Deficiencies of Micronutrients in Potential Liver Transplant Candidates: A Cross-sectional Study

Abstract

Background

Decompensated liver disease is a debilitating condition often accompanied by significant micro- and macronutrient deficiencies, which can worsen prognosis and complicate treatment, particularly in potential liver transplant candidates.

Objective

We aimed to identify nutritional deficiencies in patients with decompensated chronic liver disease (CLD), who are potential recipients for liver transplantation.

Materials and methods

This cross-sectional, single-center prospective study included consecutive patients. Blood tests were performed to measure levels of key micronutrients, including vitamin D3, zinc, calcium, magnesium, phosphorus, iron, folic acid, and vitamin B12. Nutrient deficiencies were compared in patients with a model for end-stage liver disease (MELD) score ≥15 or less, and Child-Pugh class of B and C.

Results

The cohort comprised a total of 116 patients, 79 (68.1%) males and 37 (31.9%) females. Sixty-nine patients (59.5%) were classified as Child-Pugh class B and 47 patients (40.5%) as Child-Pugh class C, and 71 (61.2%) patients had an MELD score of ≥15. The primary etiologies of CLD were hepatitis C [49 (42.2%)], non-alcoholic fatty liver disease [30 (25.9%)], alcoholic liver disease [20 (17.2%)], hepatitis B [11 (9.5%)], and autoimmune liver disease [6 (5.2%)]. The study identified higher frequencies of deficiencies in zinc (89.7%), vitamin D3 (deficient 62.1%, insufficient 23.3%), calcium (18.1%), folate (15.5%), magnesium (14.7%), iron (13.8%), phosphorus (10.3%), and vitamin B12 (5.2%) across the entire cohort. Vitamin D and magnesium deficiencies became more frequent in Child-Pugh class C compared to B (p = 0.001 and p = 0.006) and MELD score ≥15 (p = 0.001 and p ≤ 0.001).

Conclusion

The high prevalence of deficiencies of crucial micronutrients, such as vitamin D3, zinc, magnesium, and iron highlighted the necessity of comprehensive assessments of nutrition and targeted intervention in patients with decompensated CLD. Effective management of micronutrient levels could potentially reduce complications, improve patient health, and enhance outcomes in these potential liver transplant candidates.

How to cite this article

Kumar M, Abbas Z, Gazder DP, et al. Deficiencies of Micronutrients in Potential Liver Transplant Candidates: A Cross-sectional Study. Euroasian J Hepato-Gastroenterol 2025;15(1):24–28.

Introduction

The human liver, one of the largest and multifunctional organs responsible for various metabolic processes, plays an important role in maintaining health by processing nutrients crucial for bodily functions.¹ Universally, liver diseases account for a substantial portion of morbidity and fatality rates.² The World Health Organization (WHO) states that liver illnesses contribute to approximately 1.34 million deaths annually, and the incidence continues to rise.³ Decompensated liver disease signifies a critical state where the liver's ability to function is significantly impaired, leading to complications such as ascites, hepatic encephalopathy, variceal bleeding, and a compromised immune system.⁴ Amidst the multifaceted nature of liver diseases, the impact of micronutrient deficiencies on these patients has emerged as a subject of profound interest and concern in the medical community.

Micronutrients encompass a wide array of essential vitamins and minerals, including vitamins A, D, E, K, and B complex vitamins, iron, zinc, selenium, and others, each playing a pivotal role in numerous metabolic pathways and physiological functions within the human body. However, in decompensated liver disease, disruptions in liver function significantly affect the absorption, storage, and utilization of these crucial micronutrients.⁵ This interference often leads to deficiencies, exacerbating the complexities associated with liver disease and influencing disease progression, complications, and patient outcomes.

International studies showed the prevalence and impact of micronutrient deficiencies in liver disease patients, revealing concerning statistics and correlations with disease severity. Previous research by various authors highlighted the increased prevalence of specific deficiencies, such as vitamin D deficiency, correlating it with elevated mortality rates in decompensated liver disease patients.⁶ Additionally, studies highlighted deficiencies in essential micronutrients like zinc, selenium, and various B vitamins, emphasizing their association with disease complications and poorer clinical outcomes.⁷

However, from countries grappling with a substantial burden of liver diseases, an exploration into micronutrient deficiencies in decompensated liver disease patients is scant. Limited studies have endeavored to comprehensively examine the incidence and implications of these deficiencies in this specific patient demographic.⁸ We aimed to identify nutritional deficiencies and analyze their association with disease severity in our patients with decompensated chronic liver disease (CLD), who are potential recipients of liver transplantation.

Materials and Methods

This cross-sectional study was conducted over 6 months following approval from the Ethical Review Committee (ERC). Data collection involved demographic information (age and sex), smoking and alcohol use habits, presence of diabetes, reason for admission, and laboratory test results, including bilirubin levels, international normalized ratio (INR), renal function, albumin, and essential micronutrients and trace elements such as calcium, phosphorus, zinc, magnesium, iron, vitamin D3, vitamin B12, and red blood cell folate red blood cell folate (RBC) folate. The etiology of cirrhosis (whether alcoholic, hepatitis C virus (HCV), hepatitis B virus (HBV), or metabolic associated fatty liver disease (MAFLD) was also recorded. Liver dysfunction severity was evaluated using the Child-Pugh classification and model for end-stage liver disease (MELD) score, with higher scores indicating more advanced liver disease. Patients with malabsorption syndromes unrelated to cirrhosis were excluded, as were those with primary biliary cirrhosis due to the low incidence of decompensation and the potential bias in assessing fat-soluble vitamin deficiencies.

The sample size was calculated using online software, with an error margin of 5%, a confidence level of 95%, and a response distribution of 50%. The data were analyzed using SPSS version 29; descriptive statistics were used to summarize demographic and clinical variables, with categorical variables presented as frequencies and percentages and continuous variables as means and standard deviations. The Chi-square test, Fisher's exact test, and Mann–Whitney U test were employed to explore relationships between variables.

Results

The study included a total of 116 patients with a mean age of 54.32 ± 12.68 years and an age range of 18–80 years. Baseline patients' demographic characteristics are shown in Table 1, and laboratory results of micronutrients are in Figure 1 and Table 2.

Table 1.

Summary of baseline characteristics for all included patients

Variable	Value
Age	54.32 ± 12.68
Male	79 (68.1%)
Female	37 (31.9%)
Outpatient	59 (50.9%)
Inpatients	57 (49.1%)
Smoker	21 (18.1%)
Alcoholic	28 (24.1%)
Diabetes mellitus	64 (55.2%)
Hypertension	39 (33.6%)
Hepatocellular carcinoma	28 (24.1%)
Child-Pugh class B	69 (59.5%)
Child-Pugh class C	47 (40.5%)
MELD score ≥15	71 (61.2%)
Etiology of cirrhosis
Alcohol	20 (17.2%)
Hepatitis C	49 (42.2%)
Hepatitis B	11 (9.5%)
Autoimmune CLD	6 (5.2%)
MAFLD	30 (25.9%)

Data are mean ± standard deviation (SD) for quantitative variables and n (%) for qualitative variables. MELD, model for end-stage liver disease; MAFLD, metabolic-associated fatty liver disease

Fig. 1.

Comparison of micronutrient deficiency among Child-Pugh class B, C, and MELD score of ≥15 shown in diagram

Table 2.

Baseline levels for all patients

Parameters	Value	Reference value
Sodium	135.54 ± 5.45	(136–145) mEq/L
Potassium	4.08 ± 0.61	(3.5–5.1) mEq/L
Chloride	103.43 ± 5.27	(98–107) mEq/L
Bicarbonate	21.63 ± 3.82	(23–29) mEq/L
Creatinine	1.33 ± 1.17	Males (0.9–1.3) mg/dL Females (0.6–1.1) mg/dL
Corrected calcium for albumin	9.01 ± 0.62	(8.6–10.0) mg/dL
Magnesium	2.01 ± 0.38	(1.60–2.60) mg/dL
Phosphorus	3.56 ± 0.1	(2.5–4.5) mg/dL
Zinc	55.17 ± 1.2	(73–127) ug/dL
Vitamin D3	17.92 ± 1.32	Deficient (<20) ng/mL Insufficient (20–29) ng/mL Sufficient (30–100) ng/mL Potential toxicity (>100) ng/mL
Vitamin B12	960.56 ± 50.74	(150–201) pg/mL
RBC folate	643 ± 46.05	(228–999) ng/mL
Iron	73.34 ± 3.90	(33–193) ug/dL
TIBC	245 ± 9.5	(259–388) ug/dL
Iron percentage saturation	35.29 ± 2.5

Data are mean ± SD or median (range). TIBC, total iron-binding capacity

A high prevalence of deficiencies of zinc (89.7%), vitamin D3 (deficient 62.1%, insufficient 23.3%), and calcium (18.1%) was observed throughout the study. Only 17 (14.7%) patients were found to have sufficient levels of vitamin D3. The deficiencies of RBC folate, iron, magnesium, and phosphorus were found to be 15.5, 13.8, 14.7, and 10.3%, respectively. The prevalence of vitamin B12 deficiency (5.2%) was not significant. The prevalence of all deficiencies is summarized in Table 3.

Table 3.

Prevalence of micronutrient deficiencies

Micronutrient	Prevalence
Calcium	21 (18.1%)
Magnesium	17 (14.7%)
Phosphorus	12 (10.3%)
Vitamin D3
Deficient	72 (62.1%)
Insufficient	27 (23.3%)
Zinc	104 (89.7%)
Vitamin B12	6 (5.2%)
RBC folate	18 (15.5%)
Iron	16 (13.8%)

There were no notable differences in micronutrient deficiencies based on factors like age, sex, type of cirrhosis, alcohol consumption, diabetes, or body mass index. Similarly, the underlying cause of cirrhosis did not appear to influence the prevalence of these deficiencies. Detailed analysis of micronutrient deficiencies among patients with decompensated liver disease, stratified by Child-Pugh classification, revealed several differences between those in Child class B and C categories. Calcium deficiency was observed in 18.84% of patients with Child class B and 17% of those with Child C, with no significant difference between the groups (p = 0.803). However, a marked disparity was noted in magnesium deficiency, which was significantly more prevalent in Child class C patients (25.5%) compared to those in Child class B (7.2%), reflected by a p-value of 0.006.

Phosphorus deficiency was relatively uncommon, affecting 8.69% of Child class B patients and 12.7% of those with Child C, without a significant difference (p = 0.480). Zinc deficiency was widespread across both groups, impacting 92.7% of patients in Child class B and 85.1% in Child C, though the difference between Child class B and C was not statistically significant (p = 0.184).

Vitamin D3 deficiency exhibited a significant increase in disease severity; in the Child class B group, 47.82% of patients were deficient, with an additional 33.3% classified as insufficient. In contrast, among Child class C patients, 82.9% were deficient, and 8.5% were insufficient (p < 0.001), indicating a profound impact of advanced liver disease on vitamin D metabolism.

Vitamin B12 deficiency was relatively rare and similar between the groups, with 5.7% of Child class B patients and 4.2% of Child C patients affected (p = 1.00). However, RBC folate deficiency showed some difference, occurring in 13.04% of Child class B patients and 19.14% of those with Child C with no statistical significance (p = 0.373). Iron deficiency was somewhat more frequent in Child class C patients (21.27%) compared to Child B patients (8.6%), but a statistical significance (p = 0.54) was not seen. The comparison is shown in Table 4.

Table 4.

Prevalence of micronutrient deficiencies according to Child-Pugh class

Micronutrients	Child-Pugh B	Child-Pugh C	p-value
Calcium	13 (18.84%)	8 (17.02%)	0.041
Magnesium	5 (7.2%)	12 (25.53%)	0.566
Phosphorus	6 (8.6%)	6 (12.7%)	0.480
Zinc	64 (92.7%)	40 (85.1%)	0.184
Vitamin D3			< 0.001
Deficient	33 (47.8%)	39 (82.9%)
Insufficient	23 (33.3%)	4 (8.5%)
Vitamin B12	4 (5.7%)	2 (4.2%)	1.00
RBC folate	9 (13.04%)	9 (19.14%)	0.373
Iron	6 (8.69%)	10 (21.27%)	0.54

Statistical differences were noted between Child class B and C, with lower levels of vitamin D3 (p ≤ 0.001) and higher levels of vitamin B12 (p = 0.005) and RBC folate (p = 0.85) and iron (p = 0.34) in Child class C compared to Child B. However, calcium (p = 0.041), magnesium (p = 0.56), phosphorus (p = 0.092), and zinc (p = 0.89) levels showed slight to no difference between Child class B and C as shown in Table 5.

Table 5.

Serum concentrations of micronutrients according to Child-Pugh class

Micronutrients	Child-Pugh B	Child-Pugh C	p-value
Calcium	8.95 ± 0.48	9.17 ± 0.67	0.041
Magnesium	2 ± 0.35	2.01 ± 0.5	0.56
Phosphorus	3.64 ± 1.01	3.45 ± 1.21	0.092
Zinc	55.03 ± 1.47	55.3 ± 2.04	0.89
Vitamin D3	19.87 ± 1.3	15.06 ± 2.5	<0.001
Vitamin B12	844.21 ± 58.86	1131.38 ± 85.45	0.005
RBC folate	636.77 ± 55.65	654.42 ± 79.75	0.85
Iron	66.53 ± 3.61	83.34 ± 7.88	0.34

Data are mean ± SD. p-value (comparing Child-Pugh C to Child-Pugh B)

The study further analyzed micronutrient deficiencies in patients who were considered potential candidates for liver transplantation, with an MELD score of ≥15. Among the 71 patients (61.2%) who met this criterion, 33 were classified under Child-Pugh class B, while 38 were classified under Child C. Table 6 describes the incidence of micronutrient deficits based on MELD scoring.

Table 6.

Prevalence of micronutrient deficiencies according to MELD scoring

Micronutrients	Prevalence	p-value
Calcium	13 (18.30%)	0.9
Magnesium	17 (23.9%)	<0.001
Phosphorus	9 (12.6%)	0.3
Zinc	62 (87.32%)	0.3
Vitamin D3		0.001
Deficient	53 (74.64%)
Insufficient	13 (18.3%)
Vitamin B12	2 (2.8%)	0.205
RBC folate	13 (18.3%)	0.29
Iron	12 (16.9%)	0.22

The comparison of micronutrient deficiency among Child class B, C, and MELD score of ≥15 identified that zinc deficiency is the most prevalent across all groups, with particularly high rates in Child-Pugh class B (92.7%) and the MELD score of ≥15 group (87.32%). Vitamin D3 deficiency is also notably high, especially in Child-Pugh class C, where 82.9% of patients were found to be deficient, compared to 74.6% in the MELD score group and 47.8% in Child-Pugh class B. Magnesium deficiency showed a significant contrast between the groups, with 25.53% of Child C patients affected, in contrast to only 7.2% in Child B, and 23.9% in the MELD score ≥15 group. Calcium and phosphorus deficiencies are relatively consistent across the groups, with prevalence ranging from approximately 12.6 to 18.84%. Vitamin B12 and RBC folate deficiencies are less common, with prevalence below 20% in all groups.

Discussion

Micronutrients play an important role in several antioxidant, anti-inflammatory, and antiapoptotic metabolic pathways, and their deficiency is common in patients with decompensated hepatic illnesses regardless of etiology. This cross-sectional study aimed to fill the knowledge gap by assessing micronutrient deficiencies in our decompensated CLD patients, building them nutritionally, and bridging them to transplant to provide a better life.

Zinc is a crucial trace element, second in abundance; it plays a pivotal role in numerous physiological and catabolic processes.⁹ Zinc deficiency is particularly common in patients with decompensated liver disease, primarily due to impaired absorption and increased urinary excretion induced by diuretics.¹⁰ Our investigation revealed a high prevalence of zinc deficiency, affecting 89.7% of the patient population, with a clear association between deficiency and disease severity. These findings are consistent with previous research, including a 2021 study by Llibre Nieto et al., which reported an 85.6% prevalence of zinc deficiency in 125 cirrhotic patients, also highlighting the correlation with disease severity.¹¹ Similarly, Sengupta et al. found an 83% prevalence of zinc deficiency among 163 cirrhotic patients.¹² Other studies have reported prevalence rates ranging from 83 to 94%, further identifying the widespread nature of zinc deficiency in this patient population.^13,14

Vitamin D3, essential for immunity and calcium homeostasis, plays a crucial role in decompensated liver disease.¹⁵ It is closely linked to disease severity and poor prognosis.^6,16–20 Our study identified a 62.1% prevalence of vitamin D deficiency and 23.3% insufficiency, with these levels worsening as Child-Pugh classes and MELD scores increased. This aligns with findings from Jamil Z et al. in 2018, where 88% of patients had insufficient or deficient vitamin D levels, particularly in those with more advanced liver disease.¹⁸ A 2015 study also reported an 87% prevalence of vitamin D deficiency or insufficiency in 94 patients, correlating with disease severity.²¹ Similarly, a 2013 retrospective study found that 80.9% of 63 liver transplant candidates were deficient in vitamin D.²²

Phosphate, like other essential minerals, plays a vital role in numerous physiological processes, including energy metabolism, bone health, and cellular function. In patients with decompensated liver disease, disrupted phosphate homeostasis can lead to hypophosphatemia, which is associated with numerous complications and adverse outcomes. Hypophosphatemia is often exacerbated by the use of diuretics and malabsorption issues that are common in these patients. A study conducted by Dohyeong et al. involving 71 patients with cirrhosis found that 25.3% of these patients had hypophosphatemia, with the risk of developing this condition increasing up to 3.4-fold.²³ Additionally, hypophosphatemia is linked to acute liver failure and plays a role in hepatocyte regeneration.^24,25 Our results, however, indicated a lower prevalence of hypophosphatemia at 9.9%, which might be attributed to dietary differences across regions. This finding warrants further investigation. Nevertheless, the prevalence of hypophosphatemia increased with disease severity, consistent with the findings of a retrospective study by Ionele CM et al., which included 143 patients.²⁶

Similarly, calcium, the fifth most abundant element in the body, is essential for various physiological processes, such as bone metabolism, muscle function, and nerve transmission. In the context of liver disease, calcium homeostasis can be significantly disrupted, leading to deficiencies that may contribute to complications like osteoporosis and subsequent atraumatic fractures.²⁷ Nakchbandi has recommended that bone density should be evaluated in patients with liver disease, regardless of their calcium levels, and that prompt supplementation should be provided to prevent fractures.²⁸ Our study identified a higher prevalence of calcium deficiency at 18.1%, compared to a study conducted by Llibre-Nieto G, who reported a deficiency rate of 4.6% in a cohort of 87 patients.¹¹

The 2nd most abundant intracellular ion and the fourth most abundant cation in the body, magnesium plays a critical role in numerous physiological functions. It is essential for over 300 enzymatic reactions, including those involved in energy production, muscle function, and cardiovascular health. Additionally, magnesium supports bone health, nervous system function, glucose regulation, and various cellular processes, such as deoxyribonucleic acid (DNA) replication and repair, intermediary metabolism, ion transport, cell proliferation, and signal transduction.²⁹

The significance of magnesium in liver disease is well-documented. A study by Veena G et al. reported a magnesium deficiency prevalence of 71.8% among 71 patients, with rates increasing in correlation with disease severity.³⁰ Our study observed a lower prevalence of 14.7%, yet it similarly demonstrated a direct link to the severity of liver disease. Moreover, a review by Liu et al. highlighted the detrimental effects of magnesium deficiency on liver disease progression, noting its potential to exacerbate cirrhosis and contribute to liver cancer advancement. The review also suggested that supplementation could slow disease progression and reduce mortality.³¹ Another study identified a 12.8% prevalence of deficiency, which increased with disease severity, consistent with our findings.¹¹

In decompensated liver disease, deficiencies in vitamin B12 and RBC folate are attributable to the liver's compromised ability to store and release these essential nutrients. Vitamin B12 deficiency often presents paradoxically with elevated serum levels due to hepatic release and reduced uptake, yet there is a functional deficiency at the cellular level, leading to anemia and neurological symptoms and indicating higher levels were a good index of the degree of hepatocyte injury and poor prognosis.^32–34 This corresponded with our study, which identified the prevalence at 5.2%, and levels increased with disease severity.

Red blood cell folate deficiency, driven by malabsorption, dietary insufficiency, reduced hepatic stores, hemolytic anemia, and immature erythrocyte formation, contributes to macrocytic anemia and hyperhomocysteinemia, increasing cardiovascular risk.^34,35 Our study identified the prevalence at 15.5% with no significant difference in prevalence and levels with disease severity.

Conclusion

This highlights a concerning level of micronutrient deficiencies, especially in vitamin D3, zinc, magnesium, and iron, among patients with advanced liver disease, particularly those who are being considered for a liver transplant. These deficiencies were more common in patients with higher MELD scores or those in Child class B or C. The findings emphasize the importance of closely monitoring and addressing nutritional needs in these patients, as managing deficiencies could help reduce complications and improve overall health. By focusing on better nutritional care, we have the potential to improve outcomes for those waiting for a liver transplant and help them achieve better recovery and quality of life.