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ORIGINAL ARTICLE
Year : 2018  |  Volume : 15  |  Issue : 1  |  Page : 29-33

Spectrum of clinical symptomatology and its resolution following levothyroxine supplementation in primary and subclinical hypothyroidism: An Indian perspective


1 Department of Medicine, Gandhi Medical College, Bhopal, Madhya Pradesh, India
2 Department of Endocrinology, Diabetology and Metabolic Disorders, Venkateshwar Hospital, New Delhi, India

Date of Web Publication23-Mar-2018

Correspondence Address:
Prof. Deep Dutta
Department of Endocrinology, Diabetology and Metabolic Disorders, Venkateshwar Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/trp.trp_1_18

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  Abstract 


Background: Data are scant on the spectrum of features associated with subclinical hypothyroidism (ScH) and overt primary hypothyroidism (OPH). This study aimed was to determine the burden as well as predictors of the lack of resolution of symptoms of hypothyroidism in patients of ScH and OPH following levothyroxine supplementation.
Methods: A total of 505 patients were screened, of which 411 consecutive patients with ScH and 94 with OPH were evaluated. Data from 347 patients with ScH and 76 patients with overt OPH, who completed the study, were analyzed. Thyroid symptomatology was evaluated using standardized questionnaire.
Results: The median age of participants was 35 (28–41) years; 95.04% being females. Common symptoms in OPH were shortness of breath (72.36%), depression (57.89%), irritability (57.89%), periorbital edema (53.94%), “feeling tired” (51.31%), and swelling of limbs (48.68%). Common symptoms in ScH were “feeling tired” (62.82%), “unhappy with routine” (44.95%), depression (40.92%), irritability (38.90%), and “weight gain with a poor appetite” (36.31%). Goiter was documented in 31.58% OPH and 3.17% in ScH (P < 0.001). Hair loss was observed 31.57% OPH and 29.68% ScH. Median (interquartile range) dose of levothyroxine supplemented was 37.5 (12.5–50) and 100 (75–112.5) mcg, respectively. Resolution of hypothyroidism symptoms was lesser in ScH. Persisting features included goiter, irregular menstruation, “weight gain with poor appetite,” irritability, depression, “feeling tired,” body aches, and depression. Binary logistic regression revealed thyroid stimulating hormone (TSH) to be an independent predictor of symptoms resolution. Every unit increase in TSH was associated with 0.7% greater resolution.
Conclusion: Symptoms associated with hypothyroidism are diverse and nonspecific. Resolution of symptoms following levothyroxine supplementation and achieving biochemical euthyroidism is more likely in OPH that ScH.

Keywords: Hypothyroidism, subclinical hypothyroidism, symptomatology


How to cite this article:
Chittawar S, Nagdeote A, Nair A, Kawre KK, Dutta D. Spectrum of clinical symptomatology and its resolution following levothyroxine supplementation in primary and subclinical hypothyroidism: An Indian perspective. Thyroid Res Pract 2018;15:29-33

How to cite this URL:
Chittawar S, Nagdeote A, Nair A, Kawre KK, Dutta D. Spectrum of clinical symptomatology and its resolution following levothyroxine supplementation in primary and subclinical hypothyroidism: An Indian perspective. Thyroid Res Pract [serial online] 2018 [cited 2018 May 25];15:29-33. Available from: http://www.thetrp.net/text.asp?2018/15/1/29/228371




  Introduction Top


Symptoms of hypothyroidism are well known, varied and include fatigue, cold intolerance, swelling of the limbs, hoarse voice, constipation, dry and coarse skin, yellow tinge to the skin, cold extremities, weight gain despite of poor appetite, shortness of breath, menstrual disturbances such as oligomenorrhea, amenorrhea and menorrhagia, decreased libido in both sexes, poor memory and poor concentration and other psychiatric disturbances. Signs of hypothyroidism include dry and dull hair, which can be plucked easily, brittle nails, slow pulse rate, delayed relaxation of tendon reflexes.[1] In spite of this knowledge, many of these symptoms of hypothyroidism are nonspecific and can occur in many other disorders. There is also a lot of heterogeneity with regard to symptoms believed to be associated with hypothyroidism both among the patients as well as treating doctors.[2],[3] Furthermore, many patients frequently complain about the persistence of symptoms related to hypothyroidism, even after achieving biochemical euthyroidism. Data are scant evaluating the resolution of symptoms of hypothyroidism in patients with overt primary hypothyroidism (OPH) and subclinical hypothyroidism (ScH). Hence, the aim of this study was to determine the burden as well as predictors of the lack of resolution of symptoms of hypothyroidism in patients with OPH and ScH following levothyroxine supplementation.


  Methods Top


This study was conducted at two tertiary care centers of northern and central India. The study duration was from April 2016 to December 2017. Consecutive patients >18 years age, newly diagnosed with subclinical or OPH (thyroid stimulating hormone [TSH] >25 mU/ml with low free T4, treatment naïve, was considered for the study. Hypothyroid patients already on treatment, sick patients requiring hospital admission, patients with malignancy or history of malignancy in the past 5 years, pregnant hypothyroid women at the time of enrolment were not included in the study. Thorough clinical history was recorded, including enquiry regarding symptoms such as feeling tired, inability to tolerate cold, weight gain with poor appetite, constipation, shortness of breath, hoarse voice, menstrual disturbances, dry coarse skin, itching, cold extremities, swelling of limb, periorbital edema, hair loss, brittle nails, yellowish discoloration of skin, body ache, tingling sensation in extremities, goiter, and psychiatric manifestations such as irritability, depression, concentration, sleep disturbances, interest in the surroundings, happy with routine, responsibility and self-confidence, using a standardized questionnaire. The study protocol was explained, and only those who gave informed written consent were included in the study.

All patients underwent detailed clinical and anthropometric assessment. The patients were called the subsequent day in fasting state for blood sampling. Blood samples of 5 ml each were collected in plain and ethylenediaminetetraacetic acid vacutainers (Becton Dickinson) between 8 and 9 am in the morning. Serum was separated from blood collected in plain vacutainer and processed immediately for thyroid hormone analysis, and one aliquot of serum was stored at −20° C.

All the patients were initiated on levothyroxine therapy with the target of achieving euthyroidism over a period of 12 weeks. The patients were recalled at 6 weeks for reevaluation of thyroid function, and the levothyroxine dose was adjusted with the aim of maintaining/achieving biochemical euthyroidism. The patients were recalled again at 12 weeks of follow-up for evaluation of thyroid function. Only those patients who were biochemically euthryoid at 12 weeks follow-up were reevaluated for resolution of symptoms of hypothyroidism. The patients were again enquired in detail about the symptoms of hypothyroidism during this follow-up visit. Patients with persistence of at least 1 of the symptoms of hypothyroidism in the questionnaire were defined to have the lack of resolution of symptoms of hypothyroidism. Only patients with negative response to all the questions of symptoms of hypothyroidism were defined to have resolution of hypothyroidism symptoms.

Statistical analysis

Normality of the distribution of variables was checked using the Kolmogrov–Smirnov test. Independent t-test and Wilcoxon rank sum test were done for normally distributed and skewed variables, respectively. Chi-square tests were used for categorical variables. Binary logistic regression analyses were performed to determine variables that independently influenced the resolution of symptoms of hypothyroidism following levothyroxine supplementation. The value of P < 0.05 was considered statistically significant. Statistical Package for the Social Sciences (SPSS) version 20 (Chicago, IL, USA) was used for data analysis.


  Results Top


A total of 505 patients were screened for this study (288 from Center-A and 217 from Center-B). 411 consecutive patients with ScH and 94 patients with OPH were screened, of which a total of 347 patients with ScH and 76 patients with overt OPH, who fulfilled all criteria, gave informed written consent, and completed the study were analyzed.

The baseline clinical, anthropometric, and biochemical parameters of patients with ScH and OPH are elaborated in [Table 1]. The median age of the study participants was 35 (28–41) years with 95.04% of participants being females [Table 1]. Patients with ScH had significantly higher BMI and fasting blood glucose [Table 1]. Lipid parameters were comparable in ScH and OPH [Table 1]. A total of 170 patients with ScH and 52 patients with OPH were evaluated at the end of the study. 177 patients of ScH were lost to follow-up at the end of the study, thus having an attrition rate of 51%. 16 patients with OPH were lost at the end of the study, thus having an attrition rate of 21.05%. 16 patients with ScH and 8 patients with OPH failed to achieve biochemical euthyroidism at the end of the study and hence excluded from the follow-up analysis.
Table 1: Baseline and posttreatment clinical and biochemical profile of patients with primary and subclinical hypothyroidism

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Symptoms and signs associated with hypothyroidism were significantly more common in patients with OPH as compared to ScH [Table 2]. The most common symptoms observed in patients with OPH were shortness of breath (72.36%), depression (57.89%), irritability (57.89%), periorbital edema (53.94%), “feeling tired” (51.31%), and swelling of limbs (48.68%) [Table 2]. In contrast, the most common symptoms observed in patients with ScH were “feeling tired” (62.82%), “unhappy with routine” (44.95%), depression (40.92%), irritability (38.90%), and “weight gain with poor appetite” (36.31%) [Table 2]. Goiter was documented in 31.58% of patients with OPH in contrast to 3.17% in ScH (P< 0.001) [Table 2]. Hair loss was a common problem observed 31.57% of patients of OPH and 29.68% of patients with ScH [Table 2].
Table 2: Baseline and posttreatment clinical profile of thyroid symptomatology in patients with primary and subclinical hypothyroidism

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In patients with OPH, most of the symptoms and signs associated with hypothyroidism resolved after achieving euthyroidism. Persisting features in OPH included goiter (11.53%; significantly reduced with regard to baseline; P < 0.001), irregular menstruation (15.38%), weight gain with poor appetite, irritability, and depression (7.69% each; significantly lower with regards to baseline; P < 0.001), and body aches in 1 patient (1.92%) [Table 2]. In contrast, the complete resolution of symptoms in ScH was comparatively lower. Persistent features in patients with ScH included “feeling tired” (10.38%), irritability (6.49%), body aches (5.2%), swelling of legs (5.20%), and depression (3.24%) [Table 2].

Median (interquartile range) dose of levothyroxine received by patients with ScH and OPH in this study was 37.5 (12.5–50) and 100 (75–112.5) mcg, respectively. Eight out of 52 patients (15.38%) with OPH and 26 out of 170 patients (15.29%) with ScH had the lack of resolutions of all the symptoms related to hypothyroidism at the end of the study [Table 2]. Binary logistic regression revealed that only serum TSH was the independent significant predictor of resolution of symptoms of hypothyroidism [Table 3]. Every unit increase in baseline TSH (pretreatment) was associated with 0.7% greater resolution of symptoms of hypothyroidism following levothyroxine supplementation.
Table 3: Binary logistic regression analysis showing baseline factors that independently predict resolution of symptoms of hypothyroidism on levothyroxine supplementation

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  Discussion Top


The study highlighted that as commonly perceived, the symptoms associated with hypothyroidism are highly diverse and nonspecific. Tiredness, fatiguability, depression, irritability, weight gain, poor appetite, hair loss, facial, and limb swelling were the common symptoms associated with hypothyroidism in our study. Goiter was common in OPH (one-third patients) but rare in ScH. Fatigue was the most common complaint noted among all the symptoms in a large multicentric thyroid registry study, which is similar to our observations.[1] However in that study, though clinical data were collected from 1500 patients, data on biochemical status of hypothyroidism (serum TSH) was available only from 291 patients.[1] Among women in the reproductive age group, menstrual irregularities were quite common in our study (16%) as well as in the thyroid registry study.[2] The prevalence of menstrual irregularities (mainly oligomenorrhea) as reported by Krassas et al. was 23% against 8% in the control population.[4] A Swiss study involving 332 women with hypothyroidism reported that 24% of the patients with ScH exhibited typical symptoms of hypothyroidism.[5]

In the present study, only 1.7% of patients with ScH were asymptomatic, and all those who were asymptomatic were from the group of ScH with TSH <10 mIU/ml. A cross-sectional study done in Colorado, United States, included 25,862 patients and compared symptoms in hypothyroid patients, both overt and ScH with euthyroid subjects.[6] The Colorado study concluded that euthyroid subjects and patients with OPH or ScH all had similar constellations of symptoms. Individual symptoms were not very sensitive; therefore, it can be difficult to distinguish a euthyroid subject from one with either OPH or ScH on the basis of symptomatology alone.[6]

In another study was done in the year 2006 by Rolf Jorde et. Al., evaluation of the relation between neuropsychological function and ScH (serum TSH 3.5–10.0 mIU/L) was done.[7] It concluded that there is no neuropsychological dysfunction in the SCH group with TSH between 3.5 and 10 mIU/L, and compared with healthy controls, there is no difference in symptoms related to hypothyroidism.[7] One study by Gulseren et al., in the year 2005, investigated the effects of thyroid dysfunction on quality of life, levels of depression/anxiety, in both hypothyroid and hyperthyroid patients.[8] Anxiety and depressive symptoms were more severe in patients with overt hypothyroidism and hyperthyroidism. The quality of life was worse in OPH or subclinical hyperthyroidism and ScH groups than in the control group.[8] In the present study, neuropsychiatric symptoms were more frequently noticed in patients of OPH group. Altered prolactin levels have been linked to increased neuropsychiatric manifestations. We have documented increased prolactin levels in both children as well as adults with ScH.[9],[10]

An important highlight of this study is that the resolution of the symptoms and signs associated with hypothyroidism is more marked in patients with OPH as compared to ScH. Persisting features in our study included goiter (11.53%), irregular menstruation (15.38%), weight gain with poor appetite, irritability, and depression (7.69% each) among others in patients with OPH and “feeling tired” (10.38%), irritability (6.49%), body aches (5.2%), swelling of legs (5.20%), among others in ScH.

The strength of this study includes the largest number of patients ever evaluated from India, having the entire clinical and biochemical profile of hypothyroidism and analysis of symptoms after biochemical correction of hypothyroidism. Limitations of this study include the dropout of patients, especially in the ScH group. Mild hypothyroidism in ScH with associated nonspecific features, which do persist in a significant number of patients posttreatment may explain this large dropout in the ScH group.

To summarize, it may be said that symptoms associated with hypothyroidism are diverse and nonspecific. Neuropsychiatric manifestations (depression, irritability, feeling tired,” “unhappy with routine,” body aches) constitute a significant amount of the symptoms associated with hypothyroidism. Common physical symptoms include swelling, goiter, hair loss, and menstrual irregularities. Resolution of symptoms following levothyroxine supplementation and achieving biochemical euthyroidism is more likely in OPH that ScH. Hence, biochemical evaluation of thyroid function will continue to an integral part of managing ScH and OPH, and care should be taken to avoid potential labomas.[11]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sethi B, Barua S, Raghavendra MS, Gotur J, Khandelwal D, Vyas U, et al. The thyroid registry: Clinical and hormonal characteristics of adult Indian patients with hypothyroidism. Indian J Endocrinol Metab 2017;21:302-7.  Back to cited text no. 1
    
2.
Kumar P, Khandelwal D, Mittal S, Dutta D, Kalra S, Katiyar P, et al. Knowledge, awareness, practices and adherence to treatment of patients with primary hypothyroidism in Delhi. Indian J Endocrinol Metab 2017;21:429-33.  Back to cited text no. 2
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3.
Surana V, Aggarwal S, Khandelwal D, Singla R, Bhattacharya S, Chittawar S, et al. A2016 clinical practice pattern in the management of primary hypothyroidism among doctors from different clinical specialties in New Delhi. Indian J Endocrinol Metab 2017;21:165-77.  Back to cited text no. 3
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4.
Krassas GE, Pontikides N, Kaltsas T, Papadopoulou P, Paunkovic J, Paunkovic N, et al. Disturbances of menstruation in hypothyroidism. Clin Endocrinol (Oxf) 1999;50:655-9.  Back to cited text no. 4
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5.
Zulewski H, Müller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinical score: Evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997;82:771-6.  Back to cited text no. 5
    
6.
Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526-34.  Back to cited text no. 6
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7.
Jorde R, Waterloo K, Storhaug H, Nyrnes A, Sundsfjord J, Jenssen TG, et al. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab 2006;91:145-53.  Back to cited text no. 7
    
8.
Gulseren S, Gulseren L, Hekimsoy Z, Cetinay P, Ozen C, Tokatlioglu B, et al. Depression, anxiety, health-related quality of life, and disability in patients with overt and subclinical thyroid dysfunction. Arch Med Res 2006;37:133-9.  Back to cited text no. 8
    
9.
Sharma N, Dutta D, Sharma LK. Hyperprolactinemia in children with subclinical hypothyroidism. J Clin Res Pediatr Endocrinol 2017;9:350-4.  Back to cited text no. 9
    
10.
Sharma LK, Sharma N, Gadpayle AK, Dutta D. Prevalence and predictors of hyperprolactinemia in subclinical hypothyroidism. Eur J Intern Med 2016;35:106-10.  Back to cited text no. 10
[PUBMED]    
11.
Dutta D, Chowdhury S. Endocrine labomas. Indian J Endocrinol Metab 2012;16:S275-8.  Back to cited text no. 11
[PUBMED]    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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