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