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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
POST GRADUATE DISSERTATION SYNOPSIS
TOPIC
VITAMIN D LEVELS IN HYPOTHYROIDISM
Dr. POOJA PRAKASH PRABHU
M D GENERAL MEDICINE
Guide : Dr. REKHA PRADEEP
Co-Guide : Dr. JYOTHI IDICULLA
Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore
1. Name of the candidate
Dr. POOJA PRAKASH PRABHU
2. Address
DEPARTMENT OF MEDICINE
ST. JOHN’S MEDICAL COLLEGE HOSPITAL
JOHN NAGAR, BANGALORE-560034
3. Course of study and subject
4. Date of admission to course
5. Title of the topic:
M D GENERAL MEDICINE
1st of JUNE, 2013
VITAMIN D LEVELS IN HYPOTHYROIDISM
6.1. NEED FOR THE STUDY:
Hypothyroidism is one of the most common endocrine disorders. In the past,
the most common cause of primary hypothyroidism was iodine deficiency.
However, with the introduction of iodized salt, this became less common in the
industrialized nations. Among the adult patients in India, the prevalence of
hypothyroidism has been recently studied (1). In this population based study, the
prevalence of hypothyroidism was 3.9%, subclinical hypothyroidism was 9.4%. In
women, the prevalence was higher (11.4%) compared to men (6.2%).
Autoimmune hypothyroidism is probably commoner than iodine deficiency in
areas which are iodine sufficient. Today, the most common cause of
hypothyroidism in the US is Hashimoto’s thyroiditis, which commonly occurs in
the 40 – 60 year age group & tends to run in families. In India, autoimmune
hypothyroidism has been estimated to be the most frequent endocrine disorder
affecting 42 million people in India (2). In patients with Hashimoto’s thyroiditis,
90-100% have detectable anti TPO antibodies. (3)
Until recently, vitamin D deficiency was considered rare in India because of
abundant sunshine. However, a systematic study carried out in Delhi showed the
presence of low 25-hydroxy vitamin D (25(OH)2D) in a majority of subjects
including newborns, their mothers, healthy physicians, nurses, soldiers and those
with vitiligo and albinism (2). Based on these study groups, subnormal serum
25(OH)2 D levels of Asian Indians could be linked to their skin pigmentation and
poor sunshine exposure.
Studies done assessing the association between autoimmune thyroid disease &
vitamin D levels have produced conflicting results (4, 5, 6, 7). In India, only two
studies have explained the relationship between vitamin D levels & thyroid
autoimmunity. High prevalence of thyroid autoimmunity and vitamin D deficiency
in the Indian population provides us a unique opportunity to assess the association
between these two variables. Some of the symptoms of vitamin D deficiency
overlap with that of the hypothyroidism. Hence there is a need for this study.
6.2. REVIEW OF LITERATURE:
Vitamin D and Autoimmunity
Non classical actions of vitamin D were first recognized 30 years ago when
receptors for active vitamin D3 were detected in various neoplastic cell lines (8).
Other studies followed, showing that binding of the vitamin D3 to the Vitamin D
receptor (VDR) promoted anti proliferative and prodifferentiation responses in
cancer cells, highlighting an entirely new facet of vitamin D action (8). The
spectrum of non-classical responses to vitamin D was then extended to include
actions on the cells of immune system (8).
Vitamin D has an important role as an immunomodulator (9). Vitamin D
mediates its effect through binding to vitamin D receptor (VDR) and activation of
VDR responsive genes. The VDR protein has been found to be expressed in most
of the lymphocytic cells involved in immune systems such as dendritic cells, CD4lymphocytes, CD8-lymphocytes & monocyte-macrophage lineage cells (10).
The key action of vitamin D on macrophages is believed to be its ability to
stimulate differentiation of precursor monocytes to more mature phagocytic
macrophages. Normal human macrophages are able to synthesize vitamin D3 when
stimulated by IFN-γ. Thus , localized activation of Vitamin D, coupled with
expression of endogenous VDR is strongly suggestive of an autocrine or intracrine
system of vitamin D action in normal monocytes/macrophages(8).
Expression of vitamin D receptor by dendritic Cells was first reported in
1987.Studies have provide evidence that vitamin D could act to attenuate antigen
presentation capacity of these cells (8). Subsequently, in 2000, studies done by
Andorini and Kumar , showed that vitamin D inhibited the maturation of monocyte
derived dendritic cells, thereby suppressing the capacity to present antigen to the
T-cells. Based on these observations, it was proposed that “Vitamin D could act to
promote tolerance”.
The local production of 1, 25 (OH) vitamin D is thought to be important for
keeping the cell growth in check and prevent it from becoming autonomous (2). By
binding to VDRs on immune cells, vitamin D can prevent them from triggering
autoimmune destruction of cells (9). The paracrine action of locally produced
Vitamin D allows only initial presentation of antigen to T cells, while it prevents
continued maturation of dendritic cells and overstimulation of Tcells.
The initial studies of the effects of vitamin D on Tcells focused on the ability
of vitamin D to suppress T cell proliferation. Lempire and colleagues first reported
that vitamin D3 preferentially inhibited T helper cells (Th1) which is closely
associated with cellular immunity (8).
Th17 cells play an essential role in combating certain pathogens, but they
have been linked to tissue damage and inflammation. Vitamin D3 exerts some of
its effects on inflammation and autoimmune disease through the regulation of the
Th17 cells.
Vitamin D and autoimmune thyroid disease:
For many years vitamin D status was defined simply by whether or not the
patients had symptoms of the bone disease i.e., rickets in children and osteomalcia
in adults. Of late, vitamin D deficiency has been associated with increased risk of
cancer, cardiovascular disease and many autoimmune disease like type 1 diabetes
mellitus, rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease,
Crohn’s disease etc..
Recent studies have shown that vitamin D receptor polymorphisms are
associated with susceptibility to AITD (10). A study published in the journal,
‘Clinical & Experimental Immunology’ investigated the relationship between
vitamin D, thyroid hormones & NK cells. The results showed that low levels of
vitamin D and the thyroid hormones increased the population of NK cells.
However, only vitamin D level was found to be linked to the cell-destroying
activity of the innate immune system (9).
Another study from Israel (4) showed a significant prevalence of vitamin D
deficiency (72%) among patients with AITD. This study showed vitamin D
deficiency significantly correlated with the presence of anti-TPO antibody.
Similar results were reported by Gonka Tamer et.al from Turkey, where in the
prevalence of vitamin D deficiency was noted in 92% of autoimmune
hypothyroidism cases (5).
In a study published in June 2013 in the journal “Endocrine Practice” by Nujen
et.al, serum levels of 25 (OH) vitamin D of Hashimoto’s thyoiditis patients were
shown to be significantly lower than the controls & the severity of vitamin D
deficiency correlated with the duration of Hashimoto’s thyroiditis. The vitamin D
levels inversely correlated with anti–TPO levels and anti-TG levels (11).
In India, a study from AIIMS has reported vitamin D deficiency in 87% of the
subjects, anti-TPO positive in 21% of the subjects, thyroid dysfunction in 15% of
the subjects, an inverse association between vitamin D and thyroid autoimmunity
as reflected in anti-TPO titres. Though the relationship assumed statistical
significance, the R2value was only 0.006, indicating that only 0.6% variation in
thyroid autoimmunity was determined by 25(OH)2D levels in the study population
(2)
Subsequently, a series of studies have documented widespread hypovitaminosis
D in north as well as south India (12, 13,14).
However, a study published in the European Journal of Endocrinology (6) in
2012 concluded that vitamin D is not associated with early stages of autoimmune
thyroid disease. The prevalence of 25(OH) D3 deficiency was lower in cases than
in controls (48.7% vs 64.1%).The prevalence of 25(OH) D3 deficiency was not
different between AITD patients and non –AITD patients(72% vs 52%). Also, a
study done by the University of Amsterdam (7) on an AITD cohort found similar
results.
6.3 OBJECTIVES OF THE STUDY
PRIMARY OBJECTIVES
1)
2)
To estimate the levels of vitamin D in patients with hypothyroidism.
To compare vitamin D levels between anti TPO positive and negative
hypothyroid patients.
SECONDARY OBJECTIVES
1)
To correlate vitamin D levels and anti TPO levels in anti TPO positive
hypothyroidism.
2)
To correlate the vitamin D levels with TSH levels in both the groups.
7 .MATERIALS AND METHODS:
7.1 SOURCE OF DATA: All patients who are diagnosed with hypothyroidism
based on signs and symptoms, or picked upon routine screening at St. Johns
Medical College hospital between November 2013 to April 2015.
7.2 METHOD OF DATA COLLECTION
INCLUSION CRITERIA
1. All newly detected cases of hypothyroidism aged more than 18 years
presenting to St. John’s Medical College Hospital during the study period.
TSH values > 4.1 µIU/ml are taken as suggestive of hypothyroidism.
EXCLUSION CRITERIA
1. Patients with post radio –iodine hypothyroidism.
2. Patients with liver disorders, renal disorders, primary hyperparathyroidism
3. Patients on on anti-epileptic medications that might alter 25 OH Vitamin D
metabolism & thyroid functions (eg: Phenytoin, carbamazepine).
4. Patients already on treatment with vitamin D.
SAMPLE SIZE:
The study done by Kivity et al (4) on 92 patients with hypothyroidism found that
72% of patients with hypothyroidism had vitamin D deficiency. Based on the
above study, the desired sample size was estimated to be at least 120 patients in
order to achieve an accuracy of result of +/-8%.
TYPE OF STUDY:
Descriptive comparative study.
METHODOLOGY
All patients who are susupected to have hypothyroidism
based on signs and symptoms are evaluated for serum TSH levels, and if found to
be >4.1µIU/ml are included in the study.
 A detailed history and clinical examination is done (based on the proforma) to
look for the signs and sypmtoms of hypothyroidism and vitamin D deficiency in
them and will be entered into the proforma.
 TSH, Free T4, Anti-TPO antibodies as well as vitamin D levels will be assayed
for each patient.
 Subjects are compared for the differences in the vitamin D levels according to
their thyroid function status as well as antibody titres.
 All statistical analyses were made by using the software SPSS for Windows
version 18.0 and descriptive data will be computed.
 The statistical significance of the difference in vitamin D levels among the
groups is tested using Student t-test. The statistical significance of the
differences in the means of vitamin D levels in the three groups of
hypothyroidism is tested using t-test.
The correlation between levels of vitamin D and antibody titres is analysed by
regression analyses. Presence of symptoms in both groups will be compared using
Chi square test.
Proforma
Patient Particulars:
Name:
Age & Sex:
Address & Contact no.:
Hospital Identity no.:
Symptoms of hypothyroidism:
Weight gain:Y/N
Symptoms of hypothyroidism &
Vitamin D deficiency(common)
Decreased appatite:Y/N
Generalized weakness:Y/N
Cold Intolerance: Y/N
Generalized aches and pains:Y/N
Swelling of feet :Y/N
Muscle pain:Y/N
Dry, cold skin:Y/N
Muscle weakness:Y/N
Loss of hair & thinning of hair: Y/N
Bony pains:Y/N
Hoarseness of voice: Y/N
Lethargy:Y/N
Obstructive sleep apnoea:Y/N
Mood Disturbance:Y/N
Headache:Y/N
Constipation:Y/N
Any other:
Menstrual disturbances: Y/N, if yes- menorrhagia/ oligomenorrhea/amennorhea.
Neck Swelling: Y/N, if yes- painful/painless
Other autoimmune diseases (Type-1DM/RA/Multiple Sclerosis): Y/N
Family History of Hypothyroidism/Probable Auto-immune Disease: Y/N
(Diagnosis if available: __________________________________)
Medication/Other Treatment History:
On Lithium: Y/N
Amiodarone: Y/N
Radio-iodine treatment: Y/N
Anti-thyroid drugs: Y/N
Thyroid surgery: Y/N
Other medications (List):
Examination:
Weight:
Pallor:
Oedema:
Pulse rate:
BP:
skin:
Goitre: Y/N
Respiratory system:
Cardiovascular system:
Per Abdomen:
Central Nervous system:
Results of Investigations:
Hb:
ESR:
RBS:
TSH: (Value - _____mIU/L)
Free T4: (Value - _____ng/dL)
Anti-TPO antibody: Positive/Negative, Value if positive - _______IU/ml
25(OH) Vitamin D levels- _________ ng/ml:
s.Calcium:
List of references:
s.Phosphorous:
s.ALP:
1. Unnikrishnan A G, Menon U V et.al, Thyroid Disorders in India :An
Epidemiological Perspective. Indian Journal of Endocrine Metabolism 2011; 15:
78-81.
2. Goswami R , Marwaha R K , Gupta N et.al, Prevalance of vitamin D
deficiency and its relationship with thyroid autoimmunity in Asian Indian: A
community –based survey. British Journal Of Nutrition 2009; 102: 382-386.
3. Spencer C.A, Takeuchi M, Kazarosyan M et.al, serum Thyroglobulin
autoantibodies: prevalence, influence on serum thyroglobulin measurement and
prognostic significance in patients with differentaed thyroid carcinoma. Journal of
clinical endocrinology & metabolism 1998; 83: 1121-1127.
4. Kivity S, Agmon L N, Zisappl M et.al, Vitamin D and Autoimmune Thyroid
diseases. Cellular and Molecular Immunolgy 2011; 8: 243-247.
5. Tamer G ,Arik S , Tamer I et.al, Relative Vitamin D Insufficiency in
Hashimoto’s Thyroiditis. Thyroid 2011; 21(8): 891 – 896.
6. Effraimidis G, Badenhoop K, Tijssen Jan G P , Wiersinga M W et al., Vitamin
D Deficiency is not associated with early stages of thyroid autoimmunity.
European Journal of Endocrinology 2012; 167: 43 – 48.
7. Effraimidis G et.al, Early Stages of thyroid autoimmunity: follow up studies in
the Amsterdam AITD cohort. European Journal of Endocrinology 2012; 148 –
156.
8. Hewison M et.al, Vitamin D and the Immune System : New Perspective on an
Old Theme. Endocrinology Metabolism Clinics of North America 2010;39: 365379.
9. Mariani E, Ravaglia G , Forti P et.al , Vitamin D , Thyroid Hormones and
Muscle Mass influence Natural killer innate immunity in healthy nonagenarians
and centenerians. Journal Of Clinical Experimental Immunology 1999; 116: 19-27.
10. Wei-Yong Lin, Lei Wan , Chang-Hai Tsai et.al , Vitamin D Receptor Gene
Polymorphism are associated with risk of Hashimoto’s Thyroiditis in Chinese
Patients In Taiwan. Journal of Clinical Laboratory Analysis 2006; 20:109-112
11. Bozkurt N C ,Karbek B, Ucan B et.al, The Association Between Severity Of
Vitamin D Deficiency And Hashimoto’s Thyroiditis. Endocrine Practice June
2013 ; 19: 479 – 484.
12. Harinarayan et.al, High prevalence of low dietary calcium, high phytate
consumption and vitamin D deficiency in healthy South Indians. American
Journal of Clinical Nutrition April 2007; 85: 1062 – 1067.
13. Vupputuri M R et.al, Prevalence and functional significance of 25
hydroxyvitamin D deficiency and vitamin D receptor gene polymorphisms in
Asian Indians. American Journal of Clinical Nutrition June2006; 88: 1411 –
1419.
14. Goswami R et.al, Prevalence and significance of low 25 hydroxyvitamin D
concentration in healthy subjects in Delhi. American Journal of Clinical Nutrition
Aug 2000; 72: 472 – 475.
Signature of the candidate:
Remarks of the guide:
Name and signature of the guide:
Name and signature of the co-guide:
Name and signature of Head of Department:
Remarks of the Chairman and Principal:
Signature: