively. Overall, most of the previous studies such as Gupta BK et al.,12 and Fernandez NF et al.,11 also have found that higher chances of mortality among the subjects with high MELD score.
To confirm the usefulness of serum Vitamin D levels in predicting the survival of patients with cirrhosis, Kim TH et al.,13 study has used new prognostic model i.e. MELD-D score. It has better predictivity for short and long term prognosis. This was calculated by adding five points to patients with MELD score <20 and severe Vitamin D deficiency. Patients with a MELD score >20 or those without severe Vitamin D deficiency, had a MELD-D score that was same with MELD score.
The present study found statistically significant association of age, gender and BMI of the subjects with respect to the status of Vitamin D, thereby suggesting that Vitamin D status deteriorates significantly with increase in the age group and BMI, and more among males. This mimics the association observed in the studies such as Gupta BK et al.,12 Kumar R et al.,8 Putz- Bankuti C et al.,10 and Jamil Z et al.,14 which have signified the importance of characteristics of the subjects in affected the levels of Vitamin D.
Child Pugh Scores is a well-known representative of liver function in advanced liver disease. The mean Vitamin D levels in different Child Pugh Classes were statistically found to be significant with respect to severity of liver disease, there by suggesting that Vitamin D levels reduce significantly among the subjects with severe liver disease.
This can be compared with previous studies as Kumar R et al.,8 (Mean Vitamin D levels in Class C 15.6 ng/ml), Jamil Z et al.,14 (Mean Vitamin D levels in Class C 13.4 ng/ml) & Gupta BK et al.,12 (Mean Vitamin D levels in Class C 15.46 ng/ml).
The present study found statistically significant association of final outcome with respect to the status of Vitamin D. The mortality rate was 2.9% and 30.3% among the subjects with insufficient and deficient levels of Vitamin D respectively. All deceased patients belong to Child Pugh Class C, there by suggesting that deterioration in Vitamin D status increases the risk of mortality. This can be justified from the associations observed in the previous studies such as Kim TH et al.,13 & Gupta BK et al.,12 where the outcome was poor with the severe Vitamin D deficiency.
Limitations of present study were small sample size, short duration of the study and less frequency of follow-ups. Other factors such as detailed socio-demographics of the subjects, dietary patterns, adherence to the treatment etc. which may affect the results have not been recorded. We recommend that apart from evaluating the relation between Vitamin D and severity of liver disease, there is a requirement of intervention studies with supplementation of Vitamin D which could impart the significance among the patients with chronic liver disease.
Vitamin D deficiency was prevalent among more than half of the patients with chronic liver disease. In our study we have shown that, low levels of Vitamin D are associated with significant liver dysfunction and predict hepatic decompensation and high mortality in patient with chronic liver disease. High CPS, MELD score, INR, increasing age (>45years) and male gender were associated with severe vitamin D deficiency. Statistically significant difference was observed in the levels of Vitamin D with respect to the severity of liver disease based on Child Pugh Score, thereby suggesting that Vitamin D levels reduce significantly among the subjects with severe liver disease.
Conflict of Interest: None to declare
Source of funding: Nil