Vitamin D deficiency and hepatitis viruses-associated liver diseases:a literature review

The secosteroid hormone vitamin D has, in addition to its effects in bone metabolism also functions in the modulation of immune responses against infectious agents and in inhibiting tumorigenesis. Thus, deficiency of vitamin D is associated with several malignancies, but also with a plethora of infectious diseases. Among other communicable diseases, vitamin D deficiency is involved in the pathogenesis of chronic liver diseases caused by hepatitis B and C viruses(HBV, HCV) and high prevalence of vitamin D deficiency with serum levels below 20 mg/mL in patients with HBV and HCV infection are found worldwide. Several studies have assessed the effects of vitamin D supplementation on the sustained virological response(SVR) to interferon(IFN) plus ribavirin(RBV) therapy in HBV and HCV infection. In these studies, inconsistent results were reported. This review addresses general aspects of vitamin D deficiency and, in particular, the significance of vitamin D hypovitaminosis in the outcome of HBVand HCV-related chronic liver diseases. Furthermore,current literature was reviewed in order to understand the effects of vitamin D supplementation in combination with IFN-based therapy on the virological response in HBV and HCV infected patients.     

Vitamin D levels do not predict the stage of hepatic fibrosis in patients with non-alcoholic fatty liver disease: A PRISMA compliant systematic review and meta-analysis of pooled data

AIM To investigate the relationship between 25-hydroxyvitamin D [25(OH)D] levels and fibrosis stage in patients with non-alcoholic fatty liver disease(NAFLD).METHODS Two individual reviewers identified relevant studies using the Pub Med, EMBASE, Cochrane, and Scopus databases. Inclusion criteria were as follows:(1) Studies that evaluated adults with NAFLD and serum or plasma 25(OH)D levels; and(2) assessed fibrosis stage using liver biopsy. A rigorous analysis yielded six articles as having sufficient data to employ in evaluating the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. To meta-analyze vitamin D levels in F0-F2 vs F3-F4 fibrosis, a random-effects meta-analysis fit using restricted maximum likelihood was applied. To examine trends across each stage of fibrosis with respect to vitamin D levels, a meta-regression was performed. P 0.05 was considered statistically significant. RESULTS A total of 937 subjects from six studies were included in the final analysis to evaluate the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. First, the investigators performed a meta-analysis to compare serum vitamin D levels in patients with NAFLD with stage F0-F2 compared to F3-F4, which did not show significance [meta-estimate of the pooled mean difference =-0.86, P = 0.08(-4.17, 2.46)]. A metaregression evaluation of serum vitamin 25(OH)D levels across the individual stages(F0-F4) of fibrosis did not show an association for the six included studies.CONCLUSION Low vitamin D status is not associated with higher stages of liver fibrosis in patients with NAFLD.     

Dietary vitamin E and C intake is inversely associated with the severity of nonalcoholic fatty liver disease

Background & aimsAlthough antioxidants have a protective potential in nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), there is limited evidence regarding the role of dietary intake of antioxidants. The aim was to test the association between dietary vitamins E and C intake and NAFLD, NASH and fibrosis markers.MethodsCross-sectional study of a large cohort of subjects undergoing colonoscopy. The presence of NAFLD was evaluated by ultrasonography. The level of steatosis was defined using SteatoTest, moderate-severe NASH using new quantitative NashTest and borderline-significant fibrosis ≥ F1–F2 using FibroTest. Nutritional intake was measured by food frequency questionnaire (FFQ).ResultsOverall, 789 subjects were included (52.6% men, age 58.83 ± 6.58 years), 714 had reliable FibroMax. Adjusting for BMI, dietary and lifestyle factors, the upper tertile of vitamin E intake/1000 Kcal was associated with lower odds of NASH (OR = 0.64, 0.43–0.94, P = 0.024). There was an inverse association between reaching the recommended vitamin E intake and NASH (OR = 0.48, 0.30–0.77, P = 0.002). The upper tertile of vitamin C intake/1000 Kcal was associated with lower odds of NAFLD and NASH (OR = 0.68, 0.47–0.99, P = 0.045; OR = 0.57, 0.38–0.84, P = 0.004, respectively). Both vitamins were related with the level of steatosis according to SteatoTest.ConclusionVitamin E and C intake may be protective from NAFLD-related liver damage.     

Fatty liver in hepatitis C patients post-sustained virological response with direct-acting antivirals

AIM To determine steatosis and fibrosis prevalence in hepatitis C patients after a sustained virological response achieved with direct-acting antivirals.METHODS Transient elastography with controlled attenuation parameter(CAP) was used to assess hepatic steatosis post-sustained virological response(SVR);the CAP technology was not available in the United States at study initiation.Liver stiffness/fibrosis was measured before and 47 wk after treatment completion.Patients with genotype 3 and patients with cirrhosis were excluded.RESULTS One hundred and one patients were included in the study.Post-SVR there were decreases from baseline in alanine aminotransferase(ALT)(63.1 to 17.8 U/L),aspartate aminotransferase(51.8 to 21.5 U/L) and fibrosis score(7.4 to 6.1 k Pa)(P 0.05).Post-SVR,48 patients(47.5%) had steatosis on CAP;of these,6.25% had advanced fibrosis.Patients with steatosis had higher body mass index(29.0 vs 26.1 kg/m2),glucose(107.8 vs 96.6 mg/d L),ALT(20.4 vs 15.3 mg/d L),CAP score(296.3 vs 212.4 d B/m) and fibrosis score(7.0 vs 5.3 k Pa);P 0.05.Interestingly,compared to baseline,both patients with and without steatosis had change in fibrosis score post-SVR(7.7 k Pa vs 7.0 k Pa and 7.0 k Pa vs 5.3 k Pa);alternatively,(P 0.05) and therefore patients with steatosis continued to have clinically significant stiffness(≥ 7 k Pa).CONCLUSION Fatty liver is very common in hepatitis C virus(HCV) patients post-SVR.These patients continue to have elevated mean fibrosis score(≥ 7 k Pa) compared to those without fatty liver;some have advanced fibrosis.Long term follow up is needed to assess steatosis and fibrosis in HCV patients post-SVR.     

Vitamin D and histologic severity of nonalcoholic fatty liver disease: A systematic review and meta-analysis

BackgroundNAFLD and vitamin D deficiency often coexist and epidemiologic evidence has shown that both of these conditions share several risk factors. Recent studies investigating the relationship between vitamin D levels and severity of NAFLD showed conflicting results. Thus we conducted a systematic review and meta-analysis to evaluate association between vitamin D and NAFLD histologic severity.MethodsA comprehensive search of the databases of the MEDLINE and EMBASE was performed from inception through November 2016. Observational studies compared serum vitamin D levels among NAFLD patients with high and low histologic severity, which was determined by NAFLD activity score (NAS) and fibrosis score. We calculated pooled mean difference (MD) of 25-hydroxyvitamin D levels with 95% confidence intervals (CI) using random-effects model.ResultsData were extracted from 6 studies involving 974 NAFLD patients. There was no difference in 25-hydroxyvitamin D levels among NAFLD patients with high NAS (score of ≥5) versus low NAS (pooled MD = −0.93, 95%CI −2.45 to 0.58, I² = 0%) and also high fibrosis score (score of ≥3) versus low fibrosis score (pooled MD = 0.88, 95%CI −2.65 to 4.42, I² = 64%).ConclusionsDespite evidence implicating vitamin D in NAFLD pathogenesis, serum 25-hydroxyvitamin D may not be associated with NAFLD histologic severity.     

Association of nonalcoholic fatty liver disease and liver cancer

AIM:To investigate the association between nonalcoholic fatty liver disease(NAFLD) and liver cancer,and NAFLD prevalence in different liver tumors.METHODS:This is a retrospective study of the clinical,laboratory and histological data of 120 patients diagnosed with primary or secondary hepatic neoplasms and treated at a tertiary center where they underwent hepatic resection and/or liver transplantation,with subsequent evaluation of the explant or liver biopsy.The following criteria were used to exclude patients from the study:a history of alcohol abuse,hepatitis B or C infection,no tumor detected in the liver tissue examined by histological analysis,and the presence of chronic autoimmune hepatitis,hemochromatosis,Wilson’s disease,or hepatoblastoma.The occurrence of NAFLD and the association with its known risk factors were studied.The risk factors considered were diabetes mellitus,impaired glucose tolerance,impaired fasting glucose,body mass index,dyslipidemia,and arterial hypertension.Presence of reticulin fibers in the hepatic neoplasms was assessed by histological analysis using slide-mounted specimens stained with either hematoxylin and eosin or Masson’s trichrome and silver impregnation.Analysis of tumor-free liver parenchyma was carried out to determine the association between NAFLD and its histological grade.RESULTS:No difference was found in the association of NAFLD with the general population(34.2% and 30.0% respectively,95%CI:25.8-43.4).Evaluation by cancer type showed that NAFLD was more prevalent in patients with liver metastasis of colorectal cancer than in patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma(OR = 3.99,95%CI:1.78-8.94,P < 0.001 vs OR = 0.60,95%CI:0.18-2.01,P = 0.406 and OR = 0.70,95%CI:0.18-2.80,P = 0.613,respectively).There was a higher prevalence of liver fibrosis in patients with hepatocellular carcinoma(OR = 3.50,95%CI:1.06-11.57,P = 0.032).Evaluation of the relationship between the presence of NAFLD,nonalcoholic steatohepatitis,and liver fibrosis,and their risk factors,showed no significant statistical association for any of the tumors studied.CONCLUSION:NAFLD is more common in patients with liver metastases caused by colorectal cancer.     

Insulin resistance and liver steatosis in chronic hepatitis C infection genotype 3

Hepatitis C virus (HCV) infection is a common chronic liver disease worldwide. Non-alcoholic fatty liver disease and insulin resistance (IR) are the major determinants of fibrosis progression and response to antiviral therapy. The pathogenetic link between IR and chronic HCV infection is complex, and is associated with HCV genotype. Liver steatosis is the most common in the patients infected with genotype 3 virus, possibly due to direct effects of genotype 3 viral proteins. To the contrary, hepatic steatosis in the patients infected with other genotypes is thought to be mostly due to the changes in host metabolism, involving IR. In HCV genotype 3, liver steatosis correlates with viral load, reverts after reaching the sustained virologic response and reoccurs in the relapsers. A therapeutic strategy to improve IR and liver steatosis and subsequently the response to antiviral treatment in these patients is warranted.     

非酒精性脂肪性肝病合并2型糖尿病患者肝组织病理学变化研究

目的 研究非酒精性脂肪性肝病（NAFLD）合并2型糖尿病（T2DM）患者肝脏组织病理学变化。方法 分析240例行肝活检术的NAFLD患者临床资料,比较NAFLD合并T2DM与未合并T2DM患者肝组织病理学表现和评分的差异。结果 在240例NAFLD患者中,合并2型糖尿病者80例（33.3%）,未合并T2DM 者160例（66.7%）;在NAFLD合并T2DM患者中非酒精性脂肪性肝炎（NASH）60例、肝纤维化20例,未合并T2DM患者中分别为68例和92例;在NAFLD合并T2DM患者中检出肝纤维化评分≥2者30例（37.5%）、肝细胞气球样变评分≥2者23例（28.8%）和马洛里小体22例（27.5%）,均显著高于未合并T2DM患者的【20例（12.5%）、22例（13.8%）和30例（18.8%）,P<0.05】;T2DM为发生NASH（OR=3.27,95%CI：1.42~7.55）和肝纤维化（OR=3.35,95%CI：1.55~7.63）的独立危险因素。结论 合并T2DM的NAFLD患者肝组织病理学损伤更趋严重,应注意防治。     

Role of liver biopsy in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD), defined as abnormal accumulation (> 5%) of hepatic triglyceride without excess alcohol intake, is the most common form of chronic liver disease in adults and children in the United States. NAFLD encompasses a spectrum of histologic findings including uncomplicated steatosis, steatosis with inflammation and steatohepatitis [nonalcoholic steatohepatitis (NASH)]; the latter can advance to cirrhosis and hepatocellular carcinoma. NASH is currently accepted as the hepatic manifestation of the set of cardiovascular risk factors collectively known as metabolic syndrome. In 1999 a system for histologic grading and staging for NASH was proposed; this was revised by the NASH Clinical Research Network in 2005 for the entire spectrum of lesions in NAFLD, including the lesions and patterns of pediatric NAFLD, and for application in clinical research trials. Diagnosis remains distinct from grade and stage. A recent European proposal separates steatosis from activity to derive a numeric diagnosis of NASH. Even though there have been promising advancements in non-invasive testing, these tests are not yet detailed enough to replace the full range of findings provided by liver biopsy evaluation. Limitations of biopsy are acknowledged, but liver biopsy remains the “gold standard” for diagnosis and determination of amounts of necroinflammatory activity, and location of fibrosis, as well as remodeling of the parenchyma in NASH. This review focuses on the specific histologic lesions of NAFLD and NASH, grading and staging, differential diagnoses to be considered, and the continuing role of the liver biopsy in this important liver disease.     

Nonalcoholic fatty liver disease: pharmacologic and surgical options

The last decade has seen many studies examining the prevalence and natural history of NAFLD in the United States and it is clear that this disease is likely to be an important cause of liver-related morbidity in the future. Several pharmacologic therapies have shown some promise; currently, vitamin E and insulin-sensitizing agents such as pioglitazone can be considered in appropriate cases. Conservative measures to promote weight loss still have a role to play, but the obesity epidemic in the Western World has reached such proportions that bariatric surgery is proving to be an attractive option for patients with a BMI greater than 35 to 40 kg/m2. Well-designed prospective studies are required to ensure that all of these therapies are safe and effective in the long term. Newer agents will likely be investigated as the pathogenesis of NAFLD and fibrosis progression in NASH are further elucidated.     

Association between vitamin D and hepatitis C virus infection: A meta-analysis

AIM:To evaluate the association between 25-hydroxyvitamin D[25(OH)D]and sustained virological response(SVR)in hepatitis C virus(HCV)infected individuals.METHODS:Relevant studies were identified by systematically searching MEDLINE databases up to March2012 and abstracts of the European and American Congress of Hepatology conducted in 2011.Studies must provide information on SVR and the levels of 25(OH)D3and/or 25(OH)D2[henceforth referred to as 25(OH)D]in sera samples from HCV infected individuals.The inclusion criteria were:clinical studies that included HCV infected patients aged older than 18 years regardless of HCV genotype or ethnic group;provided information on SVR rates;and were reported in the English languageas full papers.Due to the heterogeneity of studies in categorizing serum vitamin D levels,a cut-off value of30 ng/mL of serum 25(OH)D was used.Heterogeneity was assessed using I2statistics.The summary odds ratios with their corresponding 95%CI were calculated based on a random-effects model.RESULTS:Overall,11 studies(8 observational and 3interventional)involving 1575 individuals were included and 1117 HCV infected individuals(71%)showed low vitamin D levels.Most of the studies included monoinfected HCV individuals with the mean age ranging from 38 to 56 years.Four studies were conducted in human immunodeficiency virus/HCV infected individuals.Regarding vitamin D measurement,most of the studies employed radioimmunoassays(n=5)followed by chemiluminescence(n=4)and just one study employed high performance/pressure liquid chromatography(HPLC).Basal vitamin D levels varied from 17 to43 ng/mL in the studies selected,and most of the HCV infected individuals had genotype 1(1068/1575)with mean viral load varying from log 4.5-5.9 UI/mL.With regard to HCV treatment,most of the studies(n=8)included HCV individuals without previous treatment,where the pooled SVR rate was 46.4%.High rates of SVR were observed in HCV individuals with vitamin D levels above 30 ng/mL(OR=1.57;95%CI:1.12-2.2)and those supplemented with     

Vitamin D supplementation for the treatment of non-alcoholic fatty liver disease: A randomized double blind placebo controlled trial

Background

Low serum vitamin D has been associated with metabolic syndrome and Non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the impact of vitamin D supplementation in treatment of patients with NAFLD.

Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD)/nonalcoholic steatohepatitis(NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers(thiazolidinediones) and antioxidants(vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.     

维生素D对非酒精性脂肪性肝病的保护作用

维生素D是一种脂溶性类固醇激素,其除从传统意义上调节钙、磷平衡及骨代谢外,还具有广泛的骨外生物学作用,如参与机体能量代谢和糖、脂代谢.维生素D缺乏可能引起代谢综合征,而非酒精性脂肪性肝病(NAFLD)是代谢综合征在肝脏中的表现形式.有证据显示,维生素D可通过介导胆汁酸代谢、减轻胰岛素抵抗以及改善肝纤维化这3条途径发挥对NAFLD的保护作用.     

Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

It is estimated that 30%of the adult population in Japan is affected by nonalcoholic fatty liver disease(NAFLD).Fatty changes of the liver are generally diagnosed using imaging methods such as abdominal ultrasonography(US)and computed tomography(CT),but the sensitivity of these imaging techniques is low in cases of mild steatosis.Alanine aminotransferase levels may be normal in some of these patients,warranting the necessity to establish a set of parameters useful for detecting NAFLD,and the more severe form of the disease,nonalcoholic steatohepatitis(NASH).Although liver biopsy is currently the gold standard for diagnosing progressive NASH,it has many drawbacks,such as sampling error,cost,and risk of complications.Furthermore,it is not realistic to perform liver biopsies on all NAFLD patients.Diagnosis of NASH using various biomarkers,scoring systems and imaging methods,such as elastography,has recently been attempted.The NAFIC score,calculated from the levels of ferritin,fasting insulin,and typeⅣcollagen 7S,is useful for the diagnosis of NASH,while the NAFLD fibrosis score and the FIB-4 index are useful for excluding NASH in cases of advanced fibrosis.This article reviews the limitations and merits of liver biopsy and noninvasive diagnostic tests in the diagnosis of NAFLD/NASH.     

Liver transplantation for nonalcoholic fatty liver disease:New challenges and new opportunities

Nonalcoholic fatty liver disease(NAFLD)is becoming rapidly one of the most common indications for orthotopic liver transplantation in the world.Development of graft steatosis is a significant problem during the posttransplant course,which may happen as a recurrence of pre-existing disease or de novo NAFLD.There are different risk factors that might play a role in development of graft steatosis including post-transplant metabolic syndrome,immune-suppressive medications,genetics and others.There are few studies that assessed the effects of NAFLD on graft and patient survival;most of them were limited by the duration of follow up or by the number of patients.With this review article we will try to shed light on post-liver transplantation NAFLD,significance of the disease,how it develops,risk factors,clinical course and treatment options.     

Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

AIM:To characterize development of diet-induced nonalcoholic steatohepatitis(NASH)by performing live biopsy in wild-type and genetically obese mice.METHODS:Male wild-type C57BL/6J(C57)mice(DIO NASH)and male Lep ob/Lep ob(ob/ob)mice(ob/ob-NASH were maintained on a diet high in trans-fat(40%)fructose(22%)and cholesterol(2%)for 26 and 12 wk respectively.A normal chow diet served as control in C57 mice(lean chow)and ob/ob mice(ob/ob chow)After the diet-induction period,mice were liver biopsied and a blinded histological assessment of steatosis and fibrosis was conducted.Mice were then stratified into groups counterbalanced for steatosis score and fibrosi stage and continued on diet and to receive daily PO dosing of vehicle for 8 wk.Global gene expression in liver tissue was assessed by RNA sequencing and bioin formatics.Metabolic parameters,plasma liver enzyme and lipids(total cholesterol,triglycerides)as well a hepatic lipids and collagen content were measured b biochemical analysis.Non-alcoholic fatty liver disease activity score(NAS)(steatosis/inflammation/ballooningdegeneration)and fibrosis were scored.Steatosis and fibrosis were also quantified using percent fractional area.RESULTS:Diet-induction for 26 and 12 wk in DIONASH and ob/ob-NASH mice,respectively,elicited progressive metabolic perturbations characterized by increased adiposity,total cholesterol and elevated plasma liver enzymes.The diet also induced clear histological features of NASH including hepatosteatosis and fibrosis.Overall,the metabolic NASH phenotype was more pronounced in ob/ob-NASH vs DIO-NASH mice.During the eight week repeated vehicle dosing period,the metabolic phenotype was sustained in DIO-NASH and ob/ob-NASH mice in conjunction with hepatomegaly and increased hepatic lipids and collagen accumulation.Histopathological scoring demonstrated significantly increased NAS of DIO-NASH mice(0 vs4.7±0.4,P0.001 compared to lean chow)and ob/ob-NASH mice(2.4±0.3 vs 6.3±0.2,P0.001compared to ob/ob chow),respectively.Furthermore,fibrosis stage was significantly elevated for DIO-NASH mice(0 vs 1.2±0.2,P0.05 compared to lean chow)and ob/ob NASH(0.1±0.1 vs 3.0±0.2,P0.001compared to ob/ob chow).Notably,fibrosis stage was significantly(P0.001)increased in ob/ob-NASH mice,when compared to DIO-NASH mice.CONCLUSION:These data introduce the obese dietinduced DIO-NASH and ob/ob-NASH mouse models with biopsy-confirmed individual disease staging as a preclinical platform for evaluation of novel NASH therapeutics.     

Non-invasive prediction of liver-related events in patients with HCV-associated compensated advanced chronic liver disease after oral antivirals

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