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Rob Gonsalves Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Kirk Aleck Division of Genetics, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Dorothee Newbern Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Gabriel Shaibi Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Chirag Kapadia Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Oliver Oatman Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Summary

Single-minded homolog 1 (SIM1) is a transcription factor that plays a role in the development of both the hypothalamus and pituitary. SIM1 gene mutations are known to cause obesity in humans, and chromosomal deletions encompassing SIM1 and other genes necessary for pituitary development can cause a Prader–Willi-like syndrome with obesity and hypopituitarism. There have been no reported cases of hypopituitarism linked to a single SIM1 mutation. A 21-month-old male presented to endocrinology clinic with excessive weight gain and severe obesity. History was also notable for excessive drinking and urination. Endocrine workup revealed central hypothyroidism, partial diabetes insipidus, and central adrenal insufficiency. Genetic evaluation revealed a novel mutation in the SIM1 gene. No other genetic abnormalities to account for his obesity and hypopituitarism were identified. While we cannot definitively state this mutation is pathogenic, it is notable that SIM1 plays a role in the development of all three of the patient’s affected hormone axes. He is now 6 years old and remains on treatment for his pituitary hormone deficiencies and continues to exhibit excessive weight gain despite lifestyle interventions.

Learning points:

  • Mutations in SIM1 are a well-recognized cause of monogenic human obesity, and there have been case reports of Prader–Willi-like syndrome and hypopituitarism in patients with chromosomal deletions that contain the SIM1 gene.

  • SIM1 is expressed during the development of the hypothalamus, specifically in neuroendocrine lineages that give rise to the hormones oxytocin, arginine vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin.

  • Pituitary testing should be considered in patients with severe obesity and a known genetic abnormality affecting the SIM1 gene, particularly in the pediatric population.

Open access
Mauro Boronat Section of Endocrinology and Nutrition, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain
Research Institute in Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

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Summary

Isolated, adult-onset central hypothyroidism is very rare, and its diagnosis can be challenging. A 42-year-old patient was referred for evaluation of a 2.8 cm thyroid nodule. She referred symptoms that could be attributed to hypothyroidism and thyroid tests showed low TSH and normal-low levels of free T4. However, evaluation of the remaining pituitary hormones and pituitary MRI were normal, yet a radionuclide scanning revealed that the thyroid nodule was ‘hot’ and the tracer uptake in the remaining thyroid tissue was suppressed. Interpretation of these studies led to a misdiagnosis of subclinical hyperthyroidism and the patient was treated with radioiodine. Soon after treatment, she developed a frank hypothyroidism without appropriate elevation of TSH and the diagnosis of central hypothyroidism was made a posteriori. Long term follow-up revealed a progressive pituitary failure, with subsequent deficiency of ACTH and GH. This case should alert to the possibility of overlooking central hypothyroidism in patients simultaneously bearing primary thyroid diseases able to cause subclinical hyperthyroidism.

Learning points:

  • Although rarely, acquired central hypothyroidism can occur in the absence of other pituitary hormone deficiencies.

  • In these cases, diagnosis is challenging, as symptoms are unspecific and usually mild, and laboratory findings are variable, including low, normal or even slightly elevated TSH levels, along with low or low-normal concentrations of free T4.

  • In cases with low TSH levels, the coexistence of otherwise common disorders able to cause primary thyroid hyperfunction, such as autonomous nodular disease, may lead to a misdiagnosis of subclinical hyperthyroidism.

Open access
Mawson Wang Department of Endocrinology and Diabetes, Blacktown Hospital, Sydney, Australia
Blacktown Clinical School, School of Medicine, Western Sydney University, Sydney, Australia

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Benjamin Jonker Department of Neurosurgery, St. Vincent’s Hospital, Sydney, Australia

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Louise Killen Department of Pathology, St. Vincent’s Hospital, Sydney, Australia

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Yvonne Bogum NSW Health Pathology East, Prince of Wales Hospital, Sydney, Australia

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Ann McCormack Department of Endocrinology, St. Vincent’s Hospital, Sydney, Australia
Garvan Institute of Medical Research, Sydney, Australia
St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia

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Ramy H Bishay Department of Endocrinology and Diabetes, Blacktown Hospital, Sydney, Australia
Blacktown Clinical School, School of Medicine, Western Sydney University, Sydney, Australia

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Summary

Cushing’s disease is a rare disorder characterised by excessive cortisol production as a consequence of a corticotroph pituitary tumour. While the primary treatment is surgical resection, post-operative radiation therapy may be used in cases of ongoing inadequate hormonal control or residual or progressive structural disease. Despite improved outcomes, radiotherapy for pituitary tumours is associated with hypopituitarism, visual deficits and, rarely, secondary malignancies. We describe an unusual case of a 67-year-old female with presumed Cushing’s disease diagnosed at the age of 37, treated with transsphenoidal resection of a pituitary tumour with post-operative external beam radiotherapy (EBRT), ketoconazole for steroidogenesis inhibition, and finally bilateral adrenalectomy for refractory disease. She presented 30 years after her treatment with a witnessed generalised tonic-clonic seizure. Radiological investigations confirmed an extracranial mass infiltrating through the temporal bone and into brain parenchyma. Due to recurrent generalised seizures, the patient was intubated and commenced on dexamethasone and anti-epileptic therapy. Resection of the tumour revealed a high-grade osteoblastic osteosarcoma. Unfortunately, the patient deteriorated in intensive care and suffered a fatal cardiac arrest following a likely aspiration event. We describe the risk factors, prevalence and treatment of radiation-induced osteosarcoma, an exceedingly rare and late complication of pituitary irradiation. To our knowledge, this is the longest reported latency period between pituitary irradiation and the development of an osteosarcoma of the skull.

Learning points:

  • Cushing’s disease is treated with transsphenoidal resection as first-line therapy, with radiotherapy used in cases of incomplete resection, disease recurrence or persistent hypercortisolism.

  • The most common long-term adverse outcome of pituitary tumour irradiation is hypopituitarism occurring in 30–60% of patients at 10 years, and less commonly, vision loss and oculomotor nerve palsies, radiation-induced brain tumours and sarcomas.

  • Currently proposed characteristics of radiation-induced osteosarcomas include: the finding of a different histological type to the primary tumour, has developed within or adjacent to the path of the radiation beam, and a latency period of at least 3 years.

  • Treatment of osteosarcoma of the skull include complete surgical excision, followed by systemic chemotherapy and/or radiotherapy.

  • Overall prognosis in radiation-induced sarcoma of bone is poor.

  • Newer techniques such as stereotactic radiosurgery may reduce the incidence of radiation-induced malignancies.

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Daramjav Narantsatsral Division of Endocrinology and Metabolism, Department of Internal Medicine

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Takagi Junko Division of Endocrinology and Metabolism, Department of Internal Medicine

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Iwayama Hideyuki Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Japan

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Inukai Daisuke Department of Otolaryngology, Aichi Medical University School of Medicine, Nagakute, Japan

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Takama Hiroyuki Department of Dermatology, Aichi Medical University School of Medicine, Nagakute, Japan

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Nomura Yuka Division of Endocrinology and Metabolism, Department of Internal Medicine

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Hirase Syo Division of Endocrinology and Metabolism, Department of Internal Medicine

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Morita Hiroyuki Division of Endocrinology and Metabolism, Department of Internal Medicine

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Otake Kazuo Division of Endocrinology and Metabolism, Department of Internal Medicine

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Ogawa Tetsuya Department of Otolaryngology, Aichi Medical University School of Medicine, Nagakute, Japan

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Takami Akiyoshi Department of Hematology, Aichi Medical University School of Medicine, Nagakute, Japan

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Summary

Dupilumab an inhibitor of the interleukin (IL)-4R-alpha subunit is used for the treatment of allergic diseases. The patient was a 49-year-old man who received dupilumab for the treatment of severe atopic dermatitis. He presented hyperthyroidism with elevated thyroglobulin and anti-thyroid antibody negativity at 4 months after the initiation of therapy. On scintigraphy, the thyroid radioiodine uptake was low. Ultrasonography showed a diffuse hypoechoic area in the thyroid gland. A pathological study revealed lymphocytic infiltration. The administration of dupilumab was continued because of his atopic dermatitis that showed an excellent response. The patient`s hyperthyroidism changed to hypothyroidism 3 weeks later. Six months later his thyroid function normalized without any treatment. We herein describe the case of a patient with atopic dermatitis who developed painless thyroiditis under treatment with dupilumab. To the best of our knowledge, this is the first report of this event in the literature.

Learning points:

  • Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has been shown to be effective in the treatment atopic dermatitis and asthma with eosinophilia.

  • Painless thyroiditis is characterized by transient hyperthyroidism and hypothyroidism and recovery without anti-thyroid treatment.

  • This is the first report of painless thyroiditis as an adverse effect of dupilumab, although conjunctivitis and nasopharyngitis are the main adverse effects of dupilumab.

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Nicolás Cruz-Dardíz Endocrinology Department, San Juan City Hospital, San Juan, Puerto Rico

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Nadyeschka Rivera-Santana Endocrinology Department, San Juan City Hospital, San Juan, Puerto Rico

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Marina Torres-Torres Internal Medicine Department, San Juan City Hospital, San Juan, Puerto Rico

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Héctor Cintrón-Colón Internal Medicine Department, San Juan City Hospital, San Juan, Puerto Rico

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Shayanne Lajud Otolaryngology Head and Neck Surgery, University of Puerto Rico, Medical Science Campus, San Juan, Puerto Rico

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Ernesto Solá-Sánchez Endocrinology Department, San Juan City Hospital, San Juan, Puerto Rico

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Michelle Mangual-García Endocrinology Department, San Juan City Hospital, San Juan, Puerto Rico

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Alex González-Bóssolo Endocrinology Department, San Juan City Hospital, San Juan, Puerto Rico

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Summary

Lingual thyroid (LT) gland is the most common type of ectopic thyroid tissue, but it is an extremely rare presentation. We present a case of a 41-year-old Hispanic female patient complaining of dysphonia and dysphagia. As part of the evaluation, fiber optic flexible indirect laryngoscopy (FIL) was performed which revealed a mass at the base of the tongue. The morphological examination was highly suspicious for ectopic thyroid tissue and the diagnosis was confirmed with neck ultrasound and thyroid scintigraphy. Although the patient presented subclinical hypothyroidism, levothyroxine therapy was initiated with a favorable response which included resolution of symptoms and mass size reduction. Our case portrays how thyroid hormone replacement therapy (THRT) may lead to a reduction in the size of the ectopic tissue and improvement of symptoms, thus avoiding the need for surgical intervention which could result in profound hypothyroidism severely affecting the patients’ quality of life.

Learning points:

  • Benign LT and malignant LT are indistinguishable clinically and radiographically for which histopathology is recommended.

  • THRT, radioactive iodine 131 (RAI) therapy, and surgical excision are potential management options for LT.

  • THRT may lead to size reduction of the ectopic tissue and resolution of symptoms avoiding surgical intervention.

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Aishah Ekhzaimy Department of Medicine and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Afshan Masood Obesity Research Center, and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Seham Alzahrani Department of Medicine and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Waleed Al-Ghamdi Department of Medicine and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Daad Alotaibi Department of Medicine and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Muhammad Mujammami Department of Medicine and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Summary

Central diabetes insipidus (CDI) and several endocrine disorders previously classified as idiopathic are now considered to be of an autoimmune etiology. Dermatomyositis (DM), a rare autoimmune condition characterized by inflammatory myopathy and skin rashes, is also known to affect the gastrointestinal, pulmonary, and rarely the cardiac systems and the joints. The association of CDI and DM is extremely rare. After an extensive literature search and to the best of our knowledge this is the first reported case in literature, we report the case of a 36-year-old male with a history of CDI, who presented to the hospital’s endocrine outpatient clinic for evaluation of a 3-week history of progressive facial rash accompanied by weakness and aching of the muscles.

Learning points:

  • Accurate biochemical diagnosis should always be followed by etiological investigation.

  • This clinical entity usually constitutes a therapeutic challenge, often requiring a multidisciplinary approach for optimal outcome.

  • Dermatomyositis is an important differential diagnosis in patients presenting with proximal muscle weakness.

  • Associated autoimmune conditions should be considered while evaluating patients with dermatomyositis.

  • Dermatomyositis can relapse at any stage, even following a very long period of remission.

  • Maintenance immunosuppressive therapy should be carefully considered in these patients.

Open access
Shivani Patel Department of Diabetes and Endocrinology, St Vincent’s Hospital Sydney, Darlinghurst, New South Wales, Australia
Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

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Venessa Chin The Kinghorn Cancer Centre, Sydney, New South Wales, Australia
St Vincent’s Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia

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Jerry R Greenfield Department of Diabetes and Endocrinology, St Vincent’s Hospital Sydney, Darlinghurst, New South Wales, Australia
Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
St Vincent’s Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia

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Summary

Durvalumab is a programmed cell death ligand 1 inhibitor, which is now approved in Australia for use in non-small-cell lung and urothelial cancers. Autoimmune diabetes is a rare immune-related adverse effect associated with the use of immune checkpoint inhibitor therapy. It is now being increasingly described reflecting the wider use of immune checkpoint inhibitor therapy. We report the case of a 49-year-old female who presented with polyuria, polydipsia and weight loss, 3 months following the commencement of durvalumab. On admission, she was in severe diabetic ketoacidosis with venous glucose: 20.1 mmol/L, pH: 7.14, bicarbonate 11.2 mmol/L and serum beta hydroxybutyrate: >8.0 mmol/L. She had no personal or family history of diabetes or autoimmune disease. Her HbA1c was 7.8% and her glutamic acid decarboxylase (GAD) antibodies were mildly elevated at 2.2 mU/L (reference range: <2 mU/L) with negative zinc transporter 8 (ZnT8) and islet cell (ICA) antibodies. Her fasting C-peptide was low at 86 pmol/L (reference range: 200–1200) with a corresponding serum glucose of 21.9 mmol/L. She was promptly stabilised with an insulin infusion in intensive care and discharged on basal bolus insulin. Durvalumab was recommenced once her glycaemic control had stabilised. Thyroid function tests at the time of admission were within normal limits with negative thyroid autoantibodies. Four weeks post discharge, repeat thyroid function tests revealed hypothyroidism, with an elevated thyroid-stimulating hormone (TSH) at 6.39 mIU/L (reference range: 0.40–4.80) and low free T4: 5.9 pmol/L (reference range: 8.0–16.0). These findings persisted with repeat testing despite an absence of clinical symptoms. Treatment with levothyroxine was commenced after excluding adrenal insufficiency (early morning cortisol: 339 nmol/L) and hypophysitis (normal pituitary on MRI).

Learning points:

  • Durvalumab use is rarely associated with fulminant autoimmune diabetes, presenting with severe DKA.

  • Multiple endocrinopathies can co-exist with the use of a single immune checkpoint inhibitors; thus, patients should be regularly monitored.

  • Regular blood glucose levels should be performed on routine pathology on all patients on immune checkpoint inhibitor.

  • Clinician awareness of immunotherapy-related diabetes needs to increase in an attempt to detect hyperglycaemia early and prevent DKA.

Open access
Nirusha Arnold Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia

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Victor O’Toole Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia

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Tien Huynh Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia

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Howard C Smith Westmead Teaching Hospital, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Catherine Luxford Kolling Institute of Medical Research, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Roderick Clifton-Bligh Kolling Institute of Medical Research, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Creswell J Eastman Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia
Westmead Teaching Hospital, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Summary

Parathyroid-independent hypercalcaemia of pregnancy, due to biallelic loss of function of the P450 enzyme CYP24A1, the principal inactivator of 1,25(OH)2D results in hypervitaminosis D, hypercalcaemia and hypercalciuria. We report two cases of this disorder, with intractable hypercalcaemia, one occurring during gestation and into the postpartum, and the other in the postpartum period. Case 1, a 47-year-old woman with a twin pregnancy conceived by embryo transfer, presented with hypercalcaemia at 23 weeks gestation with subnormal serum parathyroid hormone (PTH) and normal serum 25-OH D levels. She was admitted to hospital at 31 weeks gestation with pregnancy-induced hypertension, gestational diabetes and increasing hypercalcaemia. Caesarean section at 34 weeks gestation delivered two healthy females weighing 2.13 kg and 2.51 kg. At delivery, the patient’s serum calcium level was 2.90 mmol/L. Postpartum severe hypercalcaemia was treated successfully with Denosumab 60 mg SCI, given on two occasions. CYP24A1 testing revealed she was compound heterozygous for pathogenic variants c.427_429delGAA, (p.Glu143del) and c.1186C>T, (p.Arg396Trp). Case 2, a 36-year-old woman presented 4 days after the delivery of healthy twins with dyspnoea, bradycardia, severe headaches, hypertension and generalized tonic-clonic seizures after an uneventful pregnancy. She was hypercalcaemic with a suppressed PTH, normal 25(OH)D, and elevated 1,25(OH)2D levels. Her symptoms partially responded to i.v. saline and corticosteroids in the short term but bisphosphonates such as Pamidronate and Zoledronic acid did not result in sustained improvement. Denosumab 120 mg SCI successfully treated the hypercalcaemia which resolved completely 2 months post-partum. CYP24A1 testing revealed she was homozygous for the pathogenic variant c.427_429delGAA, (p.Glu143del).

Learning points:

  • Hypercalcaemia in pregnancy can be associated with considerable morbidity with few options available for management.

  • In non-PTH-related hypercalcaemia the diagnosis of CYP24A1 deficiency should be considered.

  • Making a definitive diagnosis of CYP24A1 deficiency by genetic testing delays the diagnosis, while the availability of serum 24,25-dihydroxyvitamin D (24,25(OH)2D) will expedite a diagnosis.

  • In pregnant women with CYP24A1 deficiency hypercalcaemia can worsen in the post-partum period and is more likely to occur with twin pregnancies but generally resolves within 2–3 months.

  • Therapeutic alternatives are limited in pregnancy and their effectiveness is short-lived and mostly ineffective. Denosumab used in both our patients after delivery was the most effective agent normalizing calcium and may have benefit as a long-term therapeutic agent in preventing complications in patients with CYP24A1 deficiency.

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Isabella Lupi Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Alessandro Brancatella Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Mirco Cosottini Neuroradiology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

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Nicola Viola Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Giulia Lanzolla Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Daniele Sgrò Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Giulia Di Dalmazi Section of Endocrinology, Department of Medicine and Aging Sciences, Ce.S.I-Me.T., “G.D’Annunzio” University of Chieti-Pescara, Chieti, Italy

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Francesco Latrofa Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Patrizio Caturegli Division of Immunology, Department of Pathology, Johns Hopkins University, Baltimore Maryland, USA

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Claudio Marcocci Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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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