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 Table of Contents  
Year : 2021  |  Volume : 10  |  Issue : 1  |  Page : 1-7

A systematic review of adrenal insufficiency among patients with pulmonary tuberculosis in Sub-Saharan Africa

1 Department of Medicine, Endocrinology Unit, University College Hospital, Ibadan, Nigeria
2 Department of Medicine, Pulmonology Unit, Evercare Hospital, Lekki, Lagos, Nigeria
3 Department of Medicine, Infectious Diseases Unit, College of Medicine and Allied Health Sciences, Freetown, Sierra Leone
4 Department of Medicine, University College Hospital, Ibadan, Nigeria

Date of Submission06-Jan-2021
Date of Acceptance02-Feb-2021
Date of Web Publication28-Feb-2021

Correspondence Address:
Taoreed Adegoke Azeez
Department of Medicine, Endocrinology Unit, University College Hospital, Ibadan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmy.ijmy_4_21

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Introduction: Tuberculosis (TB) is a disease of public health importance globally. The incidence of pulmonary TB is rising in sub-Saharan Africa. Bilateral adrenal destruction and the use of medications such as rifampicin are possible mechanisms by which TB cause adrenal insufficiency. Failure to promptly recognize adrenal insufficiency may lead to a medical crisis causing death. This systematic review aimed to identify the frequency of adrenal insufficiency, the clinical presentation and its predictors in patients with pulmonary TB in sub-Saharan Africa. Methods: The study was a systematic review. Medical databases and the grey literature were searched. Literature search and studies selection were done following the PRISMA guidelines. Results: The total sample size was 809. The frequency of adrenal insufficiency among patients with pulmonary TB in sub-Saharan Africa was 0.9%–59.8%. Patients with adrenal insufficiency had symptoms such as nausea, vomiting, darkening of the skin, salt craving, and weight loss. Other symptoms were dry, itchy skin, abdominal pain, and muscle pain. The predictors of adrenal insufficiency among patients with pulmonary TB in sub-Saharan Africa were low blood pressure, low blood glucose, presence of multidrug-resistant TB, and low CD4 count. Other predictors were abdominal pain and generalized skin hyperpigmentation. Conclusion: The frequency of adrenal insufficiency in patients with pulmonary TB can be as high as 50%. The presence of low blood pressure, low blood glucose, multidrug-resistant TB, and generalized skin hyperpigmentation is a pointer to the possibility of adrenal insufficiency in these patients.

Keywords: Adrenal insufficiency, pulmonary tuberculosis, sub-Saharan Africa, systematic review

How to cite this article:
Azeez TA, Irojah OA, Lakoh S, Lawal AO, Ajiboso OA. A systematic review of adrenal insufficiency among patients with pulmonary tuberculosis in Sub-Saharan Africa. Int J Mycobacteriol 2021;10:1-7

How to cite this URL:
Azeez TA, Irojah OA, Lakoh S, Lawal AO, Ajiboso OA. A systematic review of adrenal insufficiency among patients with pulmonary tuberculosis in Sub-Saharan Africa. Int J Mycobacteriol [serial online] 2021 [cited 2021 Jun 14];10:1-7. Available from: https://www.ijmyco.org/text.asp?2021/10/1/1/310516

  Introduction Top

Tuberculosis (TB) is an infectious disease of public health concern due to the large global population affected as well as its significant morbidity and mortality.[1] The causative agent of TB is an aerobic acid-fast bacillus called Mycobacterium tuberculosis.[2] TB is transmitted from the infected person to a susceptible host mainly through respiratory droplets which are generated during coughing, sneezing, talking and laughing.[3] The minimum infective dose is 10 bacilli.[3] The bacilli which lodge in the alveoli after infection may be cleared, remain latent or progress into active TB.[4]

Transmission is usually from persons with active TB. A person with active TB can transmit the infection to about 45% of his or her close and prolonged contacts.[5] In a cohort of persons infected with M. tuberculosis, about 5% tend to progress into active TB and the remaining 95% have a lifetime risk of progressing to active TB estimated to about 5% for each individual infected.[1] The greatest risk of progression is an immune system compromised by diseases such as human immunodeficiency virus acquired immunodeficiency syndrome, poorly controlled diabetes, usage of immunosuppressive medications such as steroids, malignancy, and chronic medical illnesses such as chronic kidney disease.[6]

TB can involve various organs in the body but the most commonly involved organ is the lung.[7] The hair, nail and teeth have, however, not been documented to be involved in extrapulmonary TB.[8] Extrapulmonary TB has not been receiving commensurate attention when compared with pulmonary TB despite the fact that it contributes significantly to the burden of TB generally.[9] Ayed et al., reported that extrapulmonary TB is often undiagnosed in low-income settings such as sub-Saharan Africa.[8] The main reason given for this was the difficulty in diagnosing extrapulmonary TB, especially when visceral organs are involved.[8] The various incidence rates of extrapulmonary TB reported in various studies are shown in [Figure 1].[10],[11],[12],[13],[14],[15],[16],[17],[18],[19] The various organs involved in extrapulmonary TB, as reported by various researchers, are shown in [Table 1].
Figure 1: Frequencies of extrapulmonary tuberculosis in various studies

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Table 1: Different organs involved in extrapulmonary tuberculosis

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TB is the 9th leading cause of mortality globally and Africa alone accounts for about 25% of the mortality.[20] It further stresses the barely adequate health-care delivery services available in sub-Saharan Africa. Due to poor reporting and less robust diagnostic facilities, estimates of the burden of TB in sub-Saharan Africa may not be accurate.[21] [Figure 2] illustrates how the estimated incidence of TB in the World Health Organization (WHO) Africa region compares with other WHO regions.[22] The figure shows that apart from the South-East Asia region, the estimated incidence of TB is higher than the incidences in other regions combined. Nigeria has the highest estimated incidence of TB in Africa.[23]
Figure 2: Estimated Incidence of tuberculosis in the different World Health Organization regions

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Adrenal insufficiency is an endocrine disorder in which glucocorticoid production by the adrenal gland is insufficient to meet the physiologic demands or the demands under stressful conditions.[24] It could be due to a destructive disease affecting the adrenal gland (primary adrenal insufficiency) or inadequate stimulation of the adrenal cortex by the adrenocorticotropic hormone secreted by the pituitary gland (secondary or central adrenal insufficiency). In general, secondary adrenal insufficiency is much more common than primary adrenal insufficiency.[24] The estimated incidence of primary adrenal insufficiency is 1 in 8000 individuals whereas secondary adrenal insufficiency has an estimated incidence of 1 in 3000 individuals.[25],[26] [Table 2] shows the various causes of secondary (central) adrenal insufficiency.[27]
Table 2: Causes of central adrenal insufficiency

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In the developed nations, autoimmune adrenalitis is the commonest cause of primary adrenal insufficiency, whereas in developing nations, as obtainable in sub-Saharan Africa, the commonest cause is TB.[24],[28] [Table 3] illustrates the causes of primary adrenal insufficiency in developed and developing countries.[29],[30]
Table 3: Causes of primary adrenal insufficiency, developing versus developed nations

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Adrenal insufficiency results from pulmonary tuberculosis mainly by two mechanisms or a combination of both.[24] First, hematogenous spread of M. tuberculosis from the lungs to the adrenal glands can cause bilateral destruction of the adrenal glands. Rifampicin, which is part of the backbone of anti-TB therapy can accelerate the hepatic metabolism of glucocorticoids.[31]

The commonest symptoms of primary adrenal insufficiency are shown in [Table 4]. This was adapted from the cross-sectional study reported by Ross and Levitt among a cohort of 148 patients with adrenal insufficiency.[32]
Table 4: Symptoms of primary adrenal insufficiency

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Adrenal insufficiency is often underdiagnosed due to the non-specific symptoms the affected patients tend to present with it.[24] Bleicken et al. reported that less than half of patients with adrenal insufficiency are diagnosed within 6 months of the onset of symptoms.[33] In their cohort, about two-thirds of the patients consulted at least three different physicians before they were eventually diagnosed.[34] Adrenal insufficiency is diagnosed when basal or stimulated (using short synacthen test) is below the reference range. This is followed by a series of investigations to identify the underlying aetiology. [Figure 3] illustrates an algorithm that can be used in assessing a patient with suspected adrenal insufficiency.
Figure 3: Algorithm for evaluating suspected adrenal insufficiency

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The aim of this review was to analyze various studies on adrenal insufficiency among patients with pulmonary TB in sub-Saharan Africa.


  1. To determine the frequency of adrenal insufficiency among patients with pulmonary TB in sub-Saharan Africa
  2. To identify the clinical presentation of patients with adrenal insufficiency among patients with pulmonary TB in sub-Saharan Africa
  3. To evaluate the predictors of adrenal insufficiency among patients with pulmonary TB in sub-Saharan Africa.

  Methods Top

Databases containing medical journals were searched for studies on adrenal insufficiency among patients with pulmonary TB in sub-Saharan Africa. The databases were PubMed, African Journals Online (AJOL), SCOPUS, Web of Science and Google Scholar. The search terms used were “adrenal insufficiency,” “hypoadrenalism,” “hypocortisolism,” and “Addison's disease.” Other terms searched included “TB,” “pulmonary TB,” “sub-saharan Africa” and “TB in sub-Saharan Africa.” In order to improve the quantity and quality of retrieved articles, “AND” as well as “OR” were used as Boolean operators. The gray literature was also searched in order to enhance the scope of the retrieved studies. [Figure 4] illustrates the PRISMA flow diagram of the literature search and selection.
Figure 4: The PRISMA flow diagram of the literature search and selection

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Included in the study were

Studies done/published between January 1, 1990, and December 10, 2020, to determine the presence of adrenal insufficiency among patients with pulmonary TB in sub-Saharan Africa.

  1. Studies whose abstracts and or full text were available at the searched databases or from the gray literature.

Exclusion criteria

Studies on tuberculosis outside sub-Saharan Africa

  1. Studies on TB in sub-Saharan Africa but not focusing on adrenal insufficiency.

All the sources of data were searched independently by the authors. The studies eventually selected were the ones considered strongly relevant and the included studies by at least three out of the five authors. The selected studies were thoroughly reviewed independently by the authors and the relevant data were extracted and presented in texts, tables, and charts below.

The total selected studies were eight. There were six cross-sectional studies, one retrospective study and one prospective study. The various studies and the respective countries where the studies were done are shown in [Table 5].
Table 5: Selected studies and locations

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  Results Top

The total sample size in the review was 809. [Table 6] shows the sample sizes in the selected studies. The frequency of adrenal insufficiency among patients with pulmonary TB in sub-Saharan Africa was 0.9%–59.8%. [Table 7] illustrates the frequencies reported in various studies. [Table 8] illustrates some of the symptoms of adrenal insufficiency in patients with pulmonary TB reported in the various studies done in sub-Saharan Africa. The predictors of adrenal insufficiency among patients with pulmonary TB in sub-Saharan Africa as reported in the selected studies are illustrated in [Table 9].
Table 6: Sample sizes of selected studies

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Table 7: Frequency of adrenal insufficiency among patients with pulmonary tuberculosis in sub-Saharan Africa

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Table 8: Symptoms of adrenal insufficiency

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Table 9: Predictors of adrenal insufficiency in patients with pulmonary tuberculosis

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  Discussion Top

The number of studies included in these review (eight studies) were rather small considering that the review spanned a period of about 31 years. Globally, the incidence of pulmonary TB has been declining and the late diagnosis or misdiagnosis of adrenal insufficiency may account for this paltry number.[33],[42] However, the incidence of TB is now rising in sub-Saharan Africa and more studies are being conducted on its potential complications.[43] This may partly explain why 75% of the studies in this review were conducted in the past 10 years despite that it is a 31-year review.

The range of the frequencies of adrenal insufficiency in patients with pulmonary TB (0.9%–59.8%) is quite wide. This may be due to differences in demographics, study design and methodology. This assertion was corroborated in the methods used in diagnosing adrenal insufficiency in the studies. Some used 250 μg short synacthen test[36],[40] while others used the 1 μg short synacthen test.[37],[39] One of the studies employed basal cortisol only, without doing the stimulation test, in diagnosing adrenal insufficiency.[41] It has been reported that the responses of individuals to the 250 μg and 1 μg vary significantly and unpredictably therefore using these tests in different studies may yield widely different results.[44]

Mechanisms by which pulmonary TB can cause adrenal insufficiency include bilateral destruction of the adrenal glands and impairment of adrenal steroidogenesis by anti-TB drugs or both.[31] Usually, adrenal TB results from a haematogenous spread of the tubercle bacilli from the lungs to the adrenal glands.[31] Rifampicin is a known cytochrome p450 inducer, thereby accelerating the metabolism of glucocorticoids and aiding the development of adrenal insufficiency.[45]

The symptoms of adrenal insufficiency documented in the selected studies of this review, such as nausea, vomiting, skin darkening, salt craving and weight loss, have been documented extensively in the literature as the usual clinical manifestations of hypoadrenalism.[29],[32],[46],[47] Moreover, other authors outside sub-Saharan Africa have reported similar symptoms in their cohorts of patients with pulmonary TB and adrenal insufficiency.[48],[49],[50]

Low blood pressure was found as a predictor of adrenal insufficiency in patients with pulmonary TB. Vinnard and Blumberg have also reported that the presence of low blood pressure is a pointer to adrenal involvement in a patient with TB.[31] They may have outright hypotension or orthostatic hypotension. Glucocorticoids have a permissive effect on catecholamines thereby helping catecholamines to keep the blood pressure stable.[51] Besides, mineralocorticoids play a central role in the maintenance of blood pressure and tuberculous necrosis of the adrenal gland affect mineralocorticoid secretion also.[52]

Low blood glucose was also found to be a predictor of adrenal insufficiency in patients with TB. Other researchers, working in different parts of the world, have also reported similar findings.[31],[49] Glucocorticoids are catabolic hormones that play crucial roles in the metabolism of carbohydrate.[53] Hypocortisolism, found in adrenal insufficiency, enhances insulin sensitivity thereby predisposing the patient to hypoglycaemia.[54]

This study also demonstrated that multidrug-resistant is more likely to have an association with adrenal insufficiency compared with drug-sensitive TB cases. Rodriguez-Gutierrez et al. as well as Prasad et al. have independently reported similar findings in their studies.[55],[56] The reasons that have been put forward to explain this observation is that MDR-TB suggests that the patient has prolonged exposure to the tubercle bacilli and the bacilli are reportedly more aggressive in these instances.[56] In addition, the presence of certain symptoms such as abdominal pain and generalized skin hyperpigmentation have been documented as predictors of adrenal insufficiency and this was also corroborated by this study.[48],[49]

  Conclusion Top

The frequency of adrenal insufficiency among patients with pulmonary TB in sub-Saharan Africa varies widely, ranging from 0.9% to 59.8%. Adrenal insufficiency in TB tends to present with non-specific symptoms such as nausea, vomiting, salt craving, generalized body darkening, abdominal pain and weight loss. The lack of specificity of the symptoms therefore means that a high index of suspicion will be required to identify patients with pulmonary TB who also have adrenal insufficiency. However, paying close attention to pointers such as low blood pressure, low blood glucose, generalized hyperpigmentation, abdominal pain and presence of MDR-TB may assist in timely recognition of adrenal insufficiency in patients with pulmonary TB.

Consent for publication

The authors hereby give the journal the consent to publish the article.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]


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