Effect on Liver Histology of Vitamin D in Patients With Non-alcoholic Steatohepatitis

Study Overview
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Brief Summary
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Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disorders characterized by predominantly macrovesicular hepatic steatosis occurring in individuals in the absence of significant alcohol consumption. In this context it is possible to distinguish a condition of simple fatty liver, where the only histologic finding is the presence of steatosis, from a state of non-alcoholic steatohepatitis (NASH), characterized by hepatocellular injury/inflammation with or without fibrosis. The prevalence of NAFLD is around 20-30% in the general population. With a rapid increase in the risk factors for metabolic syndrome, NAFLD has become the most common cause of liver disease in Western countries. The clinical relevance of NAFLD arises from the fact that a considerable proportion of subjects (20-30%) develop NASH, and this condition can progress to cirrhosis in up to 15% of patients. In addition NAFLD, and particularly NASH, represents a cardiovascular risk factor, independent of other well-known conditions contributing to heart and vascular diseases. Lifestyle modification is the effective medical treatment recommended for NASH, while there is currently no pharmacologic therapy of proven benefit in these patients. Several pilot studies, using insulin sensitizers (thiazolidinediones or metformin), and antioxidants, like vitamin E, have provided inconclusive evidence that these drugs may improve clinical and histological features of NASH. In the complex and not completely understood pathogenic puzzle of NAFLD and NASH, also vitamin D might have an important role. Vitamin D deficiency is associated with many common pathological conditions frequently observed in NAFLD, like cardiovascular disease, and insulin resistance. A recent paper by Targher and colleagues showed low vitamin D serum levels in NAFLD patients, identifying an inverse relation between vitamin D levels and the severity of liver disease. In keeping with the above data, recent experimental evidence also suggested the potential ability of vitamin D, through interaction with its nuclear receptor (vitamin D receptor - VDR), to interfere with inflammatory response, T cell function and fibrogenesis. Therefore considering the link between vitamin D serum levels, severity of NAFLD, and risk factors for NAFLD, we speculate that vitamin D might represent a new therapeutic target in the management of NASH patients.

Official Title
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A Randomised Controlled Trial of Vitamin D Plus Plus Lifestyle Versus Lifestyle in Patients With Non-alcoholic Steatohepatitis:Effect on Liver Histology and Metabolic Parameters

Conditions
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Non.Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: Vitamin D
* Behavioral: Lifestyle counseling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients older 18 years Histological diagnosis of possible or definite NASH, according to Kleiner score, within 6 months before randomization. Exclusion Criteria: Average alcohol consumption exceeding 20 g per day in women and 30 g per day in men for at least 3 consecutive months during the previous 5 years, as evaluated by self-administrated questionnaires, 7-day recall tests rand confirmed by a family member. Other causes of chronic liver disease: Wilson's disease (normal serum ceruloplasmin); alpha-1-antitrypsin deficiency (normal serum alpha-1-antitrypsin); viral hepatitis (anti-HCV and HBsAg negativity); primary biliary cirrhosis (ANA<1:160 and AMA negativity); autoimmune hepatitis (ANA, SMA and LKM <1:160 and absence of histological features of autoimmune hepatitis); HIV infection (anti-HIV negativity); hypo or hyperthyroidism (normal TSH). History of or planned gastrointestinal bypass or any additional bariatric surgery/intervention. Hepatic cirrhosis with a Child-Pugh score of B or C, and/or concomitant hepatocellular carcinoma Recent significant weight loss (>5% TBW within previous 6 months) Recent (within 6 months of baseline liver biopsy and screening visit) or concomitant use of agents known to cause hepatic steatosis (corticosteroids, amiodarone, methotrexate, tamoxifen, tetracycline, high dose estrogens (with the exclusion of standard HRT and oral contraceptive treatment), valproic acid) Recent (within 6 months of baseline liver biopsy and screening visit) change in dose/regimen or first treatment with vitamin E, Vitamin C, betaine, s-adenosyl methionine, ursodeoxycholate, sylimarin, fibrate, statin, pentoxyfilline, angiotensin II inhibitors, orlistat, sibutramine. Oral hypoglycaemic agents and insulin will be allowed, provided they had been initiated at least 6 months before enrollment and are maintained at stable doses. Ongoing or recent therapy (within 6 months of baseline liver biopsy and screening visit) with vitamin D or with medications known to affect vitamin D3 metabolism, including vitamin/mineral supplements. Any additional condition that might interfere with optimal participation in the study, according to Investigators opinion. Be pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin D and Lifestyle counseling<br> | Drug: Vitamin D<br>* 20.000 UI/week for 96 weeks<br>|
| Active Comparator: Lifestyle counseling<br> | Behavioral: Lifestyle counseling<br>* Lifestyle counseling for 96 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (a) improvement in NAS by at least 2 points spread across at least 2 of the NAS components or post-treatment NAS of 3 points or less, (b) at least 1 point improvement in the score for ballooning degeneration and (c) no worsening of the fibrosis score. |  | 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in individual components of NAS score |  | 96 WEEKS | 
| Changes in intima-media thickness |  | 96 WEEKS | 
| Changes in liver fibrosis |  | 96 weeks | 
| Changes in insulin resistance |  | 96 weeks |