PREVALENCE OF NAFLD IN DIABETIC PATIENTS The world-wide prevalence of non-alcoholic fatty liver...

PREVALENCE OF NAFLD IN DIABETIC PATIENTS

The world-wide prevalence of non-alcoholic fatty liver disease (NAFLD) is:

o Western countries: 15% to 40%

o Asian countries: 9% to 40%

NAFLD is emerging as an important cause of liver disease in India

In general Indian population, epidemiological studies have suggested the prevalence of NAFLD to be around 9% to 32%

Higher incidence has been reported in Indian patients who are overweight/obese and diabetic/prediabetic

Kalra S, et al. J Assoc Physicians India. 2013 Jul;61(7):448-53.

PREVALENCE OF NAFLD IN DIABETES PATIENTS

A study by Kalra S et al., in the year 2013, studied frequency and risk factors of NAFLD in non-alcoholic Indian type 2 diabetic (T2DM) patients

o Prevalence of NAFLD in patients with T2DM was 56.5% across India.

o Prevalence of NAFLD ranged from 44.1% in western India to 72.4% in northern states (Table 1)

o Highest prevalence was reported in age group of 6170 years (61.8%)


o Greater prevalence was seen in females (60%) as compared to males (54.3%) T2DM patients (Table 2)


PREVALENCE OF NAFLD IN DIABETES PATIENTS

NAFLD is associated with several conditions, including:1

o Obesity (69100%)

o Diabetes mellitus (365%)

o Hyperlipidemia (2081%)

Patients with T2DM and co-morbid conditions like obesity,

hypertension and dyslipidemia reported greater risk for NAFLD by

14%, 17% and 38%, respectively2

Diabetes mellitus is reported in about 75% of patients with non-

alcoholic steatohepatitis (NASH)1

On ultrasonography, more likelihood of fatty liver changes (up to

70%) in obese, middle-aged females with DM was noted1

1. Dabhi AS et al. JIACM. 2008;9(1):36-41.2. Kalra S, et al. J Assoc Physicians India. 2013 Jul;61(7):448-53.

NAFLD AND ASSOCIATED CONDITIONS

Dabhi AS et al. JIACM. 2008;9(1):36-41.

PATHOGENESIS AND NATURAL HISTORY OF NAFLD

Epidemiological studies in patients with diabetes suggest an increased risk of chronic liver disease, cirrhosis, hepatocellular carcinoma and increased mortality due to hepatic disease

There is an increased risk of developing hepatic morbidity among patients with NAFLD

NAFLD is the most common liver disease seen in diabetic patients, and it has been reported that 20% to 50% patients with NAFLD have diabetes

DM and NAFLD demonstrate a common pathogenic link i.e., insulin resistance, both hepatic as well as peripheral

Type 2 diabetes, obesity, older age and metabolic syndrome are the risk factors for rapid progression of NAFLD

Amarapurkar D. Medicine Update. 2010;20:466-469.

PATHOGENIC LINK BETWEEN NAFLD AND DIABETES MELLITUS

Diabetes development may result due to NAFLD, which accounts for increase in glucose production in the liver and exacerbation of hepatic and systemic insulin resistance possibly via systemic release of pro-inflammatory factors and some liver-secreted proteins with diabetogenic properties, such as fetuin-A, FGF-21 and RBP-4 (Figure 2)

Anstee QM et al. Nature Reviews Gastroenterology & Hepatology. 2013;10:330-344.


A close association between the presence of diabetes mellitus and NAFLD has been reported in several studies

Delivery of insulin directly to the portal vein after secretion via a similar route as absorbed glucose, and elimination of large portion of portal insulin at the first pass may a suggest significant link between T2DM, insulin resistance (IR) and NAFLD

Presence of obesity in NAFLD may be associated with dysfunctional adipose tissue, and lipotoxicity that may lead to insulin resistance and pancreatic β-cell dysfunction

Firneisz G. World J Gastroenterol .2014 July 21; 20(27): 9072-9089.


A study conducted by Prashanth M et al., in 204 Indian T2DM patients, showed hepatic fatty infiltration in 62.2% of the patients, and confirmed NAFLD by liver biopsy with 54.11% prevalence in T2DM patients (Figure 3)

Steatohepatitis and fibrosis were reported in 38.9% and 23.2% of T2DM patients, respectively

A study by Leite et al., reported 78% prevalence of NASH on histological evaluation among 100 patients with T2DM and also demonstrated ultrasonography evidence of NAFLD

Firneisz G. World J Gastroenterol 2014 July 21; 20(27): 9072-9089.


Chronic inflammatory disease such as NAFLD demonstrated lower vitamin D levels suggesting pleiotropic role in the pathogenesis of NAFLD

Insulin resistance, metabolic syndrome and proinflammatory cytokines have been associated in the development and progression of NAFLD

Negative correlation has been reported between serum levels of vitamin D and cases of insulin resistance and metabolic syndrome

Reduction in insulin resistance has been reported with vitamin D supplementation among obese children

Reduced levels of vitamin D levels are independently associated with increased severity of steatosis, necroinflammation, and fibrosis in NAFLD (Figure 4)

Yin K et al. Journal of Inflammation Research. 2014:7 69–87.

CLINICAL LINK BETWEEN VITAMIN D AND NAFLD

Yin K et al. Journal of Inflammation Research .2014:7 69–87.

CLINICAL LINK BETWEEN VITAMIN D AND NAFLD

It has been reported in several NAFLD patients that steatosis follows inflammation

Therefore, ability of vitamin D to modulate the immune/inflammation system has been reported to be associated with the development of NAFLD

Vitamin D signaling

Intracellular signals of vitamin D are mediated through its vitamin D receptor that is expressed in the liver

Over 200 genes associated with glucose and lipid metabolism, inflammation, cellular proliferation and differentiation and apoptosis are regulated by VDR

Four single nucleotide polymorphisms (SNPs) demonstrated significant association with NAFLD in a GWAS study performed in NAFLD subjects

Out of these four SNPs, GC gene was predominately expressed in hepatocytes, and was responsible for coding of vitamin D binding protein, which has been regarded as an important carrier protein for vitamin D

Eliades M, et al. World J Gastroenterol .2015; 21(6): 1718-1727.

MECHANISMS LINKING VITAMIN D DEFICIENCY TO NAFLD

Role of vitamin D in adipose tissue, insulin resistance and hepatic inflammation

In NAFLD, insulin resistance is associated with the development of oxidative stress and lipotoxicity

Accumulation of free fatty acids causing hepatic steatosis is associated with chronic hepatic inflammation

Human studies have suggested significant correlation between increased cytokine gene expression and histological severity in the liver of patients with NASH as compared to obese controls with normal liver

Further, reduced adipocyte production of adiponectin has demonstrated an essential role in the pathogenesis of NAFLD progression



Role of vitamin D in Adipose tissue, insulin resistance and hepatic inflammation

The role of vitamin D in adipokine activity has been elucidated in several studies

A study by Vaidya et al., demonstrated a positive link between levels of adiponectin and 25(OH)D concentrations in a large cohort of patients

A double-blind, randomised, controlled trial of Iranian type 2 diabetic patients, resulted in a significant increase of serum adipokines including adiponectin and decreased cellular secretion of the inflammatory cytokines IL-6 and IL-1β with daily intake of 1000 IU vitamin D either with or without extra calcium for 12 weeks

Importantly, preliminary studies have suggested that vitamin D deficiency, associated with upregulation of hepatic inflammatory and oxidative stress genes may be responsible for worsening of NAFLD. Supplementation with vitamin D have reported to be effective in reduction adipose tissue inflammation (Figure 5)



Role of vitamin D deficiency and intestinal microbiome and innate immunity in NAFLD

In a study conducted in Italy, patients with NAFLD have demonstrated increased gut permeability and small intestinal bacterial overgrowth (SIBO), which suggested correlation with the severity of steatosis, but not with presence of NASH

Vitamin D deficiency may cause activation of toll-like receptor-2 (TLR2) and TLR4 by way of CD14/LBP, and stimulation of downstream inflammatory signaling molecules that lead to steatosis and inflammation, which may be responsible for development and progression of NAFLD

However, role of vitamin D in innate immunity is still unclear



Vitamin D and hepatic fibrosis

The development of liver fibrosis in NAFLD is considered as strongest predictor for disease-specific mortality

Fibrosis may lead to liver dysfunction by causing accumulation of extracellular matrix (ECM) with subsequent destruction of the normal liver architecture

Hepatic stellate cells (HSCs) are responsible for excessive deposition of ECM proteins, predominantly type I collagen, and hence, HSCs play a critical role in the development of liver fibrosis



A study by Nwosu BU et al., was conducted to determine the link between mild hepatic dysfunction and impaired 25-hydroxylation of pre-vitamin D, and vitamin D deficiency and its effect on glycaemic control in children with T1DM (n=81) and T2DM (n=40).

47.5% patients with T2DM reported vitamin D deficiency [25(OH)D<15 ng/mL]

Elevated levels of transaminases were reported in T2DM patients compared to T1DM patients (AST 39.3 2.0 vs. 22.4 1.4, p<0.001; and ALT 30.6 1.8 vs. 18.7 1.3, p<0.001)

Significant inverse linear relation between 25(OH)D and HbA1c levels was reported in T2DM patients (= –0.40, p=0.011) [Figure 6]

Nwosu BU et al. J Pediatr Endocrinol Metab. 2012;25(1-2)181-6.

CLINICAL EVIDENCE ON LOW LEVELS OF VITAMIN D IN DIABETIC PATIENTS WITH NAFLD

Also, significant inverse relation between 25(OH)D and ALT was reported in T2DM patients (β= –0.40, p=0.02) [Figure 7]

No significant change was reported between 25(OH)D and AST in T2DM patients (β= –0.28, p=0.10)

No relation between 25(OH)D and ALT (β=0.06, p=0.77) and between 25(OH)D and AST (β=0.09, p=0.65) was observed in T1DM patients

Therefore, study results suggested that hepatic dysfunction is associated with vitamin D deficiency, which further affects glycaemic control

Nwosu BU et al. J Pediatr Endocrinol Metab. 2012;25(1-2)181-6.


In a study by Targher G et al., link between serum 25-hydroxyvitamin D3 [25(OH)D] concentrations and liver histology in patients with NAFLD was evaluated.

This study included 60 patients with NAFLD and 60 healthy controls.

Compared to controls, NAFLD patients reported marked reduction in serum 25(OH)D levels (51.0 ± 22 vs. 74.5 ± 15 nmol/L, p<0.001)

Also, the study reported that decreased 25(OH)D concentrations were closely associated with the histological severity of hepatic steatosis, necroinflammation and fibrosis (p<0.001)

Therefore, study results have suggested that status of vitamin D deficiency may be responsible for the development and progression of NAFLD

Targher G et al. Nutrition, Metabolism & Cardiovascular Diseases. 2007;17:517-524.


A meta-analysis was also conducted by Eliades M et al., to review the relation between NAFLD and vitamin D levels

A total of 17 studies were evaluated, out of which 9 studies were used for quantitative analysis

The study results demonstrated that NAFLD patients had 0.36 ng/mL lower levels of vitamin D [25(OH)D levels] as compared to controls (p<0.01)

NAFLD patients were 1.26 times more likely to be vitamin D deficient as compared to controls

Greater prevalence of vitamin D deficiency is seen in NAFLD patients (Figure 8)

Eliades M et al. Aliment Pharmacol Ther .2013; 38: 246–254.


Therefore, decreased serum 25(OH)D levels in NAFLD patients suggested that vitamin D deficiencymay play a role in the development of NAFLD

Furthermore, anti-inflammatory and immunomodulatory properties of vitamin D are known to impact progression and severity of NAFLD

Eliades M et al. Aliment Pharmacol Ther .2013; 38: 246–254.


Another study conducted by Barchetta I et al., evaluated the link between vitamin D deficiency and NAFLD in patients with various degrees of insulin-resistance and related metabolic disorders

The study results reported reduced serum 25(OH)D levels in patients with NAFLD as compared to patients without NAFLD (14.8 ± 9.2 vs. 20.5 ± 9.7 ng/mL; p<0.001)

This relationship between reduced 25(OH)D levels and NAFLD was reported to be independent of age, sex, triglycerides, high density lipoproteins (HDL) and glycaemia (p<0.005)

Also, Fatty Liver Index was reported to be inversely correlated with low 25(OH)D levels, irrespective of sex, age and HOMA-IR (p<0.007)

Therefore, this study demonstrated strong independent link between NAFLD and low serum levels of vitamin D

Barchetta I et al. BMC Med. 2011;9:85.


In a study conducted by Kucukazman M et al., conducted among 154 patients with NAFLD and 57 patients without NAFLD, significantly lower levels of vitamin D in NAFLD patients as compared to control group were reported (p<0.0001; Figure 9)

Furthermore, increase in NAFLD grade was associated with gradual decline in serum levels of vitamin D

Kucukazman M et al. Clinics (Sao Paulo). 2014;69(8):542-546.


The role of vitamin D as an immunoregulatory nutrient has been documented in several studies1

Several studies have documented association of vitamin D deficiency with insulin resistance, metabolic syndrome and NAFLD1

Significant correlation has been reported with vitamin D deficiency and severe NAFLD activity score and hepatic fibrosis1

Strong association has been reported between NAFLD and vitamin D deficiency, prediabetes, and type 2 diabetes2

Studies have suggested an effective and promising role of vitamin D supplementation in patients with diabetes mellitus2

1. Eslamparast T et al. World J Hepatol. 2015;7(2):204-212.2. Nwosu BU, et al. PLoS ONE. 9(6): e99646.

VITAMIN D SUPPLEMENTATION IN DIABETIC PATIENTS FOR TREATING NAFLD

A study by Nwosu BU et al., was conducted to evaluate the hypothesis for improvement in vitamin D status, reduced hepatic dysfunction, and improved glycaemic control with vitamin D supplementation in children and adolescents with diabetes mellitus

This study determined the effect of vitamin D supplementation on ALT, HbA1c, and 25(OH)D in patients with vitamin D deficiency and either type 1 diabetes or type 2 diabetes

In this study, 88 type 1 diabetic patients and 43 type 2 diabetic patients were included who received vitamin D supplementation

Nwosu BU, et al. PLoS ONE. 9(6): e99646.


Low levels of vitamin D were reported in 37.5% of T1D patients and 72.1% of patients with T2D (p<0.001)

Higher values for BMI SDS (p=0.001), ALT (p=0.001), but lower 25(OH)D (p<0.001) were reported in T2D patients as compared to T1D patients

Vitamin D supplementation after 3 months reported:

o Significant increase in 25(OH)D in both T2D (p=0.015), and T1D patients (p<0.001)

o Significant reduction in BMI SDS (p=0.015) in T2D than T1D patients

o Significant reduction in ALT (p=0.012) in T2D, than T1D patients

o Clinically-significant decrease in HbA1c in T2D from 8.5 ± 2.9% at baseline to 7.7 ± 2.5 at 3 months, as compared to T1D, 8.5 ± 1.2 to 8.53 ± 1.1%

Nwosu BU, et al. PLoS ONE .9(6): e99646.


o ALT decreased from 18.0 ± 6.0 U/L to 15.7 ± 2.0 (p = 0.46) in patients with type 1 diabetes; and from 50.7 ± 50.9 to 35.0 ± 31.0 (p = 0.012) in those with type 2 diabetes (Figure 10)

This suggested effective management of hepatic dysfunction as seen in NAFLD patients with diabetes

Therefore, vitamin D supplementation is effective to decrease ALT associated with vitamin D deficiency

Nwosu BU, et al. PLoS ONE. 9(6): e99646.


Non-alcoholic fatty liver disease (NAFLD) has been regarded as the commonest cause of chronic liver disease

In general Indian population, epidemiological studies suggested the prevalence of NAFLD to be 9% to 32%

Higher incidence has been reported in Indian patients who are overweight/obese and diabetic/prediabetic

Prevalence of NAFLD was reported to be 56.5%, across India in diabetic patients

NAFLD is associated with several conditions, including:

o Obesity (69100%)

o Diabetes mellitus (3675%)

o Hyperlipidemia (2081%)

Diabetes mellitus is reported in about 75% patients with NASH

SUMMARY

NAFLD is most common liver disease seen in diabetic patients, and it has been reported that 20% to 50% patients with NAFLD have diabetes

DM and NAFLD demonstrate common pathogenic link i.e., insulin resistance, both hepatic as well as peripheral

Several studies have demonstrated that vitamin D deficiency status may be responsible for the development and progression of NAFLD

Vitamin D supplementation has shown promising role in patients with diabetes mellitus in managing hepatic dysfunction

SUMMARY

PREVALENCE OF NAFLD IN DIABETIC PATIENTS The world-wide prevalence of non-alcoholic fatty liver...

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