SYNOPSIS FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
TITLE- STUDY OF CLINICAL, BIOCHEMICAL AND RADIOLOGICAL PROFILE OF NON-ALCOHOLIC FATTY LIVER DISEASE AND ITS CORRELATION WITH CARDIOVASCULAR RISK FACTORS .
BY-
DR. SWATI CHOUHAN
1st YEAR, JUNIOR RESIDENT
DEPARTMENT OF GENERAL MEDICINE,
RAJARAJESWARI MEDICAL COLLEGE AND HOSPITAL, BANGALORE- 560 074.
GUIDE: CO-GUIDE:
DR. KRISHNA M. V. DR. PRAVIN G.U
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA
SYNOPSIS FOR REGISTRATION OF SUBJECTS FOR
DISSERTATION
1. NAME OF THE CANDIDATE AND ADDRESS/ DR. SWATI CHOUHAN
C/O DR. S. P. SINGH,
PLOT NO. 1362/B, SECTOR-6, ABHINAVA BIDANASI, CUTTACK (ODISHA)- 753014.
2. NAME OF THE INSTITUTION / RAJARAJESWARI MEDICAL COLLEGE AND HOSPITAL
BANGALORE-560074
3. COURSE OF STUDY AND SUBJECT / M.D. GENERAL MEDICINE
4. DATE OF ADMISSION TO COURSE / 27th MAY, 2013
5. TITLE OF THE TOPIC / STUDY OF CLINICAL, BIOCHEMICAL AND RADIOLOGICAL PROFILE OF NON-ALCOHOLIC FATTY LIVER DISEASE AND ITS CORRELATION WITH CARDIOVASCULAR RISK FACTORS .
BRIEF RESUME OF THE INTENDED WORK:
6.1 NEED FOR THE STUDY:
Non-alcoholic fatty liver disease (NAFLD) is a broad term which includes patients with simple steatosis as well as non-alcoholic steatohepatitis (NASH).1 NASH is a recently recognized entity, which histologically simulates alcoholic hepatitis in the absence of alcohol ingestion or intake of <20g/day and has the propensity to progress on to cirrhosis of the liver and hepatocellular carcinoma (HCC).2–4 NAFLD has emerged as a major hepatic problem in developed as well as developing countries. There is wide variation in the reported prevalence of NAFLD on account of the variable defining criteria for NAFLD diagnosis and the inhomogeneous study population including widely discrepant socioeconomic status and life style in the different studies. The prevalence of NAFLD is estimated to be 15-35% of the general population in western countries5, while it is 8-40% in Asian countries.6,7,8. Although NAFLD is thought to be a relatively benign condition ranging from simple steatosis to steatohepatitis, it has now become clear that it may progress to cirrhosis, liver failure as well as to the catastrophic illness like hepatocellular carcinoma.9 There is paucity of data on the clinical and biochemical profile of NAFLD patients in general, since the published profile reflects the profile of selected subset of patients who may be having more severe variety of NAFLD.
Obesity, type 2 diabetes mellitus (T2DM) and hyperlipidaemia are coexisting conditions frequently associated with NAFLD. Because of the strong association with various metabolic abnormalities, NAFLD is now considered a part of spectrum of metabolic syndrome (MS). Patients with MS are at an increased risk for atherosclerosis and cardiovascular disease. In the Third National Health and Nutrition Examination Survey, MS was significantly related to myocardial infarction in either gender.10 In the Atherosclerosis Risk in Communities (ARIC) study, the subjects with MS were approximately 1.5–2 times more likely to develop coronary artery disease (CAD) than the controls.11 This puts patients with NAFLD also at an increased risk for atherosclerosis and cardiovascular disease. Presence of atherosclerosis can be assessed non-invasively by an increase in the CIMT (structural atherosclerosis).12 In India, sparse literature is available on the association of NAFLD with atherosclerosis and cardiovascular events. Studies from the West have suggested increased CIMT in patients with NAFLD. It is also suggested that increased risk of atherosclerosis and cardiovascular disease in patients with NAFLD may occur independent of MS.13-15
Hence, the present study is aimed to evaluate the clinical, biochemical profile and prevalence of atherosclerosis by measuring the CIMT in Indian patients with incidentally detected NAFLD and to study its relationship with MS.
6.2 REVIEW OF LITERATURE:
Recently, a lot of data from the Western literature has suggested the increased atherosclerosis and cardiovascular risk in patients with NAFLD. But it is still a matter of debate whether NAFLD per se predisposes to these abnormalities or this is all happening because of the presence of metabolic abnormalities or MS. Targheret al. found that patients with NAFLD had greater CIMT (1.14±0.20 vs. 0.82±0.12mm; p<0.001) than controls.16 They found that MS and its individual components were more frequent in those with NAFLD. The marked difference in CIMT between the groups was slightly weakened after adjustment for MS components. In a cross-sectional study, McKimme et al. evaluated the association between hepatic steatosis and coronary, aortic and carotid artery calcium and CIMT in 623 participants from diabetes heart study. They found a significant association between steatosis and aortic calcium and CIMT which completely disappeared after adjusting for other CVD risk factors including visceral obesity.17 On the other hand, Volzke and colleagues found that individuals with fatty liver had higher CIMT and more often had carotid plaques than persons without fatty liver (plaque prevalence rate 76.8% vs. 66.6%; p<0.001).18 This association persisted even after adjustment for confounding factors. Similarly in the study by Brea et al,15 CIMT was found to be higher in patients with NAFLD than in age- and sex-matched controls (p<0.01). Further, by logistic regression and adjustment for various confounders, the presence of NAFLD was associated with a higher CIMT independently of MS and all its traits.15 In a recent study from India, Thakur et al. examined the association of subclinical atherosclerosis and endothelial dysfunction in patients with NAFLD.19 They concluded that in Asian Indians, NAFLD is significantly associated with subclinical atherosclerosis and endothelial dysfunction independent of obesity and MS.19
Increased atherosclerosis has been shown to correlate well with cardiovascular risk factors and severity of coronary atherosclerosis; it reliably predicts the risk of future cardiovascular events.14, 20. Kessler et al. found a higher prevalence of NAFLD in patients with myocardial infarction (66% and 50% for women and men, respectively) compared to that found in the general population. NAFLD was also associated with greater severity of CAD. Both these findings were independent of age, gender and BMI.21 Similarly in a prospective study involving 1221 participants, Hamaguchiet al. found increased incidence of cardiovascular disease (coronary heart disease, ischaemic stroke and cerebral haemorrhage) in 231 patients with NAFLD as comparison to 990 subjects without NAFLD.22 In fact, a long-term follow-up study of patients with NAFLD and raised liver enzymes, more patients with NASH died of cardiovascular disease rather than liver disease, again suggesting not only a higher prevalence but also higher morbidity and mortality associated with cardiovascular disease in patients with NAFLD in comparison to the general population.23
Carotid intima media thickness is increasingly used as a surrogate marker for atherosclerosis. Its use relies on its ability to predict future clinical cardiovascular end points. CIMT measurement is an effective, non invasive tool which can assist in identifying people with NAFLD who are at higher risk of developing atherosclerotic cardiovascular complications. It may also help to evaluate the effectiveness of various treatment strategies used to treat people with NAFLD.
CIMT is the area of tissue starting at the luminal edge of the artery and ending at the boundary between the media and the adventitia. It is measured using B-mode ultrasound as the composite thickness of the intima and media. The ‘double-line pattern’ is thus the distance between the two echogenic lines that represent the lumen–intima interface and the media–adventitia interface. CIMT in healthy middle-aged adults measures 0.6 to 0.7 mm and greater than 1.20 mm is considered abnormal CIMT is age-dependent and increases at a rate of 0.005 to 0.010 mm/year Thus, in younger individuals, a CIMT of greater than 1.00 mm would be considered abnormal.
6.3 OBJECTIVES:
1. To study the clinical, biochemical and radiological profile of patients with incidentally detected NAFLD and to study its relationship with metabolic syndrome.
2. To evaluate the correlation between NAFLD and cardiovascular risk factors including measurement of Carotid intima-media thickness (CIMT).
7. MATERIALS AND METHODS:
7.1 SOURCE OF DATA:
Study will be conducted on patients in the age group of 25- 65 years, attending general medicine outpatient section and inpatients of Rajarajeswari medical college and hospital Bangalore for a period of 1 year from January 2014 to January 2015.
DURATION OF STUDY
One year from January 2014 to January 2015.
INCLUSION CRITERIA:
1. Non-alcoholic individuals, with age >12 years defined as either total abstainers or who consumed <20 g of alcohol per day (confirmed by two family members).
2. Ultrasound showing hyperechoic liver suggestive of fatty liver.
EXCLUSION CRITERIA:
1. Alcohol consumption of ≥20 g/d (as evident from patients’ confession or interview of close relatives)
2. Positive hepatitis B surface antigen (HBsAg).
3. Positive antibodies to hepatitis C virus (anti-HCV)
4. Positive autoimmune markers (anti-nuclear antibody, anti-smooth muscle antibody, anti-liver kidney microsomal antibody, anti-mitochondrial antibody)
5. Low ceruloplasmin level / positive Kayser–Fleischer rings.
6. Positive alpha 1 anti-trypsin enzyme.
7. Abnormal iron work-up ( high serum iron,low total iron binding capacity, high ferritin, or transferrin saturation).
8. Use of drugs such as amiodarone, corticosteroids, tamoxifen, methotrexate or high-dose oestrogens.
9. Jejunoileal bypass or extensive small bowel resection.
10. Patients on total parenteral nutrition
11. Pregnancy
12. Clinical, imaging or liver biopsy features of cirrhosis of liver
7.2 METHOD OF DATA COLLECTION-
STUDY DESIGN:
This will be a cross-sectional descriptive study which will be carried out in the medicine department of Rajarajeswari medical college and hospital Bangalore.
STUDY METHOD:
The study subjects will be in the age group of 25 – 65 years.
1. Detailed history including that of alcohol consumption will be taken after informed consent.
2. Anthropometric measurements like weight, height, Body mass index(BMI) and waist-hip ratio will be measured.
3. Systemic examination will be done.
4. Biochemical tests such as fasting blood glucose, post prandial blood glucose, Glycosylated haemoglobin (HbA1c), fasting lipid profile and liver function tests will be done.
5. Electrocardiography (ECG) and Echocardiography (ECHO) will be done.
6. Carotid Intima-Media thickness (CIMT) will be done by trained professional using high resolution B mode ultrasonography system ( Phillips HD 11XE) having an electrical linear transducer mid frequency of 7- 12 Mega Hertz. Scans will be performed on both the right and left Common Carotid Arteries at 3 points- base, mid junction and just before bifurcation. The IMT is measured as the distance from the leading edge of the first echogenic line to the second echogenic line. The first echogenic line represents the luminal intimal interface and the second line is produced by the collagen containing upper layer of intimal adventitia .At each longitudinal projection determination of IMTs will be conducted at the side of greatest thickness and at two points 1 cm upstream and 1cm downstream from the side of greatest thickness as described .The mean of a total of six IMT measurements from both sides will be used as the representative value for each subject.
The data collected will be presented in the form of percentages, frequencies and figures such as tables, charts and graphs. Data will be analysed using SPSS software. Correlation between CIMTand NAFLD will be calculated.
7.3 Does the study require any investigations or interventions to be conducted on patients or animals?
Yes, the following investigations will be peformed on the patient:
1. Blood sugar- Fasting (FBS) and Post-Prandial (PPBS)
2. Glycosylated Haemoglobin (HbA1C)
3. Fasting Lipid profile
4. Liver Function Tests
5. Electrocardigraphy (ECG)
- Echocardiography (ECHO)
- Carotid Intima-media thickness (CIMT)
7.4 Has ethical clearance been obtained from your institution in case
of 7.3
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