Beyond bones: Revisiting the role of vitamin D in chronic liver disease

Abstract

Beyond its traditional role in calcium and bone metabolism, vitamin D has emerged as a critical regulator of liver health. Its active form, calcitriol [1α,25(OH)₂D], signals through the vitamin D receptor (VDR), which is expressed in hepatic stellate cells, Kupffer cells, and cholangiocytes. Through this pathway, vitamin D modulates fibrosis, inflammation, oxidative stress, bile acid homeostasis, and immune responses. This review explores the growing body of evidence linking vitamin D deficiency to chronic liver diseases, including autoimmune hepatitis, primary biliary cholangitis, alcoholic liver disease, viral hepatitis B and C, and metabolic-associated steatotic liver disease. Low vitamin D levels are frequently observed in these conditions and are associated with disease severity, complications (such as spontaneous bacterial peritonitis, sarcopenia, and hepatic encephalopathy), and increased mortality. Mechanistically, vitamin D-VDR signaling inhibits profibrotic TGF-β1/SMAD pathways, downregulates proinflammatory cytokines, enhances regulatory T cell differentiation, and improves insulin sensitivity. Although preclinical studies support its protective effects, clinical trials of vitamin D supplementation have produced mixed results. Overall, vitamin D appears to influence multiple pathways in liver disease pathophysiology, and correcting its deficiency may offer clinical benefits. However, its integration into clinical care will depend on identifying responsive patient subgroups and defining optimal dosing strategies to maximize therapeutic benefit.

Key Words: Vitamin D; Vitamin D receptor; Fibrosis; Inflammation; Immune response; Vitamin D deficiency; Chronic liver diseases

Core Tip: Vitamin D plays diverse roles in chronic liver disease beyond bone health, including modulation of fibrosis, immune responses, bile acid metabolism, and oxidative stress via vitamin D receptor signaling. Deficiency is common across liver disease etiologies and linked to worse outcomes. Although preclinical data are promising, clinical trials have yielded inconsistent results. This review summarizes the mechanistic and clinical evidence for vitamin D in autoimmune, viral, alcoholic, and metabolic liver diseases, emphasizing its potential as a modifiable factor and the need to define patient subgroups most likely to benefit from supplementation.

INTRODUCTION

Vitamin D is a fat-soluble steroid that plays a crucial role in calcium and phosphorus homeostasis, bone health, insulin secretion, and immune system function[1]. It is also considered a prohormone, as the body converts it into its active form: Calcitriol or 1α,25(OH)₂D, which regulates numerous physiological processes[2]. Vitamin D can be found in two main forms. Vitamin D3 (cholecalciferol), of animal origin, is the most significant source in humans. It is synthesized in the skin from 7-dehydrocholesterol upon exposure to sunlight. Vitamin D2 (ergocalciferol), of plant origin, is derived from ergosterol, a precursor produced by fungi and plants[1,3]. Both vitamin D2 and vitamin D3 follow the same metabolic pathway in the body[4].

BIOCHEMICAL AND BIOLOGICAL BASIS OF VITAMIN D

Sources and metabolism

Vitamin D is obtained from two primary sources: Sunlight exposure and diet. Upon ultraviolet B (UVB) exposure (wavelength 290-315 nm), 7-dehydrocholesterol in the skin is photochemically converted into previtamin D, which is then thermally isomerized into vitamin D[5]. Dietary vitamin D is absorbed primarily in the jejunum and, to a lesser extent, in the duodenum[6], encapsulated in chylomicrons and released into the bloodstream[7]. Afterward, vitamin D is transported to the liver by the vitamin D-binding protein (VDBP), where it is metabolized by the enzymes 25-hydroxylase (CYP2R1 and CYP27A1) into 25(OH)D, also known as calcidiol, which is the main circulating form of vitamin D in the serum. Then, in the proximal tubule of the kidney, the enzyme 1α-hydroxylase (CYP27B1) converts 25(OH)D into 1α,25(OH)₂D, or calcitriol, the most biologically active form of vitamin D[1,8,9].

Calcitriol then enters the circulation and, after binding to VDBP, is delivered to target tissues[10]. In these tissues, calcitriol binds to the vitamin D receptor (VDR), a member of the nuclear receptor family of ligand-activated transcription factors, inducing both genomic and non-genomic regulation of downstream targets involved in various biological functions. Calcitriol can rapidly diffuse across cell membranes and bind VDRs. Once bound to its ligand, the VDR forms heterodimers with the retinoid X receptor (RXR) and translocates to the nucleus, where the complex binds to vitamin D response elements (VDRE) to regulate gene transcription[11].

Once both calcidiol and calcitriol are produced, their levels are tightly regulated by 24-hydroxylase (CYP24A1), the primary enzyme responsible for vitamin D inactivation. This enzyme catalyzes the hydroxylation reactions of both calcidiol and calcitriol, particularly at position 24 (C-24) of calcitriol, leading to a series of reactions that ultimately generate calcitroic acid, an inactive metabolite excreted via the bile[8,9].

In addition to CYP24A1-mediated regulation, vitamin D metabolism is modulated by two key hormones: Parathyroid hormone (PTH) and FGF23. Both are essential for maintaining calcium and phosphate homeostasis[12-14]. In response to hypocalcemia, PTH is released and stimulates the conversion of calcidiol into calcitriol in the kidneys by CYP27B1. Calcitriol, in turn, enhances intestinal calcium absorption, contributing to the normalization of serum calcium levels and supporting bone health, one of the major physiological roles of vitamin D[15]. FGF23 is secreted by osteoblasts and osteocytes in response to elevated serum phosphate and calcium levels[14]. It reduces serum calcitriol levels by inhibiting the expression of CYP27B1 while stimulating CYP24A1 expression in the kidney, although the mechanisms behind these actions are not yet fully understood[16-18] (Figure 1). Some studies suggest that 7-dehydrocholesterol and vitamin D₃ may follow an alternative metabolic pathway, as they are substrates for CYP11A1, but further research is needed to fully elucidate this mechanism[19,20].

Figure 1 An integrated view of vitamin D metabolism. UVB: Ultraviolet B; VDBP: Vitamin D-binding protein; VDR: Vitamin D receptor; RXR: Retinoid X receptor; VDRE: Vitamin D response element; PTH: Parathyroid hormone. Created in Canva (Supplementary material).

Vitamins D₂ and D₃ are fat-soluble, and are stored in adipocytes (fat cells), especially in individuals with obesity. Although people with obesity may have larger total vitamin D stores, these are less bioavailable and are not readily reflected in circulating blood levels[7]. The conversion of vitamin D₂ and D₃ into calcidiol [25(OH)D] usually occurs efficiently, but this process is impaired in obesity due to reduced expression of CYP2R1, the enzyme responsible for the first hydroxylation step. As a result, vitamin D₃ levels remain disproportionately high, while calcidiol levels are often lower compared to those in healthy individuals, despite greater vitamin D storage[7].

Vitamins D₂ and D₃ have a short half-life of approximately 24 hours[7], while calcitriol [1α,25(OH)₂D], the active form of vitamin D, has an even shorter half-life of 4-15 hours[7,21-23]. In contrast, calcidiol [25(OH)D], the main circulating metabolite, has a much longer half-life of about 2-3 weeks[7,21,22,24]. Due to this longer duration and its ability to reflect both dietary intake and sunlight exposure, serum calcidiol is the most reliable and commonly used biomarker for assessing vitamin D status in clinical practice. Measuring calcitriol levels in contrast, is more technically complex and expensive[7,23,25,26].

Currently, there is no universal consensus on the exact optimal range for vitamin D levels. Figure 2 presents a comparison of thresholds proposed by different institutions regarding adult serum levels of vitamin D (specifically calcidiol).

Figure 2 Calcidiol serum levels proposed by major professional organizations, illustrating the ranges designated as deficiency, insufficiency, sufficiency, upper safe level, and toxicity. EASL: European Association for the Study of the Liver; AGS: American Geriatrics Society; ESCEO: European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis; IOF: International Osteoporosis Foundation.

Although these recommendations differ slightly, especially in defining toxicity[21,27-29], the general thresholds for deficiency, insufficiency, and sufficiency are fairly consistent[30-32]. These variations may reflect population-specific characteristics, but the average values can serve as a useful reference for broader application.

Physiological functions: Bone and liver systems

The functions of vitamin D include bone growth and mineralization, regulation of immune function, control of insulin secretion, regulation of cell proliferation and differentiation, induction of apoptosis, and maintenance of calcium-phosphorus homeostasis, including calcium transport in muscle cells[11].

Vitamin D plays a crucial role in maintaining liver health, particularly through its active form, 1α,25(OH)₂D, which exerts its biological effects by binding to the VDR. In the liver, the VDR is primarily expressed in non-parenchymal cells, including Kupffer cells, hepatic stellate cells (HSCs), and cholangiocytes[33]. One of the key hepatic functions of vitamin D is the regulation of immune responses. Through VDR-mediated signaling, vitamin D helps modulate inflammation, protect against tissue injury, and inhibit the development of hepatic fibrosis[34]. These mechanisms are illustrated in Figure 3.

Figure 3 Vitamin D receptor signals in liver cell populations. VDR: Vitamin D receptor. Created in BioRender (Supplementary material).

The binding of calcitriol to VDR can activate both genomic and non-genomic pathways. For genomic activation, calcitriol first enters the cell and binds to inactive VDR located in the cytoplasm[35]. VDR contains a ligand-binding domain which includes a ligand-binding pocket where calcitriol docks, inducing conformational changes. This structural shift enables VDR to heterodimerize with RXR, forming the VDR-RXR complex[36]. The complex then translocates to the nucleus, where it binds to VDREs within the promoter regions of target genes. This interaction recruits co-activator proteins such as histone acetyltransferases which modify chromatin to enhance gene transcription. Subsequently, the mediator complex and RNA polymerase II are recruited, leading to the transcription of genes involved in immune regulation, cell proliferation, and differentiation[35].

In contrast, the non-genomic pathway is initiated when calcitriol binds to membrane-associated VDR. This activates GPCRs, resulting in an increase in intracellular Ca²⁺ through calcium channels. The elevated Ca²⁺ levels trigger downstream signaling cascades, including the activation of protein kinases such as PKC and ERK/MAPK. These rapid signaling events regulate processes such as autophagy, immune responses, and lipid metabolism[35].

VDR also interacts with HNF4α, a key regulator of hepatic lipid metabolism and triglyceride transport. This interaction has been shown to reduce lipid accumulation in the liver, particularly in high-fat-diet mouse models[37]. The vitamin D-VDR complex improves hepatic insulin sensitivity by enhancing the PI3K/AKT signaling pathway, suppressing FOXO1-mediated gluconeogenesis, and mediating the metabolic benefits of vitamin D. In liver regeneration, the VDR complex is essential following hepatic injury. It regulates the expression of cell-cycle genes such as cyclin D1, cyclin E1, and Cdk2, as well as the anti-apoptotic gene Bcl2, thus promoting hepatocyte survival and coordinated regeneration[38].

In HSC which are the primary drivers of fibrosis upon liver injury, VDR activation counteracts the pro-fibrogenic effects of TGF-β, a major HSC activator. In the absence of VDR, SMAD2 phosphorylation increases, enhancing the transcription of fibrogenic genes[39]. Interestingly, there is a regulatory mechanism in hepatic fibrogenesis in which initial SMAD3 activation is paradoxically required for later suppression of fibrotic gene expression. First, SMAD3 phosphorylation by TGF-β remodels chromatin, enabling VDR access. Then, VDR displaces SMAD3 and suppresses profibrotic gene transcription. This mechanism helps explain how VDR signaling modulates wound-healing responses in the liver[40]. In addition, p62, a scaffold protein that activates stress-responsive transcription factors (NRF2 and NF-κB), binds to VDR in HSCs, enhancing the VDR-RXR complex formation. This interaction is critical for VDR-mediated repression of fibrosis and inflammation[41]. Conversely, the absence of VDR increases the NF-κB activation and upregulates the expression of fibrosis-related genes[42].

In Kupffer cells (liver-resident macrophages), hepatocyte-derived danger signals and apoptotic bodies released during endoplasmic reticulum (ER) stress activate the unfolded protein response via the IRE1, PERK, and ATF6 sensors. These pathways trigger IKK-NF-κB signaling, resulting in increased production of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α. The vitamin D-VDR complex in Kupffer cells exerts strong anti-inflammatory effects by inhibiting NF-κB activation, thereby reducing cytokine production. When VDR signaling is active, it helps resolve both the ER stress and the inflammatory response[43,44].

Vitamin D also influences adaptive immunity. The vitamin D-VDR complex modulates T cell receptor signaling, suppresses T cell activation and proliferation, and inhibits Th1-type cytokine production[45]. It induces tolerogenic dendritic cells, promotes Foxp³⁺ regulatory T cells (Tregs), inhibits Th17 responses, and enhances Th2 cell polarization[46-48]. Together, these immunomodulatory effects contribute to attenuating hepatic inflammation and fibrogenesis, reinforcing the importance of adequate vitamin D levels in maintaining liver immune homeostasis and preventing disease progression.

In cholangiocytes, which line the bile ducts, VDR can be activated by lithocholic acid, a secondary bile acid (BA), and its derivatives.

Activation of the vitamin D-VDR complex increases CYP7A1 expression (rate-limiting enzyme in bile acid synthesis) and decreases the expression of small heterodimer partner, a nuclear receptor that normally represses BA synthesis[49]. These findings suggest that VDR plays a complex regulatory role, capable of modulating BA homeostasis by shifting the balance between synthetic and inhibitory pathways under specific pathological conditions. VDR deletion in mice leads to reduced BA pool size and worsens cholestatic injury[38].

In Abcb4 knockout mice, a model for chronic cholangiopathy, VDR ablation (VDR-/-; Abcb4-/-) exacerbates liver disease, promotes cholangiocyte proliferation, and increases chemokine expression (CCL2 and CCL20), amplifying macrophage recruitment and liver inflammation[50].

Clinical application and supplementation

Vitamin D can be obtained from two main sources: Sunlight exposure and diet. The majority (up to 80%) comes from skin synthesis triggered by sunlight, while the remaining 20% is derived from dietary intake[21]. The amount of vitamin D needed to maintain proper physiological function varies depending on age, sex, and individual characteristics. Table 1 presents the estimated average requirement and the recommended dietary allowance (RDA) established by the United States National Academy of Medicine. Vitamin D intake is typically measured in micrograms (µg) or international units (IUs), with 1 µg equivalent to 40 IU[28,51].

Table 1 Recommended daily intake of vitamin D by sex and age group, according to current dietary reference values.

Group	EAR (IU)	RDA (IU)
Men (year)
19-70	400	600
> 70	400 (10 μg)	800 (20 μg)
Women (year)
19-70	400 (10 μg)	600 (15 μg)
> 70	400 (10 μg)	800 (20 μg)

EAR: Estimated average requirement; RDA: Recommended dietary allowance; IU: International unit.

Most people worldwide meet at least part of their vitamin D needs through sun exposure. Factors influencing UVB exposure include season, geographic location, time of day, cloud cover, skin pigmentation, and sunscreen use. Older adults and individuals with darker skin produce less vitamin D from sunlight[51]. UVB does not penetrate glass, so sunlight exposure through windows does not result in vitamin D synthesis[52].

Guidelines recommend 5-30 minutes of direct sun exposure in the morning, with sunscreen applied afterward[53,54]. This can generate up to 3000 IU of vitamin D[54].

Only a few foods naturally contain vitamin D. Fatty fish and fish liver oils, such as trout, salmon, tuna, and mackerel, are the best natural sources. Beef liver, egg yolk, and cheese contain smaller amounts. Vitamin D in animal tissues varies with diet[51,55]. Taking vitamin D supplements with fat-containing meals improves absorption[56,57]. Table 2 lists selected foods and their vitamin D content per 100 g[58]. Dietary intake alone is usually insufficient, especially for those following plant-based diets or facing geographic or socioeconomic limitations.

Table 2 Vitamin D-rich foods ranked by content per 100 g serving.

Foods	μg/100 g	IU/100 g
Cod liver oil	250	10000
Raw mackerel	16.1	644
Raw salmon	10.9	436
Canned sardines	4.8	192
Raw trout	3.9	156
Raw tuna	1.7	68
Egg (yolk)	5.5	220
Margarine	3.7	148
Beef liver	1.2	48
Yogurt, skim milk	1.2	48
Low-fat milk	1	40
Cheddar and feta cheese	0.5	20
Butter	0.4	16
Orange juice	1	40
Raw shiitake mushrooms	0.5	20
Soy milk	0.7	28

IU: International unit.

Therefore, it is important to combine dietary intake with safe sun exposure, always following established guidelines to protect skin from damage.

Vitamin D is most commonly administered as cholecalciferol (vitamin D3), though other formulations such as ergocalciferol (vitamin D2), eldecalcitol, and calcifediol, are also available. Cholecalciferol is widely used because its dosage correlates with changes in blood levels of calcidiol [25(OH)D], which is the standard biomarker for assessing vitamin D status and is associated with key clinical outcomes[21].

The RDA is 400-800 IU/day, with a tolerable upper limit of 4000 IU/day. However, the optimal dose may vary depending on the intended health outcome, and some authors suggest that the safer upper limit may actually be lower than 4000 IU per day[59,60]. For instance, 400-800 IU daily may be sufficient to prevent clinical deficiency and maintain calcium homeostasis in healthy individuals.

On the other hand, doses exceeding the recommended upper limit may pose a risk of toxicity. Nevertheless, daily doses as high as 10000 IU have been used without safety concerns in some studies[61]. It is important to note that there is no universally accepted consensus on the ideal vitamin D supplementation regimen, as individual factors significantly influence baseline vitamin D levels and requirements.

Before initiating supplementation, serum calcidiol [25(OH)D] should be measured. Table 3 summarizes findings from several studies evaluating vitamin D supplementation in various liver diseases. More evidence is needed before drawing definitive conclusions about the effect of vitamin D supplementation on liver disease. Additional randomized clinical trials are required to assess longer treatment durations, different formulations of vitamin D (e.g., cholecalciferol vs calcidiol), and larger, more diverse patient populations. Without these elements, it may be difficult to detect meaningful effects, whether beneficial or potentially harmful, of the intervention.

Table 3 Overview of published studies on vitamin D supplementation and its therapeutic impact on hepatic conditions.

Ref.	Population	Type of study	Intervention	Outcomes
Mohamed et al[153], 2021	328 patients with SBP (168 control group vs 160 supplementation group), aged over 18 years	RCT	Supplementation: 300000 IU of cholecalciferol as a loading dose via intramuscular injection, followed by a maintenance dose of 800 IU/day orally, plus oral calcium supplements at a dose of 1000 mg. Duration: 6 months	(1) Increased serum vitamin D levels in the treatment group (P < 0.001); (2) Higher survival rate (64% vs 42%; P < 0.05); and (3) Association between vitamin D supplementation and 6-month survival (HR = 0.895, P < 0.001)
Kim et al[165], 2018	548 patients with chronic HCV (7 RCTs), aged 7-42 years	Meta-analysis	Supplementation: (1) 6 studies used: 1000/1600/2000 IU daily of cholecalciferol; and (2) 1 trial used: 15000 IU weekly of cholecalciferol. Duration: 24 weeks of pegylated interferon alpha and RBV (Peg-IFN-α + RBV) antiviral treatment	(1) Combination of Peg-IFN-α + RBV significantly increased the sustained virological response rate at 24 weeks (RR = 1.30; 95%CI: 1.04-1.62); and (2) Greatest efficacy observed in patients with HCV genotype 1
Hariri and Zohdi[166], 2019	353 patients with MASLD (6 RCTs), aged over 18 years	Systematic review	Supplementation: (1) 4 trials with: 50000 IU of cholecalciferol weekly; (2) 1 trial with: 2000 IU/day of cholecalciferol; and (3) 1 trial with: 25 µg of calcitriol/day. Duration: 6-24 weeks	(1) Improved lipid profile and inflammatory mediators compared to placebo; and (2) Reduction in liver enzymes when combined with calcium carbonate
Grover et al[167], 2021	164 patients with cirrhosis of any etiology (82 control group vs 82 supplementation group), aged 18-60 years	RCT	Supplementation: 60000 IU of cholecalciferol weekly for the first 2 months, followed by 60000 IU monthly for 10 months. Duration: 1 year	Significant increase in 25(OH)D levels in the intervention group compared to placebo
Kong et al[168], 2022	104363 participants (32 RCTs), mostly women, aged 53-85 years	Meta-analysis	Supplementation: 800-4000 IU of cholecalciferol/day. Duration: Follow-up from 9 to 120 months	Significant reduction in risk of falls (RR = 0.91) and osteoporotic fractures (RR = 0.87)
Sakpal et al[169], 2017	81 patients with MASLD (40 control group vs 41 supplementation group), aged 18-70 years	RCT	Supplementation: 600000 IU of vitamin D via a single injection, along with lifestyle modifications (exercise and diet). Duration: 6 months	(1) Significant improvement in ALT levels (87 ± 48 IU/mL to 59 ± 32 IU/mL, P < 0.001) compared to the control group (64 ± 35 to 62 ± 24 IU/mL, P = 0.70); and (2) Significant increase in adiponectin levels (P = 0.018)
Goto et al[170], 2022	Male Wistar rats (four groups of 5-8 rats), 6 weeks old	Preclinical experimental model	Supplementation: 5000 IU/kg and 10000 IU/kg of cholecalciferol in the diet. Duration: 25 weeks	(1) Reduction in hepatic collagen deposition and inflammation; (2) Increased antioxidant activity and Nrf2 protein in the liver; and (3) Higher dose (10000 IU/kg) reduced the number of hepatic adenomas and preneoplastic lesions

SBP: Spontaneous bacterial peritonitis; IU: International unit; HR: Hazard ratio; HCV: Hepatitis C virus; RCT: Randomized controlled trial; RBV: Ribavirin; HR: Hazard ratio; RR: Relative risk; 95%CI: 95% confidence interval; MASLD: Metabolic-associated steatotic liver disease; ALT: Alanine aminotransferase.

Vitamin D deficiency should be suspected in patients with liver disease, especially in advanced stages of the disease and in those with alcoholic liver disease, metabolic-associated steatotic liver disease (MASLD), or autoimmune conditions such as primary biliary cholangitis (PBC)[62]. Certain physiological conditions are also associated with an increased risk of deficiency, including postmenopausal status, advanced age, and malnutrition (sarcopenia), as well as clinical features such as osteopenia, osteoporosis, bone or muscle pain, hair loss, delayed wound healing, and frequent falls, all of which may be worsened by inadequate vitamin D levels[21]. Guidelines recommend supplementation in patients with documented deficiency, making risk assessment and screening essential in vulnerable groups[63].

In general, supplementation with vitamin D is recommended for all patients with liver disease of any etiology who present with serum vitamin D levels below 20 ng/mL[64], aiming to reach concentrations above 30 ng/mL. To achieve this, a daily dose of 400-4000 IU of cholecalciferol (vitamin D₃) is recommended, adjusted based on individual clinical characteristics. Patients with a bone densitometry T-score below -1.5 standard deviations should initiate supplementation with calcium (1000-1500 mg/day) and vitamin D (400-800 IU/day)[30].

Vitamin D supplementation in patients with liver disease may be particularly beneficial during the early stages of the disease, as it allows for more effective clinical benefits and timely correction of deficiency[65]. However, evidence regarding its impact on the progression of liver disease is still limited. Therefore, in patients with low serum vitamin D levels, supplementation may provide benefits for both skeletal health and liver function[66].

Finally, various medications can alter vitamin D metabolism, affecting absorption and bioavailability. Table 4 outlines the most relevant examples[21,67,68].

Table 4 Overview of clinical and pharmacological factors negatively impacting vitamin D bioavailability.

Clinical factors	Pharmacological factors
Liver dysfunction	Long-term therapy with antiepileptic drugs: Phenytoin, carbamazepine, primidone. These can decrease vitamin D levels and increase the risk of bone health problems
Chronic kidney failure	Orlistat: May reduce the absorption of vitamin D from food and supplements by blocking fat absorption
Inherited disorders of vitamin D metabolism	Corticosteroids: May reduce calcium absorption and impair vitamin D metabolism
Therapy for people with obesity or gastric bypass	Thiazide diuretics: Excessive vitamin D supplementation may cause hypercalcemia because thiazides decrease urinary calcium excretion
Gastrointestinal diseases: Hepatobiliary disease, malabsorption, chronic pancreatitis, celiac disease	Bile acid sequestrants: Cholestyramine and colestipol. They may impair vitamin D absorption

VITAMIN D AND ITS RELATIONSHIP WITH CHRONIC LIVER DISEASES

Autoimmune liver disease

Vitamin D deficiency is a common finding not only in non-hepatic autoimmune diseases such as type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis[69,70], but also in autoimmune liver diseases, including autoimmune hepatitis (AIH), PBC and primary sclerosing cholangitis (PSC)[62,71].

AIH is a chronic, progressive liver disease[72] in which vitamin D may influence disease severity. Several studies have investigated this association. For instance, Efe et al[73] reported significantly lower serum vitamin D levels in AIH patients compared to healthy controls (16.8 ± 9.2 vs 35.7 ± 13.6, P < 0.0001).

PBC is a chronic autoimmune cholestatic liver disease characterized by ductal epithelial damage and progressive fibrosis, which can lead to cirrhosis, liver failure, and the need for a liver transplant[74,75]. Vitamin D deficiency is highly prevalent in PBC, and decreasing levels may indicate disease progression[76].

In addition, impaired osteoblast function has been observed in patients with PBC[68,77] along with a reported association between vitamin D deficiency and increased risk of osteopenia or osteoporosis[70]. Osteoporosis is particularly prevalent in postmenopausal women with PBC, leading to a higher risk of bone fractures[78,79].

In 2019, Ebadi et al[80] reported that AIH patients with severe vitamin D deficiency (< 25 nmol/L) had an increased risk of mortality and disease progression. They also reported that vitamin D levels below 50 nmol/L were associated with increased risk of cirrhosis and liver-related mortality[75,81], supporting the idea that higher vitamin D levels may have a protective effect in PBC[82].

A reduction in the vitamin D-VDR/miRNA 155-SOCS1 axis (suppressor of cytokine signaling 1) has been proposed to contribute to insufficient downregulation of cytokine signaling, playing a role in PBC pathogenesis[83]. Additionally, proinflammatory cytokines have been implicated in the loss of bone mass observed in these patients[84]. Furthermore, vitamin D plays a vital role in T cell-mediated immunity. It can reduce the accumulation of proinflammatory CD28⁺ T cells in the livers of PSC patients. These T cells have been found clustered around bile ducts, suggesting that vitamin D may modulate immune-driven bile duct injury in PSC[85].

Alcoholic hepatitis

Chronic alcohol abuse or excessive long-term consumption leads to alcohol-associated liver disease (ALD)[86]. The pathogenesis of ALD is complex and multifactorial, involving genetic predisposition, alcohol-induced hepatocellular injury, oxidative stress, and gut-derived microbial components. These factors contribute to hepatic steatosis and promote the recruitment and activation of inflammatory cells within the liver[87].

A prospective study found that higher serum concentrations of 25(OH)D were associated with lower Child-Pugh scores in patients with alcoholic cirrhosis, suggesting a potential link between vitamin D status and disease severity[88]. Another cohort study showed that vitamin D deficiency worsens ALD pathogenesis by compromising intestinal barrier function and increasing hepatic lipopolysaccharide (LPS) levels[81].

Excessive alcohol intake disrupts tight junctions in the intestinal epithelium, leading to increased intestinal permeability and translocation of gut-derived endotoxins, such as LPS[89]. Once in the liver, LPS activates Kupffer cells (liver-resident macrophages) via the TLR4 signaling pathway, promoting the release of proinflammatory cytokines[90]. Therefore, preserving the integrity of the intestinal barrier and limiting LPS translocation to the liver may help mitigate alcohol-induced liver injury[81].

In addition, a case-control study reported significantly lower serum calcidiol [25(OH)D] levels in patients with alcoholic liver disease, and proposed that calcidiol may serve as a protective factor in this context[91].

Viral hepatitis

Vitamin D is involved in the pathogenesis of chronic liver diseases caused by hepatitis B virus (HBV) and hepatitis C virus (HCV). A high prevalence of vitamin D deficiency, defined as serum levels below 20 ng/mL, has been reported in patients with these infections. Several studies suggest that maintaining adequate vitamin D levels may enhance antiviral treatment responses in both HBV and HCV infections[92].

In cases of viral cirrhosis, particularly among postmenopausal women, elevated serum levels of sTNFR-55 have been observed in patients with osteoporosis. These levels are inversely correlated with bone mineral density, suggesting a potential link between chronic inflammation, bone loss, and vitamin D status in this population[93].

HBV

Several studies have demonstrated that serum levels of calcidiol [25(OH)D] are significantly lower in patients with chronic hepatitis B compared to healthy individuals. Moreover, vitamin D insufficiency has been associated with reduced suppression of HBV replication, suggesting a potential role in modulating viral activity[94,95].

Additional evidence suggests that calcitriol [1α,25(OH)₂D] directly inhibits HBV by interfering with viral protein production and reducing HBV replication rates[94,96,97].

HCV

In vitro studies support the role of vitamin D in chronic hepatitis C, showing it can act as suppressor of HCV replication[98,99]. Vitamin D also modulates necroinflammatory and fibrotic processes associated with HCV infection[100,101].

Mechanistically, vitamin D binding to the VDR helps regulate HCV inflammation by suppressing the TLR/NF-κB signaling pathway and downregulating proinflammatory gene expression. Additionally, calcitriol impacts HCV pathogenesis by activating VDR and inhibiting the activity of PPAR-α/β/γ[34]: (1) Repression of PPAR-α/γ inhibits viral infection; (2) Repression of PPAR-β/γ reduces nitrosative stress (i.e., excess reactive nitrogen species); and (3) Repression of PPAR-γ decreases hepatic lipid accumulation.

Although vitamin D may positively influence the progression of viral hepatitis and response to antiviral therapy, the exact mechanisms are not fully understood. Some clinical studies report no significant effect on serum markers of hepatic fibrogenesis after supplementation. Therefore, additional research is needed to clarify its therapeutic role[102,103].

MASLD

MASLD is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often linked to underlying metabolic disorders such as obesity, insulin resistance, and dyslipidemia[104]. Once MASLD develops, it can lead to hepatic insulin resistance, promoting metabolic-associated steatohepatitis. This can progress to cirrhosis, liver failure, or hepatocellular carcinoma (HCC)[105-107].

Vitamin D plays a key role in regulating adipose tissue (AT) inflammation, hepatic fibrosis, abnormal lipid accumulation, and insulin resistance[108-112]. Deficiency of vitamin D has been linked to insulin resistance-related disorders, including type 2 diabetes, metabolic syndrome, and MASLD[113]. Multiple studies have reported that vitamin D deficiency is common in adults with MASLD[114-117] and is often correlated with both disease presence and severity[104].

The vitamin D-VDR axis plays a direct role in modulating key metabolic and inflammatory pathways involved in MASLD progression, especially in individuals with overweight or obesity. VDR signaling within hepatocytes influences lipogenesis and bile metabolism, contributing to metabolic homeostasis[104]. In murine models of MASLD, vitamin D supplementation has been shown to reduce hepatic inflammation and oxidative stress, partly through inhibition of the p53-p21 signaling pathway and the suppression of cellular senescence[118].

In the context of chronic caloric excess and weight gain, dysfunction in AT is a key determinant in the development of MASLD in individuals with obesity[119]. Notably, obesity also influences bone health. Epidemiological data from postmenopausal women with obesity show an increased risk of osteoporotic fractures in the humerus and distal lower limbs, but a reduced risk in the hip, pelvis, and wrist. Although data in men are limited, a similar fracture risk pattern has been reported[120]. These fracture risks may be linked to reduced mobility as well as mechanical stress and chronic inflammation, which negatively impact bone metabolism[121-123].

AT dysfunction and accompanying metabolic deterioration are strongly associated with increased intrahepatic fat accumulation, regardless of body mass index or type 2 diabetes status[124-126]. Importantly, AT is a primary target of vitamin D action, where the hormone modulates insulin sensitivity, reduces local inflammation, regulates adipokine secretion, and helps prevent hepatic steatosis[110,113].

Vitamin D supplementation may offer therapeutic benefits for MASLD in both pediatric and adult populations. Several studies have reported positive outcomes, including improvements in liver enzymes and metabolic parameters[127-129]. However, other studies have shown minimal or no clinical benefit under similar conditions[130-132]. Therefore, larger and well-designed clinical trials are needed to clarify the therapeutic value of vitamin D supplementation in MASLD, particularly in patients with documented vitamin D deficiency.

Figure 4 illustrates the multifaceted biological functions of vitamin D when present at optimal levels.

Figure 4 Systemic effects of optimal vitamin D levels on hepatic metabolism, oxidative stress, immunity, oncogenesis, and viral hepatitis. ROS: Reactive oxygen species; HBV: Hepatitis B virus; HCV: Hepatitis C virus; VDR: Vitamin D receptor. Created in BioRender (Supplementary material).

HCC

As previously discussed, vitamin D plays a significant anti-inflammatory role in carcinogenesis[133]. Chronic inflammation induces oxidative stress, primarily through the activation of neutrophils and Kupffer cells, thereby promoting tumor development[134].

HCC is the most common primary liver cancer and typically arises in the context of chronic liver disease[135]. The rising global incidence of HCC is strongly associated with chronic HBV and HCV infections[136,137]. Other major risk factors include MASLD[138,139] and exposure to mycotoxins, such as aflatoxins[140,141].

Emerging evidence suggests that vitamin D deficiency (defined as < 20 ng/mL) may increase the risk of developing HCC[142,143] and is also associated with higher mortality rates[144]. In contrast, adequate serum levels of bioavailable 25(OH)D (≥ 30 ng/mL) have been linked to improved survival outcomes in patients with HCC[145].

Regarding supplementation, several in vitro and in vivo studies have demonstrated that vitamin D and its analogs can inhibit the proliferation of liver cancer cell lines and reduce tumor burden in murine models[146-148]. These findings support the potential therapeutic value of vitamin D in the prevention and management of HCC, although further clinical studies are needed to validate these effects in human populations.

VITAMIN D AND ITS COMPLICATIONS IN LIVER CIRRHOSIS

Vitamin D deficiency is a common feature in patients with liver cirrhosis, with a reported prevalence ranging from 64% to 92%, significantly higher than in the general population[149,150]. As vitamin D plays an important role in immune regulation, antioxidant defense, and musculoskeletal health, its deficiency has been associated with several complications related to cirrhosis.

Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SBP) is one of the most frequent and serious infections in cirrhotic patients. Vitamin D deficiency is highly prevalent among those with SBP and has been identified as an independent predictor of both infection and mortality[151-153]. As calcidiol [25(OH)D] modulates innate immune responses, low levels may impair bacterial clearance and increase susceptibility to infection.

Esophageal varices

Several studies have suggested a relationship between vitamin D deficiency and the presence of esophageal varices in cirrhotic patients[154]. Although the underlying mechanisms remain unclear, the involvement of vitamin D in vascular remodeling, inflammation and portal pressure regulation may contribute to this association. However, further research is needed.

Sarcopenia

Sarcopenia, defined as the progressive loss of skeletal muscle mass and function, is a common and debilitating complication of cirrhosis. Vitamin D supports muscle strength and regeneration, and deficiency may exacerbate sarcopenia[155]. However, more mechanistic and interventional studies are needed to determine causality and potential therapeutic value.

Hepatic encephalopathy

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome arising from hepatic insufficiency and portosystemic shunting[156]. Its pathogenesis involves hyperammonemia, astrocyte dysfunction, neuroinflammation, and oxidative stress[156,157]. Vitamin D deficiency has been associated with increased HE severity. A cross-sectional study found significantly lower serum calcidiol levels in patients with HE, with negative correlation between vitamin D levels and HE grade[158].

Vitamin D also exhibits antioxidant activity. It enhances the expression of glutathione reductase, superoxide dismutase and catalase, and upregulates genes involved in glutathione synthesis such as glutamate-cysteine ligase via VDR signaling[159]. In other neurological contexts, such as Alzheimer’s disease, vitamin D supplementation has been shown to reduce oxidative stress and improve cognitive outcomes[160] suggesting potential benefits in HE as well.

Mortality

Several studies have consistently reported that vitamin D deficiency is associated with increased mortality in patients with cirrhosis[161]. Among older adults, especially women over 70, maintaining sufficient vitamin D levels has been linked to a 6%-11% reduction in overall mortality[162].

However, more recent large-scale clinical trials have failed to show a mortality benefit from vitamin D supplementation in younger or healthier populations, likely due to lower baseline risk[163]. Nonetheless, vitamin D supplementation may still confer survival advantages in more vulnerable groups[164].

Figure 5 illustrates the clinical consequences of vitamin D deficiency across various liver diseases.

Figure 5 Clinical landscape of vitamin D deficiency in liver disease. MASLD: Metabolic-associated steatotic liver disease. Created in Canva (Supplementary material).

CONCLUSION

Vitamin D plays an active role in the pathophysiology of chronic liver diseases, influencing immune responses, fibrosis, oxidative stress, and metabolic regulation. Deficiency is common in autoimmune, viral, alcoholic, and metabolic liver conditions and is associated with an increased risk of complications and mortality. Mechanistic evidence supports its regulatory role through VDR signaling, while clinical data suggest an emerging role as a prognostic marker. However, evidence supporting supplementation remains inconsistent. Vitamin D should be recognized as a modifiable factor in liver disease progression, and further research is needed to clarify its therapeutic potential and define effective clinical strategies.