Skin Changes in Newly Diagnosed Cases of Hypothyroidism

Introduction: Thyroid disorders are frequent in our population that lead to a variety of cutaneous manifestations. Our study aimed to determine the frequencies of skin changes of hypothyroidism


Introduction
The thyroid gland is a butterfly-shaped endocrine gland situated in the lower part of the front of the neck. It is present below the larynx, in front and sides of the trachea. 1 Thyroid gland plays a major role in the metabolism, development and growth of the human body and regulates several body functions including basal metabolic rate (BMR). It stimulates somatic and psychic growth other than having important participation in calcium metabolism. 2,3 Hypothyroidism is caused by thyroid hormone deficiency either due to decreased production of hormones, defective distribution, lack of effects of thyroid hormone or consequence of drug-induced thyroid dysfunction. Central hypothyroidism may be induced by the inhibition of thyroid-stimulating hormone (TSH) by corticosteroids or immunological mechanisms (anti-CTLA4 or anti-PD-1 antibody drugs). 4 The prevalence of hypothyroidism is 4-5% in developed countries, whereas 11% in India, 4.6% in the USA and 2% in the UK. It is more common in females as compared to males. 3 Hypothyroidism can be easily diagnosed and managed. However, untreated cases may present with systemic complications as well as poor quality of life. This may even lead to death in severe cases. 5 Thyroid hormones play an important role in regulating healthy normal skin. Certain skin changes in hypothyroidism vary with the age group or gender. 6 Actions of thyroid hormone on the skin are mediated through thyroid hormones receptor (TR) i.e., present in epidermal keratinocytes, erector pili muscle, hair follicles, sebaceous gland cells, skin fibroblasts, vascular endothelial cells and Schwan cells. The epidermal homeostasis is regulated by thyroid hormones. Skin in hypothyroidism is rough, dry, and scaly over extensor surfaces. 7 The thyroid hormone increases the activity of an enzyme in cholesterol sulphate synthesis and enhances the skin barrier formation. In hypothyroidism, there is a hindrance in the barrier formation of the epidermis. 8 Dermal changes include myxoedema (due to glucoseaminoglycan deposition in the skin), oedema of hands, face, eyelid and pallor. Generalized myxoedema is a classical sign of hypothyroidism. 8 Prominent yellowish hue of skin on palms, soles and nasolabial folds known as carotenemia which is secondary to increased dermal carotene deposition. 9 Hair changes in hypothyroidism include dry brittle, coarse hair, slow-growing, patchy or diffuse hair loss (alopecia), and loss of lateral 3 rd of eyebrows (madarosis) while nail changes are coarse dull brittle striated nails, slow nail growth, longitudinal and transverse striations and onycholysis. Dry skin (xerosis) and decreased sweating secondary to sweat gland changes are also observed. Other skin manifestations include intolerance to cold, purpura, upper eyelids drooping, nerve entrapment syndromes, puffy face, Palmo-planter keratoderma, xanthelasma palpebrum. It is also associated with livedo reticularis of extremities secondary to vasoconstriction and decreased sebaceous gland secretion. Decreased skin perfusion may lead to cold, pale skin which can be examined by nail fold capillaroscopy and laser doppler. 8,10,11,12 Clinical features of hypothyroidism and subclinical hypothyroidism range from mild symptoms to lifethreatening conditions. Common symptoms in adults are fatigue, lethargy, cold intolerance, weight gain, myxedematous facies, constipation, change in voice, dry skin, poor concentration, altered mood, cognitive dysfunction, depression, menstrual irregularities, bradycardia, pericardial effusion and cardiac tamponade. These clinical features vary with age and gender. 5,11,13,14 Vitiligo, urticaria and alopecia areata may be associated with autoimmune hypothyroidism. Occasionally, dermal deposition of mucin leads to a decreased level of clotting factors and loss of vascular support leading to purpura. Hypothyroidism is associated with impaired vascular function. hypohidrosis and palmoplantar keratoderma secondary to decrease epidermal cholesterol biosynthesis. The decreased sebum production in hypothyroid patients may present with candida folliculitis. Former studies have mentioned that 40-70% of patients with melanin spots have thyroid dysfunction. Similarly, 42% of males and 62% of females with vitiligo, 50% of chronic mucocutaneous candidiasis, 34% of dermatitis herpetiformis, 8% of delayed hypersensitivity reactions and 8% of alopecia areata cases have thyroid disorders. 15,16,17,18 Certain associations of autoimmune thyroid disease are with bullous diseases like pemphigus, connective tissue disorders, Kaposi's sarcoma, pernicious anaemia, dermatomyositis, Sjogren's, syndrome, polymyositis, etc. Certain other associations are with acanthosis nigricans, McCune-Albright syndrome, sweet syndrome), CREAST syndrome, psoriasis, Cowden's syndrome, ANOTHER syndrome (alopecia, nail dystrophy, hypo-hydrosis and ephelides), acropachies, and atopic manifestations (urticaria, dermographism and angioedema. 19,20 Most of the skin changes of hypothyroidism are nonspecific and may present with or without thyroid problems. There needs to evaluate the case presenting with cutaneous manifestations associated with thyroid disease. This research was designed to determine the frequency of skin changes in hypothyroid cases and study these changes in association with gender. This may help us study the trend and gender-wise distribution of cutaneous changes in our patients that may lead to improved outcomes dermatologically, systemically as well as the quality of life. Patients with secondary hypothyroidism, sick thyroid disease and pregnant women were excluded. Also, the patients receiving thyroxin therapy for > 1 month, cases of carcinoma of the thyroid, terminal or critically ill cases requiring intensive care, patients who had undergone thyroid surgery, or who have iatrogenic thyroid disordered i.e., post thyroidectomy or post-radioactive iodine therapy was excluded. The sample size was calculated to be a minimum of 73 cases (5% prevalence of hypothyroidism, 5% precision and 95% confidence interval). 20 Total 105 confirmed cases of hypothyroidism meeting the inclusion and exclusion criteria were included by convenience sampling. Informed consent was obtained and demographic data, height, weight and BMI were calculated. Their co-morbid conditions, a detailed history and clinical examination were performed supported by relevant labs. Complete medical, as well as dermatological examination, was done. Skin findings were documented on a specially designed proforma. SPSS version 21 was used for data analysis. Quantitative variables (i.e., age and TSH levels) were presented as mean and standard deviation. Qualitative variables (i.e., gender, presence of co-morbid conditions and skin findings) as frequencies and percentages. The Chi-square test was used to study the association of various skin changes with gender, p-value<0.05 was considered statistically significant.

Discussion
In our study, there were 105 patients in which 62% were females and 38% were males which coincides with the earlier studies which showed female predominance by Haritha et al. 12 We may conclude that female predominance may be due to an increased prevalence of autoimmune disorders in females and this autoimmunity is an important cause of hypothyroidism as well. 21 The commonest skin finding of hypothyroidism in our study was dry skin that is observed in approx. 2/3 rd of our cases. This coincides with the study by Bains et all who found xerosis i.e., dry skin in 67% of cases. 22 Varying results are observed in different studies. The reasons could be environmental factors, skin types, age, gender and regional differences. Dry skin was followed by diffuse hair loss (58%) which is 2 nd most common finding of hypothyroidism in our study which is lower than observations by Haritha and Neerja et al showing 34.8% and 33.3% respectively. 12,23 Course skin was found in half of our cases, i.e., the 3 rd most common finding in our study which is higher and does not coincide with the study by Keen et al who found it in 65% of cases. 6 This may also be contributed to the environmental and other factors mentioned earlier.
Pruritis was seen in 27% of patients in our study while Keen et al found it less common i.e., 17.7% finding in his study. 24 Madarosis (i.e., loss of eyebrows) was seen in 37% of patients in our study but Neerja et al found it in 22.2% which is lower than our study. 23 Nail changes include slow nail growth (23%) and brittle nails (18%), however, Keen et all found nail changes in 2% cases which were very less than compared in our study. 24 The nail health depends on multiple factors in addition to thyroid disorders, regional deficiency of calcium and other nutrients may be responsible for this high prevalence in our cases. Skin changes secondary to autoimmunity like alopecia areata are observed to be approx. 17% in certain other studies. 23,24 Alopecia secondary to hypothyroidism is mediated via hormone that affects the initiation and duration of the hair growth cell cycle. The normal telogen anagen hair relationships can be restored by thyroid hormone replacement. A significant association is found between alopecia areata and thyroid disorders by Marahatta et al in his study as well. 25 Chronic idiopathic urticaria was reported in 17% of our study. Dogra et al, 26 Lenzoff and Sussman 27 reported 15.6% and 624 patients respectively with chronic idiopathic urticaria and angioedema and noted thyroid disorder in 90 patients while Heymann 28 couldn't establish the mechanism of autoimmunity in urticaria. A study by Neerja puri showed 6% of patients of urticaria. 23 In our study acanthosis nigricans was seen in 14.3% of patients while a study by Keen et al 24 showed acanthosis nigricans in only four patients which did not coincide with our study. An association between acanthosis nigricans and hypothyroidism have established by Kuroki et al. 29 Ivory yellow skin was seen in 12.4% in our study while 6.52% & 5.12% in studies conducted by Keen et al [24] & Rai et al 30 respectively, which was lower than our study and does not coincide with their studies and Neerja puri showed 52.75% cases which were higher than our study. 23 Purpura ecchymosis was found in 11.4% of our study while Keen at al 24 reported 4.13% and Christianson HB 31 reported 4.05% of patients which was lower than our study.
Ichthyosis was seen in 10.5% of our study while Haritha et al showed 38% of ichthyotic patients in their studies which was a higher percentage compared to our study. Herpes simplex was seen in 10.5% of patients in our study and Keen et al 24 in their study suggested that it's an association of disease. Thyroid hormone (T3) participates in the regulation of herpes simplex replication during reactivation but in vivo suggested that T3 suppressed herpes simplex virus replication. Vitiligo was seen in 0.5% of our study while Keen et al [24] found 7 patients in their study. While research conducted by Sedighe et al, 32 Gopal et al 33 have shown an association between vitiligo and hypothyroidism. Haritha et al 32 found three patients in their study which was less than our study and findings were not coincide with a study conducted by Samson et al. 34 Palmoplantar keratoderma was seen in 7% of patients while Neerja puri 23 and Keen et al 24 found in 33.3% and 19.35% respectively in their studies which were higher than our study but Rai et al 30 found 7.2% patients which were less than our study Carotenemia was found in 5% of our study which coincides with the study by Keen et al. 24 Xanthelasma palpebrum was seen in 5% of patients which did not coincide with a study by Keen et al 24 who found 1.52% and the least common finding in his study whereas the study by Dogra et al 26 noticed it in 3% of patients. Lichen planus was seen in 5% of our study while the study by K. Kirthi 32 was not coinciding with our study, they found 3% cases of lichen planus in their study. Other associated diseases like seborrheic keratosis and ephelides were noticed as less common finding only 2 cases in our study. There were no cases reported of actinic keratosis scleroderma, granuloma annulare, polymorphic light eruption and baker naevus in our study. There is limited regional data addressing skin changes of hypothyroidism. This study provides us with the various skin changes secondary to hypothyroidism in our population. There are certain limitations in our study like the small sample size and short duration of the study and lack of regional local data available. The authors recommended a better sample size and careful interpretation of data and further regional studies in this context with the prolonged duration of the study. The results of this study will help us with an earlier diagnosis and better management of patients that can prevent the systemic complications of hypothyroidism.

Conclusion
We conclude that the relationship between the skin and the thyroid gland is complex. Skin acts as an important diagnostic window to diseases affecting internal organs including thyroid disorders. Certain dermatological manifestations help in the early diagnosis and management of patients by early detection of changes in skin, hairs and nails secondary to hypothyroidism. Authors recommended screening for thyroid functions in patients presenting with suggestive dermatological manifestations irrespective of age and gender.

Conclusion
We are thankful to all participants who were involved in this study and others who have helped either directly or indirectly.