RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA.
PROFORMA FOR REGISTRATION OF SUBJECT
FOR
DISSERTATIONS
1 / NAME OF THE CANDIDATE& ADDRESS (IN BLOCK LETTERS) / DR. ANURADHA. J
DEPARTMENT OF BIOCHEMISTRY,
DR.B.R.AMBEDKARMEDICALCOLLEGE AND HOSPITAL,
K.G.HALLI,BANGALORE – 560045.
2 / NAME OF THE INSTITUTION / DR.B.R.AMBEDKARMEDICALCOLLEGE AND HOSPITAL
3 / COURSE OF STUDY
SUBJECT / M.D.
BIOCHEMISTRY
4 / DATE OF ADMISSION TO THE COURSE / 19TH AUGUST 2013
5 / TITLE OF THE TOPIC / A STUDY OF THYROID HORMONES IN ALCOHOLIC LIVER DISEASES
ALCOHOLIC LIVER DISEASES
INTRODUCTION
In India alcohol consumption has been steadily increasing. It has been estimated that there are 62.5 million alcohol users in India. The mean age of initiation of alcohol use has decreased from 23yrs in 1950-1960 to 19yrs in 1980-2000.This is due to changing social norms,urbanization,increased availability,high intensity marketing.
ALCOHOLISM:-
Alcoholism or alcohol dependence is a maladaptive pattern of chronic alcohol leading to tolerance,dependence and severe behavior impairment.
Tolerance is defined as need for markedly increased amounts of alcohol to achieve the desired effect. Dependence may be physical or psychological. Physical dependence is characterized by presence of withdrawal symptoms and tolerance. Withdrawal symptoms include sweating, handtremors, vomiting. Psychological symptoms include insomnia, anxiety, psychomotor agitation and hallucination.
An alcoholic beverage contains ethanol in varying percentages.Quantity and duration of alcohol intake are the most important risk factors involved in the development of alcoholic diseases.
Continuous alcoholic drinkers are at a high risk of developing alcoholic disease than binge drinkers.
EFFECTS OF ALCOHOL ON ORGAN SYSTEMS
1. Neurological – Peripheral neuropathy, Cerebellar degeneration, cerebral
haemorrhage.
2. Cardiac - Cardiomyopathy, Hypertension
3. Respiratory - Pulmonary TB, Pneumonia.
4. G.I.T – Oesophagitis, Gastritis, Pancreatitis, Oesophageal cancer, Mallory
Weiss syndrome, Malabsorption Oesophageal varices
5. Reproductive- Hypogonadism, Fetal alcohol syndrome
6. Musculoskeletal – Myopathy, fractures
7. Endocrine and metabolism – Pseudo-Cushing syndrome, hypoglycemia,
Gout
8. Hepatic – Alcoholic liver diseases.
CLINICAL FEATURES
The three types of alcoholic liver disease are
1:ALCOHOLIC FATTY LIVER DISEASE
It usually presents with elevated transaminases in the absence of hepatomegaly.Steatosis usually disappears after 3 months of abstinence.
2:ALCOHOLIC HEPATITIS
Clinical features are
Jaundice
Malnutrition
Hepatomegaly
Features of portal hypertension i.e. Ascites, encephalopathy.
3:CIRRHOSIS
It often presents with complications such as ascites, variceal haemorrhage
Large, normal or small liver
Stigmata of chronic liver disease
Hepatocellular carcinoma.
ALCOHOLIC LIVER DISEASES
Alcoholic liver disease is among the ten most common causes of death.Quantity and duration of alcohol are the most important risk factors involved in the development of alcoholic liver disease.The threshold of developing alcoholic liver disease in men is an intake of >60-80 g/d of alcohol for 10yrs while in women are at increased risk of developing similar degrees of liver injury by consuming 20-40 g/d.Ingestion of 160 g/d is associated with 25 fold increased risk of developing alcoholic cirrhosis
PATHOPHYSIOLOGY
Alcohol is metabolized by the liver via one of the two main pathways
80% of alcohol is metabolized to acetaldehyde by the mitochondrial enzyme,alcohol dehydrogenase. Acetaldehyde forms adduct with the cellular proteins in hepatocytes and activates the immune system leading to cell injury.
20%is metabolized by the mixed function oxidase enzymes of the smooth endoplasmic reticulum.Cytochrome CYP2E1 is an enzyme which oxidize ethanol to acetate during this process it releases oxygen free radicals which can induce mitochondrial damage.
The important functions of liver
1.Nutrient metabolism – Carbohydrate
Proteins
Lipids
- Protein synthesis- Coagulation factors
Complement factors
Haptoglobin
Ceruloplasmin
Transferin
Protease inhibitors
Albumin
Hormone binding proteins
3. Storage – of iron, copper, vit A,D and B12.
4. Formation and secretion of bile.
5. Excretion ofdrugs, cholesterol, phospholipids, bilirubin,and bilesalts.
6. Immune regulation
The functions of liver on thyroid
The liver being involved in the conjugation and deiodination of Thyroxine (T4) and tri-iodothyronine (T3)
Synthesis and secretion of major thyroid hormonebinding proteins,thyroxine-binding globulin, prealbumin and albumin
The peripheral conversion of T4 to T3 takes place in tissues such as liver,kidneyand thyroid.
THYROID GLAND
It is the largest endocrine gland. It consists of two large lateral lobes which are connected in the midline by abroad isthmus from which an occasion a pyramid lobe may protrude superiorly. It develops as tubular invagination of the endoderm from the root of the tongue called Foramen caecum about the third week of the embryonic life.
PHYSIOLOGY
Thyroid secretes two significant hormones T4 and T3.
Synthesis of thyroid hormones
Trapping of inorganic iodide from the blood.
Oxidation of iodide to iodine
Binding of iodine with tyrosine to form iodotyrosines.
Coupling of mono-iodotyrosines and di-iodotyrosines to form tri-iodo thyronine (T3) and thyroxine (T4).
T3 is also produced in the periphery by conversion from T4 in tissues such as liver, kidney and thyroid catalyzed by type 1 de-iodinase.
The hormone T3 andT4 are bound to thyroglobulin within the colloid
HORMONE TRANSPORT AND METABOLISM
When hormones are required the complex is resorbed into the cell and the thyroglobulin broken down.T3 and T4 are liberated and enter the blood where they are bound to serum protein,albumin,thyroxine binding globulin (TBG) and prealbumin(TBPA).A small amount of hormone remains free in the serum in equilibrium with protein-bound hormone and is biologically active.
Thyroid hormone undergo 70%metabolism through sequential removal of iodine.In case of T4 deiodination yields T3 and reverse T3(has no metabolic action).
The second pathway of T3/T4 metabolism is conjugation with glucuronide in liver which are deiodinated and excreted in the bile.20%of T4 disposal occur via fecal loss.
6 NEED FOR THE STUDY
Alcoholic liver disease effects most of the organs in our body. On this alcoholic liver diseases various studies have been done .It is observed that not many Indian studies on thyroid hormone functional studies in case of alcoholic liver diseases are available. The study of thyroid hormone function tests will throw a light on the functional aspects of liver diseases and gives some better understanding of the alcoholic liver disease and their interrelationship with thyroid function and thus helps in the management of alcoholic liver diseases.
6.1 REVIEW OF LITERATURE
The liver, a plays an important role in thyroid hormone metabolism, being involved in the conjugation and de-iodination of thyroxine (T4) and tri-iodothyronine (T3) as well as synthesis and secretion of major thyroid hormone binding proteins, thyroxine-binding globulin (TBG), thyroxine-binding prealbumin and albumin .1
A large group of alcoholic liver disease patients were studied for the endocrine changes and these changes were correlated to the severity of liver diseases in order to examine the underlying mechanism accounting for endocrine dysfunction. In the majority of patients examined marked changes were found in circulating thyroid hormones T3 below the normal level in the absence of significant changes in TSH. Total T4 was normal or low.They were clinically euthyroid.1
In patients with alcoholic cirrhosis the levels of serum T4, T3, reverse T3 (rT3) were determined. The results showedSerum T4, T3 levels were decreased and serum rT3 levels increased in patients with alcoholic cirrhosis. Serum T4 and T3 were lower and rT3 higher in cirrhotic patients who died within three months of study compared with those who survived. It suggests that assay of serum thyroid hormone levels may be helpful in assessing the course and prognosis of patients with liver disease.3
In alcoholic cirrhosis with clinically euthyroid patients the serum concentrations of thyroid hormones showed the mean serum Total T4 was low and the mean serum total T3 was significantly lower than the normal.The mean serum TSH is increased.5
6.2 OBJECTIVES
To study the Thyroid hormones in alcoholic liver diseases.
7. MATERIALS AND METHODS
7.1 SOURCE OF DATA
INCLUSION CRITERIA
Test subjects:- Includes 30 males of age 40-60yrs of alcoholic liver diseases
Control subjects:-Includes 30 males of age 40-60yrs who are non alcoholics.
EXCLUSION CRITERIA
Patients with clinical evidence of Diabetesmellitus,Renal diseases,Hypertension,thyroid disorders,non alcoholic liver diseases,obesity,females,vomiting,diarrhea.
STUDY PERIOD: JAN 2014 TO JAN2015
7.2 METHOD OF COLLECTION OF DATA
Test subjects are male patients of alcoholic liver disease from Dr.B.R.A.M.C.H. having no history of diseases like diabetes mellitus,hypertension,non alcoholic liver diseases,renal diseases,thyroid disorders.
Control subjects are healthy males who are hospital employees of Dr.B.R.A.M.C.H.With no current/lifetime history of alcohol drinking
All these subjects were subjected to medical examination as per a fixed proform. Their blood pressure, height, weight, BMI is recorded in both groups.
BIOCHEMICAL TESTS
THYROID FUNCTION TESTS (ELISA METHOD)
Serum T3
Serum T4
Serum TSH
LIVER FUNCTION TESTS(Routine methods using Auto Analyzers)
1. Total bilirubin - Direct
- Indirect
2. Total protein
Serum albumin
A:G ratio
3. Serum AST
Serum ALT
Serum ALP
Serum GGT
7.3. Does the study require any investigation or intervention to be conducted on
Patient or other human or animal?
Yes,investigation required as mentioned above, are non invasive
No interventions are required.
7.4 Has ethical clearance has been obtained from your institution in cases above
mentioned ?
Yes
8. LIST OF REFERENCES
1 . P. Burra, J.A. Franklyn, D.B.Ramsden, E.Elias and M.C.Sheppard .Severity
of alcoholic liver disease and markers of thyroid and steroid statusPost
graduate medical journal 1992 october;68(804-810).
2 . George C. Schussler, M.D.,Fenton Schaffner, M.D., and Felice korn M.S.
Increased serum thyroid hormone binding and decreased free hormone in
chronic liver disease.The New England Journal of Medicine 1978;299:510-
515
3. Hepner GW, Chopra IJ .Serum thyroid hormone levels in patients with liver
disease.Archive Internal Medicine .1979 Oct; 139(10); 1117-20.
4. S Nomura, C S Pittman, J B Chambers, Jr, M W Buck and T Shimizu. .Reduced
peripheral conversion of thyroxine to triiodothyronine in patients with hepatic
cirrhosis.The Journal of Clinical investigation 1975 September; 56(3) 643-652.
5. Inder J., Chopra, David, Solomon et al .Alterations in circulating thyroid
hormones and thyrotropin in hepatic cirrhosis.Evidence for Euthyroidism
despite subnormal serum triiodothyronineJournal of Clinical Endocrinology
Metabolism September 1, 1974 vol.39 no.3 501-511.
6. L`age M, Meinhold H, Wenzel KW ,Schlesinger H. Relations between serum
levels of TSH,TBG,T4,T3,rT3 and various histological classified chronic
liver diseases.Journal of Endocrinology investigations 1980 oct-dec; 3(4);
379-83.
7. Y Israel, PG Walfish, H Orrego, J Blake, H Kalant. Thyroid hormone levels
in alcoholic liver diseases. Gastroenterology Vol.76, issue 1, January 1979;
116-122
8. M Borzio, R Caldara, F Borzio, V Piepoli et al.Thyroid function tests in
chronic liver disease:evidence for multiple abnormalities despite clinical
euthyroidism.GUT,an International Journal of Gastroenterology and
Hepatology; 1983July; 24(7); 631-636.
9. Mc Connon j, Row VV, Volpe R.JThe influence of liver damage in man on
the distribution and disposal rates of thyroxine and triiodothyronine. Clinical
Endocrinology Metabolism.1972 Jan; 34 (1):144-151
10.JanniA,etal.The prognostic value of thyroid function tests in liver cirrhosis.
In Langer M Chiandussi L,Chopra I J and Martin L,eds,The Endocrines and
The Liver,London,Academic Press, 1982; 232-6
11. Malik R, Hodgson H.The relationship between the thyroid gland and the
Liver.Q J MED; 2002; 95:
A study of the endocrine manifestations of hepatic cirrhosis. (Q J M 1976.
12. The thyroid hormone picture of alcoholics in connection with their liver
Status. Minerva Med.1990.
13. Harnold Varley, etal, Practical Clinical Biochemistry – 5th Edition.
14. Carl AB, Edward RA, et al, Teitz Fundamental for Clinical Chemistry, 5th
Edition.
15. Oxford Text book of Clinical hepatology; Vol_2
16. Devlin Text book of Biochemistry with Clinical Correlation – Sixth
Edition.
- Williams Text book of Endocrinology Edition 11.Henry M. Krokenberg, Shlomo Melmed Kenneth S.Polonsky, and P.Reed Larsen.
9 / Signature of the candidate
10 / Remarks of the Guide
11.1 / Name and designation of guide / Dr.Prof.Hemalatha, M.D.,
Professor and Head,
Dept. of Biochemistry
Dr. B.R.Ambedkar Medical College
Bangalore-560045
11.2 / Signature
11.3 / Co Guide (if any)
11.4 / Signature
11.5 / Head of Department / Dr.Prof.Hemalatha, M.D.,
Professor and Head,
Dept. of Biochemistry
Dr.B.R.AmbedkarMedicalCollege
11.6 / Signature
12. / Remarks of the Principal