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Open access

J K Witczak, N Ubaysekara, R Ravindran, S Rice, Z Yousef and L D Premawardhana

Summary

Graves’ disease is associated with tachydysrythmia, cardiac ischaemia and cardiomyopathy – all uncommon in young adults without previous cardiac disease. We present three young individuals who developed cardiac complications after periods of uncontrolled Graves’ disease. Subject 1: A 34-year-old female had severe thyrotoxic symptoms for weeks. Investigations showed fT4: 98.4 (11–25 pmol/L), fT3: 46.9 (3.1–6.8 pmol/L), TSH <0.01 (0.27–4.2 mU/L) and thyrotrophin receptor antibody (TRAb): 34.8 (<0.9 U//l). She had appropriate treatment but several weeks later she became breathless despite improving thyroid function. Echocardiography showed a pericardial effusion of 2.9 cm. She responded well to steroids and NSAIDs but developed active severe Graves’ orbitopathy after early total thyroidectomy. Subject 2: A 28-year-old male developed thyrotoxic symptoms (fT4: 38 pmol/L, fT3: 13.9 pmol/L, TSH <0.01 (for over 6 months) and TRAb: 9.3 U/L). One month after starting carbimazole, he developed acute heart failure (HF) due to severe dilated cardiomyopathy – EF 10–15%. He partially recovered after treatment – EF 28% and had early radioiodine treatment. Subject 3: A 42-year-old woman who had been thyrotoxic for several months (fT4: 54.3; fT3 >46.1; TSH <0.01; TRAb: 4.5) developed atrial fibrillation (AF) and heart failure. Echocardiography showed cardiomegaly – EF 29%. She maintains sinus rhythm following early total thyroidectomy (EF 50%). Significant cardiac complications may occur in previously fit young adults, who have had uncontrolled Graves’ disease for weeks to months. Cardiac function recovers in the majority, but early definitive treatment should be discussed to avoid Graves’ disease relapse and further cardiac decompensation.

Learning points:

  • Cardiac complications of Graves’ disease are uncommon in young adults without previous cardiac disease.
  • These complications may however occur if Graves’ disease had been poorly controlled for several weeks or months prior to presentation.
  • Persistent symptoms after adequate control should alert clinicians to the possibility of cardiac disease.
  • Specific treatment of Graves’ disease and appropriate cardiac intervention results in complete recovery in the majority and carries a good prognosis.
  • Early definitive treatment should be offered to them to prevent cardiac decompensation at times of further relapse.
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

Charlotte Delcourt, Halil Yildiz, Alessandra Camboni, Eric Van den Neste, Véronique Roelants, Alexandra Kozyreff, Jean Paul Thissen, Dominique Maiter and Raluca Maria Furnica

Summary

A 26-year-old woman presented with persistent headache and tiredness. Biological investigations disclosed a moderate inflammatory syndrome, low PTH-hypercalcemia and complete anterior hypopituitarism. A magnetic resonance imaging (MRI) of the pituitary gland was performed and revealed a symmetric enlargement with a heterogeneous signal. Ophthalmological examination showed an asymptomatic bilateral anterior and posterior uveitis, and a diagnosis of pituitary sarcoidosis was suspected. As the localization of lymphadenopathies on the fused whole-body FDG-PET/computerized tomography (CT) was not evoking a sarcoidosis in first instance, an excisional biopsy of a left supraclavicular adenopathy was performed showing classic nodular sclerosis Hodgkin’s lymphoma (HL). A diagnostic transsphenoidal biopsy of the pituitary gland was proposed for accurate staging of the HL and surprisingly revealed typical granulomatous inflammation secondary to sarcoidosis, leading to the diagnosis of a sarcoidosis–lymphoma syndrome. The co-existence of these diseases constitutes a diagnostic challenge and we emphasize the necessity of exact staging of disease in order to prescribe adequate treatment.

Learning points:

  • The possibility of a sarcoidosis–lymphoma syndrome, although rare, should be kept in mind during evaluation for lymphadenopathies.
  • In the case of such association, lymphoma usually occurs after sarcoidosis. However, sarcoidosis and lymphoma can be detected simultaneously and development of sarcoidosis in a patient with previous lymphoma has also been reported.
  • An accurate diagnosis of the disease and the respective organ involvements, including biopsy, is necessary in order to prescribe adequate treatment.
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

Huilin Koh, Manish Kaushik, Julian Kenrick Loh and Chiaw Ling Chng

Summary

Thyroid storm with multi-organ failure limits the use of conventional treatment. A 44-year-old male presented with thyroid storm and experienced cardiovascular collapse after beta-blocker administration, with resultant fulminant multi-organ failure requiring inotropic support, mechanical ventilation, extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy. Hepatic and renal failure precluded the use of conventional thyroid storm treatment and early plasma exchange was instituted. The patient underwent emergency thyroidectomy after four effective exchanges, with subsequent rapid reversal of multi-organ failure. The challenges of institution of plasma exchanges with ongoing ECMO support, dialysis and timing of thyroidectomy are discussed. This case highlights the important role of early therapeutic plasma exchange (TPE) as an effective salvage therapy for lowering circulating hormones and stabilization of patients in preparation for emergency thyroidectomy in patients with thyroid storm and fulminant multi-organ failure.

Learning points:

  • Administration of beta-blockers in thyroid storm presenting with congestive cardiac failure may precipitate cardiovascular collapse due to inhibition of thyroid-induced hyperadrenergic compensation which maintains cardiac output.
  • TPE can be an effective bridging therapy to emergency total thyroidectomy when conventional thyroid storm treatment is contraindicated.
  • End-organ support using ECMO and CRRT can be combined with TPE effectively in the management of critically ill cases of thyroid storm.
  • The effectiveness of plasma exchange in lowering thyroid hormones appears to wane after 44–48 h of therapy in this case, highlighting the importance early thyroidectomy.
Open access

E Sanz-Sapera, S Sarria-Estrada, F Arikan and B Biagetti

Summary

Pituitary apoplexy is a rare but potentially life-threatening clinical syndrome characterised by ischaemic infarction or haemorrhage into a pituitary tumour that can lead to spontaneous remission of hormonal hypersecretion. We report the case of a 50-year-old man who attended the emergency department for sudden onset of headache. A computed tomography (CT) scan at admission revealed pituitary haemorrhage and the blood test confirmed the clinical suspicion of acromegaly and an associated hypopituitarism. The T1-weighted magnetic resonance imaging (MRI) showed the classic pituitary ring sign on the right side of the pituitary. Following admission, he developed acute-onset hyponatraemia that required hypertonic saline administration, improving progressively. Surprisingly, during the follow-up, IGF1 levels became normal and he progressively recovered pituitary function.

Learning points:

  • Patients with pituitary apoplexy may have spontaneous remission of hormonal hypersecretion. If it is not an emergency, we should delay a decision to undertake surgery following apoplexy and re-evaluate hormone secretion.
  • Hyponatraemia is an acute sign of hypocortisolism in pituitary apoplexy. However, SIADH although uncommon, could appear later as a consequence of direct hypothalamic insult and requires active and individualised treatment. For this reason, closely monitoring sodium at the beginning of the episode and throughout the first week is advisable to guard against SIADH.
  • Despite being less frequent, if pituitary apoplexy is limited to the tumour, the patient can recover pituitary function previously damaged by the undiagnosed macroadenoma.
Open access

H Joshi, M Hikmat, A P Devadass, S O Oyibo and S V Sagi

Summary

IgG4-related disease (IgG4-RD) is an immune-mediated fibro-inflammatory condition which can affect various organs including the pituitary gland. The true annual incidence of this condition remains widely unknown. In addition, it is unclear whether IgG4 antibodies are causative or the end result of a trigger. With no specific biomarkers available, the diagnosis of IgG4-related hypophysitis remains a challenge. Additionally, there is a wide differential diagnosis. We report a case of biopsy-proven IgG4-related hypophysitis in a young man with type 2 diabetes mellitus.

Learning points:

  • IgG4-related hypophysitis is part of a spectrum of IgG4-related diseases.
  • Clinical manifestations result from anterior pituitary hormone deficiencies with or without diabetes insipidus, which can be temporary or permanent.
  • A combination of clinical, radiological, serological and histological evidence with careful interpretation is required to make the diagnosis.
  • Tissue biopsy remains the gold standard investigation.
  • Disease monitoring and long-term management of this condition is a challenge as relapses occur frequently.
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

C Kamath, J Witczak, M A Adlan and L D Premawardhana

Summary

Thymic enlargement (TE) in Graves’ disease (GD) is often diagnosed incidentally when chest imaging is done for unrelated reasons. This is becoming more common as the frequency of chest imaging increases. There are currently no clear guidelines for managing TE in GD. Subject 1 is a 36-year-old female who presented with weight loss, increased thirst and passage of urine and postural symptoms. Investigations confirmed GD, non-PTH-dependent hypercalcaemia and Addison’s disease (AD). CT scans to exclude underlying malignancy showed TE but normal viscera. A diagnosis of hypercalcaemia due to GD and AD was made. Subject 2, a 52-year-old female, was investigated for recurrent chest infections, haemoptysis and weight loss. CT thorax to exclude chest malignancy, showed TE. Planned thoracotomy was postponed when investigations confirmed GD. Subject 3 is a 47-year-old female who presented with breathlessness, chest pain and shakiness. Investigations confirmed T3 toxicosis due to GD. A CT pulmonary angiogram to exclude pulmonary embolism showed TE. The CT appearances in all three subjects were consistent with benign TE. These subjects were given appropriate endocrine treatment only (without biopsy or thymectomy) as CT appearances showed the following appearances of benign TE – arrowhead shape, straight regular margins, absence of calcification and cyst formation and radiodensity equal to surrounding muscle. Furthermore, interval scans confirmed thymic regression of over 60% in 6 months after endocrine control. In subjects with CT appearances consistent with benign TE, a conservative policy with interval CT scans at 6 months after endocrine control will prevent inappropriate surgical intervention.

Learning points:

  • Chest imaging is common in modern clinical practice and incidental anterior mediastinal abnormalities are therefore diagnosed frequently.
  • Thymic enlargement (TE) associated with Graves’ disease (GD) is occasionally seen in view of the above.
  • There is no validated strategy to manage TE in GD at present.
  • However, CT (or MRI) scan features of the thymus may help characterise benign TE, and such subjects do not require thymic biopsy or surgery at presentation.
  • In them, an expectant ‘wait and see’ policy is recommended with GD treatment only, as the thymus will show significant regression 6 months after endocrine control.