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Sonographically diagnosed non-alcoholic fatty liver as a predictor of metabolic syndrome.

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, since its prevalence is estimated to be 20-30% in general population of Western countries. (1) Incidence of NAFLD in Indian population is on rise and its exact prevalence is not known in our part of world.

The raising incidence of NAFLD in India may be attributed to recent lifestyle changes and growing prevalence of obesity. NAFLD occurs as a histological spectrum of disease and includes the subtypes of simple steatosis and Non-Alcoholic Steatohepatitis (NASH). It was thought to be a benign condition, but is now increasingly recognized as a major cause of liver-related morbidity and mortality.

Studies have proven that NAFLD may progress to cirrhosis, liver failure and hepatocellular carcinoma. (2) in addition it has been shown that NAFLD is strongly associated to the features of metabolic syndrome. (3-7)

Metabolic syndrome (MetS) has been defined by various national and international organizations. As per joint interim statement of international diabetes federation task force on epidemiology and prevention; National Heart, Lung and Blood Institute; American Heart Association; World Health Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. (8) Presence of any three of the following cardiovascular risk factors is essential for metabolic syndrome:

1. Increased waist circumference males >90cm and females >80cm.

2. Increased serum triglycerides >150mg/dL (1.7mmol/L).

3. Decreased serum HDL (Males <40mh/dl (1mmol/L) and females <50mg/dL (1.3mmol/L).

4. Increased blood pressure (Systolic blood pressure >130mmHg and/or diastolic blood pressure >85mmHg or taking antihypertensive treatment).

5. Increased blood sugar level (Fasting blood sugar >100mg/dL (5.6mmol/L) or taking anti-diabetic treatment).

In general, NAFLD in the absence of NASH is an indolent disease with a benign course. However, as noted end-stage liver disease may occur as a consequence of NASH. The seriousness of this condition is demonstrated by the fact that approximately 50% of patients develop fibrosis, 15% develop cirrhosis and 3% may advance to liver failure requiring transplantation!9) The natural history of NAFLD is poorly understood and it is not known why some patients progress to cirrhosis while others do not. However, obesity and insulin resistance have been shown to be associated with more histological advanced disease. Long term outcome of NAFLD remains unclear and it may be a predictor of MetS, diabetes mellitus and ultimately the cardiovascular disease. A longterm followup is needed to conclude that morbidity and mortality among NAFLD patients is directed by cardiovascular risks or by liver related risks.

The aim of this observational study is to evaluate the association of sonographically diagnosed non-alcoholic fatty liver with metabolic syndrome and to estimate prevalence of non-alcoholic fatty liver in our population coming for general health check-up.

MATERIAL AND METHODS

Study Population

We recruited 556 subjects, who visited for annual general health checkup between January 2013 and June 2015 at our institute. Most of the subjects were executives in banks, post offices, other government organizations and companies. Morbidly obese patients attending general health check-up in our institute during the study period were also included. All the subjects who were alcoholic, having positive serologic marker for hepatitis B and C or other causes of chronic liver disease such as Wilson's disease, autoimmune hepatitis, etc. were excluded from the study. Based on these exclusion criteria, 148 subjects were excluded from the study. Data from the remaining 408 subjects were included in the final statistical analysis. It was a retrospective study in general health checkup subjects and written informed consent was not obtained from the subjects. No ethical issues were there in the study.

STUDY DESIGN

The health check-up programs were performed after an overnight fasting of at least 12 hours and all participants underwent a routine anthropometric, clinical and laboratory tests. The anthropometric measurements involved height, weight, blood pressure. Body Mass Index (BMI) was calculated and was used as an estimate of obesity. Blood pressure was measured in a sitting position. Blood samples were collected for biochemical analysis and values of cholesterol, triglycerides, LDL, HDL and fasting blood glucose were recorded. History of smoking, alcohol intake and physical activity was recorded from each subject.

All subjects were subjected to abdominal sonography, which is a part of general health check-up scheme in our region, ultrasound examination of abdomen was done on Philips iU22 ultrasound system using multi-frequency 1-4MHz convex transducer. B-Mode examination of each subject was done in supine and left lateral position to evaluate liver. Characteristic ultrasound features such as increased hepatic echogenicity as compared to renal cortical echogenicity with attenuation of ultrasound beam and poor visibility of diaphragm and intrahepatic vessel borders were used to diagnose hepatic steatosis (Fig. 1).

[FIGURE 1 OMITTED]

STATISTICAL EVALUATION

Metabolic syndrome was defined as per joint interim statement. Continuous variables are represented as Mean +/- S.D. Categorical variables are presented as numbers with percentage. The statistically significant difference in continuous variables between subjects with and without NAFLD was calculated by unpaired t-test. Whereas statistically significant difference in categorically variables was evaluated by Chi square test. P value <0.05 was considered statistically significant.

RESULTS

Out of total 408 subjects who met with our inclusion criterias, 144 were diagnosed as having NAFLD (35.2%) on sonography examination. Mean age of subjects in NAFLD group was 49.54 (+/-6.6) years, whereas in non-NAFLD group (n=264) mean age was 41.14 (+/-9.65) years.

Majority of subjects (73.6%) in NAFLD group were male, no significant sex discrimination was observed in non-NAFLD group. Following recommendation of WHO Asia-Pacific guideline, 28.47% of patients in NAFLD group were categorized as morbidly obese [BMI >40], 29.1% obese [having BMI 30 to 40] and 31% overweight [BMI-25 to 30]. In non NAFLD group, 10.23% subjects were categorized as morbidly obese, 15.9% as obese, 28.4% as overweight and majority 45.45% as normal [BMI<25]. Mean waist circumference in NAFLD group was 105.9cms (+/-15.42), whereas in non-NAFLD group mean waist circumference was 93.27cms (+/- 19.18).

Tobacco use was observed to be more prevalent in NAFLD group (45.14%), whereas in non-NAFLD group tobacco use was in 29.54%. Lack of physical activity was more common in NAFLD group. A baseline characteristic of study population is presented in Table 1.

As per criterias laid down by joint interim statement of international diabetes federation task force on epidemiology and prevention; National Heart, Lung and Blood Institute; American Heart Association; World Health Federation; International Atherosclerosis Society and International Association for the Study of Obesity, 63 subjects (43.75%) in NAFLD group with presence of three or more risk factors were labelled as of metabolic syndrome. In non-NAFLD group 7.2% subjects were labelled as of MetS. Components of metabolic syndrome increased waist circumference, hypertension, impaired blood glucose level, low HDL cholesterol and high triglyceride level were more frequently observed in NAFLD group (Table 2).

DISCUSSION

In this observational study carried out in subjects who turned up for annual general health checkup in our institute, prevalence of NAFLD on sonography examination was 35.2%. Majority of these were males (73.6%), the association being statistically extremely significant (P value <0.0001). Females constituted 26.4% of NAFLD group. Most of these females were postmenopausal. The difference in prevalence of NAFLD in male and female population has been attributed to protective effect of estrogen in premenopausal females. (10,11)

The incidence of NAFLD was seen increasing with increasing age of the subjects, mean age of subjects in NAFLD group was 49.54 (+/-6.6), whereas in non-NAFLD group was 41.14 (+/-9.65). This association was statistically extremely significant with P value <0.0001. Increasing age as it brings restrictions on physical mobility may contribute to abdominal obesity and dyslipidemia. In another study NAFLD was associated with increased risk of cardiovascular disease, especially among older patients with elevated C-reactive protein levels. (12) A 79% of subjects in NAFLD group in our study had BMI >25, out of which 28.47% were morbidly obese. Factors responsible for the development of NAFLD in obese patients are not clear. Insulin resistance is thought to be a primary pathophysiologic mechanism in development of fatty liver. Current understanding of the pathogenesis is as follows: Insulin resistance and visceral obesity lead to a hepatic influx of free fatty acids, resulting in increased triglyceride synthesis and decreased triglyceride export. This leads to hepatic steatosis. (13) Obesity is becoming an epidemic in Western as well as Eastern world and so the non-alcoholic fatty liver disease. (14,15) In previous reports, authors have reported NAFLD prevalence around 57%-74% and 22%-58% of obese children and adults, respectively. (16) Incidence of obesity and non-alcoholic fatty liver disease is on rise in Indians as well, which is being observed in our study.

Out of total 144 subjects with NAFLD, 63 subjects (43.75%) were having metabolic syndrome in our study. This association was statistically extremely significant (P value <0.0001). This strong association is consistent with other studies conducted on different sample sizes and different ethnic groups. (17-19) Metabolic syndrome is having higher incidence in Asian population. (20) which can be attributed to relative lack of exercises, central obesity and visceral fat deposition!21) Hypertension, one of the cardiovascular risk factors essential for metabolic syndrome was observed in 47.91% of patients in NAFLD group in our study. In their study Hsiao et al. (18) demonstrated that presence of hepatic steatosis was significantly correlated with the prevalence and degree of hypertension. A study on non-obese and non-diabetic patients with primary hypertension has shown that hepatic steatosis prevalence can double as compared with control group. (22) Association of NAFLD and hypertension in our study was statistically extremely significant with P value <0.0001.

Increased serum triglycerides and low HDL was observed in 21.5% and 36.1% of subjects in NAFLD group respectively. Cotrim et al. (23) reported the presence of hyperlipidemia in 66.8% of patients with NAFLD in Brazil. Association of high serum triglyceride with NAFLD in our study was statistically significant (P value=0.02), whereas low HDL showed extremely significant association (P value <0.0001). Marchesini G, et al. (4) reported hypertriglyceridemia and low HDL-cholesterol level in 64% and 30-42% of NAFLD patients respectively.

Impaired blood glucose was observed in 38.9% of subjects in NAFLD group in our study. The association was statistically significant with P value 0.001. In Brazil, the prevalence of metabolic syndrome and diabetes among patients with NAFLD was estimated at 41.3% and 22.7%, respectively!23:) The association of both conditions is related with more aggressive disease and increasing mortality. (24)

The association between NAFLD and MetS could be mainly explained by insulin resistance, which was the main mechanism linking NAFLD and MetS from pathophysiological perspective. (25,26) Many researches demonstrated that insulin resistance was a pathogenic factor of the metabolic syndrome and also played a major role in the development and progression of NAFLD. (27) In NAFLD population, excess fat accumulation in the hepatic parenchyma or overabundance of fatty acids was a major contributor to the development of insulin resistance and subsequent MetS. (28,29)

CONCLUSION

Issue whether or not NAFLD should be included as one of the components of the MetS is still in existence; however, it can be concluded that NAFLD is an important independent risk factor for prediction of MetS. The observations of our study might be helpful to support the clinical guideline and early intervention strategy for the NAFLD patients before being diagnosed as MetS. Therefore, as for the NAFLD detected in the health checkup programmes could help initiate weight and dietary control, so as to prevent the development of MetS and even the cardiovascular diseases.

Some limitations in our study needs to be highlighted. First, NAFLD in our study was detected on basis of grey scale sonographic features alone higher imaging modalities, such as shear-wave elastography, MRI were not soughted out and pathological correlation was not done. Secondly, our study data is based on the subjects reporting for routine health check-up system in urban population of Indore district, further longitudinal and cross-sectional studies with large sample volumes need to be done to confirm the value of NAFLD as a marker for predicting the risk of metabolic syndrome.

REFERENCES

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(7.) Smits MM, Ioannou GN, Boyko EJ, et al. (2013). Nonalcoholic fatty liver disease as an independent manifestation of the metabolic syndrome: results of an US national survey in three ethnic groups. J Gastroenterol Hepatol 28:664-70.

(8.) Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome. Circulation 2009;120:1640-5.

(9.) Sheth SG, Gordon FD, Chopra S. Non-alcoholic steatohepatitis. Ann Intern Med 1997;126:137-145.

(10.) Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev 2010;11:11-18.

(11.) Ayonrinde OT, Olynyk JK, Beilin LJ, et al. Gender-specific differences in adipose distribution and adipocytokines influence adolescent non-alcoholic fatty liver disease. Hepatology 2011;53:800-809.

(12.) Chiang CH, Huang CC, Chan WL, et al. The severity of nonalcoholic fatty liver disease correlates with high sensitivity C-reactive protein value and is independently associated with increased cardiovascular risk in healthy population. Clin Biochem 2010;43:1399-404.

(13.) Gill HK, Wu GY Non-alcoholic fatty liver disease and the metabolic syndrome: effects of weight loss and a review of popular diets. Are low carbohydrate diets the answer? World J Gastroenterol 2006;12(3):345-53.

(14.) Wong VW. Non-alcoholic fatty liver disease in Asia: a story of growth. J Gastroenterol Hepatol 2013;28:18-23.

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(16.) Tarantino G, Saldalamacchia G, Conca P, et al. Non-alcoholic fatty liver disease: further expression of the metabolic syndrome. J Gastroenterol Hepatol 2007;22:293-3.

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(18.) Hsiao PJ, Kuo KK, Shin SJ, et al. Significant correlations between severe fatty liver and risk factors for metabolic syndrome. J Gastroenterol Hepatol 2007;22:2118-23.

(19.) Marchesini G, Brizi M, Bianchi G. Non-alcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001;50:1844-50.

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(21.) Koehler EM, Schouten JN, Hansen BE, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in the elderly: results from the Rotterdam study. J Hepatol 2012;57:1305-11.

(22.) Donati G, Stagni B, Piscaglia F, et al. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut 2004;53:1020-23.

(23.) Cotrim HP, Parise ER, Oliveira CP, et al. Non-alcoholic fatty liver disease in Brazil. Clinical and histological profile. Ann Hepatol 2011;10:33-37.

(24.) Younossi ZM, Gramlich T, Matteoni CA, et al. Non-alcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol 2004;2:262-5.

(25.) Angelico F, Del BM, Conti R, et al. Insulin resistance, the metabolic syndrome and non-alcoholic fatty liver disease. J Clin Endocrinol Metab 2005;90:1578-82.

(26.) Angulo P. Non-alcoholic fatty liver disease. N Engl J Med 2002 Overseas Ed; 346:1221-31.

(27.) Tilg H, Moschen AR. Insulin resistance, inflammation and non-alcoholic fatty liver disease. Trends in endocrinology and metabolism 2008;19:371-79.

(28.) Bhatia LS, Curzen NP, Calder PC, et al. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor. Eur Heart J 2012;33:1190-200.

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Chandrajeet Yadav [1], Sandeep Dhruw [2], PulkitShekhawatia [3], Aman Gupta [4]

[1] Assistant Professor, Department of Radiodiagnosis, Sri Aurobindo Medical College, Indore, Madhya Pradesh.

[2] Assistant Professor, Department of Radiodiagnosis, Sri Aurobindo Medical College, Indore, Madhya Pradesh.

[3] Post Graduate Resident, Department of Radiodiagnosis, Sri Aurobindo Medical College, Indore, Madhya Pradesh.

[4] Professor and HOD, Department of Radiodiagnosis, Sri Aurobindo Medical College, Indore, Madhya Pradesh.

Financial or Other, Competing Interest: None.

Submission 09-01-2016, Peer Review 04-02-2016, Acceptance 10-02-2016, Published 22-02-2016.

Corresponding Author:

Dr. Aman Gupta, House No. 201, Dilpasand Avenue, 5/2, Manoramaganj, Indore-452001, Madhya Pradesh.

E-mail: aman_sono@yahoo.co.in

DOI: 10.14260/jemds/2016/166
Table 1: Baseline Characteristics of Subjects

           Variable             Non-NAFLD            NAFLD

          Sample Size              264                144

Age (In years) Mean ( SD) 41.14 ( 9.65)   49.54 ( 6.6)

Gender
(a)             Male           131 (49.62%)       106 (73.61%)
(b)            Female          133 (50.37%)       38 (26.39%)

Body Mass Index

(a)            Normal          120 (45.45%)       30 (20.83%)
(b)          Over weight        75 (28.4%)        31 (21.53%)
(c)             Obese           42 (15.9%)        42 (29.17%)
(d)        Morbidly obese      27 (10.23%)        41 (28.47%)
Physical active                80 (30.30%)         16 (11.1%)
Tobacco use                    78 (29.54%)        65 (45.14%)

           Variable               Total          P Value

          Sample Size              408

Age (In years) Mean ( SD) 43.74 ( 9.5)    < 0.0001

Gender                                          < 0.0001
(a)             Male           237 (58.09%)
(b)            Female          171 (41.91%)

Body Mass Index

(a)            Normal          150 (36.76%)     < 0.0001
(b)          Over weight       106 (25.98%)       0.13
(c)             Obese          84 (20.59%)        0.002
(d)        Morbidly obese      68 (16.67%)      < 0.0001
Physical active                 96 (23.5%)      < 0.0001
Tobacco use                    143 (35.05%)       0.002

Data are as means (Standard deviation) for continuous variable and
frequency (Percentages) for categorical variables.

Table 2: Prevalence of Components of Metabolic Syndrome (MetS)

Components of MetS         Non- NAFLD       NAFLD
                            (n=264)        (n=144)

Waist Circumference in       93.27          105.9
  cms. (Mean  SD)           (19.18)        (15.42)
Hypertension              57 (21.6 %)    69 (47.91%)
Impaired Blood Glucose     62 (23.5%)     56 (38.9%)
Low HDL                   48 (18.18%)    52 (36.11%)
High Triglyceride         34 (12.88%)     31 (21.5%)

Components of MetS           Total        P Value
                            (n=408)

Waist Circumference in        97.1       < 0.0001
  cms. (Mean  SD)           (19.77)
Hypertension              126 (30.9%)    < 0.0001
Impaired Blood Glucose    118 (28.9%)      0.001
Low HDL                   100 (24.5%)    < 0.0001
High Triglyceride          65 (15.9%)      0.02

Data are as means (Standard deviation) for continuous variable and
frequency (Percentages) for categorical variables.
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Author:Yadav, Chandrajeet; Dhruw, Sandeep; Shekhawatia, Pulkit; Gupta, Aman
Publication:Journal of Evolution of Medical and Dental Sciences
Article Type:Report
Date:Feb 22, 2016
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