Vitamin D and nonalcoholic fatty liver disease : more than just an association? EUN-JUNG RHEE DEPARTMENT OF ENDOCRINOLOGY AND METABOLISM, KANGBUK SAMSUNG HOSPITAL, Contents About NAFLD Why NAFLD and vitamin D? Mechanism for the link between NAFLD and VDD Studies on the association of NAFLD and VDD About NAFLD? Nonalcoholic fatty liver disease (NAFLD)의 정의 Fatty infiltration이 간세포의 5%이상을 차지하 고 하루에 알코올을 20g미만으로 섭취할 때 진 단된다 Exclusion criteria Excess alcohol intake - Absence of serologic evidence of viral hepatitis. - Absence of other chronic liver disease - 진단 조기에는 liver enzyme이 정상일 수 있으며 NAFLD의 70%에서 간수치는 정상 초음파는 지방이 간의 30%이상을 차지했을 때 지방간을 진단할 수 있으나, 현재로서는 진단의 용이성으로 1차적 진단 방법으로 추천되고 있 다. 그러나 어떤 비침습성 진단 방법도 염증이나 fibrosis를 진단할 수 없다 Liver biopsy : NAFLD를 진단하고 NASH나 fibrosis의 staging과 질병의 진행에 gold standard hepatic-renal echo-intensity ratio (H/R) 지방간 (알코올성 + 비알코올성) 유병율 20대 유병율 25.0 21.4 20.0 15.0 11.6 남 여 11.5 10.0 8.0 5.0 4.3 2.8 3.7 2.5 0.0 0.7 1987 0.0 1992 1997 2002 2007 출처 : 국내 직장인 73만명 – 강북삼성병원 건진자료 지방간 (알코올성 + 비알코올성) 유병율 50대 유병율 45.0 41.7 37.9 40.0 35.0 32.2 33.0 30.0 25.0 24.2 20.0 녀 16.5 15.0 10.0 5.0 15.4 8.7 9.2 10.7 0.0 1987 1992 남 1997 2002 2007 2 Hit theory FFA delivery to liver 증가 de novo FFA and TG synthesis 증가 VLDL synthesis and export 감소 FFA oxidation and metabolism 감소 Normal 1st hit Vulnerable Steatosis Oxidative stress & lipid peroxidation 증가 Proinflammatory cytokine and adipokine 증가, LPS 증가, Steatohepatitis 2nd hit The pathology of NAFLD Type 1 Type 2 Type 3 Type 4 NASH Fat alone Fat + Inflammation Fat + Ballooning degeneration Fat + fibrosis and/or Mallory body Ballooning degeneration Acidophilic body Mallory’s hyaline Perisinusoidal collagen deposition by blue staining Progression of NAFLD Bhatia et al. Eur Heart J, 2012 Metabolic alterations resulting in hepatic TG accumulation in insulin-resistance states Browning JD et al. JCI, 2004 Why NAFLD and vitamin D? Adiposity, sedentary life style and vitamin D Cheng S et al. Diabetes, 2010 Visceral adipose tissue is positively correlated with liver fat MRS performed in 271 non-diabetic subjects Kotronen A et al. JCEM 92:3490-3497, 2007 Regular exercise is associated with reduced risk for NAFLD –In 72,359 apparently healthy Korean adults –Regular exercise: > 3 times/week, >30 minutes per session, >3 consecutive months Bae JC et et al. PLoS ONE, 2012 Deposition of vitamin D3 from body fat Rosenstreich et al. JCI, 1971 Decreased bioavailability of vitamin D in obesity In 19 healthy, white obese subjects and 19 controls Wortsman J et al. Am J Clin Nutr, 2000 Vitamin D receptor nuclear receptor superfamily의 하나 1,25(OH)2D에 의해서 activation되면 1,25(OH)2D-VDR-RXR complex 형성하여 vitamin D-responsive elements에 부착하여 target gene에 작용 VDR bindiing에 2700여개의 인간유전자가 관 여하며 1,25(OH)2D는 299개의 유전자 발현에 관여한다 VDR은 적어도 37개의 세포에 발현한다 Vitamin D receptor in liver VDR reactivity mainly in nonparenchymal and biliary epithelial liver cells (Gascon-Barre M et al. Hepatology, 2003) VDR expression in primary human hepatocytes (Han S et al. Drug Metab Dispos, 2009) (Drocourt L et al. J Biol Chem, 2002) Liver VDR inversely correlates with severity of liver pathology In 61 patients (25 NASH and 36 CHC) who had undergone liver biopsy and 20 controls Higher NAS in NASH Lower NAS in NASH Severe fibrosis in CHC Mild to mod fibrosis in CHC Barchetta et al. Hepatology, 2012 The link between NAFLD and vitamin D Vitamin D homeostasis and effects of target Kwok RM et al. Hepatology, 2013 Vitamin D and immune system Bouillon R et al. Endocrine Reviews, 2008 TLR triggering of a vitamin D-mediated human antimicrobial response Liu et al. Science, 2006 Relationship between intestinal microbes, nutrients, and the immune system in the pathogenesis of NAFLD Kwok RM et al. Hepatology, 2013 Vitamin D homeostasis and effects on target Kwok RM et al. Hepatology, 2013 Effects of adiponectin in NAFLD Oil red O H&E Xu et al. JCI, 2003 Independent association between 25(OH)D and adiponectin : NHS and HPFS Vaidya A et al. Obesity 2012 Independent association between 25(OH)D and adiponectin : NHS and HPFS Vaidya A et al. Obesity 2012 Vitamin D suppresses renin expression in WT mice Chun Y et al. JCI, 2002 RAS blockade increases adiponectin mRNA expression in preadipocytes Tian FS et al. Exp Clin Endocrinol Diabetes, 2010 High dose vitamin D supplement increase serum adiponectin level in T2DM patients 47 diabetes patients divided into Tx and placebo groups, vitamin D 1000 IU/day for 12 months Breslavsky A et al. Clin Nutr, in press VDD exacerbate NAFLD in obese rats and increases hepatic resistin and TLR activation LFD WD+VDD WD WD+VDD WD WD+VDD Roth et al. Hepatology, 2012 VDD exacerbate NAFLD in obese rats and increases hepatic resistin and TLR activation Roth et al. Hepatology, 2012 Vitamin D Deficiency in NAFLD progression to NASH 1,25(OH)D3 inhibited proliferation of rat primary HSC 1,25(OH)D3 suppressed collagen deposition in a TAA-induced fibrosis model Abramovitch S et al. Gut, 2011 Impact of artificial sunlight therapy on the progression of NAFLD in rats fibrosis Nakano T et al. J Hepatology, 2011 Studies on the association of NAFLD with VDD The association of vitamin D levels with NAFLD NHANES III patients with elevated ALT was found to have lower vitamin D levels than the control group, even when controlling for metabolic syndrome, insulin resistance, and serum TG levels (Liangspunsakul S et al. Dig Dis Sci, 2011) In 262 patients referred to an endocrinology clinic, relationship between NAFLD (diagnosed by USG) and reduce vitamin D levels persisted regardless of age, sex, TG and IR (Barchetta I et al. BMC Medicine, 2011) Association of serum 25(OH)D3 and liver histology in NAFLD In 60 biopsy-proven NAFLD and 60 controls Targher G et al. NMCD, 2007 High serum vitamin D levels reduce the risk for nonalcoholic fatty liver disease in healthy men independent of metabolic syndrome EUN-JUNG RHEE ET AL DEPARTMENT OF ENDOCRINOLOGY AND METABOLISM, KANGBUK SAMSUNG HOSPITAL, Selection of the study population EJ Rhee et al. Endocrine J, in press EJ Rhee et al. Endocrine J, in press EJ Rhee et al. Endocrine J, in press Choi HS et al. JCEM, 2011 EJ Rhee et al. Endocrine J, in press EJ Rhee et al. Endocrine J, in press EJ Rhee et al. Endocrine J, in press EJ Rhee et al. Endocrine J, in press EJ Rhee et al. Endocrine J, in press Conclusion Serum 25(OH)D3 levels were significantly lower in men with NAFLD than in those without NAFLD in this sample of healthy Korean men. High vitamin D levels conferred a significantly lower risk of developing NAFLD than low vitamin D levels. This association remained significant even after adjusting for the metabolic parameters BMI and metabolic syndrome. The recognition and diagnosis of insufficient serum vitamin D in the general population is desirable to slow the rapidly increasing prevalence of NAFLD. Vitamin D homeostasis and effects of target Kwok RM et al. Hepatology, 2013 2 Hit theory FFA delivery to liver 증가 de novo FFA and TG synthesis 증가 Vitamin D VLDL synthesis and export 감소 FFA oxidation and metabolism 감소 Normal 1st hit Vulnerable Steatosis Oxidative stress & lipid peroxidation 증가 Proinflammatory cytokine and adipokine Vitamin D 증가, LPS 증가, Steatohepatitis 2nd hit NAFLD and VDD…The solution… Acknowledgment Kangbuk Samsung Hospital Ki-Won Oh Sun-Woo Kim Sung-Woo Park Won-Young Lee Se Eun Park Catholic University Moo-Il Kang Ki-Hyun Baek Mee Kyung Kim
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