|Year : 2020 | Volume
| Issue : 1 | Page : 73-78
Thyroid hormone levels and ultrasonographic changes in thyroid gland of patients on long-term lithium treatment for affective disorders: A controlled study
Shabir Ahmad Dar1, Bilal Ahmad Bhat1, Aaliya Khanam1, Zaid Ahmad Wani1, Junaid Nabi1, Shanoo Sheikh2
1 Department of Psychiatry, Government Medical College, Srinagar, Jammu and Kashmir, India
2 Department of Health and Rehabilitation, Princess Nourah Bint Abdul Rahman University, Riyadh, Saudi Arabia
|Date of Submission||19-Mar-2019|
|Date of Acceptance||09-Aug-2019|
|Date of Web Publication||16-Dec-2019|
Shabir Ahmad Dar
Kathi Darwaza, Rainawari, Srinagar - 190 003, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Background: Although lithium is known to cause thyroid dysfunction and increased thyroid gland volume, clinical examination and biochemical assessment are fundamental to thyroid workup of patients on lithium treatment. We aimed to determine the thyroid gland volume and the thyroid hormone levels of patients who have been receiving lithium treatment for affective disorders in comparison to voluntary healthy controls. Materials and Methods: This was a cross-sectional, hospital-based observational study, performed in 43 patients on long-term lithium treatment for bipolar disorder, major depressive disorder, and schizoaffective disorder. Patients with documented continuous and adequate serum lithium levels for more than or equal to 6 months recruited consecutively underwent ultrasonographic examination of the thyroid gland. Ultrasonographic examinations were also done in all gender- and age-matched healthy controls. All cases and controls underwent biochemical thyroid function tests. Results: There were no statistically significant differences in gender (P = 0.198; χ2 = 1.654) of cases and controls. Most of the cases were married; maximum number of them unemployed and belonged to the lower socioeconomic status. Total thyroid volume was significantly greater in the lithium-treated group than the control group (9.40 ± 1.41 vs. 4.79 ± 0.45). Clinical inspection and palpation only detected goiter in six (n = 6, 13.95%) of patients on lithium and none among controls. The mean triiodothyronine (T3), mean thyroxine (T4), and mean scores for thyroid-stimulating hormone were significantly increased in patients receiving lithium therapy as compared to controls. Conclusion: It would seem wise from a clinical point of view to include ultrasonographic examination of the thyroid gland as part of the standard thyroid workup before initiating lithium treatment.
Keywords: Lithium, thyroid function test, thyroid gland ultrasonography
|How to cite this article:|
Dar SA, Bhat BA, Khanam A, Wani ZA, Nabi J, Sheikh S. Thyroid hormone levels and ultrasonographic changes in thyroid gland of patients on long-term lithium treatment for affective disorders: A controlled study. Med J DY Patil Vidyapeeth 2020;13:73-8
|How to cite this URL:|
Dar SA, Bhat BA, Khanam A, Wani ZA, Nabi J, Sheikh S. Thyroid hormone levels and ultrasonographic changes in thyroid gland of patients on long-term lithium treatment for affective disorders: A controlled study. Med J DY Patil Vidyapeeth [serial online] 2020 [cited 2020 Jan 23];13:73-8. Available from: http://www.mjdrdypv.org/text.asp?2020/13/1/73/272892
| Introduction|| |
Lithium an effective ion for the treatment of acute mania, prophylaxis of bipolar disorder, treatment of unipolar recurrent depression, antisuicidal and treat resistant major depressive episodes was discovered in 1817. Lithium after its discovery was used for the treatment of gout. Patients on lithium usually require to take the drug on a long-term basis; therefore, it has long-term side effects which include thyroid function abnormalities, renal insufficiency, persistent tremor, and dermatological effects.
Treatment with lithium frequently causes hypothyroidism; however, it may also lead to hyperthyroidism on rare occasions. Lithium causes hypothyroidism by affecting various aspects of the thyroid gland function. The lithium ion is concentrated in the thyroid gland 3–4 times greater than in plasma, where it interferes with various steps in the production of thyroid hormones.
It inhibits iodine uptake and is thought to alter thyroglobulin structure, interfering with the coupling of iodotyrosine residues to form iodothyronines. It also inhibits thyroid hormone secretion, an effect which may be explained by interference with polymerization of tubulin. Lithium, a well-known goitrogen, is known to induce goiter in 5.6%–60% of lithium-treated patients. This difference in prevalence can be explained by different iodine content in the different geographical zones and the diagnostic tools used in these studies.
Thyroid morphology including volume in patients on lithium is usually monitored by thyroid ultrasonography as it has a definite role in clinical setting. Ultrasonographic abnormalities could be attributed to inhibition of the release of thyroid hormones in the course of treatment with lithium. Female gender, weight gain, preexisting autoantibodies, higher lithium levels, rapid cycling, and starting lithium at a later age are the main risk factors.,,
The lithium-induced goiter is usually smooth and nontender. With regard to ultrasonic scan abnormalities apart from increased volume, a study by Bocchetta et al., in their cohort of 6 years of lithium treatment, found that up to 97% of women and 69% of men without evidence of thyroid-circulating antibodies showed reduced echogenicity, nonhomogeneous echo pattern, and/or presence of nodules.
If lithium therapy has to be continued during pregnancy, thyroid ultrasonography being safe could be carried out in the neonate besides standard thyroid function tests in order to check for neonatal goiter and hypothyroidism. Lithium-induced influence on the hypothalamic–pituitary–thyroid (HPT) axis has also been observed.,
It has been proposed that lithium acts by inhibition of cAMP activity which results in decreased levels of serum T3 and T4. As a result of feedback inhibition on pituitary, thyroid-stimulating hormone (TSH) hypersecretion occurs. This increase in TSH concentration results in thyroid enlargement and goiter.
Lithium-induced hypothyroidism and goiter may take weeks to years after it is started., Studies have shown that the prevalence rates of lithium-induced hypothyroidism range from 3.4% to 52%, with a female-to-male ratio of approximately 5:1.,,, The clinical presentation of hypothyroidism is similar to that of patients not on lithium, and the biochemical changes are identical to those in primary hypothyroidism. It has recently been reported that there is a significant inverse relationship between mean serum free T4 level and morbidity in mentally ill patients, a low level being associated with more frequent affective episodes, and greater severity of episode of depression.
Our aim of conducting this study was to investigate the detailed sociodemographic profile of patients on lithium therapy, thyroid hormone levels, and thyroid gland volumes in comparison with healthy voluntary controls.
| Materials and Methods|| |
Forty-three consecutive lithium-treated patients of affective disorders of either gender, aged between 18 and 65 years, diagnosed according to the diagnostic criteria of the International Classification of Diseases-10-Diagnostic Criteria for Research (World Health Organization, 1992) from both the in- and outpatient units of Institute of Mental Health and Neurosciences, Kashmir, North India, were taken. It was a cross-sectional, hospital-based study in which patients were selected through nonrandomized and nonstratified sampling technique. Forty-three age- and sex-matched healthy voluntary controls were selected from nonblood relatives of patients. Informed written consent was obtained prior to inclusion in the study, and the participants were explained in detail about the nature and purpose of the study. Clearance from the institute ethics committee was taken. The controls were of either gender, aged between 18 and 65 years, had no current psychiatric diagnosis, scored <2 on the General Health Questionnaire, were receiving no psychotropic medication, and had no alcohol or substance dependence disorder, other than nicotine. The exclusion criteria for cases were:
- Extremes of age of <18 years and >65 years
- Current history of substance abuse, psychosis or eating disorder, malignancies, body mass index of higher than 30, and clinical thyrotoxicosis
- Persons having a known history of surgical thyroidectomy.
All the patients who were taken for the study had used lithium carbonate for at least 6 months. The treatment adherence of the patients was assured by the recommended serum lithium levels between ≥0.6 and 1.2 mmol/L during follow-up visits.
About 3–5 ml of venous blood was collected and centrifuged to separate serum from the cells as soon as the clot was formed. Serum aliquots were stored at 4°C to be run in batches. The samples were allowed to thaw prior to assay, mixed thoroughly. Hemolyzed and lipemic samples were rejected. Bi-level, i.e., high and low control, was run with each batch. Serum was analyzed for TSH, total thyroxine (T4), and total triiodothyronine (T3) by electrochemiluminescence immunoassay (ECLIA) method using a fully automatic analyzer ECLIA 2010 (Roche Diagnostics, Germany). Normal reference range was set up as T3 = 72–184 μg/dl, T4 = 5–13 μg/dl, and TSH = 0.5–4 μ-IU/l.
Clinical inspection and palpation of the thyroid gland was done in every participant by a consultant physician. Further, all the participants underwent detailed ultrasonographic examination of the thyroid gland. Blood samples for thyroid profile and ultrasonographic examination of the thyroid gland were done on the same day to save the financial burden on the participants. The findings of the thyroid volumes of both cases and controls were done and cross-checked by two consultant radiologists who were unaware about the lithium exposure and the serum lithium levels of understudied participants.
The maximal superoinferior, horizontal, and ventrodorsal dimensions of each lobe were measured; by multiplying these values (cm) with each other and then by 0.479, we obtained the volume (cm 3) of each thyroid lobe. The sum of the volumes of the two lobes provided the volume of the entire thyroid gland. Ultrasonography unlike other imaging techniques does not have radiation exposure and is low in cost, fast, and relatively accurate.,
Descriptive statistics were used for sociodemographic and clinical variables. For detecting group difference between variables, independent-samples t-test and Pearson's Chi-square test were used for continuous and categorical variables, respectively. SPSS version 21 Software Statistical package for the social sciences (IBM software, NY, USA) was used for the analysis of data. A confidence level of 95%, i.e., P < 0.05, was considered statistically significant.
| Results|| |
The study sample consisted of 43 patients on lithium in comparison to 43 age- and gender-matched healthy voluntary controls. Majority of the patients were male (28, 65.11%) in the lithium group as well as in the control group (29, 67.44%). There were no statistically significant differences in gender (P = 0.198; χ2 = 1.654). The mean age of patients was 30.39 ± 2.68 years in the lithium group and 30.44 ± 2.62 years in the control group. Most of the patients were married; maximum number of them unemployed and belonged to the lower socioeconomic status [Table 1]. The clinical variables of the lithium-treated patients are shown in [Table 2]. Twenty-three (53.48%) patients were receiving lithium monotherapy; 7 (16.27%) patients were using lithium and lamotrigine, 6 (13.95%) patients were using lithium and clozapine, 5 (11.63%) patients were using lithium and olanzapine, and 2 (4.65%) patients were using lithium, olanzapine, and lamotrigine. The mean duration of illness was 6.44 ± 2.32 years and the mean duration of treatment was 6.33 ± 2.37 years, as shown in [Table 2]. The average dose of lithium was 780 ± 214.6 mg/day (600–1200 mg).
|Table 1: Comparison of sociodemographic profiles between patients on lithium and healthy controls|
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|Table 2: Clinical variables of the lithium-treated patients and healthy controls|
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Thyroid was palpable only in 6 (13.95%) patients in the lithium group and not palpable in any of the participants in the control group [Table 2].
Statistically significant higher mean volumes of right lobe (5.68 ± 1.03), left lobe (3.72 ± 0.53), and total thyroid volume (9.40 ± 1.41) were observed in lithium group participants in comparison to mean right, left, and total thyroid volume in normal voluntary controls (3.30 ± 0.424, 1.49 ± 0.28, 4.79 ± 0.45, respectively) [Table 3].
|Table 3: Comparison of thyroid volumes between mood disorder patients on lithium and healthy controls|
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Significantly higher mean scores for TSH (μ-IU/ml) was observed in the lithium group (5.378 ± 3.88) in comparison to the normal control group (2.88 ± 1.59), and the difference was statistically significant. Similarly, statistically significant differences were also observed in mean serum T4 (5.85 ± 1.71) of cases and controls (7.39 ± 0.921) [Table 4]. Biochemical thyroid abnormalities have been significantly high in females in comparison to males. Similarly, significantly high mean scores for right lobe and total volume of the thyroid gland have been observed in females as compared to males [Table 5].
|Table 4: Comparison of thyroid profiles between mood disorder patients on lithium and healthy controls|
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|Table 5: Comparison of thyroid volumes and thyroid profiles (gender wise) in mood disorder patients|
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| Discussion|| |
To our knowledge, this is the first study from Kashmir (Jammu and Kashmir) and the second study from India in which ultrasonography was used to determine thyroid volume and morphology in lithium-treated patients in comparison to age- and gender-matched healthy volunteers. Male predominance in our study can be possibly explained by the stigma associated with mental illnesses and societal shame and rejection in females who infrequently visit government setup though the results were statistically insignificant. Majority of the cases and controls were from an urban area which can be explained by the geographical location of our institute.
Although examination of the thyroid gland by clinical inspection and palpation is vital to any physical examination of patients on lithium treatment, the results of findings vary widely depending on the examiner. Ultrasonographic measurement of thyroid volume has, therefore, been performed in patients on lithium and found to be very sensitive. Unlike other imaging techniques, ultrasonography does not involve any radiation exposure and is low in cost, fast, and relatively accurate.
In our study, ultrasonographically measured thyroid volume was found significantly increased in lithium-treated patients in comparison to voluntary healthy controls. The volumes of the right and the left thyroid lobe and the overall thyroid volumes were significantly higher in the lithium-treated patients than among normal controls. Several mechanisms have been proposed to explain the development of increased thyroid volume, like lithium is concentrated by the thyroid and inhibits thyroidal iodine uptake.
The most important clinically relevant action purposed is the inhibition of thyroid hormone release. This may result in the development of goiter and hypothyroidism. Independent effects on the HPT axis and the receptor-mediated mechanism of thyroid hormone action may contribute. The immunological influence of lithium on thyroid antibody concentrations leading to a more rapid onset of thyroid autoimmunity resulting in goiter and hypothyroidism and possibly also a state of hyperthyroidism in some cases has been hypothesized. It has been proposed that mechanism of the proliferation of thyrocytes in patients treated with lithium is an activation of tyrosine kinase by lithium ion and lithium effects on intracellular signaling connected with adenylate cyclase and that of Wnt/beta-catenin.
Our study results are in unison with the only Indian study by Alam et al. where it was found that lithium treatment is associated with increased individual mean thyroid lobe volume and overall mean thyroid volumes.
In 1990, the assessment made by the Danish research group of 100 patients with BD showed that goiter occurs in 44% of patients treated for 1–5 years and in 50% of those treated for more than 10 years, compared to 16% in the control group.,
In our study, significantly increased mean T3, mean T4, and mean TSH values were observed in the lithium group as compared to the control group, and the trend was toward hypothyroidism. The common side effects of lithium treatment include overt hypothyroidism in 8%–10% and subclinical hypothyroidism in 20%–25% of patients  assumed to the results from lithium interfering in the synthesis and release of thyroid hormones from the thyroid gland.
A study found substantial number of patients on long-term lithium therapy receiving additional treatment with levothyroxine. Hypothyroidism is described as a commonly known effect of lithium use as has been quoted by other studies.,
However, our study results are in contradiction to a study done by Alam et al. where hyperthyroidism was the most common finding. Hyperthyroidism associated with long-term lithium use has also been reported by many other authors., However, the most common reason cited by all these authors was the chronic use of lithium.
In this study, higher biochemical thyroid dysfunction was found in females in comparison to males. Likewise, higher mean volumes of the thyroid gland were found in women in comparison to men. Our study results are in concordance with some earlier studies. Özerdem et al. showed a higher frequency of TSH abnormalities in patients with bipolar disorders, with lithium-induced thyroid dysregulation occurring more frequently in female patients. Kirov et al. also found a higher frequency of lithium-induced thyroid dysfunction (mostly hypothyroidism) in female than in male patients, and hence, the results match our study.
Strengths of study
- Since valproic acid, carbamazepine, escitalopram, betablockers, and quetiapine treatment can lead to hypothyroidism, patients using these medications were excluded
- Measurement of thyroid gland volume was done by two consultant radiologists who were unaware of lithium exposure.
- Impairment of the HPT axis stemming from the illness may influence the changes observed in the thyroid state therefore bias our results
- This was a cross-sectional study conducted at a random point in time during long-term lithium treatment
- Small sample size, night shifting, infection, and smoking status could be a confounding factor
- Since the iodine content of the superficial layers of the soil in Kashmir is frequently washed away by heavy rains and snowfall, therefore confound results
- We could not eliminate the possibility that patients had undiagnosed thyroid disorders before lithium treatment onset because their prelithium baseline values were not known.
| Conclusion|| |
The results of our study confirm a greater susceptibility of females for disturbances in thyroid hormone levels and thyroid morphologies during lithium therapy with increased volume and features of hypothyroidism. It would seem wise from a clinical point of view to include ultrasonographic examination of thyroid volume as part of the standard thyroid workup before initiating lithium treatment. Besides, it would be wise to conduct prospective studies with greater sample size to support such results.
I would like to thank Dr. Sayar Ahmad Talay and Dr. Iqbal Hussain Dar consultant radiologists for valuable support. I would also like to thank Dr. Umar Khurshid consultant physician for his valuable support and inputs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]