THE TAMILNADU DR.M.G.R. MEDICAL...

ASSOCIATION BETWEEN SERUM URIC ACID AND

NON- ALCOHOLIC FATTY LIVER DISEASE AND ITS

CORRELATION WITH LIVER FIBROSIS AS

ASSESSED BY FIBROSCAN

DISSERTATION SUBMITTED FOR

M.D GENERAL MEDICINE

BRANCH – I

APRIL 2019

THE TAMILNADU

DR.M.G.R. MEDICAL UNIVERSITY

CHENNAI, TAMILNADU, INDIA

CERTIFICATE FROM THE DEAN

This is to certify that this dissertation entitled “ASSOCIATION

BETWEEN SERUM URIC ACID AND NON -ALCOHOLIC FATTY

LIVER DISEASE AND ITS CORRELATION WITH LIVER FIBROSIS AS

ASSESSED BY FIBROSCAN” is the bonafide work of Dr.P.VATHSALYAN

in partial fulfillment of the university regulations of the Tamil Nadu Dr. M.G.R.

Medical University, Chennai, for M.D General Medicine Branch I examination

to be held in April 2019.

DR.D.MARUTHU PANDIAN M.S.,FICS.,FRCS.,

THE DEAN,

Madurai Medical College,

Madurai.

CERTIFICATE FROM THE HOD


BETWEEN SERUM URIC ACID AND NON - ALCOHOLIC FATTY

LIVER DISEASE AND ITS CORRELATION WITH LIVER FIBROSIS

AS ASSESSED BY FIBROSCAN” is the bonafide work of Dr.P.VATHSALYAN


Medical University, Chennai, for M.D General Medicine Branch I examination

to be held in April 2019.

Dr.V.T.PREM KUMAR,M.D.,

Professor and HOD,

Department Of General Medicine,

Government Rajaji Hospital,


Madurai.

CERTIFICATE FROM THE GUIDE


BETWEEN SERUM URIC ACID AND NON- ALCOHOLIC FATTY


AS ASSESSED BY FIBROSCAN” is the bonafide work of Dr.P.VATHSALYAN


Medical University, Chennai, for M.D., General Medicine Branch I

examination to be held in April 2019.

Dr.M.NATARAJAN,M.D.,

Professor of Medicine,

Department Of General Medicine,



Madurai

DECLARATION BY THE CANDIDATE

I declare that, I carried out this work on “ASSOCIATION BETWEEN

SERUM URIC ACID AND NON- ALCOHOLIC FATTY LIVER DISEASE

AND ITS CORRELATION WITH LIVER FIBROSIS AS ASSESSED BY

FIBROSCAN” at the Department of Medicine, Govt. Rajaji Hospital during the

period MARCH 2018 TO AUGUST 2018 under the guidance and supervision

of Prof. Dr.M.NATARAJAN. I also declare that this bonafide work or a part of

this work was not submitted by me or any others for any award, degree or diploma

to any other University, Board either in India or abroad.

This dissertation is submitted to The Tamil Nadu Dr. M.G.R. Medical

University, Chennai in partial fulfillment of the rules and regulations for the

award of M.D Degree General Medicine Branch- I; examination to be held in

April 2019.

Place : Madurai Dr. P. VATHSALYAN

Post Graduate student

Date Department of General Medicine

Madurai Medical College

ACKNOWLEDGEMENT

I would like to thank DR.D.MARUTHU PANDIAN M.S.,FICS.,FRCS.,

Dean, Madurai Medical College, for permitting me to utilize the facilities of

Madurai Medical College and Government Rajaji Hospital for this dissertation.

I wish to express my respect and sincere gratitude to my beloved teacher and

head of department, Prof. Dr.V. T. PREMKUMAR, M.D.,Professor of medicine

for his valuable guidance and encouragement during the study and also throughout

my course period.

I would like to express my deep sense of gratitude, respect and thanks to my

beloved Unit Chief and Professor of Medicine Prof.Dr.M.NATARAJAN, M.D.,

for his valuable suggestions, guidance and support throughout the study and also

throughout my course period.

I am greatly indebted to my beloved Professors

Dr.R.BALAJINATHAN,M.D., Dr.G.BAGHYALAKSHMI, M.D.,

Dr.J.SANGUMANI, M.D., Dr.C.DHARMARAJ, M.D., and

Dr.R.PRABHAKARAN, M.D., Dr. RAVINDRAN M.D for their valuable

suggestions throughout the course of study.

I express my special thanks to Prof. Dr.M. KANNAN MD,DM. Professor

and HOD Department of Medical gastroenterology for permitting me to utilize the

facilities in the Department, for the purpose of this study and guiding me with

enthusiasm throughout the study period.

I am thankful to my Assistant Professors:

DR.P.S.VALLI DEVI M.D

DR. SRIDHARAN M.D

DR.SHANMUGANATHAN M.D.,

for their valid comments and suggestions.

I sincerely thank all the staffs of Department of Medicine and Department of

Medical Gastroenterology, Department of Radiology and Department of

biochemistry for their timely help rendered to me, whenever and wherever needed.

I extend my love and express my gratitude to my family and friends for their

constant support during my study period in times of need.

Finally, I thank all the patients, who form the most vital part of my work, for

their extreme patience and co-operation without whom this project would have been

a distant dream and I pray God, for their speedy recovery.

CONTENTS

S.NO

CONTENTS PAGE NO

1 INTRODUCTION

1

2 AIM OF STUDY

3

3 REVIEW OF LITERATURE

4

4 MATERIALS AND METHODS

66

5 RESULTS AND OBSERVATIONS

69

6 DISCUSSION

87

7 SUMMARY

92

8 CONCLUSION

93

ANNEXURE

BIBLIOGRAPHY

PROFORMA

ABBREVATIONS

MASTER CHART

ETHICAL COMMITTEE APPROVAL LETTER

ANTI PLAGIARISM CERTIFICATE

1

INTRODUCTION

Non alcoholic fatty liver disease (NAFLD) is one of the common causes

for chronic liver disease. The prevalence of NAFLD has increased during last

20 years , ranging from 5% to 25% in Asian countries, depending on the

population studied.

NAFLD is diagnosed when daily alcohol consumption is≤30 g/ day in men

and ≤20 g/day in women and with exclusion of other causes of disease such as

viral hepatitis autoimmune hepatitis, , steatogenic drugs, etc. It is characterized

by excessive accumulation of triglyceride (>5%) in the hepatocytes, ranging from

hepatic steatosis (Fatty Liver) which may lead on to non alcoholic steatohepatitis

(NASH), fibrosis, and liver cirrhosis & hepatocellular carcinoma (HCC).

Multiple “hits”, having metabolic syndrome as a major role and

inflammation process involving cytokines, adipokines, oxidative stress are

hypothesized to explain the complex pathogenesis and progression of NAFLD.

NAFLD, widely considered as liver manifestation of metabolic syndrome, is

associated with some clinical conditions. Obesity, hypertension, diabetes,

dyslipidemia are the most reviewed factors associated with NAFLD.

The final product of purine metabolism in humans, uric acid, is associated

with metabolic disorders. It is widely known that increased serum uric acid levels

2

often co-exist with insulin resistance, atherosclerosis, hypertension, and obesity.

Inflammation and oxidative stress are hypothesized to be the essential link in this

relationship. Recently, several observational studies suggest that hyperuricemia

(serum uric acid (SUA) level>7.0 mg/dL in men and >5.7 mg/dL in women) is a

risk factor for NAFLD among eastern Asian populations independent of the

components of metabolic syndrome

So the main goal of this study is to find the association between serum uric

acid and newly diagnosed NAFLD patients attending Outpatient department in

Government Rajaji Hospital, Madurai and to find its correlation with liver fibrosis

which is assessed by Fibroscan.

3

AIM OF THE STUDY

PRIMARY AIM

To determine the association between ultrasound defined NAFLD and

serum uric acid

To find the correlation between serum uric acid level and severity of

NAFLD by assessment of liver fibrosis by Fibroscan

4

REVIEW OF LITERATURE

Non-alcoholic fatty liver disease:

NAFLD is defined as “the accumulation of fat in the liver in the absence

of recent or ongoing intake of significant amount of alcohol”.

The significant amount of alcohol varies but a cut-off of intake up to 20

g/day seems reasonable both for males and females (approximately 30 ml whisky

= 100 ml wine = 240 ml beer = 10 g alcohol).

The definition of primary NAFLD also includes the exclusion of other

secondary causes of hepatic steatosis including various medications and hepatitis

C virus, surgical procedures, total parenteral nutrition, and inborn errors of

metabolism. The fat deposition in the liver is defined best histologically on liver

biopsy as the macrovesicular steatosis occupying at least 5% of the hepatocytes

Hepatic steatosis is usually defined on imaging with MRS being the best

modality. Since MRS is not readily available, for practical purposes, most

commonly imaging modality to define NAFLD is ultrasound abdomen. The

differentiation of simple steatosis from NASH is possible only on histology rather

than imaging.

Other causes of Fatty Liver

Alcoholic liver disease

• Hepatitis C (particularly genotype 3)

5

• Inborn errors of metabolism

• Abetalipoproteinemia

• Cholesterol ester storage disease

• Galactosemia

• Glycogen storage disease

• Hereditary fructose intolerance

• Homocystinuria

• Systemic carnitine deficiency

• Tyrosinemia

• Weber-Christian syndrome

• Wilson’s disease

• Wolman’s disease

• Miscellaneous

• Industrial exposure to petrochemical

• Inflammatory bowel disease

• Lipodystrophy

• Bacterial overgrowth

• Starvation

• Parenteral nutrition

• Surgical procedures

• Bilopancreatic diversion

• Extensive small-bowel resection

6

• Gastric bypass

• Jejunoileal bypass

• Reye’s syndrome

• Acute fatty liver of pregnancy

• HELLP syndrome (hemolytic anemia, elevated liver enzymes, low platelet

count)

Medications (shown below)

7

8

Spectrum of Non-Alcoholic Fatty Liver Diseases

Non-cirrhotic Non-alcoholic Fatty Liver Disease

NAFLD is a broad terminology consisting of patients with simple steatosis,

NASH, NASH-related cirrhosis, and NASH-related HCC. Patients with simple

steatosis have the presence of fat in the liver with or without the presence of

lobular inflammation on histology

NASH is defined as “steatosis and inflammation associated with the

presence of one of the three additional features: ballooning of hepatocytes,

Mallory hyaline, and fibrosis on liver histology”. Since these features are difficult

to diagnose non-invasively, NASH is usually a histological diagnosis except in

situations where hepatic fibrosis is diagnosed with the help of transient

elastography (TE) and hence can be a better non-invasive modality in

differentiating patients with simple steatosis and NASH.

The differentiation between NAFLD and NASH is very important in

determining the prognosis, progression, and assessing the liver-related and

cardiovascular morbidity and mortality which are more common in patients with

9

NASH than in those with NAFLD. Since liver biopsy cannot be done in all

patients, it can be directed at those likely to have severe disease. Various

parameters such as gender, age, (AST/ALT) ratio, the presence of diabetes, and

other components of MS can help in predicting severe disease i.e., NASH. Liver

biopsy is helpful not only in differentiating NASH from other conditions but also

categorizing the patients with NASH into different grades and stages based on

different classification systems

Non-alcoholic Steatohepatitis-Related Cirrhosis and Hepatocellular

Carcinoma

(NAFLD/NASH) has emerged as the most common cause of Cryptogenic

cirrhosis (CC) as shown by many studies from the West. Like any chronic liver

disease, NAFLD/NASH may be asymptomatic in the beginning and may present

later as CC or even HCC. It may be difficult in these people to recognize

NAFLD/NASH even on histology because liver fat decreases with increasing

fibrosis and the characteristic changes of NAFLD/NASH may not be evident once

it goes into cirrhosis..

10

Pathogenesis

11

The basic defect in the development of hepatic steatosis is imbalance

between import and export of fat to and from the liver. Sources of excess import

include excess dietary intake of fat if compensatory decrease in lipolysis and de-

novo synthesis does not take place. An excess de-novo fat synthesis in the liver

or lipolysis in the peripheral tissues with increased delivery of free fatty acids

(FFA) to liver also causes steatosis. Reduced beta-oxidation of fatty acids and

decreased export as VLDL also contribute to hepatic steatosis. Insulin resistance

with or without full-blown MS is the central mechanism of hepatic steatosis in

patients with NAFLD, which develops in the setting of an inappropriate diet,

sedentary lifestyle, advancing age and obesity. Role of genetic variations in

predisposing to the development of steatosis is also under investigation.

Non-alcoholic fatty liver disease patients with or without MS have been

shown to have higher IR compared to controls. Though glucose clamp studies are

the ideal method of studying IR, most studies in patients with NAFLD have used

HOMA-IR. Studies have shown that NAFLD is associated with higher IR

compared to controls, even after excluding overweight and obese subjects and

that IR increases with increasing steatosis. A comparison between patients of

different ethnicities has shown that Indians have higher IR in comparison to other

races. Data from India support the higher prevalence of IR in patients with

NAFLD. A study from Kolkata has also shown higher HOMA-IR levels in non-

obese patients with NAFLD in comparison to non-obese controls without

NAFLD.

12

Insulin resistance in NAFLD is predominantly peripheral occurring at the

skeletal muscle and adipose tissue. Peripheral IR in the skeletal muscle causes

reduced glucose uptake. In the adipose tissue, IR impairs the anti-lipolytic action

of insulin leading to increased release of Free fatty acids. Elevated plasma

concentrations of insulin, glucose, and fatty acids promote hepatic fatty acid and

triglyceride uptake, de-novo lipid synthesis via sterol-regulatory element-binding

protein and C/EBP (CCAAT/enhancer-binding protein) and impairs beta-

oxidation of fatty acids by negative feedback. Insulin resistance also increases the

intra-hepatocytic fatty acids by increasing glycolysis and decreasing

apolipoprotein B- 100 thereby blocking export of VLDL. The development of

IR in NAFLD is probably related to imbalance between pro-insulin (adiponectin)

and anti-insulin (TNFa) cytokines particularly those secreted from adipose tissue

(adipokines). Alterations in various molecules, including FFA, membrane

glycoprotein PC-1,TNF alpha and leptin interfere with the insulin signaling

pathway. Free fatty acids are both the result and cause of Insulin resistance.

Excess FFA cause hepatic IR by down regulating insulin receptor substrate-1

signaling and by activation of the inhibitor kappa bkinase (IKK-b) pathway.

13

Other Pathogenic Mechanisms in Non-alcoholic Fatty Liver Disease

Other mechanisms involved in the pathogenesis of NAFLD/NASH include the

role of lipotoxicity, serum and liver iron overload, innate and adaptive immunity,

oxidative stress and cytokines, small intestinal bacterial overgrowth, and finally

the polymorphisms of the genes involved in lipid accumulation, oxidative stress,

and hepatic fibrosis

14

Histopathology of NAFLD

15

Fatty Liver

16

Non Alcoholic Steatohepatitis

17

NASH with fibrosis

18

Natural history of Non Alcoholic Fatty Liver Disease

Isolated fatty liver rarely progresses to cirrhosis. When compared with general

population, it is not associated with increased risk of death. However, NASH is

related with increased risk of mortality due to cirrhosis, malignancy and

cardiovascular disease Progression of fibrosis in NASH is associated with severe

insulin resistance, diabetes mellitus, higher BMI and weight gain greater than

5kgs

19

DIAGNOSIS OF NON-ALCOHOLIC FATTY LIVER DISEASE

Diagnosis of Non-Alcoholic Fatty Liver Disease requires a detailed history

to exclude significant amount of alcohol intake and other secondary causes of

fatty liver. Most patients with non-cirrhotic NAFLD are asymptomatic in the

beginning with incidental detection. Some patients are detected to have fatty liver

on ultrasound and raised enzymes during work-up for other illness.

Anthropometry may reveal overweight, obesity and mild hepatomegaly

may be an important sign in half of these patients but signs of liver failure are

absent unless the patient has progressed to cirrhosis. Serum biochemistry shows

20

either normal enzymes or mildly elevated AST and ALT with ALT more than

AST.

Diagnostic modalities are thus directed to confirm the presence of fatty

liver and secondly to grade the severity of liver disease. The diagnosis of fatty

liver is usually made on ultrasound with exclusion of other causes.

Ultrasound is a reliable imaging technique for the detection of fatty liver,

as compared with histology, with a sensitivity 84.8% and a specificity 93.6% for

detecting 20–30% steatosis.

Fig.1 USG Abdomen showing Fatty liver

21

Computed tomography scan and MRI do not add much and are as good as

ultrasound for detecting fat in the liver. Magnetic resonance spectroscopy is better

in detecting fat but these modalities cannot detect the degree of inflammation and

fibrosis, hence are not good in differentiating between steatosis and histological

NASH.

Fig 2.T1- weighted MRI showing bright liver

22

Since ultrasound is easily available, inexpensive without any radiation risk,

it should be the first modality to assess the presence and grading of hepatic

steatosis and for the severity of liver disease. On ultrasound, the physician should

look for the liver echogenicity and its comparison with that of kidney and

spleen,deep attenuation of ultrasound signal and vascular blurring.

Fibroscan (transient elastography) is a new non-invasive modality in detecting

liver fibrosis and its role is still being evolved in various liver diseases. Many

patients with fatty liver on conventional imaging may turn out to have significant

fibrosis on Fibroscan and may be subjected to a liver biopsy.

Fig Fibroscan probe

23

All patients of NAFLD irrespective of the liver enzyme elevation should

undergo a detailed physical examination / anthropometry including, height,

weight, BMI, waist circumference, and waist–hip ratio for assessment of

overweight and central and overall obesity. These patients should be further

evaluated with liver function tests and for the presence of other components of

MS namely hypertension, impaired glucose tolerance serum triglycerides, and

HDL. In addition, all patients should also be screened for hepatitis B surface

antigen (HBsAg) and antibodies to hepatitis C virus. Further work-up including

autoimmune markers, celiac disease work-up, serum iron profile, and serum

ceruloplasmin should be done in susceptible patients with raised liver enzymes

depending on the age of the patient. Even though NAFLD is very common in

patients with Diabetes, the presence of diabetes in patients of NAFLD presenting

with raised transaminases is not very common when evaluated by fasting and

post-prandial plasma glucose.

Liver biopsy

Liver biopsy is an invasive test and it is not commonly performed in Non-

Alcoholic fatty liver disease. However it may be done to find the disease activity

in NAFLD and also in staging of the disease

24

25

Severity of NAFLD can be assessed either non-invasively by using various

biomarkers or with the help of imaging and liver biopsy. Since serum biomarkers

are not available routinely and lack standardization, the severity assessment is

usually based on imaging and liver biopsy. As mentioned earlier, ultrasound, CT

scan, and MRI including MRS cannot pick up ballooning or Mallory hyaline and

are poor in detecting hepatic fibrosis unless there is frank cirrhosis. Only

noninvasive imaging modality which can help picking up hepatic fibrosis is tissue

elastography [Fibroscan, acoustic radiation forced impulse (ARFI), and magnetic

resonance elastography (MRE)]. Since all forms of elastography are poorly

available and expensive, the only useful modality in assessing severity of liver

disease in patients with NAFLD is liver biopsy.

Since liver biopsy is an invasive procedure and is not free of complications,

it should be directed at patients who are likely to be most benefitted from this

procedure.

26

Even though a definite diagnosis of NAFLD/NASH can be made only on

histology, convincing the patients for liver biopsy is difficult due to the slowly

progressive nature of the disease and lack of specific treatment.

Diagnosis of Non-Alcoholic Steatohepatitis Related Cirrhosis and

Hepatocellular Carcinoma

Since liver histology is not very helpful in making the diagnosis of NASH-

related cirrhosis or HCC (liver fat decreases with the increasing fibrosis),

diagnosis of NAFLD/NASH as a cause of CC and HCC is usually based on the

presence of metabolic risk factors. Once other possible etiologies are excluded,

the diagnosis of NAFLD/NASH-related cirrhosis and HCC can be made if there

is presence of two or more components of MS. Many patients tend to lose weight

with the development of cirrhosis and HCC; So, a history of overweight or

obesity may be sufficient to include this risk factor as a component of MS. It is

advisable to calculate BMI or waist circumference when these patients are free of

ascites or pedal edema or make appropriate reductions in the body weight and

waist when calculating the overweight/obesity and central obesity in them. Many

patients with cirrhosis liver tend to develop cirrhosis-related DM which needs to

be differentiated from long-standing type 2 DM when including this risk factor

as a component of MS.

27

Treatment

“The optimal therapy for NAFLD has not been established. Clinical trials to date

have been marked by small numbers of patients as well as varying inclusion

criteria and end points. Although improvements in metabolic parameters, liver

enzyme levels, or steatosis on imaging are readily determined in clinical trials,

histologic improvement in steatosis, inflammation, and fibrosis is the ultimate

goal of treatment. A 2-point improvement in the NAS, with 1 of the points coming

from a reduction in hepatocyte ballooning degeneration, may indicate a

successful intervention. Improvement in fibrosis (which is not part of the NAS)

is also desirable, although it is difficult to conduct trials of adequate length to

allow improvement in fibrosis. Multiyear trials are rarely seen; most trials have

been 6 to 12 months in duration. Standard treatment of NAFLD has consisted of

weight loss, removal of potentially offending drugs and toxins, and control of

associated metabolic disorders, including diabetes mellitus and hyperlipidemia”

28

Lifestyle Modification

Lifestyle modification is divided into calorie reduction, with a goal of

weight loss, macronutrient modification, and physical activity. Most studies of

calorie restriction include an exercise component also, making it difficult to

assess whether diet or exercise is more beneficial. Intensive nutritional counseling

may lead to sustained weight loss and significant histologic improvement in some

persons.

29

Preliminary evidence has suggested that low-carbohydrate, calorie-restricted

approaches improve insulin sensitivity and decrease hepatic triglyceride content

more than high-carbohydrate caloric restriction. Another study, however,

compared different lifestyle modification approaches and found that all of these

approaches led to some hepatic histologic improvement, which correlated with

weight loss. Limiting the saturated fatty acids and high-fructose corn syrup may

also be beneficial because diets high in saturated fatty acids and fructose have

been associated with NASH. There are no prospective data to support omega-3

fattyacid supplementation in NASH patients; however, circumstantial evidence

suggests a benefit. Physical activity is another lifestyle intervention that can be

recommended alone or along with nutritional counseling. Patients with NAFLD

and specifically NASH are more sedentary and have less cardiovascular fitness

than general population. A pilot trial of 19 obese patients with NAFLD showed

that after 4 weeks of aerobic training 3 times a week, visceral adipose tissue

volume, intrahepatic triglycerides content, and plasma free fatty acids

concentrations all improved in the absence of weight reduction. Although

lifestyle modification appears beneficial in patients with NAFLD, no single

particular intervention can be recommended, and no single approach is suitable

for all patients. Adequate weight loss of 5% to 10% is difficult to achieve, and

more difficult to sustain over time. A reduction in the intake of high-fructose corn

syrup and increase in intake of omega-3 fatty acids and caffeinated coffee are

30

intriguing adjuvants to the multidisciplinary approach that includes caloric

reduction and increased physical activity

Pharmacotherapy

Antioxidants

Medications that reduce the generation of reactive oxygen species in the

liver is an another potential avenue for therapy. The most studied antioxidants are

vitamin E and C, betaine.

Vitamin E is an inexpensive yet potent antioxidant. It has been examined

as an agent for the treatment of NAFLD in pediatric and adult patients, with

varying outcomes. In all studies, vitamin E was well tolerated, and most studies

showed modest improvements in serum aminotransferase levels and the

sonological appearance of the liver but infrequently histologic findings. Although

a pilot trial showed a benefit to vitamin E and C together for hepatic fibrosis, a

larger randomized controlled trial did not show any improvement in hepatic

fibrosis despite a significant improvement in steatosis, inflammation, and

ballooning degeneration. In a large pediatric trial, vitamin E was not better than

placebo (or metformin) in improving the serum liver enzyme levels or hepatic

histology, with the exception of ballooning degeneration. In view of the

potentially negative effects of vitamin E on cardiovascular health, all-cause

mortality, and prostate cancer rates, caution should be exercised in treating

NAFLD with vitamin E until better studies are available. The tri-society practice

guidelines recommends vitamin E 800 IU/day as a first-line therapy in

31

nondiabetics with biopsy-proved NASH but caution against use of vitamin E in

diabetics or patients with NAFLD without a liver biopsy.

Betaine, a metabolite of choline that raises S-adenosyl methionine

levels and decreases oxidative damage, has shown promise in mouse models. A

pilot study investigating betaine as a therapeutic agent for NASH demonstrated

an improvement in hepatic steatosis.

Diabetes Medications

The association between insulin resistance and NAFLD provides a logical

target for treatment. Metformin, thiazolidinediones (TZDs), and incretin

mimetics are the diabetes medications that have been investigated in treatment of

NASH.

Metformin, a biguanide reduces hyperinsulinemia and improves hepatic

insulin sensitivity, reduces hepatomegaly and hepatic steatosis in mice, but

results in both adult and human NAFLD have been less impressive .The use of

metformin is currently not recommended as a therapy for NAFLD.

TZDs are potent PPAR-γ agonists. PPAR-γ is a nuclear receptor that is

expressed in adipose tissue,liver and muscle. In adipocytes, PPAR-γ promotes

cell differentiation and decreases lipolysis and thus FFA release. TZDs improve

insulin resistance by increasing the glucose disposal in muscle and decreasing

hepatic glucose output. Treatment with troglitazone, a first-generation TZD, was

associated with biochemical and histologic improvements in patients with NASH,

but it was withdrawn from the market because of serious hepatotoxicity.

32

Rosiglitazone and in particular pioglitazone are TZDs with low rates of

hepatotoxicity and have been investigated in several large randomized controlled

trials in which treatment was well tolerated and associated with improvement in

insulin resistance, normalization of liver biochemistry, and histologic

improvement in most patients. Several drawbacks to TZD therapy may limit their

widespread use in NASH, but Continued treatment appears to be necessary,

because subsequent studies demonstrated the recurrence of NASH off therapy.

Long-term therapy with either agent is problematic because of associated average

weight gain of 3 to 4 kg. Rosiglitazone has been linked to increased rates of

myocardial infarction. Retrospective study has linked both the agents to increased

fracture rates and decreased bone mineral density. Because of these limitations,

TZDs cannot be recommended for all patients with NASH, although use of

pioglitazone in diabetic patients with histologically advanced NASH seems

reasonable. The tri-society guidelines states pioglitazone can be used to treat

biopsy-proved NASH but emphasize that the long-term safety and efficacy have

not been established.

Incretin mimetics have been less well studied in patients with NASH but

have shown preliminary results. Exenatide and liraglutide are glucagon-like

protein-1 receptor agonists that improve the insulin sensitivity and serum glucose

levels and promote modest weight loss. Exenatide has shown promise in animal

models and human pilot trials. Nausea has been a limiting factor in the trials,

although a once-weekly formulation of exenatide may mitigate this side effect.

33

Cytoprotective Agents

Cytoprotective agents are thought to prevent apoptosis and down-regulate

the inflammatory cascade. Ursodeoxycholic acid (UDCA) is one of the

cytoprotective agents that has been investigated with mixed results in randomized

controlled trials. The largest placebo-controlled trial demonstrated equal

improvement in patients receiving UDCA and placebo. In a subsequent trial,

UDCA plus vitamin E improved hepatic steatosis and aminotransferase levels.

Two other trials have also demonstrated modest improvement in serum liver

enzyme levels, but histology was not studied in one of the trials and only lobular

inflammation improved in the other trial. These studies used high-dose UDCA,

which has been associated with increased mortality in patients with PSC. The tri-

society practice guidelines do not recommend the routine use of UDCA.

Pentoxifylline (PTX) is another cytoprotective agent that has been shown

to inhibit proinflammatory cytokines, including TNF-α, leading to decreased

production of reactive oxygen species. Two pilot trials as well as a largest

randomized controlled trial for NASH to date have shown varying degrees of

histologic improvement as well as improved liver enzyme levels and reduced

insulin resistance. The controlled trial with 55 NASH patients demonstrated a

1.6-point improvement in the NAS in PTX-treated patients compared with a 0.1-

point improvement in patients receiving placebo. A second smaller randomized

controlled trial of 30 patients showed improvement in steatosis and ballooning

34

degeneration with PTX, although improvement was not statistically better than

that for placebo group.

Lipid-Lowering Agents

Since patients with NASH have coexisting hyperlipidemia, the use of

lipid-lowering agents has been studied as a potential treatment to address both

the conditions. The most commonly used agents for hyperlipidemia are statins,

which inhibit HMG CoA reductase, the enzyme in cholesterol biosynthesis.

Statins have shown modest benefit in pilot trials. Larger trials without surrogate

end points of serum liver enzyme levels and improved hepatic steatosis have also

suggested some benefit. As of now, statins can be recommended to treat

concomitant hyperlipidemia , but further study is needed before statins are

recommended as primary therapy for NASH. Ezetimibe is a lipid-lowering agent

that has been shown benefit in improving hepatic histology in animal models as

well as one pilot trial in 24 patients with NAFLD

Metabolic Syndrome

“Metabolic syndrome (syndrome X) consists of metabolic abnormalities

that confers an increased risk of diabetes mellitus and cardiovascular disease.

Evolution of the criteria for Metabolic syndrome reflects the growing clinical

evidence and analysis by a variety of consensus conferences and professional

organizations. The major features of metabolic syndrome include,

hyperglycemia, hypertriglyceridemia, central obesity, hypertension and low

levels of high-density lipoprotein cholesterol”

35

Criteria for Metabolic Syndrome

EPIDEMIOLOGY

The most important feature to define in metabolic syndrome is the waist

circumference. Intra abdominal circumference (visceral adipose tissue) most

strongly is related with insulin resistance and risk of CVD and diabetes, and for

any given waist circumference the distribution of adipose tissue between

Subcutaneous and visceral depots varies substantially. Thus, there is a lesser vs.

greater risk at the same waist circumference within and between populations.

36

These differences in populations are reflected in the range of waist

circumferences. The prevalence of metabolic syndrome varies around the world,

in part reflecting the ethnicity and age of the populations studied and the

diagnostic criteria applied. In general, the prevalence of metabolic syndrome

increases with the age. The highest recorded prevalence worldwide was among

Native Americans, with nearly 60% of women ages 45–49 and 45% of men ages

45–49 meeting the criteria of the National Cholesterol Education Program and

Adult Treatment Panel III (NCEP:ATPIII). Rise in global industrialization is

associated with rising rates of obesity, which are expected to increase the

prevalence of the metabolic syndrome dramatically, especially as the population

ages. Moreover, the rising prevalence and severity of obesity among children is

reflected in the features of metabolic syndrome in a younger population.Increases

in waist circumference predominate among women, whereas increases in fasting

plasma triglyceride levels (i.e., to >150 mg/dL), reductions in HDL cholesterol

levels, and hyperglycemia are more common in men.

RISK FACTORS

Overweight/Obesity

“ Central adiposity is the main feature of the metabolic syndrome, and the

it’s prevalence reflects the strong relationship between increasing adiposity and

the waist circumference and. However, despite obesity, patients who of normal

weight can also be insulin resistant and shall have the metabolic syndrome”.

37

Sedantary Lifestyle

“ Many components of the metabolic syndrome are associated with a

sedentary lifestyle, including central obesity, decreased HDL cholesterol, and

increased , glucose, blood pressure and triglycerides in genetically susceptible

persons. There is two fold increased risk of metabolic syndrome in those

individuals who watch videos or television or use the computer <1 hour daily,

compared with those who do so for >4 hours daily” .

Aging

“ The metabolic syndrome affects nearly half of population older than age

50, and at >60 years of age women are more commonly affected than men. This

age dependency of the metabolic syndrome’s prevalence is seen in many

populations around the globe”.

Diabetes Mellitus

“Diabetes mellitus is included in both the NCEP and the harmonizing

definitions of metabolic syndrome. It is estimated that the majority (about 75%)

of patients with impaired glucose tolerance or type 2 diabetes mellitus have the

metabolic syndrome”.

Cardiovascular Disease

“ Individuals are twice as likely to die of cardiovascular disease as those

who do not if they have metabolic syndrome and their risk of acute myocardial

infarction or a stroke threefold higher. The prevalence of the metabolic syndrome

among coronary heart disease patients is about 50%, with about 35% prevalence

38

among patients with premature coronary artery disease (< 45years of age) and a

strikingly high prevalence among women. With appropriate lifestyle changes

and cardiac rehabilitation, the prevalence of the syndrome can be reduced”.

Lipodystrophy

“In general, lipodystrophic disorders are associated with the metabolic

syndrome. Both genetic causes of lipodystrophy (e.g., Berardinelli- Seip

congenital lipodystrophy, ) and acquired causes (e.g., HIV-related lipodystrophy

in patients receiving antiretroviral therapy) may give rise to insulin resistance

and many of the components of the metabolic syndrome”.

39

ETIOLOGY

40

Insulin Resistance

“The insulin resistance is caused by an defect in insulin action which is

incompletely understood. The onset of the insulin resistance is heralded by

postprandial hyperinsulinemia, which is followed by fasting hyperinsulinemia

and ultimately by hyperglycemia”.

“A major contributor to the emergence of insulin resistance is an

overabundance of circulating fatty acids. Insulin mediates both antilipolysis and

stimulation of lipoprotein lipase in adipose tissue. Of note, the lipolysis inhibition

in adipose tissue is the most sensitive pathway of insulin action. Thus, when

insulin resistance occurs, increased lipolysis produces more fatty acids, which

further decrease the insulin’s antilipolytic effect. Excessive fatty acids increases

substrate availability and create insulin resistance by altering the downstream

signalling pathways. Fatty acids also impair the insulin-mediated glucose uptake

and accumulate as triglycerides in both cardiac and skeletal muscles, whereas

increased triglyceride accumulation and glucose production take place in the

liver”.

“Leptin resistance has also been suggested as one of the possible

mechanisms to explain the metabolic syndrome. Physiologically, leptin enhances

insulin sensitivity, reduces the appetite and promotes energy expenditure. Also,

leptin may regulate cardiac and vascular function through a nitric oxide–

dependent mechanism. However, in obesity , hyperleptinemia ensues, with

evidence of leptin resistance in the brain and in other tissues, resulting in

41

inflammation, hyperlipidemia, insulin resistance, , and many cardiovascular

disorders, such as atherosclerosis, hypertension, CHD, and heart failure”.

“The oxidative stress hypothesis provides a theory for predisposition to the

metabolic syndrome and aging . In studies of insulin resistant subjects with

obesity or type 2 diabetes, the offspring of patients with type 2 diabetes mellitus,

and the elderly, there is a defect in mitochondrial oxidative phosphorylation that

results in accumulation of triglycerides and related lipid molecules in muscles”.

“Recently, the gut microbiome has also been identified as an important

contributor to the rise of obesity and other associated metabolic disorders,

including the metabolic syndrome. Although the mechanisms remain uncertain,

interaction among genetic predisposition, the intestinal flora and the diet seems

to be important”.

Increased Waist Circumference

“Waist circumference is a main component of the recent and frequently

applied diagnostic criteria for the metabolic syndrome. However, measuring

waist circumference does not reliably distinguish increases in subcutaneous

adipose tissue from those in visceral fat; this distinction requires MRI or CT. With

increase in visceral adipose tissue, adipose tissue–derived free fatty acids are

directed to the liver. In contrast, increase in abdominal Subcutaneous fat release

lipolysis products into the systemic circulation and avert more effects on liver

metabolism. Relative increase in visceral versus subcutaneous adipose tissue with

increasing waist circumference in Asians and Indians explain the increased

42

prevalence of the metabolic syndrome in those populations than in African-

American men, in whom subcutaneous fat predominates. It shall also be possible

that visceral fat is a marker for, but not the source of excess postprandial free fatty

acids in obesity”.

Dyslipidemia

“In general, free fatty acid flux to the liver is associated with increased

production of ApoB-containing, triacylglycerol-rich, very low-density

lipoproteins. The effect of insulin on this process is complex, but

hypertriglyceridemia is a good marker of the insulin-resistance. Not only

hypertriglyceridemia is a feature of the metabolic syndrome, but patients with the

metabolic syndrome have also high levels of ApoCIII carried on VLDLs and

other lipoproteins. This increase in ApoCIII is inhibitory to lipoprotein lipase,

further resulting in hypertriglyceridemia and also associated with more

atherosclerosis”.

“The other disturbance in the metabolic syndrome is a reduction in HDL

cholesterol. This reduction is due to the changes in HDL composition and

metabolism. In the presence of hypertriglyceridemia, a decrease in the HDL

cholesterol content is a result of reduced cholesteryl ester content of the

lipoprotein core in addition with cholesteryl ester transfer protein– mediated

alterations in triglyceride that make the particle small and dense. This change in

lipoprotein composition also causes increased clearance of HDL from

circulation. These changes in HDL have a probable indirect relationship to insulin

43

resistance, occurring along with with the changes in triglyceride-rich lipoprotein

metabolism.

In addition to HDLs, low-density lipoproteins are modified in composition

in the metabolic syndrome. There is almost always a predominance of small,

dense LDLs, which are more atherogenic . Individuals with hypertriglyceridemia

often have increase in cholesterol content of both VLDL1 and VLDL2

subfractions and in LDL particle numbers. Both these lipoprotein changes may

contribute to atherogenic risk”

Glucose Intolerance

“In the metabolic syndrome, defects in insulin action lead to impaired

suppression of glucose production by the liver and kidney and decreased glucose

uptake and metabolism in insulin-sensitive tissues such as muscle and adipose

tissue. The relationship between impaired glucose tolerance or impaired fasting

glucose and insulin resistance is well supported by studies of humans . To

compensate for defects in insulin action, insulin secretion or clearance must be

modified so that euglycemia is sustained. Finally, this compensatory mechanism

fails, because of defects in insulin secretion, resulting in progression from IFG or

IGT to diabetes mellitus”.

Hypertension

“Under physiologic conditions, insulin is a vasodilator with secondary

effects on sodium reabsorption in the kidney. However, in insulin resistance, the

vasodilatory effect of insulin is lost with the preservation of the renal effect on

44

sodium reabsorption. Sodium reabsorption is not increased in with the metabolic

syndrome in Asians and Africans. Insulin also increases the sympathetic nervous

system activity, an effect that is preserved in the setting of insulin resistance.

Insulin resistance is characterized by specific impairment in

phosphatidylinositol-3-kinase signalling pathway. In endothelium, this

impairment causes an imbalance between the nitric oxide production and

endothelin 1 secretion, with a consequent reduction in blood flow. However,

evaluation of insulin action by measurement of fasting insulin levels shows that

insulin resistance only partially contributes to the increased prevalence of

hypertension in metabolic syndrome”.

“Another mechanism underlying hypertension in the metabolic syndrome

is the role of perivascular adipose tissue. Reactive oxygen species released by

NADPH oxidase causes impairment of endothelial function resulting in local

vasoconstriction. Other paracrine effects could be mediated by leptin or other

cytokines released from adipose tissue, such as TNF α”.

“Hyperuricemia is another consequence of insulin resistance and is

commonly seen in the metabolic syndrome. There is evidence that not only uric

acid is associated with hypertension but also that reduction of uric acid

normalizes blood pressure in hyperuricemic adolescents with hypertension. The

mechanism is related to the adverse effect of uric acid on nitric acid synthase in

the macula densa of kidney and stimulation of renin-angiotensin aldosterone

system”.

45

Proinflammatory Cytokines

“The increase in proinflammatory cytokines like interleukins 1, 6, and 18;

tumor necrosis factor α; resistin and the C-reactive protein reflect overproduction

by the increased adipose tissue mass. Adipose tissue–derived macrophages may

be the major source of proinflammatory cytokines. However, it remains unclear,

how much insulin resistance is caused by by the endocrine effects and how much

the paracrine effects of these cytokines”.

Adiponectin

“Adiponectin is an anti-inflammatory cytokine produced exclusively by

adipocytes. Adiponectin increases insulin sensitivity and inhibits inflammation.

In liver, adiponectin inhibits gluconeogenesis enzymes and the rate of glucose

production. In muscle, adiponectin increases glucose transport and fatty acid

oxidation, partially through the activation of AMP kinase. Adiponectin levels are

decreased in metabolic syndrome”.

Clinical features

“The metabolic syndrome usually is not associated with symptoms. On

examination, waist circumference may be increased and blood pressure may be

elevated. The presence of either or both of these signs should prompt the

physician to search for other biochemical abnormalities that may be associated

with the metabolic syndrome. Lipoatrophy or acanthosis nigricans may be found

on examination. Because these physical findings are associated with insulin

resistance, other components of the metabolic syndrome should be expected”.

46

Associated Diseases

Cardiovascular disease

“The risk for new onset CVD in patients with the metabolic syndrome who

do not have diabetes is about 1.5–3 fold. However, an 8-year follow-up study in

the Framingham Offspring Study documented that the population-attributable

CVD risk in the metabolic syndrome was 34% among middle aged men and 16%

among middle aged women. In the same study, both the diabetes and metabolic

syndrome predicted ischemic stroke, with greater risk among patients with

metabolic syndrome than among those with diabetes mellitus alone (19% vs. 7%)

and a large difference among women (27% vs. 5%). Patients are also at increased

risk for peripheral vascular disease”.

Type 2 diabetes

“The risk for type 2 diabetes among the patients with metabolic syndrome

is increased fivefold. In a study named Framingham Offspring Stud, 8-year

follow-up of the middle-aged participants, the population-attributable risk for

developing type 2 diabetes mellitus was 62% among men and 47% among

women”.

Other Associated conditions

“Other conditions associated with metabolic syndrome occurs due to

alterations such as increases in ApoB and ApoCIII, uric acid, C-reactive protein,

prothrombotic factors (fibrinogen, plasminogen activator inhibitor 1), , white

blood cell count, asymmetric dimethylarginine, proinflammatory cytokines, non-

47

alcoholic fatty liver disease and/or nonalcoholic steatohepatitis, homocysteine ,

microalbuminuria, , PCOS, and obstructive sleep apnea”.

Nonalcoholic fatty liver disease

“Hepatic steatosis is a common condition, affecting about 25–40% of the

population. However, in non alcoholic steatohepatitis, triglyceride accumulation

and inflammation coexist. Nonalcoholic steatohepatitis is now present in 3–12%

of the population of Western countries. In patients with metabolic syndrome,

about 25–60% have NAFLD and up to 35% have NASH. As prevalence of

overweight & obesity and the metabolic syndrome increases, nonalcoholic

steatohepatitis may become one of the common causes of end-stage liver disease

and hepatocellular carcinoma”.

Hyperuricemia

“Hyperuricemia reflects defects in the insulin action on the renal tubular

reabsorption of uric acid and contributes to hypertension through its effect on

the endothelium. An increase in asymmetric dimethylarginine, an inhibitor of

nitric oxide synthase, also leads to the endothelial dysfunction.”

Polycystic ovary syndrome

“Polycystic ovary syndrome is highly associated with insulin resistance in

about 50% to 80% and the metabolic syndrome, with prevalence of the about

40% to 50%. Women with PCOS are two to four times more likely to have the

metabolic syndrome than women without PCOS”.

48

Obstructive sleep apnea

“Obstructive sleep apnea is usually associated with obesity, hypertension,

insulin resistance ,impaired glucose tolerance, and increased circulating

cytokines. When biomarkers of insulin resistance are compared between patients

with obstructive sleep apnea and weight-matched controls, insulin resistance is

more severe in those with apnea. In obstructive sleep apnea patients, continuous

positive airway pressure treatment improves the insulin sensitivity”.

Diagnosis

“The diagnosis of the metabolic syndrome depends on fulfillment of the

criteria, as assessed by tools at the bedside and in the laboratory. The medical

history should include symptom analysis for polycystic ovary syndrome in

premenopausal women and obstructive sleep apnea in all patients. Family history

will help to detect risk for diabetes mellitus and CVD. Blood pressure and waist

circumference measurements also provide information necessary for the

diagnosis”.

Laboratory Tests

“Measurement of fasting lipid profile and glucose is required in finding

whether the metabolic syndrome is present or not. The measurement of

biomarkers associated with insulin resistance can also be done. Such tests include

those for ApoB, fibrinogen, high-sensitivity C-reactive protein uric acid, urinary

albumin, and liver function test. A sleep study should be done if symptoms of

obstructive sleep apnea is present. If polycystic ovary syndrome is suspected on

49

basis of the clinical features and anovulation, luteinizing hormone, follicle-

stimulating hormone and testosterone, should be measured”.

Uric Acid

Uric acid is the final breakdown product of degradation of purine in

humans. It is a weak diprotic acid with pKa values of 5.75 and 10.3. Urates, the

ionized forms of uric acid, predominate in plasma, synovial fluid and extracellular

fluid, with ~98% existing as monosodium urate at pH 7.4. Plasma gets saturated

with monosodium urate at a concentration of 6.8 mg/dL at 37°C. At higher

concentrations, plasma is therefore supersaturated and creates the potential for

urate crystal precipitation. However, plasma urate concentrations can reach 80

mg/dL without precipitation, because of the presence of solubilizing substances.

50

The urine pH greatly influences the solubility of uric acid. At pH 5.0, urine

gets saturated with uric acid at concentrations ranging from 360 to 900 μmol/L .

At a pH of 7, saturation is reached at concentrations from 9840 to 12,000 μmol/L

Ionized forms of uric acid in urine include monosodium, disodium, ammonium,

potassium and calcium urates.

Although purine nucleotides are synthesized and degraded in all tissues,

urate is produced only in tissues that contain xanthine oxidase, primarily liver

and small intestine. Urate production varies with the purine content of the diet

and with rates of purine biosynthesis,salvage and degradation. Normally, two-

thirds to three-fourths of urate is excreted through the kidneys, and most of the

remainder gets eliminated through the intestines.

The kidneys clear urate from the plasma by utilizing specific organic anion

transporters (OATs), including urate transporter 1 (URAT1). In humans, OAT1,

OAT2 and OAT3 are located on the basolateral membrane of the renal proximal

tubule cells. OAT4, OAT10, and URAT1 are located on the apical brush-border

membrane of these cells. The latter transporters carry urate and other organic

anions into the tubular cells from the tubular lumen in exchange for intracellular

organic anions. Once inside the cell, urate must pass to the basolateral side of the

lumen in a process controlled by voltage-dependent carriers. Uricosuric

compounds directly inhibit URAT1 on the apical side of tubular cell (so-called

cis inhibition).

51

In contrast, antiuricosurics, such as nicotinate,lactate, pyrazinoate, and other

aromatic organic acids, serve as the exchange anion inside the cell, thereby

stimulating anion exchange and urate reabsorption (trans-stimulation).

The activities of URAT1, otherorganic anion transporters, and sodium

anion transporters result in excretion of 8–12% of the filtered urate as uric acid.

Most children have serum urate concentrations around 3–4 mg/dL. Levels begin

to rise in males during puberty but remain low in females upto menopause. The

most recent mean serum urate values for men and premenopausal women are

6.14 and 4.87 mg/dL respectively, according to the National Health and Nutrition

Evaluation Survey (NHANES) data for 2007–2008. After menopause, values for

women increase to approximately as those for men. In adulthood, concentrations

rise steadily over time and varies with height, body weight, blood pressure,

alcohol intake and renal function.

HYPERURICEMIA

“Hyperuricemia can result from the increased production or decreased

excretion of uric acid or from a combination of the two processes. Sustained

hyperuricemia predisposes some individuals to develop manifestations including

gouty arthritis, urolithiasis, and renal dysfunction” .

“In general, hyperuricemia is defined as plasma (or serum) urate

concentration >6.8 mg/dL. The risk of developing gouty arthritis or urolithiasis

increases with higher urate levels and increases in proportion to the degree of

52

elevation. The prevalence of hyperuricemia is increasing among ambulatory

adults and even more among hospitalized patients”.

Based on NHANES data from 2007–2008, these trends continue, with an

prevalence of gout among men of 5.9% (6.1 million) and among women of 2.0%

(2.2 million).

These rises are thought to be driven by increased obesity and hypertension

and perhaps by better medical care and increased longevity.

53

CAUSES OF HYPERURICEMIA

“Hyperuricemia may be classified as primary or secondary, depending on

whether the cause is innate or acquired disorder. It is more useful to classify

hyperuricemia in relation to the underlying pathophysiology— i.e., whether it

results from increased production, decreased excretion, or combination of the

two”.

54

Increased Urate Production

“Diet contributes to serum urate concentration in proportion to its purine

content. Strict restriction of purine intake reduces mean serum urate level by ~60

μmol/L(~1 mg/dL) and urinary uric acid excretion by ~1.2 mmol/d (~200mg/d).

Foods high in nucleic acid content include liver, “sweetbreads” (i.e., thymus and

pancreas), anchovy and kidney”.

“Endogenous sources of purine production also influence serum urate

level. De novo purine biosynthesis is a multistep process that forms inosine

monophosphate (IMP). The rates of purine biosynthesis and urate production are

predominantly determined by amidophosphoribosyltransferase, which combines

phosphoribosylpyrophosphate (PRPP) and glutamine. A secondary regulatory

pathway is the salvage of purine bases by hypoxanthine

phosphoribosyltransferase (HPRT). HPRT catalyzes the combination of purine

bases hypoxanthine and guanine with PRPP to form respective ribonucleotides

IMP and guanosine monophosphate (GMP)”.

Serum urate levels are coupled closely to the rates of de novo purine

biosynthesis, which is driven in part by the level of PRPP, as evidenced by two

X-linked inborn errors of purine metabolism. Both increased PRPP synthetase

activity and HPRT deficiency are associated with purine overproduction,

hyperuricemia, and hyperuricaciduria. Accelerated purine nucleotide degradation

also cause hyperuricemia—i.e., with conditions of rapid cell turnover,

55

proliferation, or cell death, as in blast crises, cytotoxic therapy for malignancy,

hemolysis, or rhabdomyolysis.

Hyperuricemia can result from excessive degradation of skeletal muscle

ATP after strenuous exercise or status epilepticus and in glycogen storage disease

types. The hyperuricemia of myocardial infarction, smoke inhalation, and acute

respiratory failure may also be related to the accelerated breakdown of ATP.

Decreased Uric Acid Excretion

56

More than 90% of individuals with sustained hyperuricemia have a defect

in the renal handling of uric acid. For any given plasma urate concentration,

patients who have gout excrete ~40% less uric acid than those who do not. When

plasma urate levels are raised by purine ingestion or infusion, uric acid excretion

increases in patients with and without gout; however, in those with gout, plasma

urate concentrations must be (1–2 mg/dL) higher than normal to achieve

equivalent uric acid excretion rates.

Diminished uric acid excretion could theoretically result from decreased

glomerular filtration, decreased tubular secretion, or enhanced tubular

reabsorption. Decreased filtration of urea does not appear to cause primary

hyperuricemia but does contribute to the hyperuricemia of renal insufficiency.

Although hyperuricemia is invariably present in chronic renal disease, the

correlation among serum creatinine, urate and urea nitrogen concentrations is

poor. Extrarenal uric acid clearance increases as renal damage becomes more

severe.

Many agents that cause hyperuricemia exert their effects by stimulating

reabsorption rather than inhibiting the secretion. This stimulation appears to occur

through the process of “priming” renal urate reabsorption through the sodium-

dependent loading of the proximal tubular epithelial cells with anions capable of

trans-stimulating urate reabsorption.

The sodium-coupled monocarboxyl transporters SMCT1 and 2 (SLC5A8,

SLC5A12) in the brush border of proximal tubular cells mediate sodium-

57

dependent loading of these cells with monocarboxylates. A similar transporter,

SLC13A3, mediates sodiumdependent influx of dicarboxylates into the epithelial

cell from the basolateral membrane. Some of these carboxylates are well known

to cause hyperuricemia, including pyrazinoate (from pyrazinamide treatment),

nicotinate (from niacin therapy), and the organic acids lactate, β-hydroxybutyrate,

and acetoacetate. The mono- and divalent anions then become substrates for

URAT1 and OAT4, respectively, and are exchanged for uric acid from the

proximal tubule. Increased blood levels of these anions result in their increased

glomerular filtration and greater reabsorption by proximal tubular cells. The

increased intraepithelial cell concentrations lead to increased uric acid

reabsorption by promoting URAT1-, OAT4-, and OAT10-dependent anion

exchange. Low doses of salicylates also promote hyperuricemia by this

mechanism. Sodium loading of proximal tubular cells also provokes urate

retention by reducing extracellular fluid volume and increasing release of

angiotensin II, insulin, and parathyroid hormone. Additional organic anion

transporters OAT1, OAT2, and OAT3 are involved in the movement of uric acid

through basolateral membrane.

GLUT9 is an electrogenic hexose transporter with splicing variants that

mediate co-reabsorption of uric acid along with glucose and fructose at the apical

membrane as well as through the basolateral membrane and thus into the

circulation. GLUT9 was identified recently as a high-capacity urate transporter,

with rates 45–60 times faster than the glucose/fructose transport activity. GLUT9

58

may be responsible for the association of the consumption of fructose-sweetened

soft drinks with an increased risk of hyperuricemia and gout.

“Alcohol promotes hyperuricemia because of increased urate production

and decreased uric acid excretion. Excessive alcohol consumption accelerates the

hepatic breakdown of ATP to increase urate production. Alcohol consumption

can also induce hyperlacticacidemia, which blocks uric acid secretion. The higher

purine content in some alcoholic beverages may also be a cause. Consumption of

beer confers a higher risk of gout than liquor, and moderate wine intake does not

increase gout risk”.

Intake of red meat and fructose increases the risk of gout, whereas intake

of low-fat dairy products, purine-rich vegetables, nuts and legumes, whole

grains, less sugary fruits, coffee, and vitamin C reduces the risk

The decision to treat hyperuricemia depends on the cause and the potential

consequences of hyperuricemia in each individual. Quantification of uric acid

excretion can be used to determine whether hyperuricemia is caused due to

overproduction or decreased excretion. On purine-free diet, men with normal

renal function excrete <3.6 mmol/d (600 mg/d). Thus, hyperuricemia of

individuals who excrete uric acid above this level while on a purine-free diet is

due to purine overproduction; for those who excrete lower amounts on the purine-

free diet, it is because of decreased excretion. If the assessment is performed

while patients are on a regular diet, the level of 800 mg/d can be used as the

discriminating value

59

Uric Acid & Metabolic Syndrome

Metabolic syndrome is characterized by abdominal obesity with visceral

adiposity, impaired glucose tolerance due to insulin resistance with

hyperinsulinemia, increased low-density lipoprotein cholesterol, decreased high-

density lipoprotein cholesterol, hypertriglyceridemia and hyperuricemia.

Hyperinsulinemia reduces renal excretion of uric acid and sodium.

Hyperuricemia resulting from euglycemic hyperinsulinemia may precede the

onset of type 2 diabetes mellitus, hypertension, coronary artery disease, and

gout in individuals with metabolic syndrome

60

Fibroscan

In patients with chronic liver diseases, the determination of severity of liver

fibrosis is important for prognosis, and for identifying people who may benefit

from treatment. For those patients already on treatment, assessment of liver

fibrosis can determine the treatment response . Hepatocellular carcinoma and

variceal screening can also be implemented for patients identified with

underlying cirrhosis. At present, liver biopsy remains the gold standard for

assessing liver fibrosis, though diagnostic accuracy is limited by the specimen

size , sampling error, and inter-observer variability. Accuracy of liver biopsy can

be reduced to 80% due to these limitations. Furthermore, liver biopsy is an

invasive procedure which is associated with significant morbidity, rendering it

less acceptable to patients.

In the past, however, transient elastography (FibroscanR, Echosens, France)

has been used as a non-invasive tool for assessment of liver fibrosis by measuring

liver stiffness. The probe consists of ultrasound transducer, located at the end of

a vibrating piston . The piston produces a vibration of low amplitude and

frequency, which generates a shear wave that passes through the skin and liver

tissue. The ultrasound detects the propagation of the shear wave through the liver

at a depth from 25 to 65 mm below skin surface, by measuring its velocity. The

shear wave velocity is directly related to the stiffness of tissues, with a higher

velocity equating to greater stiffness, corresponding to increasing severity of

liver fibrosis.

61

The advantages of transient elastography is that the results are immediately

available, and the procedure is rapid (~3 minutes per patient), painless and easy

to do.

Procedure

The test is performed with patient lying in supine position, with the probe

placed along the intercostal space overlying the liver.

Fig. Fibroscan being done in Govt. Rajaji hospital, Madurai

62

Fig. Fibroscan in Govt Rajaji hospital, Madurai

Measurement of liver fibrosis

Ten validated measurements are needed, with the median value taken as

final result, expressed in units - kilopascals (kPa). Transient elastography has

been shown to be highly reproducible with minimal inter-observer variability and

intra-observer variability. The range of liver stiffness values obtained with

transient elastography are from 2.5 to 75.0 kPa, with the normal liver stiffness

value for healthy individuals is around 5.5 kPa. The age of the subject does not

63

affect liver stiffness, and the males tend to have slightly higher liver stiffness

compared to females.

Although transient elastography is an easy and fast procedure, strict

adherence to quality criteria should be followed for the reliability of the results.

The interquartile range of all the readings should not exceed 30% of the final

value (the median value), and the success rate of scans should be more than 60%.

The results should be interpreted by a qualified person according to the clinical

context, taking into account the demographics, aetiology and laboratory

parameters. If the liver stiffness values appear to be discordant with that of

clinical scenario, then consider repeating the scan or proceed to do a liver biopsy.

The previous validating studies of transient elastography have been

performed on the patients with chronic hepatitis C. Many other studies have been

done since then on other liver diseases including chronic hepatitis B, hepatitis C/

HIV co-infection, primary sclerosing cholangitis, NASH, PBC and recurrent

hepatitis C after liver transplantation. In one meta-analysis of 50 studies

assessing the performance of elastography, the mean area under receiver

operating characteristics curve for diagnosis of significant fibrosis, severe

fibrosis, and cirrhosis were 0.84, 0.89, and 0.94 respectively. For lesser degrees

of fibrosis, the performance was more heterogeneous, and was dependent on the

underlying liver disease.

One of the important concerns of liver stiffness measurements is the cut-

off values that were adopted for different stages , with higher cut-off levels

64

corresponding to higher fibrosis stages. The cut-off levels are also different for

different diseases. So, it is important to interpret the results with the cut-off

values specific for the underlying diseases. Because of variability in cut-off

values (even within the same disease), use of the cut-off ranges rather than a

single cut-off value should be employed. For example, in patients with liver

stiffness <7.0 kPa, there is likely minimal fibrosis, whereas cirrhosis is likely in

patients with liver stiffness >12.5 kPa

Limitations

There is an approximately 5% failure rate associated with performance of

transient elastography. The main cause of failure is obesity. Other common

causes include narrow intercostal spaces ( mainly in young thin females) and

fatty adipose tissue overlying the thoracic area. Newer probes to address both

obese and patients with narrowed intercostal spaces shall become more widely

available in the future, and validation studies will be required to know their

diagnostic accuracy. As the pulse cannot not be transmitted well through fluid,

transient elastography is not possible in the presence of ascites.

One of the important factors that affects diagnostic accuracy is with severe

flares of hepatitis (ALT>10x ULN), during which liver stiffness values may be

spuriously high, returning to normal after resolution of the flares. Hence, transient

elastography performed at the time of flares will lead to over-diagnosis of severe

fibrosis and cirrhosis. Caution should be taken in interpreting the elevated liver

stiffness results in persons with significant elevation of ALT. There is also

65

evidence that lesser degrees of ALT elevation in both CHB and chronic hepatitis

C can also increase liver stiffness values.

The exact mechanism for increase in liver stiffness seen with liver

inflammation needs to be determined. Whether steatosis increases liver stiffness

is not known. In studies of chronic hepatitis C, steatosis did not appear to affect

the liver stiffness . Even in a study of non-alcoholic fatty liver disease, liver

stiffness correlated with that of fibrosis but not with steatosis. In non-diabetics

with genotype 1 chronic hepatitis C, insulin resistance contributed to liver

stiffness independent of fibrosis. Therefore, how steatosis may affect liver

stiffness remains unclear.

Conclusions

Despite the absence of consensus guidelines regarding use of liver stiffness

measurements in clinical practice, transient elastography is already widely used.

This widespread use is probably due to the consequence of patients and clinicians

not advocating liver biopsies respectively. Transient elastography is an excellent

diagnostic tool if strict quality criteria is applied, ensuring reliability of the

results. In addition, there are increasing evidences to suggest that liver stiffness

measurements may have longitudinal role in assessing treatment response,

disease progression and in predicting complications. These shall be confirmed

once long-term outcome data become available. Finally, the focus should be on

the development of guidelines on the use of transient elastography, and to

incorporate this technology into current treatment guidelines.

66

MATERIALS AND METHODS

SOURCE OF DATA

100 ultrasound defined newly diagnosed NAFLD patients attending

outpatient department in GRH, Madurai and 100 age and sex-matched healthy

subjects with the fulfilment of inclusion criteria and exclusion criteria were

included in the study

STUDY DESIGN:

Hospital based prospective case control study

STUDY DURATION:

6 Months (March 2018 to August 2018)

INCLUSION CRITERIA :

All newly diagnosed cases of ultrasound defined NAFLD

Age group of 25 to 65

67

EXCLUSION CRITERIA:

Patients with/on

Alcohol consumption greater than 20gm/day in men & 10gm/day in

women

HBsAg & Anti HCV positivity

History of chronic liver disease

History of Coronary Artery disease, Chronic kidney disease

On diuretics

On anti gout medications

On Anti Retroviral therapy

LABORATORY INVESTIGATIONS

Random Blood sugar, Fasting & post prandial blood sugar

Fasting lipid profile

Serum uric acid

Serum Bilirubin, SGOT,SGPT, ALP

Blood urea, serum creatinine

Complete blood count

Viral markers (HBsAg, Anti HCV)

Ultrasonography of abdomen

Fibroscan

68

DATA COLLECTION

Informed consent will be obtained from all patients to be enrolled for

the study. In all the patients relevant information will be collected in a

predesigned proforma. The patients are selected based on clinical

examinations, biochemical tests and ultrasound abdomen. Then above

mentioned lab investigations were done

STATISTICAL ANALYSIS :

Master chart was prepared with all the information collected about the

selected cases .With the help of computer Data analysis was done by using

SPSS software and Sigma Stat 3.5 version (2012). Using this software,

percentage, mean, standard deviation and `p' value were calculated through

Student 't' test, One way ANOVA, Pearson Correlation and Chi square test

and P value of < 0.05 was taken as significant.

69

OBSERVATION AND RESULTS

Table.1 Age distribution in NAFLD cases

Chart 1. Age distribution in NAFLD cases

Most cases of NAFLD (47 patients) occur in 46-55 years of age group (47%)

0

5

10

15

20

25

30

26-35 36-45 46-55 56-65

2

2426

43

17

21

3

Age distribution for NAFLD cases

Male Female

Age in years No of Cases

Male Female

26-35 2 3

36-45 24 17

46-55 26 21

56-65 4 3

70

Table 2. Age distribution in Control group

Age in years

No of Controls

Male Female

26-35 3 3

36-45 24 18

46-55 24 20

56-65 4 8

Chart 2. Age distribution in Control group

Again, in control group, most patients are from 46- 55 years of age (44%)

0

5

10

15

20

25

26-35 36-45 46-55 56-65

3

24 24

43

18

20

4

Age distribution for Control

Male Female

71

Table 3: Sex Distribution

Chart 3. Sex Distribution

Among 100 cases, 56 were males and 44 were females, while in 100 controls,

55 were males and 45 were females

0

10

20

30

40

50

60

Male Female Male Female

Case Control

56

4655

45

Sex Distribution

No of Cases No of Controls


Number 56 46 55 45

72

Table 4:BMI distribution of cases and controls

BMI



BMI<25 31 26 39 36

BMI≥25 25 18 16 9

Chart 4. BMI distribution in cases and controls

46 patients(46%) were obese in NAFLD cases when compared with 25

patients (25%) in control group

0

5

10

15

20

25

30

35

40


Case Control

31

26

3936

25

1816

9

BMI distribution

BMI<25 BMI≥25

73

Table.5 Fasting triglyceride level distribution

TGL



TGL < 150 18 12 25 23

TGL 150-199 12 12 18 14

TGL ≥ 200 26 20 12 18

Chart.5 Fasting triglyceride distribution

46 patients (46%) in case group was found to have hypertriglyceridemia

(Triglycerides >200) versus 30 patients (30%) in control group

0

5

10

15

20

25

30


Case Control

18

12

2523

12 12

18

14

26

20

12

18

Fasting Triglycerides distribution

TGL < 150 TGL 150-199 TGL ≥ 200

74

Table 6. Fasting blood sugar distribution

FBS

Case Control


FBS<100 34 32 43 37

FBS≥100 22 12 12 8

Chart 6: Fasting blood sugar distribution

Among NAFLD cases 36 patients (36%) has elevated FBS levels while 20

patients (20%) in control group have elevated FBS levels

0

5

10

15

20

25

30

35

40

45


Case Control

3432

43

37

22

12 12

8

Fasting Blood Sugar distribution

FBS<100 FBS≥100

75

Table 7. Systolic blood pressure distribution

SBP

Case Control


SBP<130 44 34 44 38

SBP≥130 12 10 11 7

Chart 7. Systolic blood pressure distribution

Elevated Systolic blood pressure is present in 22 cases (22%) and 18 patients

(18%) in control group

0

5

10

15

20

25

30

35

40

45


Case Control

44

34

44

38

1210 11

7

SBP distribution

SBP<130 SBP≥130

76

Table 8 ALT Distribution

ALT

Case Control


ALT< 35 32 33 46 39

ALT≥ 35 24 11 9 6

Chart 8. ALT distribution

Among NAFLD cases, 35 patients (35%) have elevated ALT levels while 15

patients have elevated ALT in control group

0

5

10

15

20

25

30

35

40

45

50


Case Control

32 33

46

39

24

119

6

ALT distribution

ALT< 35 ALT≥ 35

77

Table 9. AST distribution

Case Control


AST ˂ 40 44 37 45 40

AST ≤ 40 12 7 10 5

Chart 9. AST distribution

Among NAFLD cases, 19 patients(19%) have elevated AST levels while 12

patients (12%) have elevated AST levels in control group

0

5

10

15

20

25

30

35

40

45


Case Control

44

37

45

40

12

710

5

AST distribution

AST<40 AST ≤40

78

Table 10. Distribution of Serum Uric Acid levels

Case Control


Hyperuricemia 36 28 14 8

Normouricemia 20 16 41 37

Chart 10. Distribution of Serum Uric Acid levels

In our study, 64 patients (64%) in NAFLD cases have hyperuricemia while

in control group, 22 patients (22%) have elevated uric acid levels

0

5

10

15

20

25

30

35

40

45


Case Control

36

28

14

8

20

16

41

37

Serum Uric Acid distribution

Hyperuricemia Normouricemia

79

Chart 11. Distribution of serum uric acid levels in cases

Chart 12. Distribution of serum uric acid levels in control group

64%

36%

Case

Hyperuricemia

Normouricemia

22%

78%

Control

Hyperuricemia

Normouricemia

80

Table11: Association of FBS in cases and controls

The mean FBS in case group is 93.86 mg/dL & the mean FBS value in

control group is 88.03mg/dL. There is a statistical significance (p<0.05)

between both the groups

Table 12: Association of Triglycerides in case & controls

Triglycerides

Case Control

Mean 184.19 162.03

SD 22.563 30.2

p value <0.05 Significant

The mean triglycerides level in NAFLD case is 184.19 mg/dL while it

is 162.03mg/dL in control group. There is a statistical significance (p<0.05)

between both the groups

FBS

Case Control

Mean 93.86 88.03.

SD 13.65 11.59

p value <0.05 Significant

81

Table 13: Association of AST & ALT in cases & controls

LFT p value

Case

(Mean±SD)

Control

(Mean±SD)

ALT 34.44±9.61 30.39±9.08 <0.05

(significant)

AST 35.81±4.55 34.28±6.27 <0.05

(significant)

The mean ALT level in our cases is 34.44 U/L while it is 30.39 U/L in

control group. There is a statistically significant difference between both the

groups (p<0.05)

The mean AST level in NAFLD cases is 35.81 U/L while in the control

group, the mean valve is 34.28 U/L and there is a statistical significance

between both the values.

Table 14: Association of BMI in case & controls

BMI No. of cases

Case Control

Mean 24.463 23.68

SD 1.45 1.44

p' value < 0.05 Significant

The mean BMI in NAFLD cases is 24.46 kg/m2 while it is 23.63 kg/m2

in control group which again shows statistical significance (p<0.05) between

two groups

82

Table 15: Association of systolic BP in case and controls

The mean systolic BP in case group is 121.42mmHg while it is

116.52mmHg in control group. Again, there is a statistical significance

between two groups

Table 16:Serum uric acid level in Male case and controls

In males, the mean serum uric acid level is 6.959 mg/dL in NAFLD

cases while it is 5.875 in control group. Again, there is a high statistical

significance (p < 0.001) between two groups

SBP No. of cases

Case Control

Mean 121.42 116.52

SD 6.38 9.71

p value < 0.05 Significant

Male

Serum uric acid Case Control

Mean 6.959 5.875

SD 0.634 1.077


83

Table 17: Serum Uric acid level in female case and controls

In females, the mean serum uric acid level is 5.75 mg/dL while it is 4.93

in control group. There is also statistical significance (p<0.001) between two

groups

Table 18:Association of Serum Uric acid level in case and control

(overall)

The mean serum uric acid levels in NAFLD cases is 6.43 mg/dL while

it is 5.45mg/dL in control. There is a high statistical significance (p<0.001)

between two groups

Female

Serum uric acid Case Control

Mean 5.75 4.931

SD 0.634 0.953


Overall (M & F) No. of cases

Serum Uric acid Case Control

Mean 6.43 5.45

SD 0.964 1.122


84

Chart 13. Comparison of mean SUA levels in Case & Control

6.95

5.75

6.43

5.87

4.93

5.45

0

1

2

3

4

5

6

7

8

Male Female Total

Me

an

se

rum

uric a

cid

leve

ls

Mean Serum Uric Acid Levels

Case Control

85

Table :18 Association of fibrosis and serum uric acid

The association between hyperuricemia and fibrosis is assessed by chi-

square test. The chi square value is 4.127 and the p value is 0.042 (p<0.05)

which is statistically significant

Chart 14. Prevalence of fibrosis in hyperuricemia cases

Out of 64 hyperuricemic NAFLD cases, 28 patients have fibrosis which

denotes 43.75% of hyperuricemic cases, while 56.25% doesn’t have fibrosis

43.75%

56.25%

Fibrosis in Hyperuricemic cases

fibrosis

No fibrosis

Association of Fibrosis and Serum Uric Acid

Serum Uric Acid Fibrosis Total

Present Absent

Hyperuricemia 28 36 64

Normouricemia 3 33 36

Total 31 69 100

Chi square value 4.127

p value 0.042 Significant

86

Chart 15. Prevalence of fibrosis in normouricemic cases

Out of 36 normouricemic cases, 3 cases have fibrosis which denotes

8.3% while 33 cases didn’t have fibrosis which denotes 91.7% of

normouricemic cases

8.3%

91.7%

Fibrosis in Normouricemic cases

Fibrosis

No fibrosis

87

DISCUSSION

Non Alcoholic Fatty Liver Disease is often considered as the hepatic

manifestation of metabolic syndrome with insulin resistance playing a dominant

role. As a result of insulin resistance, action of insulin on hormone sensitive lipase

is attenuated resulting in increased efflux of free fatty acids into hepatocytes.

Within the hepatocytes, free fatty acids attenuate the downstream insulin

signalling pathway ultimately resulting in insulin resistance and is then

converted to triglycerides in liver. Moreover the action of AMP deaminase is

stimulated which results in ATP depletion and increased production of uric acid.

Uric acid stimulates the synthesis of IL-1, IL-6, microcyte chemoattractant

protein, , TNF alpha , all of which are pro inflammatory molecules. Hence uric

acid results in oxidative stress resulting in inflammation and necrosis. Repeated

bouts of inflammation ultimately results in fibrosis

In our study population of 100 NAFLD cases were diagnosed with the help

of ultrasound and various parameters were measured. Along with them, 100 age

and sex matched controls were taken in to study and various parameters were

measured with primary importance to uric acid level. The following observations

were made from the study

88

Age Distribution

Both in cases and controls, most of them were in age group of 46 to 55

years of age. This shows that NAFLD is more prevalent in late middle age group.

Sex distribution

There was a higher incidence of NAFLD in males (56%) when compared

with females (44%) in our study

Liver function tests

The mean ALT level in our cases is 34.44 U/L while it is 30.39 U/L in

control group. There is a statistically significant difference between both the

groups (p<0.05)

The mean AST level in NAFLD cases is 35.81 U/L while in the control

group, the mean valve is 34.28 U/L and there is a statistical significance between

both the values.

Thus, our study shows that AST, ALT levels were abnormal in NALFD

cases. This observation also seen in study done by Shih et al

Fasting triglycerides.

The mean triglycerides level in NAFLD case is 184.19 mg/dL while it is

162.03mg/dL in control group. There is a statistical significance (p<0.05)

between both the groups. Our study shows that fasting triglycerides were

abnormally high in case group which might reflect increased prevalence of

metabolic syndrome in NAFLD cases. This observation is also seen in Shih et al

89

Body Mass index

The mean BMI in NAFLD cases is 24.46 kg/m2 while it is 23.63 kg/m2 in

control group which again shows statistical significance (p<0.05) between two

groups. Hence our show shows increased prevalence of obesity in case group

which might be a component of metabolic syndrome. This observation is

consistent with the study done by Bansal et al which is held in central India

Fasting blood sugar

The mean FBS in case group is 93.86 mg/dL & the mean FBS value in

control group is 88.03mg/dL. There is a statistical significance (p<0.05) between

both the groups. This observation shows that there may be increased risk of

impaired fasting glucose in NAFLD cases. This observation is consistent with the

study done by Shih et al.

Systolic Blood pressure

The mean systolic BP in case group is 121.42mmHg while it is

116.52mmHg in control group. Again, there is a statistical significance between

two groups. Since hypertensive patients were not taken into study, this might

translate into increased prevalence of pre hypertension in NAFLD cases. This

observation is also seen in study done by J Liang et al and Shih et al

Serum Uric Acid

The mean serum uric acid levels in NAFLD cases is 6.43 mg/dL while it is

5.45mg/dL in control. There is a high statistical significance (p<0.001) between

two groups.

90

In males, the mean serum uric acid level is 6.959 mg/dL in NAFLD cases

while it is 5.875 in control group. Again, there is a high statistical significance (p

< 0.001) between two groups

In females, the mean serum uric acid level is 5.75 mg/dL while it is 4.93 in

control group. There is also statistical significance (p<0.001) between two

groups. Hence our study shows there is higher prevalence of hyperuricemia in

NAFLD cases in both males & females. Numerous studies done by Bansal et al,

Huang et al, Shih et al, J Liang et al also supports this observation

Serum Uric acid and fibrosis

In 100 NAFLD patients, Fibroscan was done and the Liver stiffness value >

7 kPa was taken as a cut off value for fibrosis. The association between

hyperuricemia and fibrosis is assessed by chi- square test. The chi square value is

4.127 and the p value is 0.042 (p<0.05) which is statistically significant. Study

done by Huang et al demonstrates the association between severity of NAFLD as

assessed by liver biopsy and serum uric acid. However no studies have yet

demonstrated the association of serum uric acid & fibrosis assessed by fibroscan.

Hence further studies are needed to strengthen this association

Thus uric acid level not only help in detection of non alcoholic fatty liver

disease , but also helps in predicting the severity of liver fibrosis which can be

assessed non invasively by fibroscan.

91

LIMITATIONS OF THE STUDY

This study has its own limitations. T he sample size is relatively small.

More over, the study population involved patients who are seeking medical

attention in our hospital which is a tertiary care centre. Hence, they may not

represent general population. Also it a single centre study. Hence study in

multiple centre with large sample size may be needed to confirm the findings of

our present study

92

SUMMARY

This prospective case control study was conducted to study “Association

between serum uric acid and non-alcoholic fatty liver disease and its correlation

with liver fibrosis as assessed by fibroscan”

The study population consisted of 100 NAFLD patients attending

General Medicine OPD as cases with age and sex matched individuals as

controls. After an institutional ethical clearance and informed consent, various

investigations pertaining to the study is done. The data were entered in Microsoft

Excel sheet and statistically analysed

The most common age group of NAFLD cases were from 46-55 years of

age. There is a slight male predominance in the study. There is a statistically

significant difference between cases and controls that involves various

parameters of metabolic syndrome such as fasting blood sugar, fasting

triglycerides, systolic BP and BMI.

The mean serum uric acid of NAFLD cases is 6.43mg/dl while that of the

control is 5.45 mg/dl. There is a statistically significant difference of serum uric

acid levels between the NAFLD cases and controls (p<0.001). Also there is a

significant association between serum uric acid and fibrosis in NAFLD cases as

assessed by chi square test (p<0.05)

Thus hyperuricemia is significantly associated with non alcoholic fatty

liver disease & with fibrosis

93

CONCLUSION

This study shows significant correlation between serum uric acid &

NAFLD. Serum uric acid is relatively inexpensive test and is readily available.

It is used mainly for detecting gout. However this study shows that presence of

hyperuricemia should alert the possibility of underlying non alcoholic fatty liver

disease if significant alcohol consumption is ruled out.

Several studies also supports this association. If hyperuricemia proves to

be in the causal pathway for NAFLD, then prevention or treatment of

hyperuricemia may reduce the risk of development or progression of NAFLD.

If hyperuricemia proves to be a consequence of NAFLD, then hyperuricemia

could serve as a trigger for physicians to screen for NAFLD.

Also there is linear association between hyperuricemia and presence of

liver fibrosis as assessed by fibroscan. Hence uric acid levels play a vital role in

detection of NAFLD and its the severity. However further studies are needed to

define this association

BIBLIOGRAPHY

1. Shih MH, Lazo M, Liu SH, Bonekamp S, Hernaez R, Clark JM.

Association between serum uric acid and nonalcoholic fatty liver disease

in the US population. J Formos Med Assoc. 2015;114(4):314–20.

2. Hwang IC, Suh SY, Suh AR, Ahn HY. The relationship between normal

serum uric acid and nonalcoholic fatty liver disease. J Korean Med Sci.

2011;386–91

3. Liang GW, Xu X, Liu Y, Liu L, Zhao N. Association between serum Uric

acid and nonalcoholic fatty liver disese in Beijing adults. J Med Res.

2011;40(12)6–9.

4. Yamada T, Suzuki S, Fukatsu M, Wada T, Yoshida T, Joh T.Elevated

serum uric acid is an independent risk factor for nonalcoholic fatty liver

disease in Japanese undergoing a health checkup. Acta Gastroenterol Belg

2010;73:12e7

5. Xu C, Yu C, Xu L, Miao M, Li Y. High serum uric acid increases the risk

for nonalcoholic fatty liver disease: a prospective observational study.

PLoS One 2010;5:e11578.

6. Afzali A, Weiss NS, Boyko EJ, Ioannou GN. Association between serum

uric acid level and chronic liver disease in the United States. Hepatol

2010;52:578e89

7. Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, et al.

Diagnostic accuracy and reliability of ultrasonography for the detection of

fatty liver: a meta-analysis. Hepatol 2011;54(3):1082e90

8. LaBrecque DR, Abbas Z, Anania F, Ferenci P, Khan AG, Goh KL.

Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Clin

Gastroenterol. 2012;48(6):467-73.

9. Petta S, Camma C, Cabibi D, Di Marco V, Craxi A. Hyperuricemia is

associated with histological liver damage in patients with non-alcoholic

fatty liver disease. Aliment Pharmacol Ther 2011;34:757e66

10. Yamada T, Fukatsu M, Suzuki S, Wada T, Joh T. Elevated serum uric acid

predicts impaired fasting glucose and type 2 diabetes only among Japanese

women undergoing health checkups. Diabetes &Metabolism.

2011;37(3):252–8.

11. Wu S, Zhu GQ, Ye BZ, et al. Association between sex-specific serum uric

acid and non-alcoholic fatty liver disease in Chinese adults. Medicine.

2015;94(17):1– 10

12. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;

346:1221e31.

13. Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-

alcoholic fatty liver disease. Dig Dis 2010;28:155e61.

14. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease

and hepatocellular carcinoma: a weighty connection. Hepatol

2010;51:1820e32.

15. Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role

of fructose in the pathogenesis of NAFLD and the metabolic syndrome.

Nat Rev Gastroenterol Hepatol 2010;7: 251e64.

16. Fan J-G, Saibara T, Chitturi S, Kim BI, Sung JJY, Chutaputti A. What are

the risk factors and settings for non-alcoholic fatty SIROTA JC,

MCFANN K, TARGHER G, JOHNSON RJ, CHONCHOL M, JALAL

DI. Elevated serum uric acid levels are associated with non-alcoholic fatty

liver disease independently of metabolic syndrome features in the United

States: Liver ultrasound data from the National Health and Nutrition

Examination Survey. Metabolism 2013; 62:392-399.

17. XIE Y, WANG M, ZHANG Y, ZHANG S, TAN A, GAO Y, LIANG Z,

SHI D, HUANG Z, ZHANG H, YANG X, LU Z, WU C, MO Z. Serum

uric acid and non-alcoholic fatty liver disease in non-diabetic Chinese

men. PLoS One 2013; 8: e67152 DOI 10.1371.

18. CHOI SS, DIEHL AM. Hepatic triglyceride synthesis and nonalcoholic

fatty liver disease. Curr Opin Lipidol 2008; 19: 295-300.

19. MARCHESINI G, BRIZI M, BIANCHI G, TOMASSETTI S,

BUGIANESI E, LENZI M, MCCULLOUGH AJ, NATALE S, FORLANI

G, MELCHIONDA N. Nonalcoholic fatty liver disease: a feature of the

metabolic syndrome. Diabetes 2001; 50: 1844-1850.

20. ALVAREZ-LARIO B, MACARRON-VICENTE J. Uric acid and

evolution. Rheumatology (Oxford) 2010; 49: 2010- 2015.

21. LI C, HSIEH MC, CHANG SJ. Metabolic syndrome, diabetes, and

hyperuricemia. Curr Opin Rheumatol 2013; 25: 210-216.

22. RYU S, CHANG Y, KIM SG, CHO J, GUALLAR E. Serum uric acid

levels predict incident nonalcoholic fatty liver disease in healthy Korean

men. Metabolism 2011; 60: 860-866

23. SERTOGLU E, ERCIN CN, CELEBI G, GUREL H, KAYADIBI H,

GENC H, KARA M, DOGRU T. The relationship of serum uric acid with

non-alcoholic fatty liver disease. Clin Biochem 2014; 47: 383-388

24. Xie YL, Wang MJ, Zhang YJ, et al. Serum uric acid and non-alcoholic

fatty liver disease in non-diabetic Chinese men. PLoS ONE.

2013;8(7):e67152.

25. Lee K. Relationship between uric acid and hepatic steatosis among

Koreans. Diab Metabolism. 2009;35:447–51.

26. Lee JW, Cho YK, Ryan MC, et al. Serum uric acid as a predictor for the

development of non-alcoholic fatty liver disease in apparently healthy

subjects: a 5-year retrospective cohort study. Gut and Liver.

2010;4(3):378–83.

27. Liang J, Pei Y, Gong Y, et al. Serum uric acid and non-alcoholic fatty liver

disease in non-hypertensive Chinese adults : the cardiometabolic risk in

Chinese (CRC) study. Eur Rev Med Pharmacol Sci. 2015;19:305–11.

28. Ryu S, Chang Y, Kim SG, Cho J, Guallar E. Serum uric acid levels predict

incident nonalcoholic fatty liver disease in healthy Korean men.

Metabolism Clin Experiment. 2011;60(6):860–6.

29. Sirota JC, McFann K, Targher G, Johnson RJ, Chonchol M, Jalal DI.

Elevated serum uric acid levels are associated with non-alcoholic fatty

liver diseaseindependently of metabolic syndrome features in the United

States: liver ultrasound data from the National Health and Nutrition

Examination Survey. Metabolism. 2013;62(3):392–9.

30. Kuo CF, Yu KH, Luo SF, et al. Gout and risk of non-alcoholic fatty liver

disease. Scand J Rheumatol. 2010;39:466-71.

31. Valiyakath S, Junise M. Association between serum uric acid and non-

alcoholic fatty liver disease in a tertiary care center in Northern

Valiyakath. GJRA. 2015;4(12):177–9.

32. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for

systematic reviews and meta- Analyses: the PRISMA Statement. PLoS

Med. 2009;6(6):e1000097.

33. Liu Z, Que S, Zhou L. Dose-response relationship of serum uric acid with

metabolic syndrome and non-alcoholic fatty liver disease incidence: a

metaanalysis of prospective studies. Scientific Reports. 2015;5:14325

34. Lanaspa MA, Sanchez-Lozada LG, Cicerchi C, et al. Uric acid stimulates

fructokinase and accelerates fructose metabolism in the development of

fatty liver. PLoS One. 2012;7(10):e47948.

35. Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA.

Hyperuricemia and coronary heart disease: a systematic review and meta-

analysis. Arthritis Care Res. 2010;62(2):170–80.

36. Kawamoto R, Tabara Y, Kohara K, Kusunoki T, Abe M, Miki T. Serum

uric acid is more strongly associated with impaired fasting glucose in

women than in men from a community-dwelling population. PLoS One.

2013;8(6):1–5.

37. Meisinger C, Döring A, Stöckl D, Thorand B, Kowall B, Rathmann W.

Uric acid is more strongly associated with impaired glucose regulation in

women than in men from the general population: The KORA F4-study.

PLoS One. 2012;7(5):3–9.

38. Shen HC, Zhao ZH, Hu YC, Chen YF, Tung TH. Relationship between

obesity, metabolic syndrome, and nonalcoholic fatty liver disease in the

elderly agricultural and fishing population of Taiwan. Clin Interv Aging.

2014;9:501–8.

39. Zhang WJ, Chen LL, Zheng J, Lin L, Zhang JY, Hu X. Association of

adult weight gain and non-alcoholic fatty liver in a cross-sectional study

in Wan Song community, China. Brazilian J Med Biol Res.

2014;47(2):151–6.

40. Lin H, Li Q, Liu X, et al. Liver fat content is associated with elevated

serum uric acid in the Chinese middleaged and elderly populations:

Shanghai Changfeng study. 2015;175:1–11.

41. Ballestri S, Romagnoli D, Nascimbeni F, Francica G, Lonardo A. Role of

ultrasound in the diagnosis and treatment of nonalcoholic fatty liver

disease and its complications. Expert Rev. Gastroenterol Hepatol.

2015;9(5):603-27.

42. Mumford SL, Dasharathy SS, Pollack AZ, et al. Serum uric acid in relation

to endogenous reproductive hormones during the menstrual cycle:

findings from the BioCycle study. Hum Reprod. 2013;28(7):1853–62.

Angulo P. GI epidemiology: non-alcoholic fatty liver disease. Aliment

Pharmacol Ther. 2007;25:883–9.

PATIENT PROFORMA

Name:

Age/ Sex:

Occupation:

Presenting complaints:

Past history:

H/O Diabetes, Systemic Hypertension, Chronic liver disease, Coronary

artery disease, Chronic kidney disease

H/O jaundice in the past

H/O blood transfusion in the past

Personal history:

Alcohol consumption

H/O extra marital contact

General Examination

Consciousness

Febrile

Pallor

Icterus

Pedal edema

Vitals

BP

Pulse rate

RR

SpO2

System Examination

CVS:

RS:

Abdomen:

CNS:

Laboratory investigations:

• Random Blood sugar, Fasting & post prandial blood sugar

• Fasting lipid profile

• Serum uric acid

• Serum Bilirubin, AST,ALT ALP

• Blood urea, serum creatinine

• Complete blood count

• Viral markers (HBsAg, Anti HCV)

• Ultrasonography of abdomen

• Fibroscan

LIST OF ABBREVIATIONS

NAFLD – Non Alcoholic fatty liver disease

NASH – Non Alcoholic Steato hepatitis

HCC- Hepatocellular Carcinoma

CC- Cryptogenic cirrhosis

LFT- Liver function test

ALT- Alanine transaminase

AST- Aspartate Transaminase

SGOT- Serum glutamate oxaloacetate transaminase

SGPT- Serum glutamate pyruvate transaminase

ALP- Alkaline phosphatase

HBsAg- Hepatitis B surface antigen

HCV- Hepatitis C Virus

FFA- Free fatty Acids

VLDL- Very low density lipoprotein

LDL- Low density lipoprotein

HDL- High density lipoprotein

TGL- Triglycerides

BMI- Body mass index

FBS- Fasting blood sugar

SBP- Systolic blood pressure

CVD- Cardiovascular disease

SUA- Serum uric acid

IR- Insulin resistance

HOMA IR- Homeostatic model assessment

TNF alpha- Tumour necrosis factor alpha

NHANES- National health and nutrition evaluation survey

MS- Metabolic syndrome

NCEP: ATP III- National Cholesterol Education Program Adult

Treatment Panel III

SREBP- Sterol regulatory element binding protein

URAT- Urate transporter

OAT- Organic Anion transporter

PRPP- Phosphoribosyl pyrophosphate

kPa- kilopascal

USG- Ultrasonogram

CT- Computed tomography

U/L- units/ litre

S.No Age Sex BMI FBS TGL SBP AST ALTS.Uric Acid

Hyperuricemia Fibrosis

1 48 M 25.6 102 224 134 32 42 7.4 Yes No2 47 M 23.8 94 145 114 30 32 5.8 No No3 36 F 25.7 116 204 120 43 46 5.9 Yes No4 40 M 26.1 104 148 120 34 35 7.2 Yes Yes5 51 M 25.8 86 212 132 36 45 7.8 Yes Yes6 47 F 24.5 78 188 110 35 34 6.4 Yes No7 37 F 23.7 83 130 114 32 36 4.3 No No8 43 M 25.7 86 204 118 36 26 6.1 No No9 32 F 22.1 76 128 114 38 30 4.1 No No

10 46 F 23.6 78 167 110 35 25 6.2 Yes No11 60 F 25.6 112 210 134 32 34 6.9 Yes Yes12 46 M 25.8 95 230 136 38 53 7.6 Yes Yes13 41 M 22.4 87 146 116 37 23 6.2 No No14 47 M 22.6 83 189 110 42 45 7.1 Yes No15 49 M 25.6 108 218 124 36 32 7.4 Yes Yes16 39 F 21.7 80 136 120 31 25 4.9 No No17 47 M 25.9 89 215 134 41 42 7.1 Yes No18 48 F 26.7 104 206 132 37 28 6.7 Yes No19 38 M 22.6 76 138 110 32 31 7.3 Yes No20 57 M 25.3 104 192 120 30 32 7.2 Yes No21 47 F 25.6 87 220 114 36 45 6.1 Yes Yes22 49 M 22.5 83 140 118 27 18 5.8 No No23 39 M 25.8 95 210 110 29 15 6.7 No Yes24 56 F 26.4 119 224 136 45 50 6.3 Yes Yes25 48 M 25.9 114 245 138 44 48 7.4 Yes Yes26 42 F 21.8 79 140 110 25 16 4.7 No No27 50 F 26.3 103 228 120 27 34 6.5 Yes Yes28 58 M 26.1 106 220 114 28 46 8.1 Yes Yes29 53 M 23.2 108 140 120 35 30 6.9 No No30 44 F 23.4 87 142 118 46 42 4.9 No No31 48 M 22.4 75 140 120 42 58 7.2 Yes No32 40 M 26.2 116 208 110 35 33 7.6 Yes Yes33 43 F 21.5 72 168 116 32 32 6.3 Yes No34 51 F 22.9 76 126 124 34 28 4.2 No No35 47 F 24.2 86 175 120 36 32 6.4 Yes No36 43 M 26.8 113 216 138 35 34 7.3 Yes Yes37 49 M 24.2 93 138 126 45 26 5.9 No No38 41 M 24.1 85 178 120 32 48 7.5 Yes No39 49 F 24.5 96 138 128 34 23 5.1 No No40 34 F 25.8 92 210 134 37 26 5.9 Yes Yes41 47 M 24.3 85 142 124 38 30 5.6 No Yes42 42 M 26 118 214 126 43 45 7.2 Yes Yes43 46 F 24.8 87 146 120 34 32 5.3 No No44 40 F 25.9 116 216 132 31 33 6.4 Yes No45 38 M 25.2 78 230 132 33 45 7.3 Yes No46 59 M 21.8 73 148 124 39 31 6.5 No No47 48 F 26.3 95 220 128 44 46 6.9 Yes Yes48 41 F 21.6 75 140 120 38 22 4.5 No No49 46 M 25.1 106 210 134 46 42 7.1 Yes No50 43 F 25.6 110 208 120 35 42 6.1 Yes No51 51 M 24.5 108 216 132 37 46 7.7 Yes Yes52 47 F 24.1 85 183 124 38 32 5.9 Yes No

53 42 F 26.5 125 222 136 42 48 6.5 Yes Yes54 39 M 23.3 103 142 110 35 24 6.3 No No55 57 M 25.8 94 210 120 34 48 7.2 Yes Yes56 46 F 25.1 92 190 132 37 30 6.7 Yes Yes57 37 F 23.8 87 216 120 37 34 5.9 Yes No58 53 M 22.4 83 140 116 32 31 6.8 No No59 39 F 23.2 86 143 110 34 22 4.8 No No60 47 M 25.5 114 196 114 42 45 7.3 Yes Yes61 40 F 24.4 95 188 120 36 26 5.1 No No62 50 F 25.6 92 210 134 34 25 6.4 Yes No63 47 F 23.9 87 178 120 32 46 6.8 Yes Yes64 39 M 26.3 81 218 116 34 32 7.5 Yes Yes65 48 M 21.8 86 148 120 36 28 6.1 No No66 41 F 22.9 88 190 110 35 20 4.3 No No67 44 M 22.7 85 182 120 32 32 7.2 Yes No68 32 M 23.8 84 223 134 31 44 7.1 Yes No69 46 M 23.1 92 140 110 35 24 5.9 No No70 42 M 24.2 104 186 120 38 26 7.3 Yes Yes71 52 F 25.4 95 206 124 36 25 5.3 No No72 44 F 23.4 83 170 110 34 32 6.2 Yes No73 47 M 25.8 97 225 124 43 54 7.6 Yes Yes74 37 M 23.1 95 160 116 36 30 6.7 No No75 48 M 25.9 107 206 120 35 44 7.4 Yes No76 41 F 23.7 89 180 110 32 31 6.2 Yes No77 49 M 24.6 79 208 126 37 45 6.8 No No78 38 M 22.2 85 147 110 38 47 7.6 Yes Yes79 30 M 23 88 173 120 34 20 5.8 No No80 40 M 25.2 95 212 132 32 30 7.2 Yes No81 51 F 26.4 118 218 136 45 48 6.9 Yes Yes82 54 F 24.1 92 205 126 34 31 6.7 Yes Yes83 40 M 25.1 98 182 120 35 43 7.3 Yes No84 42 F 25.3 104 210 126 32 28 6.5 Yes No85 43 M 22.7 84 142 110 38 42 6.2 No No86 30 F 22.9 74 136 116 30 24 4.1 No No87 49 M 24.2 78 218 120 35 31 7.1 Yes Yes88 48 F 23.2 92 178 126 34 23 4.5 No No89 41 M 25.7 95 184 120 36 30 7.5 Yes No90 52 M 24.9 89 224 120 32 28 7.3 Yes No91 57 F 25.7 118 210 134 42 44 6.3 Yes Yes92 50 M 23.5 87 158 120 35 27 5.9 No No93 39 M 26.2 142 206 132 38 33 7.8 Yes Yes94 49 F 25.7 112 220 126 34 43 6.5 Yes Yes95 43 M 22.7 86 148 110 35 27 6.3 No No96 46 M 24.2 88 166 120 38 32 7.4 Yes No97 48 M 23.8 82 140 110 45 48 6.7 No Yes98 38 F 25.2 108 204 118 35 30 5.9 Yes No99 36 M 26.4 102 212 116 42 45 7.6 Yes Yes

100 47 F 23.3 84 140 110 26 18 4.8 No No

S.No Age Sex BMI FBS TGL SBP AST ALT S.Uric Acid

Hyperuricemia

1 39 F 21.6 88 125 106 32 25 3.7 No2 50 M 25.7 106 210 134 42 46 7.6 Yes3 48 F 25.5 96 195 132 34 32 6.7 Yes4 36 M 22.3 81 130 110 32 34 4.1 No5 59 F 22.5 85 147 114 37 26 5.2 No6 39 M 23.1 82 128 100 36 29 4.4 No7 53 M 23 86 143 110 33 34 6.4 No8 38 F 21.7 73 134 112 34 32 4.1 No9 34 M 22.4 72 125 108 32 24 5.2 No

10 52 M 26.1 86 224 136 36 30 7.4 Yes11 43 F 22.5 83 169 114 35 26 4.5 No12 33 F 21.6 75 132 110 31 18 3.8 No13 51 F 23.2 103 184 132 50 46 6.3 Yes14 43 M 23.1 79 148 114 26 22 5.6 No15 46 M 25.6 108 208 112 44 48 7.2 Yes16 50 F 23.6 83 146 116 34 38 5.3 No17 44 F 22.7 76 132 114 32 37 4.3 No18 47 F 25.9 79 212 116 37 39 4.9 No19 58 M 23.8 89 220 110 34 35 6.2 No20 40 F 23.4 81 138 110 31 36 4 No21 42 M 22.2 78 158 106 30 32 5.9 No22 47 M 25.4 115 212 136 50 35 7.1 Yes23 44 M 21.9 82 159 120 29 30 6.2 No24 40 M 22.4 79 135 116 28 28 5.9 No25 49 M 23.1 85 168 118 31 34 5.8 No26 37 M 22.8 74 142 114 32 22 4.6 No27 50 M 25.6 105 196 132 48 56 7.3 Yes28 41 F 26.2 76 205 118 30 26 6 Yes29 31 F 23.6 74 131 110 26 29 3.9 No30 54 M 25.2 87 180 116 32 34 6.1 No31 40 F 25.8 112 187 114 42 48 6.6 Yes32 50 F 23.4 89 140 120 30 32 5 No33 39 M 22.8 78 158 110 26 23 5.1 No34 49 M 25.4 86 208 136 28 45 7.2 Yes35 53 F 23.6 84 158 114 37 29 4.8 No36 37 F 23.8 81 124 116 30 33 3.6 No37 34 M 21.1 79 131 112 32 20 6.3 No38 49 F 21.7 87 147 118 31 25 5.2 No39 59 F 22.9 89 163 124 35 29 5.5 No40 43 M 23.6 87 132 120 37 25 6.1 No41 52 M 23.8 85 160 126 32 32 6.4 No42 48 F 24.2 94 169 120 34 30 5.1 No43 42 F 25.7 88 206 134 30 24 5.9 Yes44 44 M 23.1 84 169 132 36 26 6.1 No45 48 M 26.8 108 202 134 42 31 7.4 Yes46 38 F 24.1 82 121 110 28 22 3.8 No47 46 F 23.8 75 128 112 32 25 4.9 No48 40 M 22.9 74 141 120 34 21 6.2 No49 58 M 23.1 81 149 124 37 30 5.3 No50 41 M 24.2 80 161 110 34 26 4.7 No51 48 M 26.3 113 215 136 35 58 7.9 Yes

52 38 F 23.3 78 130 110 28 23 3.8 No53 46 M 22.7 82 152 120 30 28 5.1 No54 41 F 26.5 116 218 132 44 24 6.3 Yes55 51 M 23.2 83 140 120 35 32 5.7 No56 53 M 25.7 87 189 134 31 33 7.3 Yes57 50 F 24.1 82 143 120 38 30 4.7 No58 39 M 23.4 78 134 110 35 21 4.1 No59 42 M 22.6 106 212 114 34 23 4.3 No60 51 F 23.6 83 140 116 32 29 5.5 No61 58 F 23.8 85 174 120 35 31 5.6 No62 49 F 24.3 82 148 116 36 24 5.2 No63 41 M 25.1 108 196 114 42 52 7.1 Yes64 59 M 23.4 86 145 120 39 28 5.9 No65 40 M 22.1 82 162 114 36 22 5.2 No66 37 M 21.1 74 130 110 38 19 4.8 No67 40 F 21.8 106 221 138 29 54 6.7 Yes68 48 M 22.1 85 140 120 31 25 6.3 No69 46 F 25.9 102 189 110 48 46 6.1 Yes70 38 M 22 78 158 112 32 21 5.3 No71 49 M 25.5 112 225 110 29 25 7.2 Yes72 44 F 22.6 76 162 104 27 24 4.1 No73 46 M 24.5 79 144 110 32 25 5.4 No74 47 F 23.5 108 158 110 31 20 4.1 No75 38 F 23.1 74 135 102 27 23 3.6 No76 36 M 23.3 75 154 100 25 21 4.1 No77 52 M 23.7 85 147 110 29 26 5.1 No78 51 F 25.3 96 138 114 32 29 5.2 No79 39 M 26.5 105 188 136 47 42 7.2 Yes80 40 F 23.6 89 132 110 34 26 3.7 No81 34 F 23.1 81 151 106 27 20 3.6 No82 50 F 23.9 106 210 110 48 50 6.1 Yes83 42 M 22.1 93 135 100 30 21 4.6 No84 46 M 25.2 76 139 110 28 24 5.1 No85 49 F 21.6 87 138 112 34 34 4.9 No86 46 M 21.3 81 164 114 32 31 5.2 No87 47 F 23.8 83 141 110 30 28 4.3 No88 43 M 26.9 110 218 132 52 45 7.5 Yes89 42 F 23.2 85 128 110 29 24 3.8 No90 49 M 23.5 95 140 114 27 27 5.6 No91 57 M 22.7 89 146 116 34 30 6.2 No92 47 M 23.4 85 163 110 31 27 5.5 No93 43 F 25.6 116 208 132 32 46 6.4 Yes94 40 M 24.1 84 132 106 48 26 5.2 No95 49 F 23.7 91 152 110 38 29 5 No96 50 M 25.7 103 210 120 54 44 7.6 Yes97 34 M 23.5 84 131 104 31 18 4.6 No98 48 F 22.1 90 164 108 37 24 4.8 No99 59 F 23.2 94 204 134 34 29 5.3 No

100 39 M 21.6 86 136 100 26 19 4.2 No

Urkund Analysis Result Analysed Document: Vathsalyan_thesis_for_plagiarism[1].docx (D42504635)Submitted: 10/13/2018 9:59:00 AM Submitted By: [email protected] Significance: 21 %

Sources included in the report:

PLAGIARISM-THESIS.docx (D42487108) sang thesis final.docx (D31292830) Thesis serum uric acid and MetS.docx (D31305103) sang thesis word.docx (D31188651) farhat.docx (D42324885) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051086/ https://ndnr.com/gastrointestinal/nafld-hepatic-manifestation-of-metabolic-syndrome/ https://www.amhsr.org/articles/diagnostic-accuracy-of-urine-microalbumin-and-serum-uric-acid-a-casecontrol-study-of-patients-with-preeclampsia-in-the-k.pdf http://www.aetna.com/cpb/medical/data/600_699/0690.html https://core.ac.uk/download/pdf/82477359.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608581/ https://www.ncbi.nlm.nih.gov/books/NBK384715/ https://www.ijpbsonline.com/uploads/1/2/1/8/12183777/01-07.pdf

Instances where selected sources appear:

45

U R K N DU

CERTIFICATE

This is to certify that this dissertation work titled “ASSOCIATION

BETWEEN SERUM URIC ACID AND NON- ALCOHOLIC FATTY


AS ASSESSED BY FIBROSCAN” of the candidate

Dr. P. VATHSALYAN with Registration Number 201611122 for the award

of MASTER DEGREE in the branch of GENERAL MEDICINE. I have

personally verified the urkund.com website for the purpose of plagiarism

check. I found that the uploaded thesis file contains from introduction to

conclusion pages and result shows 21% of plagiarism in the dissertation.

Dr.M.NATARAJAN,M.D.,

Professor of Medicine,

Department of General Medicine,



Madurai

Date post:	12-Nov-2020
Category:	Documents
Upload:	others
View:	8 times
Download:	0 times

THE TAMILNADU DR.M.G.R. MEDICAL...

Documents