Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality. ALD covers a spectrum of diseases ranging from mild and reversible hepatic steatosis to the development of fibrosis, cirrhosis, and alcohol-associated hepatitis (AH). AH is marked by a rapid onset of jaundice and elevated serum levels of aspartate aminotransferase in individuals with heavy alcohol use. It can progress to acute-on-chronic liver failure with a mortality rate of approximately 30% within the first month. Unfortunately, treatment options for AH are still limited. Cholestasis refers to an impairment in bile formation or flow, leading to clinical symptoms such as fatigue, pruritus, and jaundice. Cholestasis and biliary dysfunction are commonly seen in patients with AH and can significantly worsen the prognosis. However, the mechanisms and roles of cholestasis in ALD are not yet fully understood. In this review, we will summarize recent findings and explore the potential roles and mechanisms of cholestasis in the progression of ALD.

Vitamin D deficiency is linked to worse outcomes in patients with chronic liver diseases (CLD). However, data in patients with autoimmune hepatitis (AIH) remain limited.

We aimed to assess the impact of vitamin D deficiency on the outcomes of individuals with AIH.

This retrospective cohort study used the TriNetX research network to identify patients with AIH. Patients were matched using propensity score matching and stratified to sufficient vitamin D levels (e.g., 25 (OH) D3 ≥ 30 ng/mL), vitamin D insufficiency (25 (OH) D3: 20-29.9 ng/mL) and vitamin D deficiency (e.g., 25 (OH) D3 < 20 ng/mL). The primary outcome was the all-cause mortality among adult patients with AIH. Secondary outcomes included decompensated liver cirrhosis, acute hepatic failure, liver transplantation (LT), all-cause hospitalizations and all-cause critical care admissions.

A total of 1288 AIH patients with vitamin D deficiency were identified and propensity matched with 1288 patients with normal vitamin D levels. Patients with vitamin D deficiency had significantly increased odds for all-cause mortality compared to those with normal levels (adjusted odds ratio (aOR) = 3.2, 95%CI: 2.3-4.48). Patients with vitamin D deficiency were at increased odds of all-cause hospitalizations (aOR = 2.37, 95%CI: 1.97-2.84), critical care unit admissions (aOR = 2.8, 95%CI: 2.21-3.71), decompensated liver cirrhosis (aOR = 2.74, 95%CI: 2.13-3.54), acute hepatic failure (aOR = 3.11, 95%CI: 2.09-4.62) and LT (aOR = 3.47, 95%CI: 1.71-7.04), as compared to those with normal vitamin D levels.

This cohort study showed significantly increased odds for all-cause mortality in AIH patients with vitamin D deficiency. Vitamin D deficiency in patients with AIH was associated with increased likelihood of hospitalisation, decompensated liver cirrhosis, acute liver failure and LT.

Vitamin D deficiency (VDD) has been found among alcoholics. However, little is known about the effect of VDD on alcoholic liver disease and the molecular mechanisms remain unclear. The aim of the current study was to evaluate whether vitamin D was deficient among patients with alcoholic fatty liver disease (AFLD) and the effect of VDD on chronic alcoholic liver injury and possible molecular mechanisms in mice. Our results found that lower 25-hydroxyvitamin D [25(OH)D] concentrations in patients with AFLD. And further analysis found that 25(OH)D is a protective factor in patients with AFLD. Mice experiments indicated that VDD can alter the composition of gut microbiota, down-regulate the protein levels of intestinal tight junction protein Occludin and E-cadherin, up-regulate the expression of inflammatory cytokines (tnf-α, il-1β, il-6, il-8, ccl2, il-10) in liver and colon tissue. And further exacerbated the protein levels of p65,P-IκB,P-p65 in alcoholic liver injury mice. In conclusion, VDD aggravates chronic alcoholic liver injury by activating NF-κB signaling pathway.

This study investigates the relationship between vitamin D levels and liver cirrhosis severity, a leading cause of global morbidity and mortality. Chronic liver diseases, stemming from conditions such as hepatitis, alcohol use, non-alcoholic fatty liver disease, autoimmune diseases, and cryptogenic disorders, disrupt vitamin D metabolism, as the liver converts dietary and skin-derived vitamin D into 25-hydroxyvitamin D (25[OH]D), the primary circulating form. The cross-sectional study conducted at the Department of General Medicine of BLDE (DU) Shri. B. M. Patil Medical College Hospital and Research Centre, Vijayapura, from August 2022 to May 2024, involved 89 patients. Based on the Child-Pugh scoring system, these patients were classified into three classes: class A (good hepatic function), class B (moderate dysfunction), and class C (advanced dysfunction). The study found a significant negative correlation (Pearson r=-0.462, p<0.0001) between vitamin D levels and Child-Pugh scores, indicating that as cirrhosis severity worsens, vitamin D levels decrease. The findings highlight vitamin D deficiency as a marker of disease severity, linking it to increased morbidity and mortality and underscoring its potential as a prognostic tool in managing liver cirrhosis.

It is elusive why some heavy drinkers progress to severe alcohol-related liver disease (ALD) while others do not. This study aimed to investigate if the association between alcohol consumption and severe ALD is modified by diet. This prospective study included 303,269 UK Biobank participants. Alcohol consumption and diet were self-reported. The diet score was created from 4 items selected using LASSO. Cox proportional hazard model showed that the diet score was monotonically associated with severe ALD risk, adjusted for sociodemographics, lifestyle factors, and alcohol consumption. Relative excess risk due to interaction analysis indicated that having a higher ALD diet score and a higher alcohol consumption simultaneously confers to 2.44 times (95% CI: 1.06-3.83) higher risk than the sum of excess risk of each factor. In this work, we show that people who have a poor diet might be more susceptible to severe ALD due to alcohol consumption.

Numerous observational studies have presented an association between Vitamin D (VD) and Alcoholic Liver Disease (ALD). However, sufficient evidence from Randomized Controlled Trials (RCTs) substantiating this correlation is scarce, thus leaving the causality of this relationship ambiguous. To overcome the shortcomings of traditional observational studies, we performed a two-sample bidirectional Mendelian randomization (MR) analysis to ascertain the causal relationship between VD and ALD.

We utilized summary statistics datasets from Genome-Wide Association Studies (GWAS) for VD and ALD. We selected genetic instruments that measure circulating VD levels (n = 64,979), and retrieved ALD statistics from GWASs, inclusive of 1,416 cases and 217,376 healthy controls, while excluding chronic liver diseases such as nonalcoholic fatty liver disease, toxic liver disease, and viral hepatitis. Subsequent, MR analyses were performed to obtain effect estimates using inverse variance weighted (IVW) random effect models. Cochran's Q statistic and MR-Egger regression intercept analyses were used to assess pleiotropy. Sensitivity analyses using the MR Egger, weighted median, simple mode, and weighted mode methods were also performed. Leave-one-out analysis was used to identify SNPs with potential effect. Reverse MR analysis was also performed.

In IVW, our MR analysis incorporated 21 independent SNPs, circulating VD levels had no causal effect on ALD [OR = 0.624 (0.336-1.160), p = 0.136] and ALD had no causal effect on circulating VD [OR = 0.997 (0.986-1.008), p = 0.555]. No heterogeneity or pleiotropy was observed (p > 0.05). Other MR methods also agreed with IVW results.

This study provides the causal relationship between genetically predicted circulating Vitamin D levels and ALD and provides new insights into the genetics of ALD.

Global alcohol consumption poses a serious threat to humankind. It is estimated that between 5% and 7% of Indian adults struggle with alcohol abuse. Alcoholism is associated with a number of disorders, impacting different organ systems and nutritional status, including symptoms of withdrawal that can vary in severity from moderate symptoms to delirium tremens (DT). An increase in oxidative stress in the body is linked to alcohol withdrawal.

This study aimed to evaluate the role of vitamins with antioxidant properties on oxidative stress caused by the severe alcohol withdrawal state.

60 patients with DT and 30 control subjects were recruited using a purposive sampling method. They were evaluated for liver function test, antioxidant enzyme superoxide dismutase, glutathione peroxidase, and serum vitamin D level on day 0, day 14 and on day 0 of treatment for patients and controls, respectively.

The mean age of the study group was 41.12 years. The mean duration of substance use while coming for treatment was 22 years. Means of liver function test were found to be aspartate transaminase (AST) 196 IU/L, alanine transaminase (ALT) 71 IU/L, and alkaline phosphatase (ALP) 143 IU/L of patients on day 0 of evaluation. When comparisons of liver enzymes and antioxidant enzymes were conducted between cases and controls on day 0, significance was found. Further comparison of day 0 and day 14 levels of liver enzymes and antioxidant enzymes also had shown significant differences. However, no significant correlation was found with vitamin D level and liver enzyme, antioxidant enzyme level.

Oxidative stress evaluated via antioxidant enzyme was found to be at a higher level in patients with DT than in patients with mild withdrawal symptoms. This study has shown an association between antioxidant enzymes with severity of withdrawal; however, no such association with vitamin D level was found.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.

Vitamin D deficiency is a risk factor for liver disease, insulin resistance, and beta cell dysfunction. Individuals with alcohol use disorder (AUD) have many comorbidities, with a heavy burden of liver disease and metabolic complications, including type 2 diabetes mellitus (T2DM).

We aimed to analyze the prevalence and associations of vitamin D deficiency in patients admitted for in-hospital treatment of AUD.

A cross-sectional study was conducted in patients consecutively admitted for the treatment of AUD between January 2017 and October 2023. Sociodemographic data, substance use characteristics, and blood parameters were available at admission. Vitamin D status was assessed through the serum concentrations of 25-hydroxyvitamin D [25(OH)D] levels using a direct competitive chemiluminescent immunoassay method. Deficiency of vitamin D was defined as a concentration less than 20 ng/mL; impaired fasting glucose (IFG) was defined by fasting blood glucose >100 mg/dL (5.6 mmol/L), and advanced liver fibrosis by an FIB-4 index >3.25.

Two hundred and forty-three patients were included (75% male) with a mean age of 49 ± 10 years, mean BMI of 26.4 ± 7.3, mean alcohol consumption of 163 ± 81 g/day, and a mean duration of AUD of 18.1 ± 11.2 years. Mean 25(OH)D, fasting blood glucose, AST, ALT, and platelets were 14.4 ± 10.2 ng/mL, 103.4 ± 40.9 mg/dL, 55.1 ± 75.8 U/L, 44.8 ± 76.6 U/L, and 206.3 ± 84.8 × 109/L, respectively. The prevalence of vitamin D deficiency was 80.6%, and 41.1% of patients had levels less than 10 ng/mL. IFG was present in 32.3% of patients, and 20.5% had FIB-4 values >3.25. In the multivariable analysis, IFG (OR, 2.51; 95% CI: 1.02-6.17, p = 0.04) and advanced liver fibrosis (OR, 4.27; 95% CI: 1.21-15.0, p = 0.02) were the only factors associated with vitamin D deficiency.

Vitamin D deficiency was very prevalent in this series of patients with AUD and was associated with impaired fasting glucose and advanced liver fibrosis.

In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO). The interplay between cirrhosis and SO lies in the sharing of multiple pathogenetic mechanisms, including malnutrition/malabsorption, chronic inflammation, hyperammonemia and insulin resistance. The presence of SO worsens the outcome of cirrhotic patients, affecting overall morbidity and mortality. International nutrition and liver diseases societies strongly agree on recommending the use of food as an integral part of the healing process in the comprehensive management of these patients, including a reduction in caloric intake, protein and micronutrient supplementation and sodium restriction. Based on the pathophysiological paths shared by cirrhosis and SO, this narrative review aims to highlight the nutritional interventions currently advocated by international guidelines, as well as to provide hints on the possible role of micronutrients and nutraceuticals in the treatment of this multifaceted clinical condition.

Endogenous lipopolysaccharide (LPS) that translocates via the disrupted intestinal barrier plays an essential role in the progression of alcohol-related liver disease (ALD). Vitamin D deficiency is observed in ALD, and it participates in regulating gut barrier function. The current study aimed to examine the association between vitamin D deficiency and endotoxemia in patients with ALD-related cirrhosis. Moreover, the effect of vitamin D deficiency on ethanol (EtOH)- and carbon tetrachloride (CCl4)-induced liver injury relevant to gut barrier disruption in mice was investigated. Patients with ALD-related cirrhosis (Child-Pugh Class A/B/C; n=56/15/7) had lower 25(OH)D levels and higher endotoxin activities than non-drinking healthy controls (n=19). The serum 25(OH)D levels were found to be negatively correlated with endotoxin activity (R=-0.481, P<.0001). The EtOH/CCl4-treated mice developed hepatic inflammation and fibrosis, which were significantly enhanced by vitamin D-deficient diet. Vitamin D deficiency enhanced gut hyperpermeability by inhibiting the intestinal expressions of tight junction proteins including ZO-1, occludin, and claudin-2/5/12/15 in the EtOH/CCl4-treated mice. Consequently, it promoted the accumulation of lipid peroxidases, increased the expression of NADPH oxidases, and induced Kupffer cell infiltration and LPS/toll-like receptor 4 signaling-mediated proinflammatory response. Based on the in vitro assay, vitamin D-mediated vitamin D receptor activation inhibited EtOH-stimulated paracellular permeability and the downregulation of tight junction proteins via the upregulation of caudal-type homeobox 1 in Caco-2 cells. Hence, vitamin D deficiency exacerbates the pathogenesis of ALD via gut barrier disruption and hepatic overload of LPS.

Interleukin 17A (IL-17A) is a major member of the IL-17 cytokine family and is produced mainly by T helper 17 (Th17) cells. Other cells such as CD8+ T cells, γδ T cells, natural killer T cells and innate lymphoid-like cells can also produce IL-17A. In healthy individuals, IL-17A has a host-protective capacity, but excessive elevation of IL-17A is associated with the development of autoimmune diseases and cancer. Monoclonal antibodies (mAbs) targeting IL-17A (e.g., ixekizumab and secukinumab) or IL-17A receptor (IL-17RA) (e.g., brodalumab) would be investigated as potential treatments for these diseases. Currently, the application of IL-17A-targeted drugs in autoimmune diseases will provide new ideas for the treatment of tumors, and its combined application with immune checkpoint inhibitors has become a research hotspot. This article reviews the mechanism of action of IL-17A and the application of anti-IL-17A antibodies, focusing on the research progress on the mechanism of action and therapeutic blockade of IL-17A in various tumors such as colorectal cancer (CRC), lung cancer, gastric cancer and breast cancer. Moreover, we also include the results of therapeutic blockade in the field of cancer as well as recent advances in the regulation of IL-17A signaling.

Liver diseases are the major predisposing conditions for the development of malnutrition, sarcopenia, and frailty. Recently, the mechanism of the onset of these complications has been better established. Regardless of the etiology of the underlying liver disease, the clinical manifestations are common. The main consequences are impaired dietary intake, altered macro- and micronutrient metabolism, energy metabolism disturbances, an increase in energy expenditure, nutrient malabsorption, sarcopenia, frailty, and osteopathy. These complications have direct effects on clinical outcomes, survival, and quality of life. The nutritional status should be assessed systematically and periodically during follow-up in these patients. Maintaining and preserving an adequate nutritional status is crucial and should be a mainstay of treatment. Although general nutritional interventions have been established, special considerations are needed in specific settings such as decompensated cirrhosis, alcohol-related liver disease, and metabolic-dysfunction-associated fatty liver disease. In this review, we summarize the physiopathology and factors that impact the nutritional status of liver disease. We review how to assess malnutrition and sarcopenia and how to prevent and manage these complications in this setting.

Sarcopenia and severe vitamin D deficiency are associated with malnutrition and poor prognosis. We investigated the impact of the comorbidity of Child-Pugh (CP) class B/C cirrhosis and the aforementioned complications on the prognosis of patients with cirrhosis.

We retrospectively evaluated 104 patients with cirrhosis. The cumulative survival rates were compared between patients with and without both or either of these disease conditions: CP class B/C and complications (sarcopenia or severe vitamin D deficiency). Sarcopenia was diagnosed according to the Japan Society of Hepatology criteria. Severe vitamin D deficiency was defined as levels of 25-hydroxyvitamin D <10 ng/mL in serum.

The prevalence of CP class B/C, sarcopenia, and severe vitamin D deficiency was 26.9%, 38.5%, and 24.0%, respectively. Patients with both CP class B/C and sarcopenia had significantly lower survival rates than those without both (hazard ratio [HR] = 6.101; P < 0.001) and with either condition (HR = 6.137; P = 0.001). Similarly, patients with both CP class B/C and severe vitamin D deficiency or with either condition had significantly lower survival rates than those without both conditions (HR = 8.135 or 3.189; P < 0.001 or =0.025, respectively). CP class B/C (HR = 3.354; P = 0.006) and severe vitamin D deficiency (HR = 2.445; P = 0.044) were independent prognostic factors.

The coexistence of CP class B/C and sarcopenia or severe vitamin D deficiency worsened the prognosis of patients with cirrhosis. Nutritional assessments such as sarcopenia and vitamin D status should be considered to better evaluate disease conditions and patient prognosis.

Bariatric surgery can increase the risk of addictive disorders and nutritional deficiencies. The aim of this study was to evaluate the association between bariatric surgery and alcohol use disorder (AUD), alcohol-related liver disease (ALD), and psychiatric disorders associated with AUD. The impact of vitamin D deficiency in these associations was also investigated.

A cross-sectional study was performed using the National Inpatient Sample database and its ICD-9 codes information. Diagnostic and comorbidity data from hospital discharges were obtained from patients with bariatric surgery and other abdominal surgeries between 2005 and 2015. The two groups were then compared for alcohol-related outcomes after propensity-score matching.

The final study cohort included 537,757 patients with bariatric surgery and 537,757 with other abdominal surgeries. The bariatric surgery group had an increased risk of AUD [odds ratio (OR): 1.90; 95% CI: 1.85-1.95], ALD [OR: 1.29; 95% CI: 1.22-1.37], cirrhosis [OR, 1.39; 95% CI: 1.37-1.42], and psychiatric disorders associated with AUD [OR, 3.59; 95% CI: 3.37-3.84]. Vitamin D deficiency did not impact in the association between bariatric surgery and AUD, ALD, or psychiatric disorders associated with AUD.

Bariatric surgery is associated with an increased prevalence of AUD, ALD, and psychiatric disorders associated with AUD. These associations appear to be independent from vitamin D deficiency.

Cirrhosis-related acute-on-chronic liver failure (ACLF) is associated with high morbidity and mortality rates. Prognostic models of ACLF have been developed; however, few studies have focused on the occurrence of ACLF. This study aimed to identify the factors that predict the development of ACLF, hepatic encephalopathy (HE), and infection in patients with cirrhosis.

Patients with cirrhosis were enrolled, and the serum levels of calcitriol, Cluster of Differentiation 26 (CD206), and macrophage-inducible lectin receptor (Mincle) were measured, and lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio were calculated; all the patients were tracked for 6 months. A generalized estimating equation (GEE) was used to assess the factors associated with ACLF development, HE, and infection. The aforementioned model was derived based on immunological markers, and receiver operating characteristic analysis with area under the curve (AUC) was adopted to evaluate accuracy.

After screening 325 patients with cirrhosis, 65 patients were eligible. In the GEE model, low levels of calcitriol (odds ratio [OR] = 3.259; 95% confidence interval [CI] = 1.118-8.929) and CD206 (OR = 2.666; 95% CI = 1.082-6.567) were associated with the development of ACLF, and the LMR was a protective factor (OR = 0.356; 95% CI = 0.147-0.861). Low calcitriol levels were a risk factor for HE (OR = 3.827) and infection (OR = 2.489). LMR was found to be a protective factor against HE (OR = 0.388). An immunological model for the discrimination of ACLF development within 6 months was proposed, with an AUC of 0.734 (95% CI = 0.598-0.869).

Single and combined immunological markers, including low LMR and low levels of calcitriol and CD206, were promising for early prediction of the development of ACLF, HE, and infection in patients with cirrhosis.

Vitamin D deficiency has been linked with adverse events in various liver diseases. The present study aimed to recognize the association between severe vitamin D deficiency and disease progression, hepatobiliary malignancies, liver-related mortality, and the need for liver transplantation in primary sclerosing cholangitis (PSC). Patients with a diagnosis of PSC (n = 354), followed by the autoimmune liver disease clinic at the University of Alberta, were included. Patients with vitamin D levels < 25 nmol/L were defined as severely deficient. Univariate and multivariate analyses were conducted using the Cox proportional hazards regression models. The mean vitamin D level was 59 ± 2 nmol/L, and 63 patients (18%) had a severe vitamin D deficiency. Patients with a severe vitamin D deficiency were 2.5 times more likely to experience hepatobiliary malignancies (HR 2.55, 95% CI, 1.02-6.40, p = 0.046). A severe vitamin D deficiency at diagnosis (HR 1.82, 95% CI, 1.05-3.15, p = 0.03) and persistent deficiencies over time (HR 2.26, 95% CI, 1.17-4.37, p = 0.02) were independently associated with a higher risk of poor clinical liver outcomes. A severe vitamin D deficiency at diagnosis and persistent deficiency at longitudinal assessments were associated with liver-related mortality or the need for liver transplantation.

According to the World Health Organization (WHO) report, viral hepatitis has been a problem in human society. Vitamins play a significant role in preventing the hepatocarcinoma and liver cirrhosis. In this report, we will first focus on the vitamin D function in the immune system reactions, and then investigate its role in the viral infections and the signaling pathway of hepatitis B virus. The existence of the cytochrome P450 (CYP) 27B1 enzyme, which is involved in vitamin D synthesis in immune system cells, has drawn researchers ' attention to the field of immune system. Toll like receptor (TLR) play a significant role in the immune system, and are one of the primary receptors of the innate immune system. In addition, the synthesis of inflammatory cytokines, such as Interferon γ (IFNγ) and Interleukin-2 (IL-2) is one of the key roles of T helper type 1 (Th1) cells; these cells can suppress two cited cytokines via vitamin D. In the chronic phase of hepatitis B, Cytotoxic T lymphocytes (CTLs) cells have weaker performance than the acute phase of the disease. The association between vitamin D physiologies with viral infections is also confirmed by genetic studies, carried out on genetic variations of vitamin D receptor (VDR) R-encoding disease susceptibility gene. Vitamin D affects different phases of the disease. Therefore, further experiments in this area are proposed.

Vitamin D is a crucial nutrient with many pleiotropic effects on health and various chronic diseases. The purpose of this review is to provide a detailed report on the pathophysiological mechanisms underlying vitamin D deficiency in patients with chronic liver disease, addressing the different liver etiologies and the condition of advanced chronic liver disease (cirrhosis) with related complications. To date, patients with liver disease, regardless of underlying etiology, have been shown to have reduced levels of vitamin D. There is also evidence of the predictive role of vitamin D values in complications and progression of advanced disease. However, specific indications of vitamin D supplementation are not conclusive concerning what is already recommended in the general population. Future studies should make an effort to unify and validate the role of vitamin D supplementation in chronic liver disease.

There is consistent evidence that vitamin D deficiency is strongly associated with liver dysfunction, disease severity, and poor prognosis in patients with liver disease. Vitamin D and its receptor (VDR) contribute to the regulation of innate and adaptive immune responses. The presence of genetic variants of vitamin D- and VDR-associated genes has been associated with liver disease progression. In our recent work, we summarized the progress in understanding the molecular mechanisms involved in vitamin D-VDR signaling and discussed the functional significance of VDR signaling in specific cell populations in liver disease. The current review focuses on the complex interaction between immune and liver cells in the maintenance of liver homeostasis and the development of liver injury, the interplay of vitamin D and VDR in the development and outcome of liver disease, the role of vitamin D- and VDR-associated genetic variants in modulating the occurrence and severity of liver disease, and the therapeutic value of vitamin D supplementation in various liver diseases. The association of the vitamin D-VDR complex with liver dysfunction shows great potential for clinical application and supports its use as a prognostic index and diagnostic tool.

Over the past few years, growing interest has been shown for the impact of dietary requirements and nutritional factors on chronic diseases. As a result, nutritional programs have been reinforced by public health policies. The precise role of micronutrients in chronic liver disease is currently receiving particular attention since abnormalities in vitamin levels are often detected. At present, treatment programs are focused on correcting vitamin deficiencies, which are frequently correlated to higher rates of comorbidities with poor outcomes. The literature reviewed here indicates that liver diseases are often related to vitamin disorders, due to both liver impairment and abnormal intake. More specific knowledge about the role of vitamins in liver disease is currently emerging from various results and recent evidence. The most significant benefits in this area may be observed when improved vitamin intake is combined with a pharmacological treatment that may also affect the progression of the liver disease, especially in the case of liver tumors. However, further studies are needed.

We sought to (1) determine the prevalence of cardiac changes in patients with ESLD awaiting OLT (2) determine relationship between nutritional indices and cardiac changes.

Retrospective review of transthoracic ECHO, clinical and nutritional information of pediatric patients evaluated for OLT. ECHO was analyzed for LVH, defined as LVMI > 95 g/m^2.7 and/or RWT > 0.42. These findings were correlated with age, ESLD etiology, growth and nutritional parameters as well as pre- and post-OLT.

Sixty-five patients were included, all had normal left ventricular systolic function. Nine patients (14%) had LVMI > 95 g/m^2.7 , five patients (8%) had RWT > 0.42, none met both criteria. None had thickened interventricular septal wall. Fourteen patients (20%) had significant left ventricular dilation. Nutritional deprivation was modestly present-weight under third percentile in 22%, length under third percentile in 24%, and both weight and length under third percentile in 17%. There were 12 patients (17%) with MUAC below two standard deviations for age; of these one had an elevated LVMI and another had an RWT > 0.42.

In this contemporary cross-sectional evaluation, a smaller proportion of patients with ESLD had LVH in contrast to prior studies. Despite a comparable disease burden, our cohort had better nutritional status. Though there was a trend between nutritional and LVH indices, this correlation may be better assessed prospectively in a larger cohort.

Vitamin D deficiency is often reported in people with chronic liver diseases. Improving vitamin D status could therefore be beneficial for people with chronic liver diseases.

To assess the beneficial and harmful effects of vitamin D supplementation in adults with chronic liver diseases.

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We also searched ClinicalTrials.gov  and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and enquired experts and pharmaceutical companies as to additional trials. All searches were up to November 2020.

Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D₃ (cholecalciferol) or vitamin D₂ (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)).

We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of evidence.

We included 27 randomised clinical trials with 1979 adult participants. This review update added 12 trials with 945 participants. We assessed all trials as at high risk of bias. All trials had a parallel-group design. Eleven trials were conducted in high-income countries and 16 trials in middle-income countries. Ten trials included participants with chronic hepatitis C, five trials participants with liver cirrhosis, 11 trials participants with non-alcoholic fatty liver disease, and one trial liver transplant recipients. All of the included trials reported the baseline vitamin D status of participants. Participants in nine trials had baseline serum 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), whilst participants in the remaining 18 trials were vitamin D insufficient (less than 20 ng/mL). Twenty-four trials administered vitamin D orally, two trials intramuscularly, and one trial intramuscularly and orally. In all 27 trials, the mean duration of vitamin D supplementation was 6 months, and the mean follow-up of participants from randomisation was 7 months. Twenty trials (1592 participants; 44% women; mean age 48 years) tested vitamin D₃ (cholecalciferol); three trials (156 participants; 28% women; mean age 54 years) tested vitamin D₂; four trials (291 participants; 60% women; mean age 52 years) tested 1,25-dihydroxyvitamin D; and one trial (18 participants; 0% women; mean age 52 years) tested 25-hydroxyvitamin D. One trial did not report the form of vitamin D. Twelve trials used a placebo, whilst the other 15 trials used no intervention in the control group. Fourteen trials appeared to be free of vested interest. Eleven trials did not provide any information on clinical trial support or sponsorship. Two trials were funded by industry. We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on all-cause mortality (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.51 to 1.45; 27 trials; 1979 participants). The mean follow-up was 7 months (range 1 to 18 months). We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) (follow-up: 12 months); serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants); myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants); thyroiditis (RR 0.33, 95% CI 0.01 to 7.91; 1 trial; 68 participants); circular haemorrhoidal prolapse (RR 3.00, 95% CI 0.14 to 65.9; 1 trial; 20 participants); bronchopneumonia (RR 0.33, 95% CI 0.02 to 7.32; 1 trial 20 participants); and non-serious adverse events. The certainty of evidence for all outcomes is very low. We found no data on liver-related morbidity such as gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, ascites, or liver cancer. There were also no data on health-related quality of life. The evidence is also very uncertain regarding the effect of vitamin D versus placebo or no intervention on rapid, early, and sustained virological response in people with chronic hepatitis C.

Given the high risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, vitamin D supplementation versus placebo or no intervention may increase or reduce all-cause mortality, liver-related mortality, serious adverse events, or non-serious adverse events in adults with chronic liver diseases. There is a lack of data on liver-related morbidity and health-related quality of life. Further evidence on clinically important outcomes analysed in this review is needed.

The natural history of moderate alcoholic hepatitis (AH) is not well known. It is a frequent disease with a probable underestimated incidence compared with its severe form. Among the different prognostic scores predicting short-term mortality in AH, MELD seems to be the most accurate. The mortality of moderate AH is 3% to 7% in the short to medium term and 13% to 20% at 1 year, mainly because of liver-related complications, including severe infections. Long-term abstinence is the main goal of the treatment. There is still need for the development of new therapies for AH, including the less severe forms.

Liver transplantation represents a life-saving treatment for patients with decompensated cirrhosis, a severe condition associated with a high risk of waiting list mortality. When decompensation occurs rapidly in the presence of extrahepatic organ failures, the condition is called acute-on-chronic liver failure, which is associated with an even higher risk of death, though liver transplantation can also markedly improve survival in affected patients. However, there are still gaps in our understanding of how to optimise prioritisation and organ allocation, as well as survival among patients with acute-on-chronic liver failure (both before and after transplant). Moreover, it is urgent to address inequalities in access to liver transplantation in patients with severe alcoholic hepatitis and non-alcoholic steatohepatitis. Several controversies still exist regarding gender and regional disparities, as well as the use of suboptimal donor grafts. In this review, we aim to provide a critical perspective on the role of liver transplantation in patients with decompensated cirrhosis and address areas of ongoing uncertainty.

Few studies have reported the relationship between spontaneous peritonitis in cirrhosis and vitamin D, and the result is not very convincing.

To conduct a meta-analysis to clarify the relationship between vitamin D and spontaneous peritonitis.

Articles published up to 1 October 2019 in the PubMed, Medline, and Embase databases were searched. According to the inclusion and exclusion criteria, relevant statistical data were extracted and analysed by STATA.

Six articles met the inclusion criteria. It was demonstrated that the average 25(OH)D level in spontaneous peritonitis patients was 2.36 less than that in control individuals (SMD = -2.36, 95% CI: -3.92, -0.8, I ² = 97.2%, p < 0.01). Moreover, it found that spontaneous peritonitis patients were 4.33 times more likely to be vitamin D deficient than controls (OR = 4.33, 95% CI: 1.57, 11.93, I ² = 50.1%, p = 0.111). Sensitivity analysis showed that the meta-analysis results were stable and reliable.

Vitamin D may be an importantly protective factor in spontaneous peritonitis.

Spontaneous bacterial peritonitis (SBP) is considered the paradigmatic model of infection in patients with liver cirrhosis. Therefore, there is a need for an accurate and rapid method for SBP diagnosis. The aim of this study was to evaluate the validity of serum-ascites 25-hydroxyvitamin D (25-OH vitamin D) gradient (SADG) as a marker for diagnosing SBP in patients with cirrhotic ascites.

We conducted a cross-sectional analytic study of 88 patients with portal hypertensive ascites resulting from liver cirrhosis of any etiology. The demographic, clinical, and laboratory characteristics of the patients were recorded. The level of 25-OH vitamin D in serum and ascitic fluid was measured using high-performance liquid chromatography autoanalyzer. The SADG was calculated with the formula: 25-OH vitamin D in serum - 25-OH vitamin D in ascites.

Vitamin D deficiency was detected in 89.8% of the studied patients. The SADG values ranged between 0 and 69.2 ng/mL, with a median value of 5.58 ng/mL. It was significantly lower in patients with SBP than in those without SBP (P = .004). The area under the curve for SADG in exclusion of SBP was 0.67 at a cutoff value of ≥5.57 ng/mL.

We found that SADG may be a valid marker of SBP in patients with cirrhotic ascites.

Cholangiopathies are chronic liver diseases in which damaged cholangiocytes trigger a proinflammatory and profibrotic reaction. The nuclear vitamin D receptor (VDR) is highly expressed in cholangiocytes and exerts immune-regulatory functions in these cells. In the present study, we examined the protective function of VDR and other vitamin D signaling pathways in chronic cholangiopathy and cholangiocytes.

Vdr was invalidated in Abcb4 knockout mice, a widely used animal model of chronic cholangiopathy. The impact of vitamin D signaling on cholangiopathy features was examined in vivo and in cholangiocytes (primary and cell lines).

Cholangiopathy features (i.e, cholestasis, ductular reaction and fibrosis) were aggravated in Vdr;Abcb4 double knockout mice compared to the Abcb4 simple knockout, and associated with an overexpression of proinflammatory factors. The proinflammatory phenotype of cholangiocytes was also exacerbated following VDR silencing in vitro. The expression of proinflammatory factors and the severity of cholangiopathy were reduced in the double knockout mice treated with the vitamin D analog calcipotriol or with vitamin D. In vitro, the inflammatory response to TNFα was significantly reduced by calcipotriol in biliary cells silenced for VDR, and this effect was abolished by co-silencing the plasma membrane receptor of vitamin D, protein disulfide-isomerase A3 (PDIA3).

Our results demonstrate an anti-inflammatory role of VDR signaling in cholangiocytes and cholangiopathy. They also provide evidence for PDIA3-mediated anti-inflammatory effects of vitamin D and vitamin D analog in these settings.

Statistical models provide a quantitative structure with which clinicians can evaluate their hypotheses to explain patterns in observed data and generate forecasts. In contrast, vitamin D is an important immune modulator that plays an emerging role in liver diseases such as chronic hepatitis B (CHB). Therefore, we quantified 25(OH)D₃ serum levels in 292 CHB patients tested for their association with clinical parameters. Of 292 patients, 69 (63%), 95 (47%), and 39 (19%) had severe vitamin D deficiency (25(OH)D₃ < 10 ng/mL), vitamin D insufficiency (25(OH)D₃10 and < 20 ng/mL), or adequate vitamin D serum levels (25(OH)D₃ 20 ng/mL), respectively. In both univariate and multivariate analyses, zinc serum level was a strong predictor of low 25(OH)D₃ serum levels (P < 0.001). Results of fitted models showed that lower vitamin D levels were significantly associated with: younger age, lower uric acid levels, HBeAg-positive status, lower calcium levels (p < 0.05). Vitamin D deficiency (<20 ng/ml) or severe deficiency (<10 ng/ml) was observed more frequently among HBV patients (52%). Vitamin D deficiency was observed in most CHB patients. Generally, our results recommend that substitution of vitamin D can be a substitution method in the treatment of patients with HBV-associated disorders.

Patients with liver cirrhosis experience a large variety of metabolic disorders associated with more hepatic decompensation. Hepatic encephalopathy (HE) is a significant complication in liver cirrhosis patients, presenting a wide spectrum of neuropsychological symptoms. A deficiency of 25-hydroxy vitamin D (25-OHD) in the general population is associated with a loss of cognitive function, dementia, and Alzheimer's disease. Aim of the Study. Our study aims to check the relationship between low serum 25-OHD and HE in patients with HCV-related liver cirrhosis and assess its link with patient mortality. Patients and Methods. This study was observationally carried out on 100 patients with HCV-related liver cirrhosis. The patients were divided into 2 groups: Group A-included 50 HCV-related cirrhotic patients with HE, and Group B-included 50 HCV-related cirrhotic patients without HE. Assessment of disease severity using the end-stage liver disease (MELD) model and Child Turcotte Pugh (CTP) scores were done, and 25-OHD levels were measured. Comparison of vitamin D levels in different etiologies and different CTP categories was made using one-way ANOVA. Pearson's correlation between the level of vitamin D and other biomarkers was applied.

There was a statistically significant Vitamin D level difference between the two groups. A lower level of vitamin D was observed in the HE group where the severe deficiency was 16%, while it was 6% in the other group and the moderate deficiency was 24% in HE group as compared to 10% in the other group. The insufficient vitamin D level represented 46% of the non-HE group while none of the HE group falls in this category. Vitamin D level was statistically higher in Grade 1 HE than in Grade 2 which is higher than in Grades 3 to 4. Vitamin D level was also significantly higher in those who improved from HE as compared to those who died.

The lower levels of 25-OHD were associated with the higher incidence of HE in cirrhotic HCV patients. The worsening vitamin D deficiency was associated with increased severity of the liver disease, so vitamin D may be considered a prognostic factor for the severity of liver cirrhosis and high mortality rate in HE patients.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, with about 841,000 new cases and 782,000 deaths annually. Given the clearly defined population at risk, mostly patients with liver cirrhosis, prevention of HCC could be highly effective.

Besides regular ultrasound surveillance, numerous publications have suggested protective effects of diverse drugs and nutrients. However, none of those preventive options has made it into clinical routine or practice guidelines. We therefore summarize the current status of preventive effects of drugs such as statins, acetylsalicylic acid (ASA), and metformin, but also dietary aspects and nutrients such as coffee, tea, and vitamin D supplementation. A successful implementation of some of these strategies may potentially lead to improved prevention of HCC development in patients with liver cirrhosis. Key Messages: Accumulating data suggest that particularly ASA, antidiabetic therapies, and statins may substantially decrease HCC incidence in patients at risk.

Excessive ethanol consumption causes cellular damage, leading to fetal alcohol syndrome and alcohol liver diseases, which are frequently seen with vitamin D (VD) deficiency. A great deal of progress has been achieved in the mechanisms of ethanol-induced hepatocyte damage. However, there are limited intervention means to reduce or rescue hepatocytes damage caused by ethanol. On the basis of our preliminary limited screen process, calcitriol showed a positive effect on protecting hepatocyte viability. Therefore, the molecular basis is worth elucidating. We found that calcitriol pretreatment markedly improved the cell viability, decreased cell apoptosis and oxidative stress and alleviated the abnormal mitochondrial morphology and membrane potential of hepatocytes induced by ethanol. Notably, autophagy was significantly enhanced by calcitriol, as evident by the increasing number of autophagosomes and autolysosomes, upregulated LC3B-Ⅱ and ATG5 levels, and promotion of p62 degradation. Furthermore, calcitriol pretreatment increased the colocalization of GFP-LC3-labeled autophagosomes with mitochondria, suggesting that calcitriol effectively promoted ethanol-induced mitophagy in hepatocytes. In addition, the inhibition of autophagy attenuated the protective and preventive effect of calcitriol. Furthermore, the effect of calcitriol on autophagy was regulated by AMPK/mTOR signaling, and signaling transduction was dependent on the Vitamin D receptor (VDR). In conclusion, calcitriol ameliorates ethanol-induced hepatocyte damage by enhancing autophagy. It may offer a convenient preventive and hepatoprotective mean for people on occasional social drink.

Non-alcoholic fatty liver disease (NAFLD) refers to an accumulation of excess fat in liver due to causes other than alcohol use. The relationship between vitamin D (VD) and NAFLD has been previously studied. Therefore, we aimed to explore the mechanism involved active VD regulating the progression of NAFLD by inhibiting cell senescence and to provide a potential approach for further nutritional treatment of NAFLD.

Following the induction with high-fat diet and intraperitoneal injection of corn oil, the successfully established NAFLD rat models were treated with 1,25(OH)₂D₃ at 1μg/kg, 5μg/kg or 10μg/kg. Meanwhile, the levels of factors related to oxidative stress, cell senescence, the p53-p21 signaling pathway and inflammation in liver were determined. Then, cell senescence was also measured by using senescence-associated β-galactosidase (SAβ-gal) staining.

It was also found that active VD increased the concentration of VD in serum and VDR in liver of NAFLD rats, and alleviated hepatic fibrosis. Besides, treatment of 1,25(OH)₂D₃ at 1μg/kg, 5μg/kg or 10μg/kg reduced oxidative stress and inflammation, inhibited the p53-p21 signaling pathway and consequent cell senescence. Furthermore, treatment of 1,25(OH)₂D₃ at a dosage of 5μg/kg made the most impact on these factors.

Collectively, the evidences from this study demonstrated that active VD could alleviate the development of NAFLD through blocking the p53-p21 signaling pathway, which provided a novel nutritional therapeutic insight for NAFLD.

Alcoholic liver disease (ALD) remains an important health problem worldwide. Perturbation of micronutrients has been broadly reported to be a common characteristic in patients with ALD, given the fact that micronutrients often act as composition or coenzymes of many biochemical enzymes responsible for the inflammatory response, oxidative stress, and cell proliferation. Mapping the metabolic pattern and the function of these micronutrients is a prerequisite before targeted intervention can be delivered in clinical practice. Recent years have registered a significant improvement in our understanding of the role of micronutrients on the pathogenesis and progression of ALD. However, how and to what extent these micronutrients are involved in the pathophysiology of ALD remains largely unknown. In the current study, we provide a review of recent studies that investigated the imbalance of micronutrients in patients with ALD with a focus on zinc, iron, copper, magnesium, selenium, vitamin D and vitamin E, and determine how disturbances in micronutrients relates to the pathophysiology of ALD. Overall, zinc, selenium, vitamin D, and vitamin E uniformly exhibited a deficiency, and iron demonstrated an elevated trend. While for copper, both an elevation and deficiency were observed from existing literature. More importantly, we also highlight several challenges in terms of low sample size, study design discrepancies, sample heterogeneity across studies, and the use of machine learning approaches.

Alcohol-related liver disease has become the leading indication for liver transplantation in the USA, partly due to an increase in the prevalence of high-risk drinking behaviour and alcohol use disorder, particularly among young women. Achieving sustained alcohol abstinence might not only prevent the development and progression of alcohol-related liver disease, but could also lead to clinically significant improvements, even in the advanced stages of disease. In this Series paper, we discuss the diagnosis and outpatient management of alcohol-related liver disease, with an emphasis on treatment options for alcohol use disorder and the assessment of nutritional status.

Increasing evidence indicates that vitamin D status is linked to severity of liver cirrhosis and patients' survival. However, the potential role of vitamin D-related immunomodulation in hepatic decompensation and patients' mortality in relation to vitamin D deficiency remains unknown. The aim of the current study is to evaluate the association between vitamin D status and vitamin D binding protein (VDBP) levels with serum cytokine and lipopolysaccharide binding protein (LBP) and to examine their role on disease severity and cirrhotics' mortality.

One hundred consecutive Caucasian patients with liver cirrhosis were enrolled in the study. 25(OH)D, VDBP, and LBP concentrations were assessed by ELISA. Cytokine tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), IL-1β, IL-8, IL-10, and IL-12 levels were determined by Cytometric Bead Array.

25(OH)D levels were inversely correlated with CP score, MELD, IL-6, and CP stage and VDBP levels with CP score, MELD, IL-6, IL-8, LBP, and CP stage. Cirrhotics with 25(OH)D deficiency and severe deficiency had significantly higher CP score, increased IL-6 levels and lower VDBP levels. In the multivariate analysis, the independent prognostic factors associated with patients' survival were CP stage B [hazard ratio = 6.75; 95% confidence interval (CI) 1.32, 34.43; P = 0.022], CP stage C (hazard ratio = 7.39; 95% CI 1.41, 38.81; P = 0.018), the presence of hepatocellular carcinoma (hazard ratio = 4.50; 95% CI 1.54, 13.13; P = 0.006) and 25(OH)D levels (hazard ratio = 0.87; 95% CI 0.80, 0.95; P = 0.002).

The results show that vitamin D status and VDBP levels are associated with liver cirrhosis severity and patients' mortality, possibly through a proinflammatory immune response.

Prognosis of patients with diverse chronic diseases is reportedly associated with 25-hydroxyvitamin D levels. In this study, we investigated the potential role of 25-hydroxyvitamin D3 (25[OH]D3) levels in improving the predictive power of conventional prognostic models for patients with liver cirrhosis.

We investigated clinical findings, including serum 25(OH)D3 levels at admission, of 155 patients with cirrhosis who were followed up for a median of 16.9 months.

Median 25(OH)D3 levels were significantly different among patients exhibiting Child-Pugh grades A, B, and C. Mortality, including urgent transplantation, was significantly associated with 25(OH)D3 levels in univariate analysis. Severe vitamin-D deficiency (serum 25[OH]D3 level < 5.0 ng/mL) was significantly related to increased mortality, even after adjusting for Child-Pugh and Model for End-stage Liver Disease (MELD) scores. In particular, the presence of severe vitamin D deficiency clearly defined a subgroup with significantly poorer survival among patients with Child-Pugh scores of 5-10 or MELD scores ≤ 20. A new combination model of MELD score and severe vitamin D deficiency showed significantly more accurate predictive power for short- and long-term mortality than MELD scores alone. Additionally, serum 25(OH)D3 levels and new model scores were significantly associated with the development of spontaneous bacterial peritonitis, overt encephalopathy, and acute kidney injury.

Serum 25(OH)D3 level is an independent prognostic factor for patients with liver cirrhosis and has a differential impact on disease outcomes according to MELD and Child-Pugh scores.

Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA.

Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens.

We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra^-/- and major urinary protein-urokinase-type plasminogen activator/Il-17ra^-/- mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the development of HCC was decreased in both alcohol-fed Il-17ra^ΔMΦ and Il-17ra^ΔHep mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in Il-17ra^ΔHSC mice (deficient in IL-17RA in hepatic stellate cells). Deletion of Il-17ra in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed Il-17ra^ΔMΦ mice. Remarkably, despite a normal inflammatory response, alcohol-fed Il-17ra^ΔHep mice developed the fewest tumors (compared with Il-17ra^ΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D₃. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC.

Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC.

IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.