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St Vincent’s Clinical School, University of New South Wales, Sydney, Australia
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Cancer Genetics Unit, Kolling Institute of Medical Research, Sydney, Australia
Northern Clinical School, University of Sydney Faculty of Medicine and Health, Sydney, Australia
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Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Sydney, Australia
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Cancer Genetics Unit, Kolling Institute of Medical Research, Sydney, Australia
Northern Clinical School, University of Sydney Faculty of Medicine and Health, Sydney, Australia
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Summary
RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition.
Learning points
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Patients with RET-altered MTC can experience rapid disease improvement and sustained disease stability with selective RET blockade (selpercatinib).
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LCH is a clonal neoplasm driven by MAPK activation, for which the most common mechanism is BRAF mutation.
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Both MTC and pulmonary LCH are driven by dysregulated MAPK signalling pathway activation.
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We hypothesise that the RET-specific inhibitor selpercatinib may have caused the activation of dormant LCH secondary to selective pressure and clonal proliferation.
Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy
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Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
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Summary
Psoriasis is often associated with abdominal obesity and type-2 diabetes (T2D). The inflammatory process in psoriasis can target adipose tissue depots, especially those surrounding the heart and coronary arteries, exposing to an increased risk of cardiovascular diseases. A 50-year-old female patient referred to us for abdominal obesity and T2D, which were not controlled with lifestyle modifications. She had suffered from psoriasis for some years and was treated with guselkumab, without success. Epicardial adipose tissue (EAT) attenuation and pericoronary adipose tissue (PCAT) attenuation for each coronary, defined as mean attenuation expressed in Hounsfield unit (HU), were assessed by routine coronary computed tomography angiography. At baseline, EAT attenuation was −80 HU and PCAT attenuation of the right coronary artery (RCA) was −68 HU, values associated with an increased cardiac mortality risk. Psoriasis area and severity index (PASI) was 12.0, indicating severe psoriasis, while dermatology life quality index (DLQI) was 20, indicating a negative effect on the patient’s life. Semaglutide (starting with 0.25 mg/week for 4 weeks, increased to 0.50 mg/week for 16 weeks, and then to 1 mg/week) was started. After 10 months, semaglutide treatment normalized glycated hemoglobin and induced weight loss, particularly at abdominal level, also followed by a reduction in computed tomography-measured EAT volume. EAT attenuation and PCAT attenuation of RCA decreased, showing an important reduction of 17.5 and 5.9% respectively, compared with baseline. PASI and DLQI decreased by 98.3 and 95% respectively, indicating an improvement in psoriasis skin lesions and an important amelioration of the patient’s quality of life, compared with baseline.
Learning points
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Psoriasis patients affected by obesity and type-2 diabetes (T2D) are often resistant to biologic therapies.
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Psoriasis is often associated with abdominal obesity, T2D, and cardiovascular diseases (CVD), given their shared inflammatory properties and pathogenic similarities.
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Epicardial adipose tissue (EAT) inflammation can cause the distinctive pattern of CVD seen in psoriasis.
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EAT and pericoronary adipose tissue (PCAT) attenuation, assessed by routine coronary computed tomography angiography (CCTA), can be used as biomarkers of inflammation and allow monitoring of medical anti-inflammatory therapies.
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The actions of semaglutide to reduce energy intake, improve glycemic control, and produce effective weight loss, particularly at the visceral fat depot level, can diminish adipose tissue dysfunction, reduce EAT attenuation and PCAT attenuation of the right coronary artery (RCA) and concomitantly ameliorate the clinical severity of psoriasis.
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Semaglutide therapy may be considered in psoriasis patients affected by T2D and abdominal obesity, despite low cardiovascular risk by traditional risk scores, who are resistant to biologic therapies.
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Faculdade de Medicina, Universidade de Coimbra, Portugal
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Summary
We report a case of a woman with a diagnosis of breast cancer who unintentionally started gaining weight, feeling tired, and constipated 44 weeks after the initiation of trastuzumab. Hypothyroidism secondary to an autoimmune thyroiditis associated with trastuzumab was diagnosed, the first case described in Portugal and the fourth case described worldwide. Our intention regarding the publication of this case report is to alert the clinicians treating people with trastuzumab that they should ask the patients about symptoms of hypothyroidism and should screen the thyroid function of the patients before, during, and after the initiation of trastuzumab.
Learning points
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Trastuzumab is a humanized MAB used in HER2-positive breast and gastric cancer.
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Trastuzumab-associated autoimmune thyroid disease (AITD) is rare (incidence rate in an RCT of 0.3%).
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Manifestations of autoimmune thyroiditis associated with trastuzumab resemble those of hypothyroidism in other clinical contexts, but the presence of goiter is highlighted as a reason for medical evaluation. Biochemically, it is characterized by an increased thyroid-stimulating hormone (TSH) with or without a low FT4/FT3, and sonographically with a pattern of thyroiditis.
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The treatment consists of levothyroxine, in a dose of 1.6–1.8 µg/kg/day, with re-evaluation of the thyroid function in 4–6 weeks.
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We report the first case of autoimmune thyroiditis secondary to trastuzumab in Portugal.
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It is important to evaluate the thyroid function before, during, and after the initiation of this therapeutic agent.
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Summary
A 31-year-old woman with complete androgen insensitivity syndrome (CAIS) experienced breast volume fluctuations during biphasic hormone replacement therapy consisting of estradiol and cyclical dydrogesterone, a progestin. 3D breast volume measurements showed a 100 cc volume (17%) difference between estradiol monotherapy and combined estradiol and dydrogesterone treatment. Progestogen-dependent breast volume changes have not been reported in the literature. Our findings suggest a correlation between progestogen use and breast volume. Due to the rapid cyclical changes, we hypothesize that the effect is caused by fluid retention.
Learning points
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There is limited reports available on the effects of progesterone on breast development and volume.
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3D imaging provides an easy-to-use method to quantify breast volume.
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The patient in our case description clearly showed that cyclic progesterone use might induce substantial cyclic changes in breast volume.
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In women with complete androgen insensitivity syndrome (CAIS), monotherapy with estrogen or continuous supplementation of progesterone might be preferable over cyclic progesterone use.
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Summary
Depot medroxyprogesterone acetate, also known as Depo-Provera, is a progesterone-only contraceptive that is administered by injection to patients every three months. We describe the case of a 19-year-old female who was diagnosed with central diabetes insipidus following the administration of the contraceptive injection Depo-Provera. The patient was diagnosed with polycystic ovarian syndrome at age 16 and was originally prescribed oral contraceptives to restore menstrual regularity. Three years later, Depo-Provera was substituted for convenience, and symptoms of polyuria and polydipsia appeared one month after initiating the progesterone-only regimen. We are proposing that central diabetes insipidus may be a possible adverse effect of Depo-Provera in women with polycystic ovarian syndrome who receive the progesterone-only contraception, due to the interference of their arginine vasopressin mechanism through the alteration of estrogen levels. We review potential mechanisms through the presentation of previously completed research in polycystic ovarian syndrome.
Learning points
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We propose that although rare, the decrease in estrogen that is experienced during the administration of Depo-Provera can interfere with arginine vasopressin release in patients with polycystic ovarian syndrome (PCOS).
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Increased awareness of possible lasting adverse effects on fluid balance with unopposed progesterone administration in PCOS is important, as this case of the development of diabetes insipidus suggests.
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Discussion of such potential side effects is important when considering contraceptive options for the regulation of menses in patients with PCOS.
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Summary
Subacute thyroiditis is an inflammatory disorder of the thyroid gland that has previously been described following viral illnesses and occasionally post vaccination such as influenza vaccine. 2021 was a revolutionary year for the development of SARS-CoV-2 vaccinations with multiple different vaccines now available. There are increasing numbers of case reports of thyroiditis following these vaccinations. We report a case of a 50-year-old female who developed subacute thyroiditis 6 days post ChAdOx1 nCoV-19 vaccine (AZD1222 produced by AstraZeneca Vaxzevria). The initial thyrotoxic phase was followed by overt hypothyroidism. This resolved spontaneously within 5 months without levothyroxine replacement. We hope that our case will add to the growing literature of cases of thyroiditis occurring after multiple different types of SARS-CoV-2 vaccination and create awareness of this rare but treatable adverse effect. We also review the literature on the proposed mechanisms behind this adverse effect.
Learning points
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Subacute thyroiditis is an inflammatory disorder of the thyroid gland that can occur after a viral illness or vaccination against certain infections.
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Subacute thyroiditis is a rare adverse effect that has been reported to occur after different types of SARS-CoV-2 vaccinations.
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Subacute thyroiditis post vaccination is relatively straightforward to manage, with some patients requiring non-steroidal anti-inflammatory drugs and beta-blockers, while more severe cases may require corticosteroid therapy. This adverse effect should not dissuade vaccination use at a population level.
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There are many postulated mechanisms for the development of subacute thyroiditis following vaccination including the presence of the ACE-2 receptor for SARS-CoV-2 on the thyroid gland, an inflammatory/immune response as is seen in COVID-19 infection itself and molecular mimicry between SARS-CoV-2 spike protein and healthy thyroid antigen.
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Summary
Milk–alkali syndrome (MAS) is a triad of hypercalcaemia, metabolic alkalosis and renal insufficiency. In this study, we present a case of milk–alkali syndrome secondary to concurrent use of over-the-counter (OTC) calcium carbonate-containing antacid tablets (Rennie®) for dyspepsia and calcium carbonate with vitamin D3 (Adcal D3) for osteoporosis. A 72-year-old woman presented with a 2-day history of nausea, vomiting, epigastric pain, constipation, lethargy and mild delirium. Past medical history included osteoporosis treated with daily Adcal D3. Initial blood tests showed elevated serum-adjusted calcium of 3.77 mmol/L (normal range, 2.2–2.6) and creatinine of 292 µmol/L (45–84) from a baseline of 84. This was corrected with i.v. pamidronate and i.v. fluids. She developed asymptomatic hypocalcaemia and rebound hyperparathyroidism. Myeloma screen, vasculitis screen and serum angiotensin-converting enzyme (ACE) were normal, while the CT of the chest, abdomen and pelvis showed renal stones but no malignancy. A bone marrow biopsy showed no evidence of malignancy. Once the delirium resolved, we established that prior to admission, she had been excessively self-medicating with over-the-counter antacids (Rennie®) as required for epigastric pain. The increasing use of calcium preparations for the management of osteoporosis in addition to easily available OTC dyspepsia preparations has made MAS the third most common cause of hypercalcaemia hospitalisations. Educating patients and healthcare professionals on the risks associated with these seemingly safe medications is required. Appropriate warning labels on both calcium preparations used in the management of osteoporosis and OTC calcium-containing preparations would prevent further similar cases and unnecessary morbidity and hospital admission.
Learning points
What is known?
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An association between high-dose calcium supplementation and hypercalcaemia crisis has been seen in case studies.
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After as little as 1 week of excessive calcium carbonate ingestion, patients can present with symptomatic hypercalcemia, acute renal failure and metabolic alkalosis (1).
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Women aged 50 and younger need 1 g of calcium per day, while aged 51 and older need 1.2 g (1).
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Although the amount of calcium required for MAS is generally thought to be more than 4 g per day, there have been reports at intakes as low as 1.0–1.5 g per day in pre-existing risk factors including renal impairment (2).
What this study adds?
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The danger of excessive ingestion of antacid is not adequately highlighted to prescribers and patients.
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Appropriate warning labels on OTC calcium-containing preparations could prevent unnecessary morbidity and hospital admission.
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Summary
Immunotherapy has become an important pillar for the management of advanced cancer. Immune-related adverse events including endocrinopathies have been well described with programmed cell death 1 inhibitors such as pembrolizumab. While thyroid dysfunction is the most common endocrinopathy associated with pembrolizumab, new-onset autoimmune diabetes mellitus (DM) is extremely rare. The authors report a case of pembrolizumab-induced primary hypothyroidism and type 1 diabetes mellitus presenting with diabetic ketoacidosis (DKA). A 59-year-old female patient was treated with pembrolizumab for a stage 4 lung adenocarcinoma. She presented to the emergency department with hyperglycaemia-related signs and symptoms, such as polyuria, polydipsia, weight loss, vomiting, asthenia and dehydration, 3 weeks after her first dose of pembrolizumab. Laboratory evaluation revealed hyperglycaemia, hyperketonaemia and high anion gap metabolic acidaemia consistent with DKA. After prompt and adequate treatment of DKA, she transitioned to s.c. basal-bolus insulin. The diagnose of autoimmune DM was established based on the undetectable C-peptide levels and seropositivity for antiglutamic acid decarboxylase antibodies. Additional hormonal parameters revealed overt hypothyroidism and levothyroxine therapy was initiated. This case highlights the importance of blood glucose and thyroid function monitoring as an integral part of cancer treatment protocols for pembrolizumab and other immune checkpoint inhibitors.
Learning points
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Programmed cell death 1 (PD1) inhibitors such as pembrolizumab can cause endocrine immune-related adverse events (irAE), including thyroid dysfunction and type 1 diabetes mellitus (T1DM).
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Thyroid dysfunction is the most frequent endocrine irAE secondary to PD1 inhibitors.
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Autoimmune diabetes and possible resultant diabetic ketoacidosis are rare, but life-threatening adverse events associated with pembrolizumab.
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Pembrolizumab-induced T1DM often present with relatively low HbAlc levels, reflecting the fulminant onset of β-cell destruction.
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Patients treated with pembrolizumab and other immune checkpoints inhibitors should be monitored regularly for hyperglycaemia and thyroid dysfunction.
Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
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St Vincent’s Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia
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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:
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Durvalumab use is rarely associated with fulminant autoimmune diabetes, presenting with severe DKA.
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Multiple endocrinopathies can co-exist with the use of a single immune checkpoint inhibitors; thus, patients should be regularly monitored.
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Regular blood glucose levels should be performed on routine pathology on all patients on immune checkpoint inhibitor.
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Clinician awareness of immunotherapy-related diabetes needs to increase in an attempt to detect hyperglycaemia early and prevent DKA.
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Summary
Mifepristone is a promising option for the management of hypercortisolism associated with hyperglycemia. However, its use may result in serious electrolyte imbalances, especially during dose escalation. In our patient with adrenocorticotropic hormone-independent macro-nodular adrenal hyperplasia, unilateral adrenalectomy resulted in biochemical and clinical improvement, but subclinical hypercortisolism persisted following adrenalectomy. She was started on mifepristone. Unfortunately, she missed her follow-up appointments following dosage escalation and required hospitalization at an intensive care level for severe refractory hypokalemia.
