Complete recovery after glucocorticoid replacement therapy in a case of primary adrenal insufficiency caused by adrenal tuberculosis infection

Summary Symptoms of primary adrenal insufficiency (PAI) are commonly nonspecific, causing the disease to be misdiagnosed or often delayed, and patients may present to the hospital with a life-threatening crisis. Previous case reports have documented that patients in this condition often require lifelong glucocorticoid replacement therapy. This study aimed to present a noteworthy outcome of PAI caused by adrenal tuberculosis infection, demonstrating complete recovery after six months of glucocorticoid replacement therapy. A 38-year-old Indonesian man presented to the endocrinology clinic in a tertiary hospital with a chief complaint of epigastric pain. The patient experienced nausea, vomiting, loss of consciousness, weight loss, excessive sweat, decreased appetite, weakness, and dizziness in the past 2 weeks. Laboratory examinations revealed hyponatremia, elevated adrenocorticotropic hormone, and suppressed morning plasma cortisol level. A non-contrast-enhanced abdominal MRI showed unilateral right-side adrenal enlargement and calcification. The patient’s Mantoux test was positive. Corticosteroids and anti-tuberculosis therapy were administered. After 6 months, hydrocortisone was discontinued due to the patient’s good clinical condition and normal morning plasma cortisol levels. After a 1-year follow-up, the patient remained asymptomatic with normal cortisol levels. We hypothesized several reasons for this unique outcome: (i) the patient was relatively young compared to previous cases, suggesting an adequate immune system may play a role; (ii) despite a 1-month delay in diagnosis and treatment, the absence of skin hyperpigmentation suggested an acute presentation, potentially contributing to the favorable outcome; and (iii) the absence of comorbidities potentially positively impacted the patient's outcome. Learning points Symptoms of adrenal insufficiency are often nonspecific and may only become apparent once significant damage has occurred to the adrenal gland. Clinical adjustments and a comprehensive understanding of epidemiological knowledge are necessary for diagnosing patients with endocrine diseases in limited-resource settings. Complete recovery in primary adrenal insufficiency caused by tuberculosis infection might be due to younger age, acute presentation, and absence of comorbidities


Learning points
• Symptoms of adrenal insufficiency are often nonspecific and may only become apparent once significant damage has occurred to the adrenal gland.
• Clinical adjustments and a comprehensive understanding of epidemiological knowledge are necessary for diagnosing patients with endocrine diseases in limited-resource settings.
• Complete recovery in primary adrenal insufficiency caused by tuberculosis infection might be due to younger age, acute presentation, and absence of comorbidities https://edm.bioscientifica.com/ 2

Background
Primary adrenal insufficiency (PAI) is a rare disease that can potentially cause life-threatening conditions (1).Adrenal insufficiency occurs when the adrenal cortex fails to produce enough cortisol due to gland dysfunction or damage (i.e.PAI) (2).PAI is often misdiagnosed due to its clinical manifestations being similar to other diseases (3).Despite global efforts to combat tuberculosis (TB), the disease continues to pose a considerable health burden, with around 10 million new cases reported each year (4).The prevalence of PAI is estimated at 82-144 cases per million, with TB being the leading cause in developing countries (5,6).
To the best of our knowledge, recent studies have only reported ten PAI cases caused by adrenal tuberculosis infection.Symptoms of adrenal insufficiency are often nonspecific and may only become apparent once significant damage has occurred to the adrenal gland (at least 90%) (5).Unfortunately, this implies that diagnosis is often delayed, and patients may present with lifethreatening conditions.Early detection of PAI is therefore critical for better outcomes.
Previous case reports have documented the patient in this condition often require lifelong glucocorticoid replacement therapy.The case report (CARE) Guidelines are followed in this case report, presenting a patient with PAI caused by adrenal tuberculosis infection.Remarkably, the patient achieved complete recovery, and glucocorticoid replacement therapy was discontinued after 6 months, marking a noteworthy outcome.Additionally, a review of the diagnostic test for this specific condition is also discussed.

Case presentation
A 38-year-old Indonesian male patient was presented to the endocrinology clinic at a tertiary teaching hospital in Banda Aceh, Indonesia, with a chief complaint of epigastric pain.The patient experienced nausea, vomiting, loss of consciousness, weight loss, excessive sweat, decreased appetite, weakness, and dizziness in the past two weeks.Skin hyperpigmentation was not found in the patient.Despite being referred to two secondary hospitals, a definitive diagnosis was unable to be made due to the unclear clinical manifestations.Polyuria was presented, occurring 5-10 times a day and occasionally reaching volumes as high as 4500 mL per day.Anxiety persisted in the patient for over a decade with the fear of driving and heights.There were no comorbidities identified and no history of active tuberculosis (TB) pulmonary infection was documented.The patient's family members have no similar condition as the patient.Physical examinations were within normal limits.

Investigation
Laboratory examinations showed results of hyponatremia (107 mmol/L, reference range (RR): 136-145 mmol/L), elevated adrenocorticotropic hormone (785 pg/mL, RR: 0-46 pg/mL), and suppressed morning plasma cortisol (1.2 µg/dL, RR: 3.7-19.4µg/dL).A noncontrast-enhanced abdominal MRI revealed unilateral right-side adrenal hypertrophy and calcification (Fig. 1).The patient's Mantoux test results were positive.Chest CT scan and x-ray results showed no pulmonary abnormalities.Based on clinical investigation, the patient was diagnosed with PAI caused by adrenal TB. https://edm.bioscientifica.com/ 3 Treatment Intravenous saline 0.9% was immediately administered to ameliorate hyponatremia.The patient received a single intravenous hydrocortisone dosage of 100 mg, followed by 200 mg every 24 h for 3 days.For 3 weeks, the patient was switched to 15 mg/day of oral prednisone; the dose was divided into a morning dose of 10 mg and an afternoon dose of 5 mg.After 15 days, the patient's morning plasma cortisol level increased from 1.2 g/dL to 10.5 g/dL and was discharged from the hospital.The patient was given 10 mg of long-term oral replacement hydrocortisone once a day.The patient was also administered anti-TB medications (rifampicin, isoniazid, pyrazinamide, and ethambutol) for 9 months.To clarify, Fig. 2 shows the timeline of diagnosis, intervention, and outcome of the patient.

Outcome and follow-up
The attending endocrinologist (HZ) maintained regular phone follow-ups with the patient; the patient reported excellent adherence to corticosteroids and anti-TB medication.The patient reported no recurrence of previous symptoms six months after initiating hydrocortisone, and morning plasma cortisol levels were within the normal limits (RR: 7.2-63.3pg/ mL); hence, the consumption of hydrocortisone was discontinued.Furthermore, after receiving anti-TB treatment for 9 months, the patient was documented free of TB.The patient had no adverse effects as a result of the treatment.On the 1-year follow-up, the patient remained asymptomatic, and the morning plasma cortisol level was consistently within the normal range.

Discussion
PAI is an uncommon condition, and its clinical signs may be unfamiliar to certain healthcare practitioners.
The case presented in this study was challenging due to the patient's nonspecific symptoms of PAI, causing the patient to be referred to two secondary hospitals without a definitive diagnosis.The clinical symptoms of PAI are gradually progressing, such as fatigue, weakness, loss of appetite, weight loss, nausea, vomiting, and postural hypotension; consequently, PAI can be easily misdiagnosed as other disorders with similar symptoms (7).Skin hyperpigmentation is present in up to 94% of cases of PAI and can be used to differentiate it from secondary adrenal insufficiency (8).Gastrointestinal symptoms were the primary concern for the patient in this case, and the absence of skin hyperpigmentation made diagnosis challenging.The presence of hyponatremia prompted the attending endocrinologist (HZ) to order cortisol level and adrenocorticotropic hormone testing, which ultimately led to the diagnosis.
To diagnose a case of PAI, in addition to hormonal level tests, the primary test that should be performed is the 21-hydroxylase (21-OH) autoantibodies test.This test helps determine whether the disease is caused by autoimmune disease, malignancy, TB, and so on.However, the 21-OH antibody test is rarely available in limited-resource settings, which were not performed for the present patient.However, we were able to diagnose the patient with PAI caused by TB without conducting the 21-OH autoantibodies test.Indonesia has been listed as having the second largest TB burden globally.Moreover, most cases of autoimmune Addison's disease tend to affect young and middle-aged women, but this case presented in a 38-year-old male patient.Therefore, clinical adjustments and a comprehensive understanding of epidemiological knowledge are necessary for diagnosing patients with endocrine diseases in limitedresource settings.
The patient was able to be diagnosed using simple diagnostic modalities.In real-world practice, especially in developing countries, access to more advanced diagnostic tests, such as corticotropin stimulation tests, TB tests, CT scans, and MRI, may be limited due to financial and resource constraints.As a result, the lack of accessibility to advanced diagnostic tests may lead to delayed diagnoses of PAI in primary or secondary health-care facilities.The Mantoux test is a low-cost and easily performed option that is sensitive but not specific for the diagnosis of active TB (20).By considering the patient's clinical presentation, morning plasma cortisol levels, Mantoux test results, and MRI imaging result, the attending endocrinologists (HZ, KWS, and AED) had sufficient evidence to diagnose PAI caused by TB infection.
A pathological biopsy is often necessary to establish a definitive diagnosis of adrenal insufficiency (21).Histopathological and immunohistochemical analysis revealed primary adrenal TB; but the procedure was not performed in this case due to financial and facility constraints.Measuring adrenocorticotropic hormone levels is the first step in diagnosing adrenal insufficiency, and in PAI, these levels are typically above 100 pg/mL (22 pmol/L) (2,22).Additionally, elevated plasma renin levels and low serum aldosterone are also common findings (22).In the present case, the patient was administered oral prednisone instead of hydrocortisone during hospitalization.Hydrocortisone should have been administered as the first-line therapy for the patient.
However, in the present case, it was not possible to do so because hydrocortisone was unavailable in our hospital at the time, and therefore prednisone was used as a substitute.In limited-resource settings, sometimes the Referred to a tertiary hospital (present study) Signs and symptoms: Dyspepsia, nausea, vomiting, abdominal pain, loss of consciousness, weight loss, excessive sweat, decreased appetite, weakness, and dizziness in the past two weeks.Skin hyperpigmentation was absent.

Day 13 Laboratory finding:
Low morning plasma cortisol level

Intervention:
Intravenous hydrocortisone at 100 mg once and followed by 200 mg per 24 h for 3 consecutive days

Day 17 Abdominal MRI without contrast:
Unilateral right-side adrenal enlargement and calcification

Intervention:
Oral prednisone of 15 mg/day which was divided into a morning dose of 10 mg and an afternoon dose of 5 mg for 3 consecutive weeks

Day 22
Discharged from hospital Administered long-term oral replacement hydrocortisone once a day for a dose of 10 mg and antituberculosis drugs

Month 6
Stopped taking hydrocortisone drug Morning plasma cortisol level was stable within the normal range

Month 12
Follow-up: Morning plasma cortisol level was stable within the normal range

Day 1
Visited secondary hospital A  required medications are unavailable, necessitating flexibility in therapeutic management based on the patient's clinical condition.We decided to administer oral prednisone with the assumption that it is equivalent to hydrocortisone and would yield the same outcome for the patient.
To avoid adrenal crises, patients with adrenal insufficiency often require lifelong glucocorticoid replacement therapy and stress management (23).In this case, hydrocortisone was discontinued due to the patient's good clinical condition and normal morning plasma cortisol levels.After a 1-year follow-up, the patient remained asymptomatic with normal cortisol levels, marking a noteworthy complete recovery, no previous studies have reported the same outcome as the present case.We hypothesized several reasons for this unique outcome: (i) The patient, at 38 years, was relatively young compared to previous cases, suggesting that an adequate immune system may play a role; (ii) despite a one-month delay in diagnosis and treatment, the absence of skin hyperpigmentation suggested an acute presentation, potentially contributing to the favorable outcome; and (iii) The absence of comorbidities such as diabetes mellitus, hypertension, or human immunodeficiency virus infection was documented in this case, potentially positively impacting the patient's outcome.
On April 4, 2023, a search for published studies was conducted on PubMed and Google Scholar using a combination of keywords ('Addison disease' OR 'Primary adrenal insufficiency' OR 'adrenal tuberculosis') NOT Autoimmune AND Tuberculosis, with a title-only filter.The inclusion criteria were patients diagnosed with primary adrenal insufficiency caused by adrenal TB and studies published between 2000 and 2023.Studies published in languages other than English and those that were not randomized controlled trials, observational studies, or case reports were excluded.A total of 71 articles were identified from both databases and after removing duplicates and applying the eligibility criteria, 12 articles (10 case reports and two observational studies) were included in the review (see Table 1).
By reviewing various studies, in limited resources setting, attending physicians can rely on a patient's specific manifestation, such as skin hyperpigmentation, nausea, vomiting, abdominal pain, fatigue, weakness, decreased appetite, weight loss, and depressive symptoms, to differentiate diagnoses.A metabolic imbalance or its associated symptoms may prompt laboratory analysis of cortisol levels.The majority of individuals with adrenal TB have hyponatremia, hyperkalemia, hypoglycemia, and hypotension.If TSPOT.TB or gamma interferon (IFN-γ) release assays are unavailable, the Mantoux test is a reliable method for confirming TB infection.In cases where laboratory abnormalities are detected, abdominal grayscale ultrasonography, CT scans, and MRI examinations are recommended to confirm whether adrenal insufficiency is due to TB or other adrenal malignant diseases.Abdominal grayscale ultrasonography can be particularly useful in limited resource settings, as it can reveal solid masses in the bilateral adrenal glands.CT scans may show bilateral adrenal enlargement and calcifications, while MRI scans may reveal bilateral involvement, T2 hypointense or isointense signals in the central zone, and peripheral rim enhancement. https://edm.bioscientifica.com/8

Figure 1
Figure 1Abdominal MRI examination showed right-side adrenal enlargement and calcification (red arrow).

Table 1 Summary
of clinical manifestations of primary adrenal insufficiency caused by adrenal TB infection.