Case
Mr NJ, a 45 year old male, was referred to Endocrinology for investigation of hyponatremia during an admission with acute gastroenteritis complicated by acute kidney injury and hypotension.
Past history was significant for haemochromatosis, diagnosed age 19 after noticing skin bronzing. Genotypic analysis demonstrated compound heterozygosity for C282Y and H63D mutations. Despite previously requiring fortnightly venesections, his last venesection was 18 months prior and his most recent ferritin was 150microg/L (30-400microg/L). Liver ultrasound did not demonstrate cirrhotic features. His family history is significant for two brothers with compound heterozygous haemochromatosis, and one half-sister with hypothyroidism. Mr NJ lives at home with his wife and 3 biological children.
Investigations included a morning cortisol level of 58nmol/L performed on 2 separate occasions, with markedly elevated ACTH level of 941ng/L (7.2-63ng/L) consistent with primary adrenal insufficiency. Potassium levels were within normal limits. In retrospect, Mr N did note intermittent postural symptoms and lethargy at home. He denied weight loss, abdominal symptoms or any further changes to his skin colour.
Mr N was initially commenced on Hydrocortisone 20mg mane 10mg nocte, as well as fludrocortisone 100mcg daily with improvement in his Na levels, blood pressure and postural symptoms. CT abdomen and pelvis demonstrated shrunken adrenal glands. Thyroid function tests demonstrated mild primary hypothyroidism with a Thyroid Stimulating Hormone (TSH) of 9.64mIU/L and free T4 11.5pmol/L (12-22pmol/L), and he was commenced on thyroxine 50mcg daily.
Anti Thyroid Peroxidase (TPO) antibodies, anti Thyroglobulin (Tg) antibodies and Thyroid Stimulating Hormone Receptor antibodies (TSHrAbs) were all negative. Anti-adrenal cortical cell antibodies were also negative, raising the possibility of endocrine organ failure due to ferritin deposition from haemochromatosis. Further tests to exclude alternate causes of primary adrenal insufficiency, including 25-alpha hydroxylase antibodies and long chain fatty acids (to exclude a mild form of adrenoleukodystrophy), have been delayed due to the current COVID pandemic restrictions. Other relevant tests include normal LH of 4 IU/L (2-10 IU/L) and FSH of 4 IU/L (2-10 IU/L) with corresponding morning fasting total testosterone of 14.1nmol/L (9 - 35 nmol/L). Renin levels 2 months post commencement of fludrocortisone were 32mIU/L (10-50mIU/L). HbA1c was 5.2%.
Mr NJ’s TSH and T4 have normalised with 50mcg daily thyroxine. However, despite changing his hydrocortisone to thrice daily dosing with a total daily dose of 32mg, he is still experiencing persistent lethargy and symptoms of hypocortisolemia. He is awaiting further review by the haematologists in regards to his haemochromatosis.
Review of the literature
Haemochromatosis is an autosomal recessive inherited condition, caused by defects in the HFE gene. Clinical manifestations commonly occur in patients with homozygous C282Y gene mutations, however heterozygotes with H63D and C282Y mutations may, in 10-15% of cases, develop clinical disease1. Clinical manifestations are generally the result of progressive iron overload, due to decreased expression of hepcidin, and resultant loss of inhibition of iron reabsorption from the gut and recycling of iron from red blood cells2. Haemachromatosis can manifest in cirrhosis, joint arthralgias and cardiomyopathy.
Endocrine dysfunction in haemochromatosis is a known phenomenon, and most commonly induces “bronze” diabetes, hypogonadotrophic hypogonadism, and osteoporosis3. Diabetes most commonly manifests in a Type 2 diabetes phenotype, although the pathophysiology is a combination of decreased insulin secretion due to damaged pancreatic islet cells, as well as increased insulin resistance due to hepatic dysfunction3.
Endocrine disease is usually triggered by progressive years of iron loading, and is associated with cirrhosis. Incidence rates of endocrine disease (previously up to 80%) have dropped considerably, as disease is frequently ameliorated by venesection and lowering ferritin.
Adrenal insufficiency has been seen in 13 - 46% of patients with thalassemia, in the context of secondary haemochromatosis from transfusion dependence and subsequent iron deposition, manifesting in both primary and secondary adrenal insufficiency3. In hereditary haemochromatosis, isolated case reports of primary adrenal insufficiency have been seen, and iron deposition of the adrenal glands has been postulated as the cause3. Autopsy studies of patients with hereditary haemochromatosis have demonstrated iron deposition in the adrenal glands, although primarily in the zona glomerulosa rather than the fasciculata layer.
Iron deposition has also been seen in the thyroid gland of patients with hereditary haemochromatosis, although clinical hypothyroidism is rare4. A case series of 34 patients with hereditary haemochromatosis with cirrhosis secondary to iron accumulation, showed 8% (3) of patients had hypothyroidism, although all 3 patients subsequently tested positive to anti-TPO antibody testing4 . Subsequent studies have demonstrated incidence rates of 1% of thyroid disease, primarily hypothyroidism, in patients with haemochromatosis, which is similar to the general population.
Quality of life is a common persistent concern in patients with treated adrenal insufficiency. Studies have demonstrated deficits in vitality, mental health, physical functioning and general health perception5. Thrice daily compared to twice daily hydrocortisone dosing has shown benefits in Health Related Quality of Life (HRQoL) scores, however pharmacological studies still demonstrate inconsistent target concentrations of glucocorticoid levels 6. Daily prednisolone is an alternative glucocorticoid option, however its pharmacokinetic profile does not replicate the physiological diurnal variation of endogenous cortisol, and consequently may worsen both the lipid profile and bone health7.
Plenadren, a modified release hydrocortisone, has become available in Europe, and has demonstrated pharmacokinetic similarities to normal endogenous production of cortisol. In spite of this, adequate quality of life improvement data is lacking, and trials have shown modest but not substantial improvements7. Chronocort, an alternate modified release hydrocortisone, which induces a physiological ‘peak’ in cortisol levels during the early hours of the morning, has shown some efficacy in the congenital adrenal hyperplasia population, and is currently in development for use in Addison’s disease8. Subcutaneous hydrocortisone infusions have also been used on a case by case basis8.
Differing routines can also complicate glucocorticoid regimens in patients with Addison’s disease, and will require amendments to standard management. In fasting periods, such as during Ramadan, switching to once daily prednisolone to be taken at dawn, and ensuring intramuscular hydrocortisone is available are necessary considerations9. Similarly, patients who undertake shift work, particularly night shifts, may require an extra dose of hydrocortisone prior to commencing work.
In summary, although endocrine dysfunction is a common manifestation of hereditary haemochromatosis, the incidence is decreasing with early detection and initiation of venesection in patients. Primary hypothyroidism and primary adrenal insufficiency are exceedingly rare manifestations of disease. The solution to impaired quality of life in these patients has not been solved with currently available medications.
Take home points