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Open access

Stephanie Wei Ping Wong, Yew Wen Yap, Ram Prakash Narayanan, Mohammad Al-Jubouri, Ashley Grossman, Christina Daousi and Yahya Mahgoub

Summary

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.

Learning points:

  • 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.

Open access

Punith Kempegowda, Lauren Quinn, Lisa Shepherd, Samina Kauser, Briony Johnson, Alex Lawson and Andrew Bates

Summary

A 62-year-old Asian British female presented with increasing tiredness. She had multiple co-morbidities and was prescribed steroid inhalers for asthma. She had also received short courses of oral prednisolone for acute asthma exacerbations in the last 2 years. Unfortunately, the frequency and dose of steroids for asthma was unclear from history. Her type 2 diabetes mellitus (DM) control had deteriorated over a short period of time (HbA1c: 48–85 mmol/mol). Blood tests revealed undetectable cortisol and ACTH (<28 mmol/L, <5.0 ng/L). Renin, electrolytes and thyroid function were within normal limits. A diagnosis of secondary adrenal insufficiency, likely due to long-term steroid inhaler and recurrent short courses of oral steroids for asthma exacerbations was made. Patient was commenced on hydrocortisone 10 mg, 5 mg and 5 mg regimen. Steroid inhaler was discontinued following consultation with respiratory physicians. Despite discontinuation of inhaled steroids, patient continued not to mount a response to Synacthen®. Upon further detailed history, patient admitted taking a ‘herbal’ preparation for chronic osteoarthritic knee pain. Toxicology analysis showed presence of dexamethasone, ciprofloxacin, paracetamol, diclofenac, ibuprofen and cimetidine in the herbal medication. Patient was advised to discontinue her herbal preparation. We believe the cause of secondary adrenal insufficiency in our patient was the herbal remedy containing dexamethasone, explaining persistent adrenal suppression despite discontinuation of all prescribed steroids, further possibly contributing to obesity, hypertension and suboptimal control of DM. In conclusion, a comprehensive drug history including herbal and over-the-counter preparations should be elucidated. Investigation for the presence of steroids in these preparations should be considered when patients persist to have secondary adrenal insufficiency despite discontinuation of prescribed steroid medications.

Learning points:

  • The likelihood of complementary and alternative medicines (CAMs) in medication-induced secondary adrenal insufficiency should be considered in any patient presenting with potential symptoms of adrenal insufficiency.

  • If the contents of CAM preparation cannot be ascertained, toxicology screening should be considered.

  • Patients should be advised to stop taking CAM preparation when it contains steroids and hydrocortisone replacement therapy commenced, with periodic reassessment of adrenal function, and then if indicated weaned accordingly.

  • Patients should be informed about the contents of CAM therapies, so they can make a truly informed choice regarding the risks and benefits.

  • This case also highlights a need to increase regulatory processes over CAM therapies, given their propensity to contain a number of undisclosed medications and potent steroids.

Open access

Wei Yang, David Pham, Aren T Vierra, Sarah Azam, Dorina Gui and John C Yoon

Summary

Ectopic ACTH-secreting pulmonary neuroendocrine tumors are rare and account for less than 5% of endogenous Cushing’s syndrome cases. We describe an unusual case of metastatic bronchial carcinoid tumor in a young woman presenting with unprovoked pulmonary emboli, which initially prevented the detection of the primary tumor on imaging. The source of ectopic ACTH was ultimately localized by a Gallium-DOTATATE scan, which demonstrated increased tracer uptake in a right middle lobe lung nodule and multiple liver nodules. The histological diagnosis was established based on a core biopsy of a hepatic lesion and the patient was started on a glucocorticoid receptor antagonist and a somatostatin analog. This case illustrates that hypercogulability can further aggravate the diagnostic challenges in ectopic ACTH syndrome. We discuss the literature on the current diagnosis and management strategies for ectopic ACTH syndrome.

Learning points:

  • In a young patient with concurrent hypokalemia and uncontrolled hypertension on multiple antihypertensive agents, secondary causes of hypertension should be evaluated.

  • Patients with Cushing’s syndrome can develop an acquired hypercoagulable state leading to spontaneous and postoperative venous thromboembolism.

  • Pulmonary emboli may complicate the imaging of the bronchial carcinoid tumor in ectopic ACTH syndrome.

  • Imaging with Gallium-68 DOTATATE PET/CT scan has the highest sensitivity and specificity in detecting ectopic ACTH-secreting tumors.

  • A combination of various noninvasive biochemical tests can enhance the diagnostic accuracy in differentiating Cushing’s disease from ectopic ACTH syndrome provided they have concordant results. Bilateral inferior petrosal sinus sampling remains the gold standard.

Open access

Teresa M Canteros, Valeria De Miguel and Patricia Fainstein-Day

Summary

Severe Cushing syndrome (SCS) is considered an emergency that requires immediate treatment to lower serum cortisol levels. Fluconazole may be considered an alternative treatment in Cushing syndrome when ketoconazole is not tolerated or unavailable. We report a 39-year-old woman with a history of partial pancreaticoduodenectomy due to a periampullary neuroendocrine tumor with locoregional extension. Three years after surgery, she developed liver metastases and was started on 120 mg of lanreotide/month, despite which, liver metastases progressed in the following 6 months. The patient showed extreme fatigue, muscle weakness, delirium, moon face, hirsutism and severe proximal weakness. Laboratory tests showed anemia, hyperglycemia and severe hypokalemia. 24-h urinary free cortisol: 2152 nmol/day (reference range (RR): <276), morning serum cortisol 4883.4 nmol/L (RR: 138–690), ACTH 127.3 pmol/L (RR: 2.2–10). She was diagnosed with ectopic ACTH syndrome (EAS). On admission, she presented with acute upper gastrointestinal tract bleeding and hemodynamic instability. Intravenous fluconazole 400 mg/day was started. After 48 h, her mental state improved and morning cortisol decreased by 25%. The dose was titrated to 600 mg/day which resulted in a 55% decrease in cortisol levels in 1 week, but then had to be decreased to 400 mg/day because transaminase levels increased over 3 times the upper normal level. After 18 days of treatment, hemodynamic stability, lower cortisol levels and better overall clinical status enabled successful bilateral adrenalectomy. This case report shows that intravenous fluconazole effectively decreased cortisol levels in SCS due to EAS.

Learning points:

  • Severe Cushing syndrome can be effectively treated with fluconazole to achieve a significant improvement of hypercortisolism prior to bilateral adrenalectomy.

  • Intravenous fluconazole is an alternative treatment when ketoconazole is not tolerated and etomidate is not available.

  • Fluconazole is well tolerated with mild side effects. Hepatotoxicity is usually mild and resolves after drug discontinuation.

Open access

Gemma White, Nicola Tufton and Scott A Akker

Summary

At least 40% of phaeochromocytomas and paraganglioma’s (PPGLs) are associated with an underlying genetic mutation. The understanding of the genetic landscape of these tumours has rapidly evolved, with 18 associated genes now identified. Among these, mutations in the subunits of succinate dehydrogenase complex (SDH) are the most common, causing around half of familial PPGL cases. Occurrence of PPGLs in carriers of SDHB, SDHC and SDHD subunit mutations has been long reported, but it is only recently that variants in the SDHA subunit have been linked to PPGL formation. Previously documented cases have, to our knowledge, only been found in isolated cases where pathogenic SDHA variants were identified retrospectively. We report the case of an asymptomatic suspected carotid body tumour found during surveillance screening in a 72-year-old female who is a known carrier of a germline SDHA pathogenic variant. To our knowledge, this is the first screen that detected PPGL found in a previously identified SDHA pathogenic variant carrier, during surveillance imaging. This finding supports the use of cascade genetic testing and surveillance screening in all carriers of a pathogenic SDHA variant.

Learning points:

  • SDH mutations are important causes of PPGL disease.

  • SDHA is much rarer compared to SDHB and SDHD mutations.

  • Pathogenicity and penetrance are yet to be fully determined in cases of SDHA-related PPGL.

  • Surveillance screening should be used for SDHA PPGL cases to identify recurrence, metastasis or metachronous disease.

  • Surveillance screening for SDH-related disease should be performed in identified carriers of a pathogenic SDHA variant.

Open access

Pedro Marques, Nicola Tufton, Satya Bhattacharya, Mark Caulfield and Scott A Akker

Summary

Mineralocorticoid hypertension is most often caused by autonomous overproduction of aldosterone, but excess of other mineralocorticoid precursors can lead to a similar presentation. 11-Deoxycorticosterone (DOC) excess, which can occur in 11-β hydroxylase or 17-α hydroxylase deficiencies, in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. We report a 35-year-old woman who in the third trimester of pregnancy was found to have a large adrenal mass on routine obstetric ultrasound. On referral to our unit, persistent hypertension and long-standing hypokalaemia was noted, despite good compliance with multiple antihypertensives. Ten years earlier, she had hypertension noted in pregnancy which had persisted after delivery. A MRI scan confirmed the presence of a 12 cm adrenal mass and biochemistry revealed high levels of DOC and low/normal renin, aldosterone and dehydroepiandrosterone, with normal catecholamine levels. The patient was treated with antihypertensives until obstetric delivery, following which she underwent an adrenalectomy. Histology confirmed a large adrenal cortical neoplasm of uncertain malignant potential. Postoperatively, blood pressure and serum potassium normalised, and the antihypertensive medication was stopped. Over 10 years of follow-up, she remains asymptomatic with normal DOC measurements. This case should alert clinicians to the possibility of a diagnosis of a DOC-producing adrenal tumours in patients with adrenal nodules and apparent mineralocorticoid hypertension in the presence of low or normal levels of aldosterone. The associated diagnostic and management challenges are discussed.

Learning points:

  • Hypermineralocorticoidism is characterised by hypertension, volume expansion and hypokalaemic alkalosis and is most commonly due to overproduction of aldosterone. However, excess of other mineralocorticoid products, such as DOC, lead to the same syndrome but with normal or low aldosterone levels.

  • The differential diagnosis of resistant hypertension with low renin and low/normal aldosterone includes congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid excess, Cushing’s syndrome, Liddle’s syndrome and 11-deoxycorticosterone-producing tumours.

  • DOC is one intermediate product in the mineralocorticoid synthesis with weaker activity than aldosterone. However, marked DOC excess seen in 11-β hydroxylase or 17-α hydroxylase deficiencies in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension.

  • Excessive production of DOC in adrenocortical tumours has been attributed to reduced activity of the enzymes 11-β hydroxylase and 17-α hydroxylase and increased activity of 21-α hydroxylase.

  • The diagnosis of DOC-producing adrenal tumours is challenging because of its rarity and poor availability of DOC laboratory assays.

Open access

Vasileios Chortis, Christine J H May, Kassiani Skordilis, John Ayuk, Wiebke Arlt and Rachel K Crowley

Summary

Context

Adrenal incidentalomas (AI) represent an increasingly common problem in modern endocrine practice. The diagnostic approach to AIs can be challenging and occasionally reveals surprising features. Here we describe two rare cases of complex adrenal lesions consisting of phaeochromocytomas with synchronous metastases from extra-adrenal primaries.

Case descriptions

Patient 1 – a 65-year-old gentleman with a newly diagnosed malignant melanoma was found to harbour an adrenal lesion with suspicious radiographic characteristics. Percutaneous adrenal biopsy was consistent with adrenocortical adenoma. After excision of the skin melanoma and regional lymphatic metastases, he was followed up without imaging. Three years later, he presented with abdominal discomfort and enlargement of his adrenal lesion, associated with high plasma metanephrines. Adrenalectomy revealed a mixed tumour consisting of a large phaeochromocytoma with an embedded melanoma metastasis in its core. Patient 2 – a 63-year-old lady with a history of NF-1-related phaeochromocytoma 20 years ago and previous breast cancer presented with a new adrenal lesion on the contralateral side. Plasma normetanephrine was markedly elevated. Elective adrenalectomy revealed an adrenal tumour consisting of chromaffin cells intermixed with breast carcinoma cells.

Conclusions

Adrenal incidentalomas require careful evaluation to exclude metastatic disease, especially in the context of a history of previous malignancy. Adrenal biopsy provides limited and potentially misleading information. Phaeochromocytomas are highly vascularised tumours that may function as a sieve, extracting and retaining irregularly shaped cancer cells, thereby yielding adrenal masses with intriguing dual pathology.

Learning points:

  • Adrenal incidentalomas require careful evaluation focused on exclusion of underlying hormone excess and malignant pathology.

  • Adrenal biopsy can be misleading and should only be considered in select cases.

  • Phaeochromocytomas harbouring intratumoural metastases from other, extra-adrenal primary malignancies represent rare pathological entities that highlight the complexities that can be presented by adrenal tumours.

Open access

Catherine D Zhang, Pavel N Pichurin, Aleh Bobr, Melanie L Lyden, William F Young Jr and Irina Bancos

Summary

Carney complex (CNC) is a rare multiple neoplasia syndrome characterized by spotty pigmentation of the skin and mucosa in association with various non-endocrine and endocrine tumors, including primary pigmented nodular adrenocortical disease (PPNAD). A 20-year-old woman was referred for suspected Cushing syndrome. She had signs of cortisol excess as well as skin lentigines on physical examination. Biochemical investigation was suggestive of corticotropin (ACTH)-independent Cushing syndrome. Unenhanced computed tomography scan of the abdomen did not reveal an obvious adrenal mass. She subsequently underwent bilateral laparoscopic adrenalectomy, and histopathology was consistent with PPNAD. Genetic testing revealed a novel frameshift pathogenic variant c.488delC/p.Thr163MetfsX2 (ClinVar Variation ID: 424516) in the PRKAR1A gene, consistent with clinical suspicion for CNC. Evaluation for other clinical features of the complex was unrevealing. We present a case of PPNAD-associated Cushing syndrome leading to the diagnosis of CNC due to a novel PRKAR1A pathogenic variant.

Learning points:

  • PPNAD should be considered in the differential for ACTH-independent Cushing syndrome, especially when adrenal imaging appears normal.

  • The diagnosis of PPNAD should prompt screening for CNC.

  • CNC is a rare multiple neoplasia syndrome caused by inactivating pathogenic variants in the PRKAR1A gene.

  • Timely diagnosis of CNC and careful surveillance can help prevent potentially fatal complications of the disease.

Open access

Ilan Rahmani Tzvi-Ran, Judith Olchowski, Merav Fraenkel, Asher Bashiri and Leonid Barski

Summary

A previously healthy 24-year-old female underwent an emergent caesarean section without a major bleeding described. During the first post-operative days (POD) she complained of fatigue, headache and a failure to lactate with no specific and conclusive findings on head CT. On the following days, fever rose with a suspicion of an obstetric surgery-related infection, again with no evidence to support the diagnosis. On POD5 a new-onset hyponatremia was documented. The urine analysis suggested SIADH, and following a treatment failure, further investigation was performed and demonstrated both central hypothyroidism and adrenal insufficiency. The patient was immediately treated with hydrocortisone followed by levothyroxine with a rapid resolution of symptoms and hyponatremia. Further laboratory investigation demonstrated anterior hypopituitarism. The main differential diagnosis was Sheehan’s syndrome vs lymphocytic hypophysitis. Brain MRI was performed as soon as it was available and findings consistent with Sheehan’s syndrome confirmed the diagnosis. Lifelong hormonal replacement therapy was initiated. Further complaints on polyuria and polydipsia have led to a water deprivation testing and the diagnosis of partial central insipidus and appropriate treatment with DDAVP.

Learning points:

  • Sheehan’s syndrome can occur, though rarely, without an obvious major post-partum hemorrhage.

  • The syndrome may resemble lymphocytic hypophysitis clinically and imaging studies may be crucial in order to differentiate both conditions.

  • Hypopituitarism presentation may be variable and depends on the specific hormone deficit.

  • Euvolemic hyponatremia workup must include thyroid function test and 08:00 AM cortisol levels.

Open access

Matthieu St-Jean, Jessica MacKenzie-Feder, Isabelle Bourdeau and André Lacroix

Summary

A 29-year-old G4A3 woman presented at 25 weeks of pregnancy with progressive signs of Cushing’s syndrome (CS), gestational diabetes requiring insulin and hypertension. A 3.4 × 3.3 cm right adrenal adenoma was identified during abdominal ultrasound imaging for nephrolithiasis. Investigation revealed elevated levels of plasma cortisol, 24 h urinary free cortisol (UFC) and late-night salivary cortisol (LNSC). Serum ACTH levels were not fully suppressed (4 and 5 pmol/L (N: 2–11)). One month post-partum, CS regressed, 24-h UFC had normalised while ACTH levels were now less than 2 pmol/L; however, dexamethasone failed to suppress cortisol levels. Tests performed in vivo 6 weeks post-partum to identify aberrant hormone receptors showed no cortisol stimulation by various tests (including 300 IU hLH i.v.) except after administration of 250 µg i.v. Cosyntropin 1–24. Right adrenalectomy demonstrated an adrenocortical adenoma and atrophy of adjacent cortex. Quantitative RT-PCR analysis of the adenoma revealed the presence of ACTH (MC2) receptor mRNA, while LHCG receptor mRNA was almost undetectable. This case reveals that CS exacerbation in the context of pregnancy can result from the placental-derived ACTH stimulation of MC2 receptors on the adrenocortical adenoma. Possible contribution of other placental-derived factors such as oestrogens, CRH or CRH-like peptides cannot be ruled out.

Learning points:

  • Diagnosis of Cushing’s syndrome during pregnancy is complicated by several physiological alterations in hypothalamic–pituitary–adrenal axis regulation occurring in normal pregnancy.

  • Cushing’s syndrome (CS) exacerbation during pregnancy can be associated with aberrant expression of LHCG receptor on primary adrenocortical tumour or hyperplasia in some cases, but not in this patient.

  • Placental-derived ACTH, which is not subject to glucocorticoid negative feedback, stimulated cortisol secretion from this adrenal adenoma causing transient CS exacerbation during pregnancy.

  • Following delivery and tumour removal, suppression of HPA axis can require several months to recover and requires glucocorticoid replacement therapy.