European Journal of Cardiovascular Medicine

Tuberculosis (TB) has left an indelible mark on human history, emerging as one of the oldest known infectious diseases. It continues to challenge public health systems worldwide, with its complex interplay of biology, social determinants, and healthcare infrastructure. From its discovery to the present day, TB has shaped medical research, public policy, and the lives of millions.

MDR-TB strains resist two key first-line anti-TB drugs: isoniazid and rifampicin. This resistance complicates treatment, extending therapy duration and increasing healthcare expenses. Rifampicin-resistant tuberculosis (RR-TB) strains, being resistant to rifampicin, are considered unaffected by this drug are managed using multidrug-resistant (MDR) treatment protocols. MDR-TB and RR-TB cases are combined under the heading MDR/RR-TB in guidelines and they are treated with same approach.

Worldwide, the estimated percentage of new tuberculosis (TB) cases with multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB) decreased from 4.0% in 2015 to 3.3% in 2022. For previously treated cases, the estimated proportion with MDR/RR-TB dropped from 25% in 2015 to 17% in 2022(1).

Hypothyroidism is also a very common health problem among Indian population. According to different study prevalence of hypothyroidism in Indian population around 10-11%(2). Hypothyroidism is categorised in two categories subclinical and clinical. Subclinical hypothyroidism characteristically presents with normal thyroxine (T4) levels and elevated thyroid stimulating hormone (TSH) levels where as clinical hypothyroidism is defined as low TSH with low level of FT3 and FT4.Subclinical hypothyroidism is also  correlates with an increased risk of fatal and non-fatal coronary artery disease events, congestive heart failure, and fatal stroke (3). In recent years, increasing evidence has shown that thyroid hormones (THs) have a direct impact on the immune system. Both innate and adaptive immune cells express various components involved in local TH action and are responsive to THs, which affect immune cell function(4).

 There is bidirectional relationship between tuberculosis and hypothyroidism.Patients with hypothyroidism have a 2.91 times higher risk of developing TB than those without hypothyroidism, and that patients with TB have a 2.01 times higher risk of developing hypothyroidism than that those without(5).

There is limited data on prevalence of thyroid dysfunction in MDR/RR TB patients.2^nd line drugs (ethionamide, prothionamide, and para-aminosalicylic acid) which are used in the treatment can also cause hypothyroidism(6). So thyroid function assessment at baseline before starting the 2^nd line treatment is essential in MDR/RR TB patients. Most of the studies available in this spectrum have analysed the effect of 2^nd line drug on developing hypothyroidism in MDR/RR TB patients. In this study we have focused on thyroid dysfunction and its incidence among MDR/RR TB patients in central India.

Data of 51 patients newly diagnosed MDR/RR TB patients including pulmonary and extrapulmonary tuberculosis between September 2022 to June 2024 from the DRTB register was taken and it was recorded in excel sheet. All patients were more than 18 years of age. TSH, FT3, FT4 value was also documented from register. Data were then further analysed. Ethical clearance was taken from institutional ethical board before data collection of the data.

Data collection:

This study involved fifty-onenewly diagnosed patients with multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR TB) who sought treatment at MY Hospital, Indore, between November 2022 and June 2024. All participants were over 18 years old and had microbiologically confirmed cases of MDR/RR TB. The study included both pulmonary tuberculosis (TB) and extrapulmonary tuberculosis (EPTB) cases. Data such as the name, age, sex, and Nikshay ID of these 51 patients were collected from the DRTB register. Their baseline thyroid function reports (TSH, T4, T3) before starting treatment were also recorded from the DRTB register. All this information was then entered into an Excel sheet for further analysis. Based on the thyroid function reports, patients were categorized into normal, subclinical hypothyroidism, and clinical hypothyroidism groups.

Subclinical hypothyroidism characteristically presents with normal thyroxine (T4) levels and elevated thyroid stimulating hormone (TSH) levels.

Overt or clinical primary hypothyroidism is defined as thyroid-stimulating hormone (TSH) concentrations above the reference range and free thyroxine concentrations below the reference range(7)

In our study, the normal reference range for TSH was 0.2–5.5 uIU/ml. The normal reference values for T4 and T3 were 0.61–1.12 µg/dl and 2.5–3.9 ng/dl, respectively.

This study was done as a sub study under the project “A study to evaluate safety, tolerability, and adverse effect profile of bedaquiline therapy in MDR (multiple drug resistance) /RR (rifampicin resistance) tb patients” and ethical clearance was taken before starting of the study(EC/MGM/NOV-22/17).

Total of 51 patients were included in the study out of them 27 patients were male and 24 were female (figure-1) and all patients were more than 18 years of age. Minimum and maximum age of our study participant were 18 and 72 years respectively with a standard deviation of 14.45 years (Table-1).

Table 1 (mean age with standard deviation of study population)

Fig-1 showing male and female distribution among study population

Of the 51 patients, 42 exhibited normal thyroid function, as indicated by their TSH, FT3, and FT4 levels. Hypothyroidism was found in 9 patients, representing 17.64% of the total. Among these, 7 patients (13.72%) had subclinical hypothyroidism, while 2 patients (3.91%) had clinical hypothyroidism (refer to Table-2 and Figure-2). None of our study population showed hyperthyroidism.

TABLE:2(normal, clinical, and subclinical hypothyroidism incidence percentage wise)

Figure 2 : pie diagram showing normal, clinical and subclinical hypothyroidism incidence percentage wise

TSH value of these all 51 patients were analysed, minimum value of TSH among study population was 0.35and maximum value was 10.92 with standard deviation of 2.27 (Table-3)

Table -3 (minimum, maximum, mean, and standard deviation of TSH[1] value among study population)

In our study we have analysed data of 51 microbiologically confirmed newly diagnosed MDR/RR TB patients (both pulmonary and extrapulmonary). Out ofthese 51 patients 9 patients were hypothyroid (both clinical and subclinical). Out of these 9 patients 2 patients had clinical hypothyroidism where as 7 patients had subclinical hypothyroidism. As we have already discussed that according to different study incidence of hypothyroidism among Indian population is around 10-11%. So, from above analysis it is also quite evident that incidence of hypothyroidism is also higher among MDR/RR TB patients in comparison to general population.Therefore, hypothyroidism, particularly subclinical hypothyroidism, is a significant co-morbid condition commonly associated with MDR/RR TB patients, and it requires careful attention alongside other co-morbidities. There is multiple factor that can increase incidence of hypothyroidism among MDR/RR TB patients. As tuberculosis is a chronic inflammatory condition and different inflammatory mediators can alter the thyroid function and eventually can lead to hypothyroidism. Another aspect as we have already discussed that normal thyroid hormone level is also essential for proper functioning of our immune system, so subclinical hypothyroid and clinical hypothyroid patients who are not timely diagnosed and who have not received any management (pharmacological or lifestyle modification) can have a suboptimal immune response that can act as a predisposing factor for development of tuberculosis in such patients. Further studies in this spectrum are needed for better understanding such association.  MDR/RR TB patients who are treated with 2^nd line anti tubercular drug and some of those drugs can also cause hypothyroidism, so addressing hypothyroid status in these patients at baseline and adequate monitoring and managing is essential for successful treatment outcome.

From the above analysis we can conclude that incidence of hypothyroidism especially subclinical hypothyroidism is much more in MDR/RR TB patients at baseline before starting of treatment, in comparison to general population. So, addressing such co morbid condition and prompt management is essential as this can affect the overall treatment outcome. Moreover some 2^nd line antitubercular drug which are used in the management of MDR/RR TB patients are already known to be associated with adverse effect like hypothyroidism can aggravate the already existing subclinical and clinical hypothyroidism status. So thyroid function should be assessed before starting the 2^nd line treatment and regular follow-up and monitoring of thyroid function status should be done in MDR/RR TB patients.

List of Abbreviations:

MDR TB- Multi drug resistant tuberculosis

RRTB- Rifampicin resistance tuberculosis

DRTB – Drug resistant tuberculosis

EPTB – Extra pulmonary tuberculosis

TSH -Thyroid stimulating hormone

Conflict of interest: There is no conflict of interest in this study

Funding – NIL

Acknowledgement - NIL

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