Recurrent nocturnal hypoglycaemia as a cause of morning fatigue in treated Addison’s disease – favourable response to dietary management: a case report

The patient was a 43 year old Caucasian woman who had a three year history of diagnosed Addison’s disease (PAI). At the time of presentation with PAI, she reported weight loss of at least 4 kg over 6 months, fatigue and hyperpigmentation. Biochemistry revealed a serum sodium of 132 mmol/L (R 137–145 mmol/L) and potassium of 5.4 mmol/L (R 3.5–4.9 mmol/L), plasma cortisol of 16 nmol/L and an ACTH level of 1097 pmol/L (R 10–60 pmol/L). A 250mcg ACTH stimulation test showed a non-significant rise in serum cortisol from baseline 16 nmol/L to 17 nmol/L (R >500 nmol/L) at both 30 and 60 min. The plasma renin concentration was > 500 uIU/mL (R 7–50 uIU/mL) and plasma aldosterone <30 pmol/L (110–860 pmol/L). Primary hypothyroidism was evident with a TSH of 46 mIU/mL (R 0.5-4.0 mIU/mL) and a free T4 of 10 nmol/L (R 10–25 nmol/L). Elevated thyroid peroxidase antibodies and a firm small goitre were consistent with Hashimoto’s disease. Twelve months before diagnosis of PAI, mild normocytic anaemia was detected; Hb 89 g/L and biochemically confirmed iron deficiency (ferritin 12 μg/L [15–250 μg/L], transferrin saturation 6 % [10-35 %], transferrin 2.79 g/L [2.0-4.0 g/L], with normal B12 and folate levels. Oral iron supplements led to recovery of anaemia and normal iron studies. At the time of diagnosis of PAI she was found to have strongly positive endomysial and gliadin antibodies, consistent with coeliac disease, confirmed on jejunal biopsy. Adrenal hormone replacement included hydrocortisone (HC), initially in a thrice daily regimen at 0700 h, 1200 h, 1600 h in doses of 10/10/4 mg respectively, fludrocortisone 0.1 mg daily (after initial lower doses due to oedema), thyroxine 75mcg daily and a gluten free diet. Follow up revealed improved well-being, normalization of electrolytes, haemoglobin, plasma renin and TSH, as well as resolution of coeliac antibodies and a normal jejunal biopsy.

However, ongoing fatigue prompted trials of various GC regimens. Prednisolone 5 mg in the morning and 1–2 mg afternoon (0700 h, 1400 h) was not effective in relieving fatigue and a thrice daily regimen (0600 h, 1145 h, 1700 h) of HC 10/8/5 mg, equating to a total dose of 0.44 mg/kg or 15 mg/m² was employed, encompassing the period where CGMS measures were later performed. A trial of dehydroepiandrosterone (DHEA) was used in an attempt to alleviate the patient’s fatigue in doses up to 25 mg daily with normalization of DHEA levels that were initially undetectable. Unfortunately, this resulted in subtle hirsutism with hair growth around the chin and sideburn area, and the dose was reduced by the patient down to 5 mg daily; overall there was no consistent effect of DHEA on wellbeing.

No definite cause for the patient’s ongoing fatigue could be determined on clinical grounds. A particular characteristic of the fatigue was its severity and timing, occurring each morning and described by the patient as “extreme” “very hard to get up” “like being hit by a train” subsequently taking approximately 20 min to significantly resolve, after the usual morning HC and breakfast. There were also frequent non-migrainous morning headaches. There was no consistent excessive nocturnal wakening but poor or broken sleep was encountered on occasion. There were no episodes of nocturnal diaphoresis.

Hypoglycaemia was suspected and a continuous glucose monitor system (CGMS) was used to collect interstitial glucose levels over four days (Fig 1a). The CGMS revealed hypoglycaemia on three of four days tested, which was lasted up to six hours throughout one night. Calibration was performed against finger prick blood glucose levels (BGL), which were performed four times daily (i.e. before each meal and before bed). Dietary manipulation to address the hypoglycaemia was attempted and the patient was advised to have an evening low glycaemic index (GI) snack incorporating a fat load; specifically a whole-grain rice cake or multi-grain gluten free bread topped with cheese, cream cheese or peanut butter. The patient consumed this snack between 2030–2100 h during a repeat period of CGMS assessment, which was performed over seven days. The repeat CGMS measurements (Fig. 1b) showed resolution of the hypoglycaemia. The CGMS values were validated as per usual practice against finger prick capillary blood glucose values. The dietary changes resulted in resolution of headaches and improved energy after waking, although there was persistent daytime fatigue.