Abstract
The etiology, presentation and mortality of patients with primary adrenal insufficiency (PAI) in developing countries may differ from economically developed nations. However, information in this regard is scanty. The aim of this study was to determine the etiology and compare the clinical characteristics and mortality in infectious and autoimmune causes of PAI in Indian patients. All eligible (n = 89) patients (ages 15–83 years) diagnosed with PAI between 2006 and 2019 were studied. Patients were followed for a median duration of 5.9 (range 0.1–15.7) years. Eighty-six subjects underwent an abdominal computerized tomography scan or ultrasonography, and adrenal biopsy was performed in 60 patients. The most frequent etiologies of PAI were adrenal histoplasmosis (AH, 45%), adrenal tuberculosis (AT, 15%), autoimmunity (AI, 25%) and primary lymphoma (6%). Forty-two percent of patients presented with an acute adrenal crisis. AH and AT could not be differentiated on the basis of clinical features, except for a greater frequency of hepatomegaly–splenomegaly and type 2 diabetes mellitus (63% vs 15%, P < 0.01) in the former. Patients with an autoimmune etiology had a higher frequency of 21-hydroxylase antibodies (41% vs 3%) and autoimmune thyroid disease (46% vs 5%) vs those with infectious etiologies. Mortality was significantly higher in AH (45%) compared with AT (8%) or AI (5%) (P = 0.001). Causes of death included adrenal crises, progressive AH and unexplained acute events occurring at home. In conclusion, infections, especially AH, were the most frequent cause of PAI in north India. Despite appropriate therapy, AH had very high mortality as compared with AT and AI.
Primary adrenal insufficiency (PAI) or Addison’s disease is an uncommon disorder resulting from deficiency of cortisol and aldosterone due to the destruction of adrenal cortices (1, 2). Early diagnosis and prompt institution of treatment is essential to prevent both mortality and morbidity. With physiological replacement of glucocorticoids and mineralocorticoids, PAI has an excellent prognosis (3).
Most studies on PAI have been conducted in European and North American populations (4, 5, 6, 7). These have reported that 80–90% of cases result from an autoimmune destruction of the adrenal glands. In contrast, there are only few studies on the etiology or prognosis of PAI from countries of lower and lower-middle economic strata (8, 9, 10, 11, 12). Due to the high incidence of tuberculosis in these countries, PAI due to adrenal tuberculosis (AT) is likely to be an important etiology (9, 11, 12). In addition, PAI secondary to disseminated Histoplasma capsulatum infection is being reported with increasing frequency from some regions of the world, including parts of Southeast Asia and India (10, 13, 14, 15, 16, 17). However, only a few detailed studies on AH are available (10). As noted in studies from other countries, disseminated histoplasmosis (DH) occurs in patients with exposure to a high concentration of Histoplasma spores, for example bird fanciers or cave explorers (18). It is frequent in immunocompromised conditions, for example in those with human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS) and those on immunosuppressive drugs (18, 19).
Differences in the etiology of PAI, decreased awareness of the illness among physicians and patients and inadequate medical facilities in some regions are likely to result in differences in the clinical presentation and outcomes of PAI in developing countries as compared to that reported in Western series. In view of the lacunae in our current knowledge, we studied the etiology, clinical aspects and mortality in 89 consecutive well-characterized patients with PAI who presented to our hospital between 2006 and 2019.
Patients and methods
We studied 94 consecutive patients with PAI who presented to our hospital between 2006 and 2019 (Fig. 1). The hospital is a state government-funded referral center. Five patients, whose information was not available in the case records, were excluded, and the data of 89 patients were analyzed in this report. Of these, 72 patients were studied retrospectively from their records and 17 patients (October 2017 onward) were prospectively enrolled. The patients had an age ≥15 years at enrollment (mean ± s.d., 47 ±15 years; range, 15–83 years). All patients were prospectively followed, with their last visit or telephonic contact in January–May 2022 (median (range) 5.9 years (0.1–15.7 years)).
Recruitment and investigations in patients with primary adrenal insufficiency.
Citation: Endocrine Connections 12, 3; 10.1530/EC-22-0439
The diagnosis of PAI was suspected clinically (weight loss, fatigue, nausea, vomiting, diarrhea, hyperpigmentation, hyponatremia and hyperkalemia) and confirmed by measuring serum cortisol at 8:00 to 9:00 h and 1 h after intramuscular stimulation with 250 µg synthetic 1-24 adrenocorticotropic hormone (ACTH) (Synacthen®, Ciba Geigy, Basel, Switzerland). A value <500 nmol/L was diagnostic of cortisol deficiency. In 25 (28%) patients, the diagnosis was made on the basis of plasma cortisol <140 nmol/L alone at the time of acute stress at presentation, and 14 of 25 cases had undetectable cortisol (<27 nmol/L). Plasma ACTH (normal range 2.2–13.3 pmol/L) was elevated (15–1085 pmol/L) in 72 of 78 patients in whom it was tested. In the remaining six patients, ACTH had been collected without stopping glucocorticoid treatment. Data on 29 patients with AH with a shorter follow-up have been reported earlier (10). All patients gave written informed consent, and the study was approved by the 105th Institutional Ethics Committee meeting of Sanjay Gandhi Postgraduate Institute of Medical Sciences (IEC code 2018-119 IMP-105).
All patients had a detailed clinical evaluation at presentation. Acute adrenal crisis was diagnosed by the presence of hypotension responsive to intravenous hydrocortisone and saline infusion (2). Evidence of infection with tuberculosis (current or past history of extra-AT and prescription of treatment with anti-tuberculous drugs) or Histoplasma (history of exposure to birds, cave exploration and farming occupation) was sought. Clinical and biochemical evidence of other organ-specific autoimmune disorders were assessed.
All patients underwent an abdominal computerized tomography (CT) with contrast (n = 84) or ultrasonography (n = 2) to visualize the adrenal glands (Fig. 1). Abdominal imaging was not performed in three patients (one each with Allgrove’s syndrome and autoimmune polyglandular syndrome type 1 and 2). Adrenal biopsy (n = 50) or fine needle aspiration (FNA) (n = 10) was performed in 60 patients with enlarged adrenal glands. It was not successful due to poor access in four patients and not attempted in a patient with anti-phospholipid syndrome. All tissue samples were processed to detect Mycobacterium tuberculosis using Ziehl–Neelsen stain and cultured on Lowenstein Jensen medium. Genetic testing for M tuberculosis (Xpert MTB,RIF, Cepheid, Sunnyvale, CA, USA) was available for three patients. All samples were also stained for Histoplasma using periodic acid Schiff and Gomori–Grocott silver stain. For culture of Histoplasma, specimens were incubated for 4–6 weeks using Sabouraud dextrose agar medium followed by transfer into phase conversion medium. Testing for Histoplasma antigen is not available in India.
Definitions
The diagnosis of autoimmune PAI was made on the basis of normal, atrophic adrenal glands without calcification and an absence of evidence of current or previous tuberculosis. 21-hydroxylase (21-OH) antibodies were measured in all suspected patients. AH was diagnosed by findings of enlarged adrenal glands on radiology and demonstration of Histoplasma by staining and/or culture of adrenal tissue. Diagnosis of AT was made by the findings of enlarged adrenal glands, granulomas on histology and positive culture or genetic testing for M tuberculosis. Where adrenal biopsy or FNA was not feasible (n = 3) or non-diagnostic (n = 3), AT was diagnosed by a response to anti-tuberculous drugs with resolution of fever and toxemia or documentary evidence of current or previous tuberculosis at other sites. Four patients (4.5%) with enlarged glands could not be classified.
Patients with AH were treated with oral itraconazole (600 mg/day for 3 days, followed by 400 mg/day), with or without parenteral amphotericin B, according to guidelines (20). Itraconazole was continued for a period of 12–18 months. Patients with AT were treated with four drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) for 2 months followed by isoniazid and rifampicin for a further 4 months. All patients received physiological doses of glucocorticoids (prednisolone (82 patients, dose 2.5–5 mg/day in two divided doses) and hydrocortisone (7 patients,15–25 mg/day in three divided doses)) and fludrocortisone (50–125 µg/day). The dose of prednisolone or hydrocortisone was doubled for the duration of rifampicin use, which is known to induce acceleration of cortisol metabolism. Advice on stress dosing was provided at every visit.
Follow-up
All patients were seen regularly in our endocrinology clinic, initially at intervals of 3 months and subsequently 6-monthly. Recurrence of infection (fever, anorexia and weight loss) and adequacy of steroid replacement were ascertained at each visit. Patients were encouraged to contact the treating endocrinologist for any emergency. All patients were last evaluated in the endocrinology clinic or contacted telephonically between January and May 2022; the duration of follow-up was 5.9 years (0.1–15.7 years). In case of patients who died during follow-up, all attempts were made to ascertain the cause of mortality by contacting the family. Unfortunately, 14 patients died at home, and death summaries were not available in most instances. The cause of death could not be ascertained in seven patients.
Comparison of etiology of PAI between current and earlier study
We compared the etiologies of PAI in the present report with an earlier study conducted in our hospital between 1991 and 1999 (9). The areas of patient referral (mainly eastern Uttar Pradesh and adjoining state of Bihar) in both studies were similar, as were the diagnostic criteria which were based on adrenal size measured by CT scan or ultrasonography and adrenal biopsy or FNA.
Assays
21-OH antibodies were measured in 63 patients by an in-house immunoprecipitation assay using in vitro transcribed and translated 21-OH (21). A value >0.15 was considered positive. Thyroid peroxidase antibodies were measured by a chemiluminescence assay (Immulite1000, Siemens) and parietal cell antibody by indirect immunofluorescence using rat stomach as substrate (Aesku Diagnostics, Wendelsheim, Germany).
Statistical analysis
Continuous variables were expressed as mean ± s.d. or median (range) as appropriate. Continuous variables were compared by Student’s t-test or Mann–Whitney U test, while more than two groups were compared by either ANOVA or Kruskal–Wallis test followed by post hoc analysis using the Bonferroni test for comparison between two groups. Categorical variables were analyzed by the chi-square test. Survival analysis was performed by the Kaplan–Meier test. A two-tailed P-value of <0.05 was taken as significant. SPSS version 23 (IBM) was used for data analysis.
Results
Etiology
Sixty percent of patients had an infective etiology, while an autoimmune etiology was diagnosed in 25% (Fig. 2). The most common etiology was AH (45%), while 15% of patients were diagnosed to be due to tuberculosis. While eight patients of AH were diagnosed between 2006 and 2010, an increasing number of patients (32 patients) were detected between 2010 and 2019. Prior to their referral, 45% of the patients with AH had been incorrectly diagnosed as AT and received anti-tuberculous therapy. Among the other etiologies (n = 14), adrenal lymphoma (n = 5) and metastases (n = 3: lung carcinoma, 2 patients; colon carcinoma, 1 patient) were the most frequent (Fig. 2). Adrenal lymphoma was primary non-Hodgkin’s (diffuse large B-cell) type. In four patients, no specific etiology could be elucidated.
Etiology of primary adrenal insufficiency. Other causes (n = 14) included lymphoma (n = 5), metastases (n = 3), anti-phospholipidsyndrome (n = 1) and Allgrove’s syndrome (n = 1). In four patients (5%), no specific classification could be made.
Citation: Endocrine Connections 12, 3; 10.1530/EC-22-0439
Clinical features
The median duration of symptoms prior to diagnosis was 6 months (1–84 months) (Table 1). Clinical features at onset included anorexia and weight loss (each 97%), hyperpigmentation (89%), abdominal pain (36%), emesis (38%), hyponatremia (49%) and hyperkalemia (37%). In addition, 48% of patients were febrile. Forty-two (47%) patients presented with acute adrenal crisis at onset, but there was no mortality during its management. One-third had a low body mass index (<18.5 kg/m2).
Clinical features of different etiologies of primary adrenal insufficiency.
| Etiology | All patients (n = 89) | Histoplasmosis (n = 40) | Tuberculosis (n = 13) | Autoimmune/idiopathic (n = 22) | Other etiologies (n = 14) | Pa |
|---|---|---|---|---|---|---|
| Males | 76 (85%) | 39 (98%)b | 12 (92%)d | 12 (55%) | 13 (93%) | <0.001 |
| Females | 13 (15%) | 1 (2.5%)b | 1 (8%) | 10 (45%) | 1 (7%) | <0.001 |
| Age at diagnosis (years) | 47.8 ± 15 | 54.6 ± 12b | 47.0 ± 11e | 35.3 ±13 | 48 ± 16.5 | <0.001 |
| Duration of symptoms (months) | 6 (1–84) | 6 (2–36)c | 6 (1–36)e | 12 (2–84) | 3.5 (3–13.5) | 0.002 |
| Follow-up (years) | 5.9 (0.1–15.7) | 6 (0.1–15.7) | 7.6 (0.7–13.2) | 6.3 (1.3–13.9) | 0.7 (0.3–7.5) | 0.55 |
| Pyrexia | 44 (49%) | 29 (73%)b | 8 (62%)d | 2 (9%) | 5 (36%) | <0.001 |
| Weight loss | 86 (98%) | 39 (97.5%) | 13 (100%) | 20 (95%) | 14 (100%) | 0.46 |
| Mucocutaneous hyperpigmentation | 79 (89%) | 34 (85%) | 13 (100%) | 20 (95%) | 12 (86%) | 0.15 |
| Hepatomegaly | 27 (30%) | 22 (55%)b,f | 2 (15%) | 0 | 3 (21%) | <0.001 |
| Splenomegaly | 19 (21%) | 17 (43%)b,f | 0 | 0 | 2 (14%) | <0.001 |
| Adrenal crisis at presentation | 42 (47%) | 22 (55%) | 6 (46%) | 9 (41%) | 5 (36%) | 0.56 |
| BMI (kg/m2) (in males) | 20.7 ± 3.5 | 20.7 ± 3.2 | 22.0 ± 4.5e | 19.0 ± 2.9 | 22.7 ± 2.8 | 0.03 |
| Hyponatremia (serum Na+<135 mEq/L) | 44 (49%) | 25 (63%)c | 6 (46%) | 6 (27%) | 7 (50%) | 0.03 |
| Hyperkalemia (serum K+>5 mEq/L) | 33 (37%) | 15 (38%) | 6 (46%) | 6 (27%) | 6 (43%) | 0.5 |
| Diabetes mellitusg | 30 (34%) | 25 (63%)b,f | 2 (15%) | 2 (9%) | 1 (7%) | < 0.001 |
| History of extra adrenal tuberculosis | 12 (13%) | 6 (15%) | 4 (31%) | 2 (9%) | 0 | 0.52 |
| Farming profession | 19 (21%) | 18 (45%) | 0 | 0 | 1 (7%) | <0.001 |
| Autoimmune thyroid diseaseh,i | 14/75 (19%) | 2 (5%)b | 0d | 12 (55%) | 0 | <0.001 |
| Thyroid peroxidase antibody | 23/69 (33%) | 6/32 (19%)b | 3/11 (27%) | 13/21 (62%) | 1/5 (20%) | 0.004 |
| 21-hydroxylase antibody | 10/63 (16%) | 1/31 (3%)b | 0/7e | 9/22 (41%) | 0/3 | <0.001 |
| Parietal cell antibody | 8/69 (12%) | 4/32 (13%) | 0/11 (0) | 4/21 (19%) | 0/5 | 0.37 |
| Mortality | 29 (32%) | 18 (45%)c,f | 1 (7.7%) | 1 (4.5%) | 8 (57%) | 0.001 |
‘Other etiologies’ included lymphoma (n = 5), metastases (n = 3), autoimmune phospholipid syndrome (n = 1), triple A syndrome (n = 1) and unclassified (n = 4). Mean ± s.d. or median (range).
aP-value for comparison between three etiological groups (AH, AT and AI) using ANOVA or Kruskal–Wallis test; bAH vs AI, P < 0.01; cAH vs AI, P < 0.05; dAT vs AI, P < 0.01; eAT vs AI, P < 0.05; fAH vs AT, P < 0.05; gdiabetes mellitus at last follow-up; all patients had type 2 diabetes mellitus; hincludes Graves’ disease (n = 2) and autoimmune hypothyroidism (n = 10); ipernicious anemia-2 (9%), premature ovarian insufficiency-1 (5%) and hypoparathyroidism-1 (5%) were present exclusively in autoimmune category.
AH, adrenal histoplasmosis; AI, adrenal autoimmunity; AT, adrenal tuberculosis; BMI, body mass index.
On comparison of patients with AH, AT and autoimmunity (AI), the frequency of acute adrenal crises at presentation was similar. Patients with an infectious etiology had a marked male predominance (AH, 98%; AT, 92%), as compared with an autoimmune etiology (55%) (Table 1). Patients with AH were significantly older compared to those with AI and had a shorter duration of symptoms prior to diagnosis (median 6 vs 12 months, P < 0.01). AH and AT were difficult to differentiate on the basis of their clinical features alone (Table 1). However, the former had a higher frequency of hepatomegaly and splenomegaly. Thirty-one percent of patients with AT had previous evidence of extra-AT. A history of farming profession was significantly more frequent in patients with AH. Type 2 diabetes mellitus was more frequent in patients with AH compared to those with AT (63% vs 15%). In 92% of patients, diabetes was present before diagnosis of PAI.
Adrenal imaging
All patients with adrenal histoplasmosis (AH) had bilateral adrenal enlargement with central hypodense areas. Of the 13 patients with AT, 12 (92%) had bilateral adrenal enlargement, while 1 patient had bilateral adrenal calcification without enlargement.
Autoimmunity
Fifty-five percent of patients with an autoimmune PAI had evidence of autoimmune thyroid disease (Table 1). Other autoimmune disorders (pernicious anemia (9%), premature ovarian insufficiency (5%) and hypoparathyroidism (5%)) were detected only in patients with autoimmune PAI. 21-OH antibodies were present in 41% of patients with an autoimmune etiology and in only 1 (3%) patient with granulomatous PAI. 21-OH antibody positive patients had a similar clinical profile as compared to those who were negative (Supplementary Table 1, see section on supplementary materials given at the end of this article). No antibody-negative male patient had clinical features suggestive of adrenoleukodystrophy. A 22-year-old patient with behavioral difficulty and seizures had normal very long-chain fatty acid levels.
Mortality
The case-fatality ratio among the entire cohort was 31%. On comparison of patients with infectious and autoimmune PAI (follow-up 17 months (6–92 months)), case fatality was considerably higher among patients with AH (45%), as compared to those with AT (8%) or AI (5%) (P < 0.001) (Table 1, Fig. 3). Among patients with AH, 5 (28%) patients died within 12 months of diagnosis, while 13 (72%) died after 1 year. Mortality was 66% among those not completing full 1 year of itraconazole treatment vs 39% among those completing therapy (P = NS). The most frequent causes for mortality were progressive infection, adrenal crises and unexplained acute death after a short illness (Table 2). Six of the seven patients who had an unexplained death had a previous history of cardiovascular disease (CVD). While these patients apparently continued prednisolone during this time, it is not possible to rule out if adrenal insufficiency contributed to these deaths in the absence of death certificates. Many patients who died had multiple comorbidities, such as age >80 years (n = 1), malignancy (n = 2), chronic liver disease (n = 1), diabetes (n = 14), CVD (n = 8) and concomitant tuberculosis (n = 1). No patient with AH had HIV antibodies.
Cumulative survival among patients of primary adrenal insufficiency. Kaplan–Meier plot of cumulative survival among patients of primary adrenal insufficiency due to histoplasmosis, tuberculosis and autoimmunity (P = 0.045 by log rank test).
Citation: Endocrine Connections 12, 3; 10.1530/EC-22-0439
Causes of mortality among different etiological groups.
| Histoplasmosis (n = 40) | Tuberculosis (n = 13) | Autoimmunity (n = 22) | |
|---|---|---|---|
| Mortality n (%) | 18 (45) | 1 (8) | 1 (4.5) |
| Adrenal crisisa | 4 | 0 | 1 |
| Progressive histoplasmosis | 4 | 0 | 0 |
| Unexplained (acute) deathb | 7 | 1 | 0 |
| CVD | 1 | 0 | 0 |
| Othersc | 2 | 0 | 0 |
aMetastatic prostatic malignancy and CNS tuberculosis each in one patient; bthese deaths occurred at home after short illness, previous history of CVD in six patients and no history of stopping steroid replacement; coral carcinoma with emaciation (n = 1) and chronic liver disease with hepatic encephalopathy (n = 1).
CNS, central nervous system; CVD, cardiovascular disease.
Change in etiology of PAI
The etiology of PAI was compared in two studies performed 20 years apart (Table 3). In the earlier study of 43 patients, conducted between 1991 and 1999, the two common etiologies were tuberculosis (47%) and idiopathic/autoimmune (51%). No patient with AH was detected (Table 3). In contrast, in the current study, AH (45%) replaced AT (15%) and AI (25%) as the most frequent etiology.
Etiology of primary adrenal insufficiency in 1991–1999 and in current study (2006-2019).
| Study | 1991–1999 a | 2006–2019 |
|---|---|---|
| N | 43 | 89 |
| Idiopathic/ autoimmune | 22 (51) | 22 (25) |
| Tuberculosis | 20 (47) | 13 (15) |
| Histoplasmosis | 0 | 40 (45) |
| Others | 1 (2)b | 14 (16)c |
Values are given as N (%).
a(9); bPneumocystis jirovecii infection; cnon-Hodgkin’s lymphoma (n = 5), bilateral adrenal metastases (n = 3), Allgrove’s syndrome (n = 1), secondary antiphospholipid syndrome (n = 1) and indeterminate (n = 4).
Discussion
In contrast to recent reports from Europe and North America, granulomatous infectious diseases (AH and AT) were the preponderant etiology of PAI in this study. Differentiation between AT and AH was difficult on the basis of clinical characteristics alone. Patients with AH had a significantly higher mortality compared with AT and autoimmune etiologies of PAI.
Apart from the frequently described features of PAI (2, 4, 5, 22), nearly 70% of patients with AH and AT in this study were febrile. In contrast to the female preponderance noted in studies in developed countries (4, 6), there was a male excess, especially among patients with AH and AT. A similar male preponderance has previously been noted in patients with DH (13, 14, 15, 16, 17, 18) as well as tuberculosis in low-income regions (23). In the case of AH, 45% of men were involved in farming, and an increased chance of inhaling conidia during this activity may be partly responsible. Nearly half of the patients presented with an acute adrenal crisis and required emergency hospitalization. The frequency of crises at presentation in different studies in developing countries varies from 20 to 50% (8, 11, 12, 24).
Infectious etiologies, AH and AT, constituted the majority of patients in this series (60%), while autoimmune PAI was less frequent (25%). This finding is in contrast to reports in European series where AI is the predominant etiology (80–90%). In this context, Mofokeng et al. reported that AT was more common (54% vs 8%), while AI as a cause of PAI was infrequent (7.4% vs 66.2%), in public/academic vs private settings respectively in South African patients (11). In the current study, it was not possible to distinguish between AT and AH on clinical or radiological features alone, and an adrenal biopsy was essential. Conventional risk factors predisposing to AH such as HIV-AIDS, significant exposure to birds or disorders resulting in immunodeficiency (18) were absent in this study. Forty-five percent of patients with AH gave their profession as farming, suggesting that inhalation of Histoplasma spores may be an important risk factor (13). Type 2 diabetes mellitus was present in close to two-thirds of patients with AH and was significantly higher than in other etiological groups. While a similar association has been noted in a study of DH from China (25), the mechanisms by which diabetes may predispose to the infection is currently not delineated. Diabetes can impair macrophage function as well as cytokine signaling, both of which may be important for protection against AH.
Patients with an autoimmune etiology had a larger proportion of females, an earlier onset of illness and longer duration of symptoms prior to diagnosis, compared with those with AH and AT. Similar to reports in European patients, associated autoimmune disorders, mainly autoimmune thyroiditis, were present in half of these patients (1, 2, 4, 5, 6). Antibodies against 21-OH were detected in 41% of patients but were absent in other etiological groups except, unexpectedly, one patient with AH. It is feasible that in this instance the adrenal glands were initially affected by AI and later infected by Histoplasma. In an earlier report, 21-OH antibodies were reported in 21% of Indian patients with idiopathic PAI (26). The frequency of 21-OH antibody is lower than that reported in studies from reports in European series, where 70–90% of patients at diagnosis are positive (4, 6, 27). The genetic susceptibility to 21-OH antibodies is related to specific human leukocyte antigen (HLA) class II loci (28). The lower prevalence of the antibodies in the current study may be related to differences in frequency of predisposing alleles, such as DRB1*03, in the Indian compared with European population (29).
Mortality was significantly higher among patients with AH as compared to those with AT and AI. Despite receiving the recommended treatment of AH, 45% of patients with AH died during a median follow-up of 6 years. This was in contrast to patients with AT and AI, where only one death was noted in each group. Death resulted from widespread AH, acute adrenal crises or, most commonly, unexplained acute illness. This last group of patients had objective evidence of CVD in the past and no history of stopping prednisolone replacement. While mortality in AH has not been reported separately, in earlier studies of DH, it has ranged from 80% to 90% in untreated patients (30), with a better prognosis being reported in more recent studies (31, 32). A recent study reports a mortality of 37% in patients of HIV-AIDS with DH (33).
We compared the etiology of PAI between our earlier study, performed between 1991 and 1999 (9), and the current study conducted approximately 20 years later. In the first report, the two main etiologies of PAI were tuberculosis and AI (idiopathic), and no patient with AH was diagnosed. However, in the current study, AH was the most frequent etiology, affecting close to half the patients. The areas of patient referral and diagnostic evaluation have remained largely unchanged. While tuberculosis has been declining in India, the incidence and death rates remain significant (34). Hence, this cannot be the sole reason for the decline in AT in the current study. Recently, AH is increasingly reported from different regions of north India (13, 15, 16, 17, 35). Scarcity of land for cultivation and exposure to soil enriched with Histoplasma spores may have resulted in increased exposure, though this needs to be proven (13).
The current report is one of the largest series of well-documented patients with PAI from a developing country, with detailed clinical information. In addition, an adequate follow-up was available for assessment of mortality. However, our study had some shortcomings. Since it was mainly a retrospective study, some data collection was not complete. In addition, we were unable to test for plasma very long-chain fatty acid (VLCFA) levels in all 21-OH-negative patients. However, no patient had features of adrenoleukodystrophy. One patient with seizures and poor scholastic performance tested negative for VLCFA. Lastly, since this is a single-center report, the etiology of PAI may differ in other parts of the Indian subcontinent.
In summary, infectious etiologies contributed to nearly 60% of the cases of PAI in this study from north India. AH was the most common etiology, and its frequency has increased in the last two decades. AH and AT were difficult to difficult to differentiate on clinical features alone. Despite appropriate treatment, mortality was significantly higher among patients with AH in comparison with other etiologies and remains a matter of concern.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EC-22-0439.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
The grant was supported by a grant by the Sanjay Gandhi Postgraduate Institute, Lucknow (A-04-PGI/IMP/78/2018).
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