In this cross-sectional study of 272 HIV-TB co-infected adults in Uganda, approximately two-thirds had FAI. Mean serum cortisol levels were significantly lower among DR-TB participants, who had five times higher odds of FAI compared with DS-TB patients. The odds of FAI were higher with DR-TB co-infection, history of abdominal pain and treatment duration >1 month, but lower among men and participants with skin hyperpigmentation.
We found that a higher proportion of participants in our study had FAI than previously reported in India , Nigeria  and Uganda [16, 22], perhaps because of inclusion of persons with HIV co-infection which causes infectious adrenalitis . By contrast, a study in Mexico among HIV-negative DR-TB patients, with equal numbers of primary and secondary multi-drug resistant TB cases, found a baseline prevalence of 4.2% using a serum cortisol cutoff of 500 nmol/L, and a prevalence of 8.3% when the cutoff was 550 nmol/L . Delayed diagnosis and initiation of TB treatment in our setting may have led to hematogenous spread to the adrenal glands. Additionally, previous use of rifampicin, which enhances cortisol metabolism [16, 23], may account for the high occurrence of FAI observed. Our data suggest that clinical management of TB-HIV co-infected patients should include assessment of adrenal function because FAI increases morbidity and mortality .
DR-TB participants had lower mean cortisol levels and higher odds of FAI than DS-TB. Prevalence of DR-TB is higher in previously treated TB patients , and the lower cortisol levels we observed in DR-TB patients were likely due to delays in initiating TB treatment or to previous TB episodes increasing the likelihood of adrenal gland infiltration . Additionally, standard TB treatment regimens include rifampicin which accelerates cortisol breakdown resulting in low cortisol levels; treatment duration >1 month was associated with FAI among DS-TB patients in subgroup analyses . These findings are in agreement with prior studies suggesting an association of adrenal insufficiency with rifampicin which is used for DS-TB treatment categories 1 and 2 . We found that men had lower odds of adrenal insufficiency. Although TB is more prevalent in males, estrogen increases hepatic cortisol-binding globulin which lowers active free cortisol [18, 29]. Our finding agrees with prior work that showed that males have significantly higher free cortisol levels than females .
Infectious adrenalitis can be difficult to recognize clinically . In low-income settings, where synthetic ACTH is not readily available for the gold-standard stimulation test, relying on symptoms and signs may result in incorrect or delayed diagnosis . However, symptoms including weakness, fatigue, anorexia, nausea, vomiting, abdominal pain, myalgia, arthralgia, postural dizziness, craving for salt, headache, depression and memory impairment may be suggestive of FAI  [32, 33]. In our study, abdominal pain and treatment duration were associated with FAI, contrary to prior studies in which primary adrenal insufficiency was associated with hyperpigmentation of the buccal mucosa, palms and scarred skin [22, 34]. Darkening of the palms, persistent postural dizziness, fatigability, profound general body weakness, and syncope have been reported in a case of HIV-associated Addison’s disease without symptoms of PTB . Skin hyperpigmentation is a specific sign of adrenal insufficiency, due to stimulation of melanocortin-1 receptors by the high levels of corticotrophin hormone resulting from lack of feedback from reduced cortisol levels .
In agreement with prior work , we found that history of abdominal pain was more likely among participants with FAI. Abdominal, flank and back pain is a common presentation in acute adrenal crisis mainly due to increased adrenal blood flow induced by increased secretion of ACTH . Clinical manifestations of adrenal insufficiency result from deficiency of adrenocortical hormones secondary to adrenal cortex destruction; in subgroup analyses, DS-TB patients with FAI had 2-times higher odds of abdominal pain [36, 38]. Hypotension in adrenal insufficiency is caused by increases in arginine vasopressin, reduced aldosterone and sodium wasting . Prior work in Uganda, found that 43% of patients with FAI had systolic hypotension and 19% had postural hypotension. Other work in the same setting found that 50% participants with adrenal insufficiency had systolic hypotension, and 29.2% had mucosal hyperpigmentation .