ACTH-dependent hypercortisolism is caused by an ectopic ACTH syndrome (EAS) in 20% of cases. We report a rare cause of EAS in a 41-year-old woman, presenting with clinical features of Cushing’s syndrome which developed over several months. Biochemical tests revealed hypokalemic metabolic alkalosis and high morning cortisol and ACTH levels. Further testing, including 24-hour urine analysis, late-night saliva and low-dose dexamethasone suppression test, confirmed hypercortisolism. An MRI of the pituitary gland was normal. Inferior petrosal sinus sampling (IPSS) revealed inconsistent results, with a raised basal gradient but no rise after CRH stimulation. Additional PET-CT showed intense metabolic activity in the left nasal vault. Biopsy of this lesion revealed an unsuspected cause of Cushing’s syndrome: an olfactory neuroblastoma (ONB) with positive immunostaining for ACTH. Our patient underwent transnasal resection of the tumour mass, followed by adjuvant radiotherapy. Normalisation of cortisol and ACTH levels was seen immediately after surgery. Hydrocortisone substitution was started to prevent withdrawal symptoms. As the hypothalamic–pituitary–axis slowly recovered, daily hydrocortisone doses were tapered and stopped 4 months after surgery. Clinical Cushing’s stigmata improved gradually.
Ectopic ACTH syndrome can originate from tumours outside the thoracoabdominal region, like the sinonasal cavity.
The diagnostic accuracy of IPSS is not 100%: both false positives and false negatives may occur and might be due to a sinonasal tumour with ectopic ACTH secretion.
Olfactory neuroblastoma (syn. esthesioneuroblastoma), named because of its sensory (olfactory) and neuroectodermal origin in the upper nasal cavity, is a rare malignant neoplasm. It should not be confused with neuroblastoma, a tumour of the sympathetic nervous system typically occurring in children.
If one criticises MRI of the pituitary gland because of ACTH-dependent hypercortisolism, one should take a close look at the sinonasal field as well.
We report our experience on managing a case of florid Cushing’s disease with Methicillin-resistant Staphylococcus aureus (MRSA) sepsis using intravenous etomidate in the intensive care unit of a UK district general hospital.
Severe Cushing’s syndrome is associated with high morbidity and mortality.
Etomidate is a safe and effective medical therapy to rapidly lower cortisol levels even in the context of severe sepsis and immunosuppression.
Etomidate should ideally be administered in an intensive care unit but is still feasible in a district general hospital.
During treatment with etomidate, accumulation of serum 11β-deoxycortisol (11DOC) levels can cross-react with laboratory cortisol measurement leading to falsely elevated serum cortisol levels. For this reason, serum cortisol measurement using a mass spectrometry assay should ideally be used to guide etomidate prescription.
Addison’s disease (AD) is the most common endocrine manifestation of antiphospholipid syndrome (APS), but it remains a very rare complication of the syndrome. It is caused by adrenal venous thrombosis and consequent hemorrhagic infarction or by spontaneous (without thrombosis) adrenal hemorrhage, usually occurring after surgery or anticoagulant therapy. We present a clinical case of a 36-year-old female patient with a previous diagnosis of APS. She presented with multiple thrombotic events, including spontaneous abortions. During evaluation by the third episode of abortion, a CT imaging revealed an adrenal hematoma, but the patient was discharged without further investigation. A few weeks later, she presented in the emergency department with manifestations suggestive of adrenal insufficiency. Based on that assumption, she started therapy with glucocorticoids, with significant clinical improvement. After stabilization, additional investigation confirmed AD and excluded other etiologies; she also started mineralocorticoid replacement. This case illustrates a rare complication of APS that, if misdiagnosed, may be life threatening. A high index of suspicion is necessary for its diagnosis, and prompt treatment is crucial to reduce the morbidity and mortality potentially associated.
AD is a rare but life-threatening complication of APS.
It is important to look for AD in patients with APS and a suggestive clinical scenario.
APS must be excluded in patients with primary adrenal insufficiency and adrenal imaging revealing thrombosis/hemorrhage.
Glucocorticoid therapy should be promptly initiated when AD is suspected.
Mineralocorticoid replacement must be started when there is confirmed aldosterone deficiency.
Hypertension is a common feature of APS; in patients with APS and AD, replacement therapy with glucocorticoids and mineralocorticoids may jeopardize hypertension management.
Peter TaylorDepartment of Diabetes and Endocrinology, University Hospital of Wales, Heath Park, Cardiff, UK Thyroid Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, UK
Mohd S DramanDepartment of Diabetes and Endocrinology, University Hospital of Wales, Heath Park, Cardiff, UK Thyroid Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, UK
Aled ReesDepartment of Diabetes and Endocrinology, University Hospital of Wales, Heath Park, Cardiff, UK Institute of Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, UK
Hyponatraemia is the most commonly encountered electrolyte disturbance in neurological high dependency and intensive care units. Cerebral salt wasting (CSW) is the most elusive and challenging of the causes of hyponatraemia, and it is vital to distinguish it from the more familiar syndrome of inappropriate antidiuretic hormone (SIADH). Managing CSW requires correction of the intravascular volume depletion and hyponatraemia, as well as mitigation of on-going substantial sodium losses. Herein we describe a challenging case of CSW requiring large doses of hypertonic saline and the subsequent substantial benefit with the addition of fludrocortisone.
The diagnosis of CSW requires a high index of suspicion. Distinguishing it from SIADH is essential to enable prompt treatment in order to prevent severe hyponatraemia.
The hallmarks of substantial CSW are hyponatraemia, reduced volume status and inappropriately high renal sodium loss.
Substantial volumes of hypertonic saline may be required for a prolonged period of time to correct volume and sodium deficits.
Fludrocortisone has a role in the management of CSW. It likely reduces the doses of hypertonic saline required and can maintain serum sodium levels of hypertonic saline.
K C ConlonDepartments of Professional Surgical Unit, Adelaide and Meath Hospitals, incorporating the National Children’s Hospital, Tallaght, Dublin 24, Ireland Departments of Surgery, Trinity College, Dublin, Ireland
M SherlockDepartments of Endocrinology, Adelaide and Meath Hospitals, incorporating the National Children’s Hospital, Tallaght, Dublin 24, Ireland Departments of Endocrinology, Trinity College, Dublin, Ireland
J GibneyDepartments of Endocrinology, Adelaide and Meath Hospitals, incorporating the National Children’s Hospital, Tallaght, Dublin 24, Ireland Departments of Endocrinology, Trinity College, Dublin, Ireland
Avascular necrosis (AVN) is a rare presenting feature of endogenous hypercortisolism. If left untreated, complete collapse of the femoral head may ensue, necessitating hip replacement in up to 70% of patients. The majority of the described patients with AVN due to endogenous hypercortisolaemia required surgical intervention. A 36-year-old female, investigated for right leg pain, reported rapid weight gain, bruising and secondary amenorrhoea. She had abdominal adiposity with violaceous striae, facial plethora and hirsutism, atrophic skin, ecchymosis and proximal myopathy. Investigations confirmed cortisol excess (cortisol following low-dose 48h dexamethasone suppression test 807nmol/L; 24h urinary free cortisol 1443nmol (normal<290nmol)). Adrenocorticotrophic hormone (ACTH) was <5.0pg/mL. CT demonstrated subtle left adrenal gland hypertrophy. Hypercortisolaemia persisted after left adrenalectomy. Histology revealed primary pigmented micronodular adrenal disease. Post-operatively, right leg pain worsened and left leg pain developed, affecting mobility. MRI showed bilateral femoral head AVN. She underwent right adrenalectomy and steroid replacement was commenced. Four months after surgery, leg pain had resolved and mobility was normal. Repeat MRI showed marked improvement of radiological abnormalities in both femoral heads, consistent with spontaneous healing of AVN. We report a case of Cushing’s syndrome due to primary pigmented nodular adrenocortical disease, presenting with symptomatic AVN of both hips. This was managed conservatively from an orthopaedic perspective. Following cure of hypercortisolaemia, the patient experienced excellent recovery and remains symptom free 4 years after adrenalectomy. This is the first report of a favourable outcome over long-term follow-up of a patient with bilateral AVN of the hip, which reversed with treatment of endogenous hypercortisolaemia.
AVN of femoral head can be a presenting feature of hypercortisolism, both endogenous and exogenous.
Rarely, treatment of hypercortisolaemia can reverse AVN without the need for orthopaedic intervention.
Primary pigmented nodular adrenal disease is a rare cause of ACTH-independent Cushing’s syndrome.
Jenny E GuntonDepartment of Diabetes and Endocrinology, Westmead Hospital, Sydney, 2145, Australia Faculty of Medicine, Westmead Hospital, University of Sydney, Sydney, 2145, Australia St Vincent's Clinical School, University of New South Wales, Sydney, 2010, Australia Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, 2010, Australia Department of Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, 2045, Australia
Ketoconazole was a first-line agent for suppressing steroidogenesis in Cushing's disease. It now has limited availability. Fluconazole, another azole antifungal, is an alternative, although its in vivo efficacy is unclear. A 61-year-old female presented with weight gain, abdominal striae and worsening depression. HbA1c increased to 76 mmol/mol despite increasing insulin. Investigations confirmed cortisol excess; afternoon serum cortisol was 552 nmol/l with an inappropriate ACTH of 9.3 pmol/l. In total, 24-h urinary free cortisol (UFC):creatinine ratio was 150 nmol/mmol with failure to suppress after 48 h of low-dose dexamethasone. Pituitary MRI revealed a 4-mm microadenoma. Inferior petrosal sinus sampling confirmed Cushing's disease. Transsphenoidal resection was performed and symptoms improved. However, disease recurred 6 months later with elevated 24-h UFC >2200 nmol/day. Metyrapone was commenced at 750 mg tds. Ketoconazole was later added at 400 mg daily, with dose reduction in metyrapone. When ketoconazole became unavailable, fluconazole 200 mg daily was substituted. Urine cortisol:creatinine ratio rose, and the dose was increased to 400 mg daily with normalisation of urine hormone levels. Serum cortisol and urine cortisol:creatinine ratios remain normal on this regimen at 6 months. In conclusion, to our knowledge, this is the first case demonstrating prolonged in vivo efficacy of fluconazole in combination with low-dose metyrapone for the treatment of Cushing's disease. Fluconazole has a more favourable toxicity profile, and we suggest that it is a potential alternative for medical management of Cushing's disease.
Surgery remains first line for the management of Cushing's disease with pharmacotherapy used where surgery is unsuccessful or there is persistence of cortisol excess.
Ketoconazole has previously been used to treat cortisol excess through inhibition of CYP450 enzymes 11-β-hydroxylase and 17-α-hydroxylase, though its availability is limited in many countries.
Fluconazole shares similar properties to ketoconazole, although it has less associated toxicity.
Fluconazole represents a suitable alternative for the medical management of Cushing's disease and proved an effective addition to metyrapone in the management of this case.
Harish VenugopalDepartment of Diabetes and Endocrinology, Gold Coast, University Hospital, School of Medicine, Griffith University, 1 Hospital Boulevard, Southport, QLD 4215QLD 4215, Queensland, Australia
Katherine GriffinDepartment of Diabetes and Endocrinology, Gold Coast, University Hospital, School of Medicine, Griffith University, 1 Hospital Boulevard, Southport, QLD 4215QLD 4215, Queensland, Australia
Resection of primary tumour is the management of choice in patients with ectopic ACTH syndrome. However, tumours may remain unidentified or occult in spite of extensive efforts at trying to locate them. This can, therefore, pose a major management issue as uncontrolled hypercortisolaemia can lead to life-threatening infections. We present the case of a 66-year-old gentleman with ectopic ACTH syndrome from an occult primary tumour with multiple significant complications from hypercortisolaemia. Ectopic nature of his ACTH-dependent Cushing's syndrome was confirmed by non-suppression with high-dose dexamethasone suppression test and bilateral inferior petrosal sinus sampling. The primary ectopic source remained unidentified in spite of extensive anatomical and functional imaging studies, including CT scans and Dotatate-PET scan. Medical adrenolytic treatment at maximum tolerated doses failed to control his hypercortisolaemia, which led to recurrent intra-abdominal and pelvic abscesses, requiring multiple surgical interventions. Laparoscopic bilateral adrenalectomy was considered but decided against given concerns of technical difficulties due to recurrent intra-abdominal infections and his moribund state. Eventually, alcohol ablation of adrenal glands by retrograde adrenal vein approach was attempted, which resulted in biochemical remission of Cushing's syndrome. Our case emphasizes the importance of aggressive management of hypercortisolaemia in order to reduce the associated morbidity and mortality and also demonstrates that techniques like percutaneous adrenal ablation using a retrograde venous approach may be extremely helpful in patients who are otherwise unable to undergo bilateral adrenalectomy.
Evaluation and management of patients with ectopic ACTH syndrome from an unidentified primary tumour can be very challenging.
Persisting hypercortisolaemia in this setting can lead to debilitating and even life-threatening complications and hence needs to be managed aggressively.
Bilateral adrenalectomy should be considered when medical treatment is ineffective or poorly tolerated.
Percutaneous adrenal ablation may be considered in patients who are otherwise unable to undergo bilateral adrenalectomy.