In September 2010, this 67-year-old man presented with fever, productive cough, and vomiting for 1 week. This was associated with progressive weight loss, poor appetite, lethargy, and increasing confusion over the past 3 weeks. He did not have abdominal pain, chronic cough, night sweats, or altered bowel habit. There was no headache, palpitations, or diaphoresis.
His past medical history included hypertension, hyperlipidemia, and right inguinal hernia, which was operated on 10 years ago. Chronic medications included amlodipine, lisinopril, and simvastatin. He was not on corticosteroids, diuretics, lithium, antacids, calcium, or vitamin D supplementation. Four weeks prior, he underwent saucerization of a right forearm abscess and received a course of antimicrobials. He did not consume alcohol or recreational drug.
On examination, he was confused with a Glasgow Coma scale (GCS) of 14. He was febrile and hemodynamically unstable with blood pressure of 80/50 mmHg, heart rate of 80 beats per minute, and oxygen saturation of 99% on room air. He was clinically dehydrated. Cardiovascular, respiratory, and abdominal examination was unremarkable, with no focal neurological deficit or neck rigidity. He did not have any features of Cushing's syndrome, and there were no hyperpigmented skin creases or buccal mucosa.
Initial investigations showed left upper lobe consolidation on chest radiograph and raised inflammatory markers. Computed tomography (CT) scan of the brain was unremarkable. Biochemical investigation revealed acute renal failure (creatinine at 407 micromol/L, from 84 micromol/L 3 weeks prior) and severe hypercalcemia of 3.55 mmol/L, which was deemed the likely cause of his altered sensorium. Intact parathyroid hormone (iPTH) was low at 0.81 pmol/L (reference: 1.3-7.6 pmol/L). Electrocardiogram revealed normal sinus rhythm with no shortened QTc interval. There was mild hyponatremia (serum sodium of 132 mmol/L) with normokalemia.
The initial impression was pneumonia complicated by septic shock and acute renal failure and hypercalcemia secondary to underlying malignancy in view of his loss of weight. He was immediately initiated on intravenous (IV) 0.9% sodium chloride drip and IV antibiotics (piperacillin/tazobactam and azithromycin) for healthcare-associated pneumonia. Despite 4.5 L of IV fluids, he had refractory hypotension and was put on ionotropic support, followed by IV hydrocortisone of 100 mg every 8 h as per conventional treatment of septic shock. He was intubated for airway protection in view of dropping GCS. Subsequently, he underwent continuous renal replacement therapy (CRRT) with low-calcium dialysate for acute renal failure with pulmonary congestion and persistent hypercalcemia.
After 5 days, his hemodynamics and renal function improved, and he was weaned off ionotropic support, hydrocortisone, and CRRT. Despite resolution of pneumonia and normalization of serum calcium, he remained persistently drowsy and febrile. Antimicrobial therapy was escalated to cover for presumptive meningoencephalitis with IV meropenem, vancomycin, and acyclovir. Magnetic resonance imaging (MRI) of his brain was unremarkable, and cerebrospinal fluid (CSF) study was negative for acid fast bacilli, fungal, bacteria, and neurotropic viruses, although electroencephalogram showed severe diffuse encephalopathy with no epileptiform activity. Although his fever resolved and overall condition improved, he remained confused when he was transferred out of the intensive care unit (ICU) on day 17 of admission.
His calcium levels (corrected for albumin and ionized calcium) returned to normal after IV fluids, hydrocortisone, and CRRT. Ionized calcium was monitored in ICU during CRRT that can alter total serum calcium, as well as hypoalbuminuria and acid base disturbances. Ionized calcium level remained normal for 12 days after cessation of CRRT and hydrocortisone. However, after transfer out of ICU, hypercalcemia recurred with peak corrected calcium of 3.16 mmol/L on day 19 of admission ( Figure 1 ). He received IV NS hydration and IV pamidronate of 90 mg slow infusion on recurrence of hypercalcemia with little effect.
Initial serum phosphate was high normal at 1.62 mmol/L (reference: 0.65-1.65 mmol/L), and he was vitamin D-insufficient (25-hydroxyvitamin D at 22.6 microg/L). Severe PTH-independent hypercalcemia is most commonly secondary to hypercalcemia of malignancy, and this was consistent with his history of weight loss. However, there was no evidence of malignancy on CT thorax, abdomen, pelvis, and MRI brain. His alkaline phosphatase (ALP) was normal at 58 U/L (reference: 32-103 U/L), which suggested the absence of bone lesions, and myeloma panel was negative. There was no mediastinal enlargement, lymphadenopathy, or hepatosplenomegaly suggesting sarcoidosis or lymphoma on imaging. The endotracheal aspirate and CSF studies were negative for tuberculosis and fungi. Immobilization can cause hypercalcemia in the presence of high bone turnover conditions, but there was no prolonged immobilization prior to admission nor elevated ALP suggesting Paget's disease of the bone or hyperthyroidism. Vitamin A level was sent and returned several weeks later, as low, at 0.2 mg/L (reference: 0.3-0.8 mg/L).
Although his hypotension and hyponatremia had resolved, a short Synacthen test was performed the following morning, with a blunted response: baseline undetecable, <8 nmol/L; and peak serum cortisol, 12 nmol/L. Serum cortisol had not been assessed prior to hydrocortisone initiation in the ICU. Immediately, IV hydrocortisone of 50 mg every 8 h was reinitiated. Adrenocorticotropic hormone (ACTH) level was low at 3.2 ng/L (reference: 10-60 ng/L), consistent with secondary adrenal insufficiency. His other pituitary hormones were normal: free T4, 13.7 pmol/L; thyroid-stimulating hormone, 2.84 mIU/L; Insulin-like Growth Factor-1 (IGF-1), 62.6 ng/ml; prolactin, 141.8 mIU/L; and total testosterone, 15.4 nmol/L. His calcium level improved markedly after 3 days of IV hydrocortisone, and it was converted to oral hydrocortisone of 20 mg every 8 h and subsequently tailed down to 20 mg daily in divided doses. His altered mentation resolved more gradually, and, by 7 days, he made a complete recovery.
On further questioning, he revealed that he previously consumed "Jamu" (traditional Malay medication) to improve vitality but had stopped 5 years prior to admission. "Jamu" are often made up from blends of herbal ingredients. As they are unregulated, they may contain unusually high amount of corticosteroids. There was no other exogenous steroid consumption or application. However, he was prescribed oral fluconazole of 200 mg twice daily for 4 weeks for his forearm abscess, as cultures showed "unspecified mould". He had been consuming this up till this admission.
There was no history of previous head trauma, surgery, or radiotherapy. MRI pituitary gland was normal with no adenoma, stalk thickening, or loss of T2 bright spot suggesting lymphocytic hypophysitis. One year later, although all the other anterior pituitary hormones remained normal, serum cortisol remained low, at 15 nmol/L, whereas ACTH increased to 78.2 ng/L, suggesting recovery process of the hypothalamic-pituitary-adrenal (HPA) axis from chronic suppression with exogenous steroid. Serum aldosterone was normal at 17 ng/dl, with plasma renin activity at 4.5 ng/ml/h. Furthermore, previous CT imaging of his abdomen did not show any adrenal masses, hemorrhage, or atrophy.
We established a final diagnosis of adrenal insufficiency secondary to HPA axis suppression from chronic traditional medication use, with Addisonian crisis and hypercalcemia precipitated by fluconazole use. Whereas his ACTH increased after the first year, his cortisol levels rose more gradually. After 8 years, glucocorticoid replacement was completely stopped. He has since been off steroids for 2 years, without any further recurrences of hypercalcemia, or Addisonian crisis since his initial presentation.