Subclinical hypothyroidism as a cause of leg swelling in patients attending tertiary level hospital in Kathmandu

Edema is an accumulation of fluid in the intercellular tissue that results from an abnormal expansion in interstitial fluid volume. The fluid between the interstitial and intravascular spaces is regulated by the capillary hydrostatic pressure gradient and the oncotic pressure gradient across the capillary. The accumulation of fluid occurs when local or systemic conditions disrupt this equilibrium leading to increased capillary hydrostatic pressure, increased plasma volume, decreased plasma oncotic pressure (hypoalbuminemia), increased capillary permeability, or lymphatic obstruction.1 Common causes of limb swellings are liver and cardiac in-sufficiency, mal-absorption of nutrients, protein and 1368


INTRODUCTION
Edema is an accumulation of fluid in the intercellular tissue that results from an abnormal expansion in interstitial fluid volume.The fluid between the interstitial and intravascular spaces is regulated by the capillary hydrostatic pressure gradient and the oncotic pressure gradient across the capillary.The accumulation of fluid occurs when local or systemic conditions disrupt this equilibrium leading to increased capillary hydrostatic pressure, increased plasma volume, decreased plasma oncotic pressure (hypoalbuminemia), increased capillary permeability, or lymphatic obstruction. 1  Common causes of limb swellings are liver and cardiac in-sufficiency, mal-absorption of nutrients, protein and calorie deficiency, venous and lymphatic incompetence and renal disease.One of the endocrinal causes of edema is hypothyroidism. 2Swelling of limbs in hypothyroidisms is mainly due to deposition of substances Hyaluronic acid (HA) is a non-sulfated glycosaminoglycan that is present throughout the body metabolism of which is affected by thyroid hormone mainly circulating T3 level. 3Apart from this the swelling may be contributed by low body temperature as seen in Wilsons temperature syndrome with low circulating thyroid hormone which is very rarely reported in medical literature.
Although there are list of medical conditions causing bilateral limb swelling during medical work up it is difficult to label a diagnosis in few patients. 4Thyroid dysfunction is mentioned as a cause of edema, however there has not been any large scale study implicating pedal edema with thyroid failure.Few articles reports that patients with mild thyroid failure, and even subjects with high normal serum TSH values, have evidence of endothelial dysfunction, manifested by impaired flow-mediated, endothelialdependent vasodilatation which may result in limb swelling. 4,5is study aims at finding out the incidence of subclinical hypothyroidism in patients presenting as pedal edema after ruling out cardiac disease, hepatic dysfunction, renal abnormalities and protein energy mal-absorption.

MATERIALS AND METHODS
This is a cross-sectional observational hospital based study done in patients who visited Medical OPD Nepal Medical College Teaching Hospital for painless pedal edema.Study period was 2 years, from May 2014 to April 2016.A total of 300 patients presented with symptoms of limb swelling.In various steps of history, clinical evaluation and laboratory testing, if they are found to have non-thyroidal illness contributing to the swelling, they are excluded.A total of 154 patients had thyroid function test along with other tests.Further 108 patients found to have investigations results could be attributable to the limb swelling are further excluded leading only to 46 patients.Eighty two patients, who were taking medications for hypertension, kidney disease and liver disease were excluded.Out of them, history of hypertension was present in 60, Kidney disease in 10 and Liver disease was present on 12 patients.They were evaluated appropriately.Further 26 patients who were giving history of ayurvedic medications were also excluded from history step only.Likewise, further 36 patients were not included as 26 of them had hypertension, 4 had irregular pulse and 6 had predominantly unilateral edema on clinical evaluation.They were evaluated depending on clinical indications.Remaining 154 patient were investigated by laboratory and imaging study.They had complete blood count, renal function test, liver function test, ECG, Chest x-ray, Echocardiography and thyroid function test.Total T3, T4 and TSH was done.Patients having abnormal Liver Function Test including low albumin were 33, those having abnormal renal function test including urine routine showing even trace albumin were 25,they were appropriately evaluated and not included in this study.Clinical hypo or hyperthyroidism was detected in 2cases, 1 hypo 1 hyperthyroidism.Chest x-ray was abnormal in 28 cases and Echocardiography was abnormal in 20 patients.These 48 patients were further excluded from the study.Finally 46 cases that had all other systemic disease excluded were included in study.After taking consent their age, sex , height , weight were taken and Body Mass Index(BMI) were calculated Thyroid Stimulating Hormone (TSH)measurements were noted.TSH were measured in the hospital laboratory by Chemiluminescence Immunoassay (CLIA) and cut off value is taken as given in laboratory

DISCUSSION
Subclinical hypothyroidism is biochemically defined as an elevated serum thyrotropin level in combination with a serum free T4 level that is within the population reference. 6revalence of abnormal thyroid function continues to be debated.Numerous studies from various countries differ in their prevalence estimates for both hypothyroidism and hyperthyroidism.In perhaps the best longitudinal study conducted to date, Tunbridge et al 7 found that 7.5% of women and 2.8% of men of all ages in Whickham, England, had serum thyrotropin (TSH) levels greater than 6 mIU/L.After reviewing 12 such studies across many different cultures, Vanderpump and Tunbridge concluded that primary thyroid gland failure (TSH >6 mIU/L) occurs in 5% of multiple populations. 8There is no large scale prevalence data available in Nepal.However a hospital based study of eastern Nepal shows about 20% of their patient sent for laboratory evaluation had subclinical hypothyroidisms(TSH >6.2mIU/L) 9 In our study out of 46 patient, 57% were having high TSH which higher than the study done in eastern Nepal and probably points towards etiology of the swelling.
There are numerous direct and indirect biochemical responses to hypothyroidism that affect nearly all organ systems.At the capillary level, there is increased permeability resulting in the accumulation of proteins and mucopolysaccharides in the interstitium, followed by sodium and water.There is a concomitant expansion in total body water and sodium. 10Although there are few case repots of subclinical hypothyroidism causing edema, there has not been any study looking specifically subclinical hypothyroidism as a cause of pedal edema.Increased rates of fatigue, muscle weakness, weight gain, cold intolerance, and constipation have also been reported variably in association with subclinical hypothyroidism. 11here has been description of patients presenting with swelling and accumulation of fluid in serous cavities with subclinical hypothyroidism.Parving et al demonstrated that combination of increased extravasations of plasma protein and lack of compensatory lymph flow and protein return rate swelling and fluid collection in serous cavity. 12It has been reported that development of pleural effusion depends on duration of hypothyroidism than degree of hypothyroidism 13 Furthermore tissue hypothyroidism at peripheral target organ may be different for different individual, there have been reports that people having severe biochemical derangement had only mild signs while those having mild derangement had severe signs and symptoms. 14bclinical hypothyroidism is mainly found in female.In a study done in Pakistan shows only 6.2% of the people presenting with subclinical hypothyroidism were male. 15his is in par with our study where out of 46 patients only 3 are male.Most common age of presentation in our study is 30-50 years of age.This is similar to a study done in Uzbekistan which shows prevalence of 64% age more than 40 year of age. 16gh TSH level for the test ha also to be viewed in context variability of TSH in various age, sex, ethnicity and body mass index.A study done in more than 4000 Delhi adults shows that mean TSH value was 2.2 ± 0.9 mIU/L. 17In another study done in India shows that TSH with increasing BMI.As the BMI increased, mean TSH in the BMI range also increased.The individuals with higher BMI had higher TSH and this trend continued from underweight to Obese.

CONCLUSION
In this observational study done in a medical college, patients with painless pedal edema were found to have higher BMI and high TSH value.TSH value was significantly co-related with swelling.It is logical to ask for thyroid function test to evaluate bilateral painless limb swelling; however there need to be more data on such cases and interventional trials to show that people with high TSH benefit from thyroxine therapy.

Table 4 : Subclinical hypothyroid and Pedal edema
40%) of the people were either obese or overweight but mean TSH value is almost four times the level of TSH in obese people in Indian study.So it is unlikely that only obesity is contributing to the high TSH in this study.Severe Subclinical hypothyroidism were observed in 7 (15%) of DOI : 10.3126/jpn.v%vi%i.20875