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Open access

Isabella Lupi, Alessandro Brancatella, Mirco Cosottini, Nicola Viola, Giulia Lanzolla, Daniele Sgrò, Giulia Di Dalmazi, Francesco Latrofa, Patrizio Caturegli and Claudio Marcocci

Summary

Programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte antigen 4/B7 (CTLA-4/B7) pathways are key regulators in T-cell activation and tolerance. Nivolumab, pembrolizumab (PD-1 inhibitors), atezolizumab (PD-L1 inhibitor) and ipilimumab (CTLA-4 inhibitor) are monoclonal antibodies approved for treatment of several advanced cancers. Immune checkpoint inhibitors (ICIs)-related hypophysitis is described more frequently in patients treated with anti-CTLA-4; however, recent studies reported an increasing prevalence of anti-PD-1/PD-L1-induced hypophysitis which also exhibits slightly different clinical features. We report our experience on hypophysitis induced by anti-PD-1/anti-PD-L1 treatment. We present four cases, diagnosed in the past 12 months, of hypophysitis occurring in two patients receiving anti-PD-1, in one patient receiving anti-PD-1 and anti-CTLA-4 combined therapy and in one patient receiving anti-PD-L1. In this case series, timing, clinical presentation and association with other immune-related adverse events appeared to be extremely variable; central hypoadrenalism and hyponatremia were constantly detected although sellar magnetic resonance imaging did not reveal specific signs of pituitary inflammation. These differences highlight the complexity of ICI-related hypophysitis and the existence of different mechanisms of action leading to heterogeneity of clinical presentation in patients receiving immunotherapy.

Learning points:

  • PD-1/PD-L1 blockade can induce hypophysitis with a different clinical presentation when compared to CTLA-4 blockade.

  • Diagnosis of PD-1/PD-L1 induced hypophysitis is mainly made on clinical grounds and sellar MRI does not show radiological abnormalities.

  • Hyponatremia due to acute secondary adrenal insufficiency is often the principal sign of PD-1/PD-L1-induced hypophysitis and can be masked by other symptoms due to oncologic disease.

  • PD-1/PD-L1-induced hypophysitis can present as an isolated manifestation of irAEs or be in association with other autoimmune diseases

Open access

Yuri Tanaka, Taisuke Uchida, Hideki Yamaguchi, Yohei Kudo, Tadato Yonekawa and Masamitsu Nakazato

Summary

We report the case of a 48-year-old man with thyroid storm associated with fulminant hepatitis and elevated levels of soluble interleukin-2 receptor (sIL-2R). Fatigue, low-grade fever, shortness of breath, and weight loss developed over several months. The patient was admitted to the hospital because of tachycardia-induced heart failure and liver dysfunction. Graves’ disease with heart failure was diagnosed. He was treated with methimazole, inorganic iodide, and a β-blocker. On the day after admission, he became unconscious with a high fever and was transferred to the intensive care unit. Cardiogenic shock with atrial flutter was treated with intra-aortic balloon pumping and cardioversion. Hyperthyroidism decreased over 10 days, but hepatic failure developed. He was diagnosed with thyroid storm accompanied by fulminant hepatitis. Laboratory investigations revealed elevated levels of sIL-2R (9770 U/mL). The fulminant hepatitis was refractory to plasma exchange and plasma filtration with dialysis, and no donors for liver transplantation were available. He died of hemoperitoneum and gastrointestinal hemorrhage due to fulminant hepatitis 62 days after admission. Elevated circulating levels of sIL-2R might be a marker of poor prognosis in thyroid storm with fulminant hepatitis.

Learning points:

  • The prognosis of thyroid storm when fulminant hepatitis occurs is poor.

  • Liver transplantation is the preferred treatment for fulminant hepatitis induced by thyroid storm refractory to plasma exchange.

  • Elevated levels of soluble interleukin-2 receptor might be a marker of poor prognosis in patients with thyroid storm.

Open access

Joanna Prokop, João Estorninho, Sara Marote, Teresa Sabino, Aida Botelho de Sousa, Eduardo Silva and Ana Agapito

Summary

POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes) is a rare multisystemic disease. Clinical presentation is variable, the only mandatory criteria being polyneuropathy and monoclonal gammapathy in association with one major and one minor criterion. Primary adrenal insufficiency is rarely reported. We describe a case of a 33-year-old patient, in whom the presenting symptoms were mandibular mass, chronic sensory-motor peripheral polyneuropathy and adrenal insufficiency. The laboratory evaluation revealed thrombocytosis, severe hyperkalemia with normal renal function, normal protein electrophoresis and negative serum immunofixation for monoclonal protein. Endocrinologic laboratory work-up confirmed Addison’s disease and revealed subclinical primary hypothyroidism. Thoracic abdominal CT showed hepatosplenomegaly, multiple sclerotic lesions in thoracic vertebra and ribs. The histopathologic examination of the mandibular mass was nondiagnostic. Bone marrow biopsy revealed plasma cell dyscrasia and confirmed POEMS syndrome. Axillary lymphadenopathy biopsy: Castleman’s disease. Gluco-mineralocorticoid substitution and levothyroxine therapy were started with clinical improvement. Autologous hematopoietic cell transplantation (HCT) was planned, cyclophosphamide induction was started. Meanwhile the patient suffered two ischemic strokes which resulted in aphasia and hemiparesis. Cerebral angiography revealed vascular lesions compatible with vasculitis and stenosis of two cerebral arteries. The patient deceased 14 months after the diagnosis. The young age at presentation, multiplicity of manifestations and difficulties in investigation along with the absence of serum monoclonal protein made the diagnosis challenging. We report this case to highlight the need to consider POEMS syndrome in differential diagnosis of peripheral neuropathy in association with endocrine abnormalities even in young patients.

Learning points:

  • POEMS syndrome is considered a ‘low tumor burden disease’ and the monoclonal protein in 15% of cases is not found by immunofixation.

  • Neuropathy is the dominant characteristic of POEMS syndrome and it is peripheral, ascending, symmetric and affecting both sensation and motor function.

  • Endocrinopathies are a frequent feature of POEMS syndrome, but the cause is unknown.

  • The most common endocrinopathies are hypogonadism, primary hypothyroidism and abnormalities in glucose metabolism.

  • There is no standard therapy; however, patients with disseminated bone marrow involvement are treated with chemotherapy with or without HCT.

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

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

G Leksic, A M Alduk, V Molnar, A Haxhiu, A Haxhiu, A Balasko, N Knezevic, T Dusek and D Kastelan

Summary

Primary aldosteronism (PA) is characterised by aldosterone hypersecretion and represents a common cause of secondary hypertension. During diagnostic evaluation, it is essential to determine the aetiology of PA since the treatment of unilateral and bilateral disease differs significantly. Adrenal vein sampling (AVS) has been implemented as a gold standard test for the diagnosis of PA subtype. However, due to the AVS complexity, costs and limited availability, many patients with PA are being treated based on the computed tomography (CT) findings. In this article, we present two patients with discrepant CT and AVS results, demonstrating that AVS is the only reliable method for localising the source of aldosterone excess.

Learning points:

  • CT is an unreliable method for distinguishing aldosterone-producing adenoma (APA) from bilateral adrenal hyperplasia (BAH).

  • CT can be misleading in defining lateralisation of the aldosterone excess in case of unilateral disease (APA).

  • AVS is the gold standard test for defining the PA subtype.

Open access

A Chinoy, N B Wright, M Bone and R Padidela

Summary

Hypokalaemia at presentation of diabetic ketoacidosis is uncommon as insulin deficiency and metabolic acidosis shifts potassium extracellularly. However, hypokalaemia is a recognised complication of the management of diabetic ketoacidosis as insulin administration and correction of metabolic acidosis shifts potassium intracellularly. We describe the case of a 9-year-old girl with newly diagnosed type 1 diabetes mellitus presenting in diabetic ketoacidosis, with severe hypokalaemia at presentation due to severe and prolonged emesis. After commencing management for her diabetic ketoacidosis, her serum sodium and osmolality increased rapidly. However, despite maximal potassium concentrations running through peripheral access, and multiple intravenous potassium ‘corrections’, her hypokalaemia persisted. Seventy two hours after presentation, she became drowsy and confused, with imaging demonstrating central pontine myelinolysis – a rare entity seldom seen in diabetic ketoacidosis management in children despite rapid shifts in serum sodium and osmolality. We review the literature associating central pontine myelinolysis with hypokalaemia and hypothesise as to how the hypokalaemia may have contributed to the development of central pontine myelinolysis. We also recommend an approach to the management of a child in diabetic ketoacidosis with hypokalaemia at presentation.

Learning points:

  • Hypokalaemia is a recognised complication of treatment of paediatric diabetic ketoacidosis that should be aggressively managed to prevent acute complications.

  • Central pontine myelinolysis is rare in children, and usually observed in the presence of rapid correction of hyponatraemia. However, there is observational evidence of an association between hypokalaemia and central pontine myelinolysis, potentially by priming the endothelial cell membrane to injury by lesser fluctuations in osmotic pressure.

  • Consider central pontine myelinolysis as a complication of the management of paediatric diabetic ketoacidosis in the presence of relevant symptoms with profound hypokalaemia and/or fluctuations in serum sodium levels.

  • We have suggested an approach to the management strategies of hypokalaemia in paediatric diabetic ketoacidosis which includes oral potassium supplements if tolerated, minimising the duration and the rate of insulin infusion and increasing the concentration of potassium intravenously (via central line if necessary).

Open access

Himangshu S Bose, Alan M Rice, Brendan Marshall, Fadi Gebrail, David Kupshik and Elizabeth W Perry

Summary

Steroid hormones are essential for the survival of all mammals. In adrenal glands and gonads, cytochrome P450 side chain cleavage enzyme (SCC or CYP11A1), catalyzes conversion of cholesterol to pregnenolone. We studied a patient with ambiguous genitalia by the absence of Müllerian ducts and the presence of an incompletely formed vagina, who had extremely high adrenocorticotropic hormone (ACTH) and reduced pregnenolone levels with enlarged adrenal glands. The testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells. Electron microscopy showed that the patient’s testicular mitochondrial size was small with little SCC expression within the mitochondria. The mitochondria were not close to the mitochondria-associated ER membrane (MAM), and cells were filled with the microfilaments. Our result revealed that absence of pregnenolone is associated with organelle stress, leading to altered protein organization that likely created steric hindrance in testicular cells.

Learning points:

  • Testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells;

  • Testicular mitochondrial size was small with little SCC expression within the mitochondria;

  • Absence of pregnenolone is associated with organelle stress.

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

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.