|Year : 2020 | Volume
| Issue : 3 | Page : 235-241
Evaluation of significance of hyponatremia in hypothyroidism in an urban female population of Eastern India: A cross-sectional study
Samarjit Koner1, Arunima Chaudhuri2
1 Department of Biochemistry, College of Medicine and Sagore Dutta Hospital (Affiliated to West Bengal University of Health Sciences), Kamarhati, West Bengal, India
2 Department of Physiology, Rampurhat Government Medical College and Hospital (Affiliated to West Bengal University of Health Sciences), Rampurhat, West Bengal, India
|Date of Submission||27-Feb-2019|
|Date of Acceptance||12-Aug-2019|
|Date of Web Publication||3-Jun-2020|
Department of Physiology, Rampurhat Government Medical College and Hospital (Affiliated to West Bengal University of Health Sciences), Rampurhat, West Bengal
Source of Support: None, Conflict of Interest: None
Background: Hypothyroid patients may have reduced sodium levels, but the strength of such a link is still not clearly defined. Aims: This study aims to evaluate the significance of hyponatremia in hypothyroidism in an urban young female population of eastern India. Materials and Methods: This cross-sectional study was conducted on 200 hypothyroid patients in Burdwan Medical College in a period of 12 months after taking Institutional Ethical Clearance. 100 controls were taken for the study. Serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), and sodium levels were estimated. The individuals were age matched. The computer software Statistical Package for the Social Sciences, version 16.0 was used for analyzing data. Results: 200 hypothyroid patients were enrolled for the study. 31 hypothyroid patients presented with reduced serum sodium level (15.5%). Significant difference was observed between controls and hypothyroid patients for mean TSH (P < 0.0001), mean FT4 (P < 0.0001), and mean sodium (P < 0.0001). No significant difference of age was observed between two groups. Serum sodium level was negatively correlated with TSH (r: -0.59, P < 0.00001), and serum sodium was positively correlated with serum FT4 (r: 0.29, P: <0.0000). Conclusions: Hypothyroid females in reproductive age group may have significant decrease in serum sodium levels as compared to normal individuals, and serum sodium needs to be estimated in hypothyroid patients for better management of patients.
Keywords: Hyponatremia, hypothyroidism, Indian female population
|How to cite this article:|
Koner S, Chaudhuri A. Evaluation of significance of hyponatremia in hypothyroidism in an urban female population of Eastern India: A cross-sectional study. Med J DY Patil Vidyapeeth 2020;13:235-41
|How to cite this URL:|
Koner S, Chaudhuri A. Evaluation of significance of hyponatremia in hypothyroidism in an urban female population of Eastern India: A cross-sectional study. Med J DY Patil Vidyapeeth [serial online] 2020 [cited 2020 Oct 25];13:235-41. Available from: https://www.mjdrdypv.org/text.asp?2020/13/3/235/285772
| Introduction|| |
Thyroid diseases are among the most common endocrine disorders worldwide. 42 million people in India have been estimated to be suffering from thyroid diseases. Early diagnosis and treatment remain the cornerstone of effective management.,
Hormones play a significant role in regulation of electrolyte homeostasis. Hypothyroidism has long been linked with the development of hyponatremia. Increase in vasopressin (antidiuretic hormone [ADH]) release and decrease in glomerular filtration rate (GFR) are included as the proposed mechanism of hypothyroidism-induced hyponatremia.,, Alteration in ADH or GFR diminishes renal capacity for excretion of free water and causes water retention leading to hyponatremia. Hyponatremia and hypothyroidism are quite common in the general population, with either acute or chronic illness, and found to be more common in the hospitalized patients. Hence, their simultaneous occurrence is not at all surprising, and it should not be concluded that their common occurrence establishes causality. They are likely to be additional confounding factors and comorbidities in these cases that may be driving the development of the hyponatremia, rather than the hypothyroidism alone.,,
Some studies have noticed weak or no relation between hypothyroidism and hyponatremia.,, Hyponatremia may not be a consequence of hypothyroidism. Hence, other etiologies of hyponatremia need to be sought out.
Metabolic disorders and modification of the normal metabolic pathways in different organs including kidney is directly caused by change in serum thyroid hormones. Hypothyroidism decreases metabolism of electrolytes including sodium.
In hypothyroidism, Na+ K+ ATPase pump activity is lowered which leads to reduction of Na + reabsorption. Renin biosynthesis is decreased in kidney in hypothyroidism, and it causes reduction of angiotensin 1 from angiotensinogen which results in reduction of angiotensin II synthesis. Angiotensin II is the key hormone of Na + reabsorption from the kidney.,
Sodium iodide symporter-mediated iodide transport is also caused by the sodium gradient by the Na + K + ATPase.,
Renin–angiotensin–aldosterone system primarily regulates sodium balance. Extracellular fluid sodium concentration and also osmoregulatory system regulated by posterior pituitary hormone arginine vasopressin, show the overall sodium content of the body.
Renal hemodynamics, kidney structure, GFR, sodium, and water hemostasis are influenced by thyroid hormone. Na + K + ATPase activity and Na + H + exchanger are affected by thyroid hormones.
Another possible mechanism of hyponatremia in hypothyroidism is syndrome of inappropriate antidiuretic hormone (SIADH). Hyponatremia in SIADH caused by medication is extremely infrequent, and hyponatremia is resolved quickly by treatment of hypothyroidism despite continuation of these medications.
The present study was conducted to examine the prevalence of hyponatremia in hypothyroidism and to evaluate significance of hyponatremia in hypothyroidism in an urban female population of eastern India. Hypothyroidism is more common in females as compared to males, so they were chosen as the study population. Women have a life expectancy advantage over men, but a marked disadvantage with regard to morbidity. Thyroid disorders are common in India, but scarce data exist on its prevalence in young women. Hence, females in reproductive age group were selected for the present study.
| Materials and Methods|| |
This cross-sectional study was conducted in Burdwan Medical College on 200 newly diagnosed hypothyroid female individuals during a time span of 12 months after taking institutional ethical clearance and informed consent of the individuals. 100 controls were taken for the study. The formula we used for the calculation of the size of the required sample was n = (z)2 P (1 − p)/d2, n = sample size, z = z statistic for a level of confidence (95% level of confidence used, so z value is 1.96, P = expected prevalence of proportion, d = desired precision taken as 6%. Previous studies were taken into consideration.,
200 newly diagnosed hypothyroid female individuals of reproductive age group attending in the Department of Biochemistry, Burdwan Medical College were taken for the study and 100 controls were enrolled.
The exclusion criteria include the patients with
- Usage of drugs causing hyponatremia, especially diuretics (thiazides)/some antidepressants and pain medications
- Heart failure
- Diarrhea/severe vomiting
- Liver diseases (liverfunction test done)
- Kidney diseases (serum creatinine done)
- History of drinking too much water
- Adrenal gland insufficiency (Addison's disease)
- Prolonged exercise and sweating
- Usage of amphetamines
- Thyroid-stimulating hormone (TSH)
- Free thyroxine (FT4)
- Serum sodium.
Approval from the institutional ethics committee was taken before conduction of the study, and informed consent was taken from the participants. Individuals were selected by random sampling using an online randomizer. Detailed history was taken from each individual as per case record format.
Blood samples were collected from individuals by sterile needle and syringes and sent to biochemical laboratory in sterile vials for analysis.
Estimation of serum TSH was done by quantitative determination of TSH concentration by microplate immunoenzymometric assay using Monobind Inc. USA-manufactured TSH AccuBind ELISA Kit (normal value: 0.39–6.16 μ IU/ml).
Estimation of serum FT4 level was done by Quantitative determination of FT4 concentration by microplate enzyme immunoassay using Monobind Inc. USA-manufactured FreeT4 AccuBind ELISA Kit (normal value: 0.8–2.0 ng/dl).
Estimation of thyroid-stimulating hormone
Measurement of serum TSH is generally regarded as the most sensitive indicator for the diagnosis of hypothyroidism.
Test principle (immunoenzymometric assay)
The immobilization occurs at the surface of microplate well between the interaction of streptavidin coated on the well and biotinylated monoclonal anti-TSH antibody. By mixing the monoclonal biotinylated antibody, the enzyme-labeled antibody, and a serum-containing native antigen, reaction occurs between native antigen and the antibodies to form a soluble sandwich complex. Then, the complex is deposited to the well. After equilibrium is achieved, the antibody bound fraction is separated from unbound antigen by aspiration or decantation. The enzymatic activity of the antibody bound fraction which is directly proportional to the native-free antigen concentration is measured by adding substrate. By utilizing calibrators of known antigen concentrations, a dose–response curve can be generated from which the antigen concentration of an unknown sample can be ascertained.
- Streptavidin-coated microplates – 96 wells coated with streptavidin and packaged in an aluminum bag with a drying agent
- TSH enzyme reagent – 13 ml/vial containing enzyme-labeled polyclonal antibody, biotinylated monoclonal IgG in buffer, dye, and preservative
- Thyrotropin calibrators – seven vials (0.5 ml/vial) of references for TSH Antigen at levels of 0, 0.5, 2.5, 5.0, 10, 20 and 40 μIU/ml
- Substrate A (7 ml/vial) – one bottle containing tetramethylbenzidine (TMB) in buffer
- Substrate B (7 ml/vial) – one bottle containing hydrogen peroxide (H2O2) in buffer.
- Stop solution (8 ml/vial) – one bottle containing a strong acid (1 N HCL)
- Wash solution concentrate (20 ml) – one vial containing a surfactant in buffered saline. A preservative has been added.
Calculation of results
- Calculation of the mean absorbance value of calibrator and samples was done at 450 nm
- A point-to-point curve was plotted by plotting the absorbance of each calibrator on the vertical Y-axis against concentration of each calibrator on the horizontal or X-axis
- Using the absorbance value for each sample, the corresponding concentration of TSH was determined in μIU/ml from the standard curve.
Controls were assayed at levels in the low, normal, and high range for monitoring assay performance. These controls were regarded as unknowns and values determined in every test procedure performed. Quality control charts were maintained to follow the performance of the supplied reagents. Pertinent statistical methods were employed to get trends. Acceptable assay performance limits were set. Other parameters monitored included the 80%, 50%, and 20% intercepts of the dose–response curve for run-to-run reproducibility. Maximum absorbance was consistent with previous experience. Significant deviation from established performance can indicate unnoticed change in experimental conditions or degradation of kit reagents. Fresh reagents were used to determine the cause for the variations.
Estimation of free thyroxine
Thyroxine circulates in blood almost bound to carrier proteins. Thyroxine-binding globulin is the main carrier protein. Only the free (unbound) fraction of thyroxine is biologically active. Concentrations of the carrier proteins are altered in different clinical conditions. Hence, the FT4 concentration remains constant. The measurement of FT4 concentration correlates better than total thyroxine level.
Test principle (competitive enzyme immunoassay)
In competitive enzyme immunoassay, a competitive reaction results between the native-free antigen and enzyme-antigen conjugate for limited number of insolubilized binding sites on antibody coated on the micro well. After the equilibrium is attained, the antibody-bound fraction is separated from unbound antigen by aspiration or decantation. The enzymatic activity of the antibody-bound fraction which is inversely proportional to the native-free antigen concentration is measured by adding substrate. By utilizing calibrators of known antigen concentrations, a dose–response curve can be generated from which the antigen concentration of an unknown sample can be found out.
- FT4 antibody-coated microplate (96 wells) – one 96 well microplate coated with antithyroxine serum
- Enzyme reagent (13 ml/vial) – one vial of thyroxine-horseradish peroxidase conjugate in a protein-stabilized matrix
- FT4 calibrators (0.5 ml/vial) – six vials of human serum-based reference calibrators for free thyroxine
- Substrate A (7 ml/vial) – one bottle containing TMB in acetate buffer
- Substrate B (7 ml/vial) – one bottle containing H2O2 in acetate buffer
- Wash solution concentrate (20 ml) – one vial containing a surfactant in buffered saline
- Stop solution (8 ml/vial) – one bottle containing a strong acid (1 N HCL).
- Calculation of absorbance value was done at 450 nm
- A point-to-point curve was plotted by plotting the absorbance of each calibrator on Y axis against concentration of each calibrator on X axis
- Using the absorbance value for each sample, the corresponding concentration of FT4 was determined in ng/dl from the standard curve.
Controls were assayed at levels in the hypothyroid, euthyroid, and hyperthyroid range for monitoring assay performance. These controls were treated as unknowns and values determined in every test procedure performed. Quality control charts were maintained to follow the performance of the supplied reagents. Pertinent statistical methods were employed to ascertain trends. Significant deviation from established performance can indicate unnoticed change in experimental conditions or degradation of kit reagents. Fresh reagents were used to determine the reason for the variation
Estimation of serum sodium
Serum sodium was estimated by ion-selective electrode which is a transducer that converts the activity of a specific ion dissolved in a solution into an electrical potential.
Medica EasyLyte Analyzer was used for the estimation of serum sodium (normal value: 136–146 mEq/L or mmol/L).
Principle of the procedure
The EasyLyte analyzer measures sodium in human serum, plasma, whole blood and urine using ionselective electrode technology. The flow-through sodium electrode uses a selective membrane that is especially formulated to be sensitive to sodium ions. The potential of each electrode is measured relative to a fixed and stable voltage that is established by the double-junction silver/silver chloride reference electrode. An ion-selective electrode develops a voltage that varies with the concentration of the ion to which it responds. The relationship between the voltage developed and the concentration of the sensed ion is logarithmic, as expressed by the Nerst equation:
Where: E = The potential of the electrode in sample solution
E0= The potential developed under standard conditions
RT/nF = A temperature dependent “constant,” termed the slope (s)
n = 1 for sodium, potassium, lithium
Log = Base ten logarithm function
g = Activity coefficient of the measured ion in the solution
C = Concentration of the measured ion in the solution.
Controls were used on a daily basis to verify the accuracy and precision of analyzer. EasyLyte was calibrated, and then, quality control results obtained were observed whether within specified range or not. Controls were assayed at levels in the low, normal, and high range for monitoring assay performance.
Expected value ranges for the specified lots of controls were listed on the sheet. Approximately 95% of means from analyzer, operating according to specification, were expected to fall within ranges.
Hypothyroidism was defined as an elevated TSH (>6.16 μIU/ml) with a decreased (<0.8 ng/dl) or normal serum FT4 level (range: 0.8–2.0 ng/dl) as per kit values.
Hyponatremia was considered as decreased level of serum sodium concentration below 136 mEq/L as per laboratory value.
All the individuals were examined in the postmenstrual phase as there is normal retention of fluid in the premenstrual phase.
Statistical data analysis
The computer software “Statistical Package for the Social Sciences (SPSS) version 16 (SPSS Inc., Released 2007. SPSS for Windows, Version 16.0. Chicago, IL, USA)” was used to analyze the data, P < 0.05 was considered as significant, and P < 0.01 was considered as highly significant.
| Results|| |
200 newly diagnosed hypothyroid female individuals and 100 controls were enrolled in our study. 31 individuals were having hyponatremia out of 200. There was no significant difference in age between the two groups (age in years: 30.82 ± 6.55 vs. 31.54 ± 6.68; P: 0.376). The prevalence of hyponatremia was 15.5% in hypothyroid patients.
Significant difference was observed between controls and hypothyroid patients for mean TSH (P < 0.0001), mean FT4 (P < 0.0001), and mean serum sodium (P < 0.0001). No significant difference was observed for mean age between controls and hypothyroid patients [Table 1] and [Figure 1].
|Table 1: Age, thyroid-stimulating hormone, free thyroxine, and serum sodium values of controls and hypothyroid patients|
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|Figure 1: The difference of age, thyroid-stimulating hormone, free thyroxine, and serum sodium values between controls and hypothyroid patients|
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Serum sodium level was negatively correlated with serum TSH (r: -0.59, P < 0.00001) [Figure 2] and serum sodium was positively correlated with Sr. FT4 (r: 0.28, P < 0.00001) [Figure 3].
|Figure 2: Serum sodium level was negatively correlated with serum thyroid-stimulating hormone (r: -0.59, P<0.00001)|
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|Figure 3: Serum sodium level was positively correlated with serum free thyroxine (r: 0.2965, P: <0.00001)|
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[Table 1] shows that the difference of TSH, FT4, and serum sodium were highly significant.
| Discussion|| |
It is a well-known fact that thyroid disorders are common in India. India is undergoing a transition from iodine-deficient to iodine-sufficient state. Hypothyroidism in young women is also linked to menstrual irregularities, polycystic ovaries, and infertility. The present study was conducted to evaluate significance of hyponatremia in hypothyroid individuals in an urban female population of reproductive age group. We had enrolled 200 hypothyroid female individuals and 100 controls in our study. Significant difference was observed between controls and hypothyroid patients for mean TSH (P < 0.0001), mean FT4 (P < 0.0001), and mean serum sodium (P < 0.0001). No significant difference of age was observed between two groups. Factors causing hyponatremia other than hypothyroidism were excluded from our study.
Hyponatremia in hypothyroidism may result due to the decreased capacity of free water excretion by increased antidiuretic hormone (ADH) level, and impaired water excretion is mediated by the upregulation of ADH-induced expression of aquaporin 2 in the collecting tubules. Nakana et al. in a study noticed hypothyroidism showing hyponatremia and increased plasma ADH without hypovolemia. Hypothyroidism is one of the causes of hyponatremia; thus, TSH determination is mandatory during the evaluation of patients with reduced serum sodium levels. The main mechanism for the development of hyponatremia in patients with chronic hypothyroidism is the decreased capacity of free water excretion due to elevated ADH levels, which are mainly attributed to the hypothyroidism-induced decrease in cardiac output. Recent data suggest that the hypothyroidism-induced hyponatremia is rather rare and probably occurs only in severe hypothyroidism and myxedema. Other possible causes and superimposed factors of hyponatremia (e.g., drugs, infections, and adrenal insufficiency) should be considered in patients with mild/moderate hypothyroidism. Treatment of hypothyroidism and fluid restriction are necessarily adequate for the management of mild hyponatremia in patients with hypothyroidism. All hypothyroid patients with low serum sodium levels need to be evaluated for other causes and superimposed factors of hyponatremia and treated accordingly.,,,,,,,
Hypothyroidism can cause global developmental abnormalities and acute metabolic disorders. Most cases of hypothyroid hyponatremia occurred in clinical practice in inpatient setting where additional confounding factors comorbidities may be the driving factors of hyponatremia rather than hypothyroidism alone.
A case report in 2000 showed that hyponatremia was due to acute adrenal insufficiency and hypothyroidism. Schmitz et al. observed in their study that hyponatremia was due to a pure renal mechanism not due to inappropriate secretion of ADH. Diverse etiologies associated with hyponatremia create challenges to manage this problem.
A study in 2017 showed 5.56% hyponatremia in hypothyroid patients, and there was a very weak but statistically significant positive association between thyroid function and serum sodium (Na +/thyrotropin: r: 0.022, P: 0.046, Na/free thyroxine: r: −0.047, P < 0.0001).
Cantoni et al. in 2017 in their study observed hypothyroidism-induced hyponatremia. A study by Nagata et al. observed no significant relationship between Na and TSH among patients having subclinical hypothyroidism and overt hypothyroidism, respectively.
In the present study, we observed 15.5% hyponatremia in hypothyroid patients (31/200). Serum sodium was negatively correlated with serum TSH (r: −0.5944, P < 0.00001) and serum sodium was positively correlated with serum FT4 (r: 0.2836, P = 0.000047). There are also other studies in which similar relation between sodium and thyroid function has been noticed.,,,,,,,,,,,,,
In patient with a marked decrease of Na levels and an undetermined status of thyroid, clinicians should consider regarding evaluation of thyroid function in the patient's work-up.
| Conclusions|| |
Hypothyroid females in reproductive age group may have significant decrease in serum sodium levels as compared to normal individuals, and serum sodium needs to be estimated in hypothyroid patients for better management of patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]