THESIS PROTOCOL

DNB GENERAL MEDICINE

DR.GATTU.SANTOSH

2017-2020

DEPARTMENT OF GENERAL MEDICINE

ANANTHAPURI HOSPITALS AND RESEARCH INSTITUTE

THIRUVANANTHAPURAM

KERALA.
THESIS TITILE
SPECTRUM OF NAFLD IN DIABETIC PATIENTS
WITH MICROVASCULAR COMPLICATIONS IN A
TERITIARY CARE SETTING.
NAME OF THE CANDIDATE: DR.GATTU SANTOSH

DNB RESIDENT IN GENERAL MEDICINE

ANANTHAPURI HOSPITALS & RESEARCH INSTITUTE

THIRUVANANTHAPURAM, KERALA.

GUIDE : DR.MADHUSUDHAN

SENIOR CONSULTANT & PHYSICIAN

DEPARTMENT OF GENERAL MEDICINE

ANANTHAPURI HOSPITALS & RESEARCH INSTITUTE

THIRUVANANTHAPURAM, KERALA.

CO-GUIDE : DR.W.BOBBY MOSSES

CONSULTANT PHYSICIAN & DIABETOLOGIST

ANANTHAPURI HOSPITALS & RESEARCH INSTITUTE

THIRUVANANTHAPURAM, KERALA.
CONTENTS

1. INTRODUCTION

2. REVIEW OF LITERATURE

3. AIMS AND OBJECTIVES

4. MATERIALS AND METHODS

5. REFERENCES

6. APPENDIX

a) STUDY PROFORMA

b) INFORMED WRITTEN

CONSENT.

INTRODUCTION
Diabetes mellitus is one of the major non-communicable diseases in the world
whose prevalence is increasing exponentially. India presently has more than 50
million diabetic patients making India “ The diabetic capital of the world “.
Globally, an estimated 422 million adults are living with diabetes mellitus,
according to the latest 2016 data from the World Health Organization (WHO)
(1) of which 62 million diabetics are from our country (2). The number is
almost projected to double by 2030. The increase in incidence in developing
countries follows the trend of urbanization and lifestyle changes, including
increasingly sedentary lifestyles, less physically demanding work and the global
nutrition transition, marked by increased intake of foods that are high energy-
dense but nutrient-poor (often high in sugar and saturated fats).

Type 2 diabetes mellitus (T2DM) patients potentially are at risk of developing

non-alcoholic fatty liver disease. Apart from kidney, eye, heart and blood
vessels, liver is also indirectly related with diabetes mellitus. Virtually the
entire spectrum of liver disease is seen in patients with type 2 diabetes. This
includes abnormal liver enzymes, nonalcoholic fatty liver disease (NAFLD),
cirrhosis, hepatocellular carcinoma, and acute liver failure making early
detection and prevention of diabetic liver disease important. Finally, the
prevalence of diabetes in cirrhosis is 12.3–57%. Thus, patients with diabetes
have a high prevalence of liver disease.

NAFLD

Ludwig introduced the term Nonalcoholic steatohepatitis (NASH) to describe a

form of liver disease that has been histologically indistinguishable from
alcoholic hepatitis but occurs in people who do not consume excess ethanol
(3).
There is renewed interest in Nonalcoholic fatty liver disease (NAFLD) recently
because of its increased prevalence in diabetes. NAFLD is the most common
liver disease and the third leading indication for liver transplantation (4).

NAFLD represents a spectrum of clinico-pathological features ranging from

simple steatosis (fatty liver), to steatosis with inflammation, necrosis, and
possible cirrhosis. Nearly 70-80% of the diabetic subjects have been reported
to have hepatic fat accumulation, referred to as NAFLD Which is only 15-20% in
general population (5).

Only recently liver disease has been recognized as a major complication of T2

DM with increased mortality rates for cirrhosis (6). It may be the most common
cause of liver enzyme elevation in adults as well as one of the leading cause for
cirrhosis in the world. The prevalence of NAFLD has increased in joint with the
epidemics of obesity and T2 DM, which are the major risk factors for NAFLD
(7).

There are also several studies based on fatty infiltration proven by imaging.
However there are only very few studies involving the clinical correlation with
NAFLD with biochemical as well as sonological evidence.

Studies showed that liver adiposity is independently associated with Insulin

Resistance and can substantially increase the risk of various micro and
macrovascular complications of diabetes mellitus (8).

A very recent study showed that NAFLD was independently associated with an
increased prevalence of chronic kidney disease and retinopathy in type 2
diabetic patients (8). Fatty liver, as an independent risk factor for cardiac
disease has been well studied. (9).
Prevalence reports on NAFLD are available both from India and abroad, but
there is lack of data on the association of NAFLD with diabetic micro- and
macrovascular complications from India (10). There are not enough studies
done on the hepatic status of diabetic patients in our country. Hence this study
aims to look at the spectrum of NAFLD in diabetic patients with microvascular
complications and their correlation.

REVIEW OF LITERATURE

Nonalcoholic fatty liver disease is one of the most common liver diseases in
developed Western countries and Asia and it is recognized currently as the
most common cause of elevated liver enymes. In recent years, due to change
in lifestyle [diet, low physical activity and obesity] its prevalence is increasing
(11). Fatty liver patients, especially those with high liver enzymes, are in
serious risk of developing NAFLD. The association of T2 DM with NAFLD is a
recently recognized entity and less well known (7).

ASSOCIATION WITH THE DURATION OF DIABETES MELLITUS: Prevalence of

diabetes found to be increased with age. The prevalence of NAFLD was also
noticed to be directly proportional to the duration of diabetes (12). In a study,
the group of patients with more than 5 year duration of diabetes were found
to have an incidence of 46.2%. A declining trend in the incidence of NAFLD was
noted with a decline in the duration of diabetes.

Duvnjak et al : which reports that the highest prevalence of

NAFLD occurs in those aged 40-60 years. (13). Banerjee et al., found that a
longer duration of T2DM was significantly associated with NAFLD (13).
It has been shown to be a predisposing factor for insulin resistance and
hyperinsulinemia, a major cause of cryptogenic cirrhosis and may even lead to
hepatocellular carcinoma (14,15,16).

Diabetes mellitus and obesity may lead to increased liver fibrosis through
different mechanism, the effect of these two conditions may be additive when
they both exist in the same individual (17).

DIAGNOSTIC MODALITIES:

The diagnosis of NAFLD requires a high index of suspicion, especially in obese

patients over the age of 45 years who have diabetes, because these patients
are at greatest risk of developing cirrhosis. As most patients who have NAFLD
have no specific signs or symptoms, it goes unnoticed. Elevated liver enzymes
must be diagonised early which must prompt clinicians for further diagnostic
workup. NAFLD is generally diagnosed by ultrasonographic examination that
has a sensitivity of 90% and specificity of 95% in detection moderate to severe
hepatic steatosis (18).

Transient elastography (Fibroscan), which is a radiological modality used with

high accuracy to non-invasively assess the degree of fibrosis based on the
measurement of liver stiffness (19,20). It might detect even low-grade
steatosis because of a recently described novel ultrasound controlled
attenuation parameter of the machine (21). However, liver biopsy is the most
accurate diagnostic modality for NAFLD.

The association of various complications of diabetes like neuropathy,

nephropathy, and retinopathy with fatty liver is an emerging concept that is
under further validation (9).
REVIEW OF STUDIES:

Nagaraj S et al ; Study of prevalence of non-alcoholic fatty liver disease in type

2 DM patients and variations in liver function tests, lipid profile (2017) :
Conducted in karnataka which included 97 T2 DM patients stated that liver
size & echotexture, liver enzymes such as AST, ALT, ALP and GGT, serum
cholesterol, TGL and LDLC were found to be statistically significantly increased
in T2DM patients when compared to controls. Early detection and optimum
control of diabetes mellitus is important to minimize the effect of diabetes on
liver. Hence, assay of serum levels of hepatic enzymes and USG abdomen to
detect NAFLD should be done in all patients with T2DM as preliminary
diagnostic tests (22) .

Sangappa Virupaxappa Kashinakunti et al ; The biochemical parameters FBS,

HbA1c, blood urea, serum bilirubin, liver enzymes namely AST, ALT, ALP, GGT
and lipid profile were raised significantly in T2DM patients compared to
controls. AST showed significant positive correlation with TGL, TC, VLDL-C and
LDL-C. The study concluded stating that routine analysis of liver enzymes and
lipid profile in type II diabetes mellitus patients, helps in early detection and
prevention of liver injury (23) .

Vijay Viswanantham et al (2017) ; Association of non-alcoholic fatty liver

disease with diabetic microvascular and macrovascular complications in South
Indian diabetic subjects at MV hospital Chennai : Prevalence of obesity,
hypertension, and dyslipidemia were significantly higher in subjects with
NAFLD. They had higher prevalence of retinopathy (29.4% vs. 9.8%, P < 0.001),
neuropathy (27.5% vs. 10.5%, P < 0.001), nephropathy (32% vs. 25%, P = 0.2).
The prevalence of CAD among NAFLD (11.5% vs. 1.4%, P = 0.01) was higher and
POVD was similar in both the groups (24) .
Jaseem Ansari , Roshan M et al ; study of non-alcoholic fatty liver disease in
type 2 DM with clinical correlation (2017) : It was found to be more common in
the fourth decade of life with equal distribution among men and women.
Among them 53.6% had NAFLD of which 73% had elevated cholesterol & 26%
of the patients in the study were found to have sonological features suggestive
of NAFLD (25) .

Desaleng Dango1 , Melaku Umeta et al ; Profile of liver function tests among

type 2 DM patients receving different anti-diabetic drugs in a medical school in
Ehiopia (2016) : which is a Hospital based cross-sectional study stated mean
value of liver enzymes and lipid profiles were slightly lowered in patients
receiving mono therapy of insulin and metformin than insulin plus metformin,
whereas BMI and FBS were lowered in their combination therapy receiving
group. Similarly mean value of FBS, ALT, TC, HDL, LDL and lipid profiles were
lowered in patients receiving glibenclamide and metformin. The anti-diabetic
drugs were found to have an effect in lowering liver enzymes and lipid profiles
in type 2 diabetic patients (26) .

Debmalya Sanyal, Pradip Mukherjee et al ; Profile of liver enzymes in non-

alcoholic fatty liver disease in patients with impaired glucose tolerance and
newly detected untreated type 2 diabetes (2015) : NAFLD prevalence was
associated with liver enzymes and lipid profile & insulin resisitance so novel
cut-offs for liver enzymes are warranted for early detection of NAFLD to reduce
the risk of cirrhosis and hepatocellular carcinoma (27) .

Ashutosh M et al (2014) ; Study of association of non alcoholic fatty liver

disease (NAFLD) with micro and macrovascular complications of type 2
diabetes mellitus (Type 2 DM) Govt medical college Maharashtra : Prevalence
of fatty liver was 56% on ultrasound. NAFLD had higher prevalence of
nephropathy (83.82% vs.53.84%, P = 0.0003) , neuropathy(52.94% vs. 19.23%,
P = 0.0002) , retinopathy (67.67% vs. 17.30%, P <0.001). The prevalence of
CAD (70.58% ) POVD was 10.25% among NAFLD individuals. Obesity,
dysglycemia, dyslipidemia, elevated liver enzymes and coronary artery disease
are seen to be significantly associated with fatty liver than non-fatty liver type
2 diabetic patients (28) .

Wen-Shan Lv, Rui-Xia Sun ET AL (2013) ; Nonalcoholic fatty liver disease and
microvascular complications in type 2 diabetes : Approximately 61% of
inpatients with T2DM in China had NAFLD, which decreased significantly with
increase in age and prolonged course of diabetes. The prevalence of NAFLD in
patients presenting with DN, DPN and DR was 49.4%, 57.2% and 54.9%,
respectively. These rates were significantly lower than those of patients
without DN, DPN and DR (29) .

Lazo M , Ruben Hernaez et al (2013) ; Across race and sex categories, the
prevalence of NAFLD was lower among people aged 20–39 years compared
with those aged ≥40 years. The highest observed prevalence was 33% among
Mexican-American men aged 40–59 years and more among men than women
(30) .

Suresh V et al (2013) ; in GSL general hospital Rajahmundry, Association of

micro and macrovascular complications with fatty liver in patients with type 2
DM patients : Neuropathy was leading complication (31.2%), followed by
nephropathy (11.3 %), retinopathy (10.6 %), cardiac disease (9.2%) and
peripheral vascular disease (3.55). Between FL and NFL groups, Diabetic
neuropathy (40.8% vs 23.9%) and cardiac disease (16.3% vs 5.4%) showed
statical significance (p<0.05), while other complications were more or less
equally prevalent in the two groups (31) .
Robert P Meyers et al (2011) ; A study using fibro scan to evaluate the liver
stiffness : Which concluded that the majority (63%) was male and the median
age was 50 years (interquartile range [IQR] 43-57). Forty-two percent of
patients had chronic hepatitis B and/or C (32% with coexistent steatosis) and
46% had NAFLD. The prevalence of diabetes mellitus was 24% (viral 16%,
NAFLD 33%, other 21%) and 33% had moderate to severe (>33%) steatosis
(32).

Behnam Rabiee et al ; An Iranian study which included 5052 participants,The

prevalence of DM was estimated in individuals with and without NAFLD. The
association between NAFLD and T2DM was evaluated using logistic regression
with the adjustment of confounding effects of age, sex, body mass index, lipid
profiles, and fasting insulin (33) .

Agarwal SR et al ; clinical, biochemical and histological profile of non alcoholic

steatohepatitis : Clinical & biochemically three were obese, seven had
hyperlipidemia and two had impaired glucose tolerance. Thirteen patients
presented with pain in the right hypochondrium, three with fatigue and
weakness, and nine were asymptomatic. Twenty-three of the 25 patients had
ALT/AST ratio >1.0. Liver histology revealed macrovesicular steatosis in all, with
mild inflammatory activity in the majority (70%). Fibrosis was seen in 12
patients-portal fibrosis in six, periportal fibrosis in three and bridging fibrosis in
another three patients. NASH severity is better assessed by liver histology
than clinical assessment (34) .

Jean-Marc Schwartz et al ; Hepatic denovo lipogenesis in normoinsulinemic

and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-
fat, high-carbohydrate isoenergetic diets : With the high-fat, low-carbohydrate
diet, hyperinsulinemic obese subjects had a 3.7–5.3-fold higher fractional DNL
(8.5 ± 0.7%) than did normoinsulinemic lean (1.6 ± 0.5%) or obese (2.3 ± 0.3%)
subjects. With the low-fat, high-carbohydrate diet, normoinsulinemic lean and
hyperinsulinemic obese subjects had similarly high fractional Denovo
lipogenesis (DNL) (13 ± 5.1% and 12.8 ± 1.4%, respectively (35) .

G. Targher et al ; NAFLD patients had higher (p<0.001) age- and sex-adjusted

prevalence rates of both non-proliferative (39 vs 34%) and proliferative/laser-
treated retinopathy (11 vs 5%), and CKD (15 vs 9%) than counterparts without
NAFLD independently of age, sex, BMI, waist circumference, hypertension,
diabetes duration, lipids, smoking status and medications (36) .

AIM AND OBJECTIVES

AIM: Spectrum of NAFLD in diabetic patients already diagnosed with

microvascular complications in a Teritiary care setting.

OBJECTIVES:

Primary objective: To study the prevalence of NAFLD in diabetic patients with

D.Neuropathy, D.Nephropathy & D.Retinopathy.

Secondary objective: To study the relation between NAFLD with the duration

of diabetes.
MATERIALS AND METHODS

Study site : Study will be conducted in Ananthapuri Hospitals and Research

and Institute , Thiruvananthapuram, Kerala with approval from Institutional
Scientific and Ethics Committee and Written informed Consent from all the
patient who will participate in the study.
Study population: Diabetic patients with micro vascular complications
(D.Neuropathy, D.Nephropathy, & D.Retinopathy) coming to Ananthapuri
Hospitals both inpatients and outpatient.

Study design : A cross-sectional study.

Sample size: 98.

Study period : Feb 2018 to Sep 2019.

INCLUSION CRITERIA:

Diabetic patients with microvascular complications (D. Neuropathy, D.

Nephropathy & D. Retinopathy) coming to Ananthapuri Hospitals, both
outpatients and inpatient.

Informed consent will be obtained from all the patients before inclusion in the
study.

EXCLUSION CRITERIA:

1. Chronic liver disease due to etiology other than NAFLD.

2. Acute hepatitis due to:

a) Viral

b) Alcohol
 c) Drugs

d) Autoimmune etiology.

3. Patients with Congestive cardiac failure.

SAMPLE SIZE CALCULATION:

𝒛𝟐 𝜶 𝒑(𝟏−𝒑)
𝟏−𝟐
Formula for calculating sample size N =
𝜹𝟐

Where,

p : Expected proportion

δ : Relative precision

1- : Desired Confidence level = (95%)
2

According to similar study " Nonalcoholic fatty liver disease and microvascular
complications in type 2 diabetes".

Wen-Shan Lv, Rui-Xia Sun, Yan-Yan Gao, Jun-Ping Wen, Rong-Fang Pan, Li
Li, Jing Wang, Yu-Xin Xian, Cai-Xia Cao, and Ming Zheng

The study reveals that the prevalence of NAFLD in patients presenting with DN
was 49.4%,

Expected proportion = 49.4%

here p = 49.2%

δ : Relative precision (20% of p)


1- : Desired Confidence level = (95%)
2

N = 98
Statistical analysis:
Quantitative Variables will be expressed as mean and standard deviation.
Qualitative variables will be expressed as frequency and percentage. Chi
square test will be used for comparison of categorical variables, while
continuous variables will be compared using the student t test for independent
groups. ANOVA with Scheffe's post hoc analysis will be used for comparison for
means between 3 or more groups. All p- values will be two tailed and p- values
<0.05 will be considered statistically significant. All confidence levels will be
calculated at 95% level All statistical data will be analyzed using SPSS version
22.
METHODOLOGY
Each patient’s baseline demographic data, age, sex, location, and duration of
diabetes, history of previous illness, medication they were currently taking are
noted. Diabetic patients with obvious liver disease due to other causes
(Hepatitis B,C), patients with a history of exposure to hepatotoxic agents like
alcohol, Statins, Anti-tubercular therapy etc. were excluded from the study.
Anthropometric measurements including height and weight and thus the body
mass index (BMI) will be noted. A Detailed physical examination along with
signs of insulin resistance-central obesity, xanthelesma, acanthosis nigricans.

Systemic examination will be performed especially GIT examination for

Hepatomegaly.

Glycemic status at the time of inclusion in the study will be assesed by

FBS, PPBS, HbA1c. LFT, Fasting lipid profile will be done.

a) Fatty liver can be diagnosed with Ultrasound and graded accordingly.

b) Degree of fibrosis by Fibroscan.

c) While Cirrhosis by both Ultrasound & Fibroscan.

All patients are subjected to abdominal ultrasound to assess the liver status
and graded accordingly.

Grading:

Grade I: diffusely increased hepatic echogenicity but periportal and

diaphragmatic echogenicity is still appreciable.

Grade II: diffusely increased hepatic echogenicity obscuring periportal

echogenicity but diaphragmatic echogenicity is still appreciable.
Grade III: diffusely increased hepatic echogenicity obscuring periportal as well
as diaphragmatic echogenicity.

All patients are subjected to Fibroscan to assess the level of fibrosis

METAVIR scoring system

Fo: No fibrosis.

F 1: Mild fibrosis- portal fibrosis without septa.

F 2: Moderate fibrosis- portal fibrosis with few septa.

F 3: Severe fibrosis- numerous septa without cirrhosis.

F4: cirrhosis.

Results were analysed and compared.

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STUDY PROFORMA:

MRD NUM: STUDY NUM:

NAME: AGE: SEX:

OCCUPATION:

PAST HISTORY:

DM: DURATION:

DYSLIPIDEMIA:

D.NEUROPATHY: D.NEPHROPATHY:

D.RETINOPATHY:

S.HTN:

PERSONAL HISTORY:

DIABETIC DIET: Yes (1) No (2)

GENERAL EXAMINATION:

Built: Nutritonal status:

Signs of insulin resistance: Yes (1) No (2)

If yes, Central obesity:

Xanthelesma:

Acanthosis nigricans:
HEIGHT: cms WEIGHT: kg BMI:

TEMP: PULSE RATE:

RESPIRATORY RATE: BP: mm/hg

SYSTEMIC EXAMINATION:

a) Cardiovascular system

b) Respiratory system

c) Abdomen: HEPATOMEGALY (±)

d) Nervous system

INVESTIGATIONS:

GLYCEMIC CONTROL: FBS (mg%)

PPBS (mg%)

HbA1c

FASTING LIPID PROFILE: Total cholesterol

Triglycerides

HDL

LDL

LIVER STATUS : LFT

USG ABDOMEN:

Grade I:

Grade II:

Grade III:

FIBROSCAN:

METAVIR scoring system

Fo:

F 1:

F 2:

F 3:

F4:
 INFORMED CONSENT FORM
Subject identification number for this trial ______________________

Title of the project : SPECTRUM OF NAFLD IN DIABETIC PATIENTS WITH

MICROVASCULAR COMPLICATIONS IN A TERITIARY CARE SETTING.

Name of the principal investigator Dr. Gattu.Santosh

Tel No 7569962770

I have received the information sheet on the above study and have read and /
understood the written information.

I have been given the chance to discuss the study and ask questions .

I consent to take part in the study and I am aware that my participation is

voluntary .

I understand that I may withdraw at any time without this affecting my future
care .

I understand that information is collected about me from my participation in

this research and sections of any of my medical notes may be looked at by
responsible persons (ethics committee members/ regulatory authorities ) . I
give access to my records .

I understand I will receive a copy of the patient information sheet and

informed consent form .

_________________________________ _________________

Signature /Thumb impression of subject Date of signature

_______________________________

Printed name of the subject in capitals

__________________________________ __________________

Signature / Thumb impression of legally Date of signature

Accepted representative
“The legally acceptable representatives signature should be added if the
subject is a minor or is unable to sign for themselves . The relationship
between the subject and the legally acceptable representative should be
stated . The impartial witness signature should be added if the subject / legally
acceptable representative is unable to read or write and consent should be
obtained in his presence “

________________________________________________

Printed name of legally acceptable representative in capitals

____________________________________________________

Relationship of legally acceptable representative to subject in capitals

_______________________________________________ ____________

Signature of the person conducting the informed consent Date of

signature

in capitals

_______________________________________________

Printed name of person conducting the informed consent discussion in capitals

__________________________________ _______________

Signature of impartial witness Date of signature

_________________________________________

Printed name of impartial witness in capitals

 ഗഗഗഗഗഗഗഗഗഗ ഗഗഗഗഗഗഗഗഗഗഗഗഗഗഗഗഗഗ
ഗഗഗഗഗഗഗഗഗഗ
പപപപപപപപ പപപപപപപപപപപപപപ പപപപപപപപപപപ പപപപപപപപപപപ പപപപപ
_________

ഗഗഗ ഗഗഗഗഗഗ:

പപപ പപപപപപപ പപപപ പപപപപപപപപപപപ പപപപപപപ പപപപപപപപപപ

പപപപപപപപപപപപപപ പപപപപപ പപപപപപപപപപ പപപപപപപപപപപപപപപപപ
പപപപപപപപ പപപ പപപപപപപപപപപപപപപപപപപപപ പപപ പപപപ.

പപപപപപ പപപപപപപപപ പപപo: പപപപപ.പപപപപപപ.

പപപ പപപപപ : 7569962770.

പ പപപപപപപ പപപപപപപപപപ പപപപപപപപപപപപ പപപപപപപ പപപപപപ പപപപപപപ

പപപപപപപപപപപ പപപപപപപപപപ പപപ പപപപപപപപ പപപപപപപപപപപപപപപപ
പപപപപപ .

പ പപപപപപപപപപപപ പപപപപ പപപപപപപപപപപ പപപപപപ

പപപപപപപപപപപപപപപപപ പപപപപ പപപപപപപ പപപപപപപ .

പ പപപപപപപപപപ പപപപ പപപപപ പപപപപപപപപപപ പപപപപപപപ

പപപപപപപപപപപപപ പ പപപപപപപപ പപപപപപപ പപപപപപപ പപപപപപ
പപപപപപപപപപപപ പപപപപപപപപപപപപപപ പപപ പപപപപ പപപപപപപപപ പപപപപപ
പപപപപപപപപപ പപപപപപപപപപപപപപപപപപപപ പപപ പപപപപപപപപപപപപപപപ .

പ പപപപപപപപപപപ പപപപപപപപപപ പപപപപ പപപപപപപപപപപപപപ പപപപപപ

പപപപപപപപപ പപപപപപപപ പപപപപപപപ പപപപപപപപ പപപപപപപപപപപപപ പപ
പപപപപപപ പപപപപപപപപപപപ പപപപപപപപപപപപപപപപപപപപപപപപ .പ പപപപപ
പപപപപപപപപപപപപപപപപപപ പപപപപപപപപപപപപപപപപപപ പപപപപപപപപപപപ
പപപ പപപപപപ പപപപപപപപ .പ പപപപപപപപ പപപപപപപപപപപപപപപപപപ
പപപപപപപപപപപപപപപപപപ പപപപപ പപപപപപപപപപപപ പപപപപപപപപപപപ
പപപപപപപപപ പപപപപപപപപപപപപപപപപപപപപ .

പ പപപപപപപ പപപപപപപപപപ പപപപ പപപപപപപപ പപപപപപപപപ പപപപപപപപപ

പപപപപപപപപപപപ പപപപപപപ പപപപപപപപപപപപപപ .

____________________________________________ ___________

പപപപപപപപപപപപപപ പപപപപപപപപപപ പപപപപ / പപപപപപപപപ പപപപപ

_______________________________________ പപപപപപപപപപപപപപ
പപപപപപപപപപപ പപപപ

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പപപപപപപപപപ പപപപപപപപപപപപപപപപ പപപപപപപപപപപ പപപപപ
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പപപപപപപപപപപ പപപപപപപപപപപപപപ പപപപപ പപപപപപപപപപപപപപപപ >>

___________________________________________ ____________

പപപപപപപപ പപപപപപപപപപ പപപപപപപപപപപപപപപപ പപപപപ

പപപപപപപപപപപ പപപപപ / പപപപപപപപപ

___________________________________________

പപപപപപപപ പപപപപപപപപപ പപപപപപപപപപപപപപപപ പപപപപപപപപപപ പപപപ

__________________________________________

പപപപപപപപ പപപപപപപപപപ പപപപപപപപപപപപപപപപ പപപപപപപപപപ

പപപപപപപപപപ പപപപപ

______________________________________________ ____________

പപപപപപപപപപ പപപപപപപപപപപപപപ പപപപപപപപപ പപപപപ പപപപപ

______________________________________________

പപപപപപപപപപ പപപപപപപപപപപപപപ പപപപപപപപപ പപപപ

__________________________________________________________

പപപപപപപപപപ പപപപപ പപപപപപപപപപ പപപപപപപപപപപ പപപപപപപപപപപ

പപപപപ

__________________________________________________________

പപപപപപപപപപ പപപപപ പപപപപപപപപപ പപപപപപപപപപപ പപപപപപപപപപപ പപപപ