Summary

This study compares the effects of metformin, sulfonylurea derivative (SU) and no treatment in HNF4A-MODY on glycemic control. In two patients with HNF4A-MODY, we changed the existing metformin treatment to SU derivative. The effect on the glycemic control was registered with a Freestyle Libre Flash glucose monitoring device. Each treatment period had a duration of 2 consecutive weeks, and in between, an intermediate period without medication. Data from the first 2 days after changing medications were excluded. We calculated time in range (TIR), and differences in the mean glucose level were tested with a one-way ANOVA test. The 24-h average glucose levels were significantly lower with either metformin (7.7 mmol/L; P < 0.001 and 6.3 mmol/L; P < 0.001) or gliclazide (7.6 mmol/L; P < 0.001 and 5.8 mmol/L; P < 0.001) compared to no treatment (9.4 and 8.9 mmol/L). The TIR with metformin or gliclazide was higher than without treatment (patient 1: 87 and 83 vs 61% and patient 2: 83 and 93 vs 67%). Treatment with either metformin or gliclazide effectively decreases blood glucose, rendering both drugs appropriate for treating HNF4A-MODY.

Learning points

• HNF4A-MODY has a mild phenotype.

• Blood glucose was responsive to long-term metformin treatment in HNF4A-MODY.

• Metformin and gliclazide seem appropriate treatments for HNF4A-MODY.

Summary

A 72-year-old man with type 2 diabetes volunteered to participate in the control group of a clinical study. The study evaluated non-alcoholic fatty liver disease in patients with kidney disease. The patient was followed at a gastroenterology department due to Crohn’s disease and post-operative bile acid malabsorption. The patient had no symptoms or biochemical findings suggesting liver disease. Surprisingly, a transient elastography (FibroScan^®) suggested advanced fibrosis with a median of 16.1 kPa. A liver biopsy showed non-alcoholic steatohepatitis (NASH)-cirrhosis. The diagnosis was only made incidentally and highlights how NASH-cirrhosis may be overlooked due to the lack of symptoms.

Learning points

• Clinicians treating high-risk populations, including patients with type 2 diabetes and/or components of the metabolic syndrome, should be aware of the frequently occurring co-existence with non-alcoholic fatty liver disease (NAFLD) and especially non-alcoholic steatohepatitis (NASH).

• Liver enzymes may be in the normal range even in people with steatosis, NASH, or even cirrhosis.

• The diagnosis of NAFLD should include evaluation of hepatic fibrosis as this is the most important prognostic factor for liver-related complications and mortality.

• Guidelines about systematic screening for NAFLD in patients with type 2 diabetes are incongruent.

Summary

Adult-onset nesidioblastosis is a rare complication of Roux-en-Y gastric bypass surgery and may occur months to years after the initial surgical procedure. It is manifested by a hyperinsulinemic, hypoglycemic state. The annual incidence of adult-onset hyperinsulinemic hypoglycemia is believed to be less than 0.1 in 1 000 000 with a mean age of onset of 47 years (1). Here, we describe a patient who presented with worsening hypoglycemic symptoms for 1 year prior to presentation that eventually progressed to hypoglycemic seizures. The onset of this hypoglycemia was 5 years after Roux-en-Y gastric bypass surgery. A full neurological evaluation, which included an EEG, head CT, and MRI, was performed to rule out epilepsy and other seizure-related disorders. After hypoglycemia was confirmed, extensive laboratory studies were obtained to elucidate the cause of the hypoglycemia and differentiate nesidioblastosis from insulinoma. Once the diagnosis of nesidioblastosis was established, a sub-total pancreatectomy was performed, and the patient was discharged and placed on acarbose, a competitive reversible inhibitor of pancreatic α-amylase and intestinal brush border α-glucosidases which slows carbohydrate absorption. The lack of information and understanding of nesidioblastosis due to its rarity makes any knowledge of this rare but important surgical complication essential. As incidence of obesity increases, the number of gastric bypasses being performed increases with it, and understanding this disease process will be essential for the primary care provider. This is the primary reason for the writing of this publication.

Learning points

• Nesidioblastosis is a persistent hyperinsulinemic, hypoglycemic state, mostly seen after Roux-en-Y gastric bypass surgery, with symptoms occurring postprandially.

• The incidence is 0.1–0.3% of all post Roux-en-Y gastric bypass patients.

• The key diagnostic clue to identifying nesidioblastosis is a positive selective arterial calcium stimulation test, showing a diffuse pattern of increased basal hepatic venous insulin concentration, whereas insulinomas would show focal increases.

• Pathological specimen of pancreas will show diffuse hypertrophy of beta cells.

• Management includes acarbose and total or subtotal pancreatectomy, which can be curative.

• With the prevalence of obesity increasing and more patients turning to Roux-en-Y gastric bypass, more patients may be at risk of this potential surgical complication.

Summary

Tumor-induced osteomalacia (TIO) is a rare form of osteomalacia caused by fibroblast growth factor-23 (FGF23)-secreting tumors. Most of these tumors are phosphaturic mesenchymal tumors (PMTs) typically involving soft tissue in the extremities and bone of the appendicular skeleton and cranium. We report the case of a 60-year-old woman with about 3 years of persistent bone pain and multiple fractures, initially diagnosed as osteoporosis, who was found to have hypophosphatemia with low 1,25-dihydroxyvitamin D and elevated alkaline phosphatase and inappropriately normal FGF23 consistent with TIO. Her symptoms improved with phosphate supplementation, vitamin D and calcitriol. ⁶⁸Ga-DOTATATE imaging revealed a T12 vertebral body lesion confirmed on biopsy to be a PMT. She underwent resection of the PMT with resolution of TIO and increased bone density. This rare case of TIO secondary to a PMT of the thoracic spine highlights some of the common features of PMT-associated TIO and draws attention to PMT-associated TIO as a possible cause of unexplained persistent bone pain, a disease entity that often goes undiagnosed and untreated for years.

Learning points

• Tumor-induced osteomalacia (TIO) is typically caused by phosphaturic mesenchymal tumors (PMTs) that are usually found in the soft tissue of the extremities and bone of the appendicular skeleton/cranium and rarely in the spine.

• TIO may be misdiagnosed as osteoporosis or spondyloarthritis, and the correct diagnosis is often delayed for years. However, osteoporosis, in the absence of fracture, is not associated with bone pain.

• The hallmark of TIO is hypophosphatemia with inappropriately normal or low 1,25-dihydroxyvitamin D and elevated or inappropriately normal fibroblast growth factor-23 (FGF23) levels.

• In patients with unexplained persistent bone pain, a serum phosphate should be measured. Consider PMT-associated TIO as a potential cause of unexplained persistent bone pain and hypophosphatemia.

• PMTs express somatostatin receptors and may be identified with ⁶⁸Ga-DOTATATE imaging.

• Complete surgical resection is the preferred treatment for spinal PMTs associated with TIO.

Summary

The rapid rise in the use of immune checkpoint inhibitors as systemic cancer therapy has seen the emergence of immunotherapy-induced diabetes, a severe irreversible immunotherapy-related adverse event. Affected patients typically present with diabetic ketoacidosis (DKA) and low C-peptide consistent with insulin deficiency secondary to autoimmune β-cell destruction. We present the unusual case of a 61-year-old female with metastatic ampullary duodenal adenocarcinoma with primary tumour adjacent to the pancreatic head. She was commenced on immunotherapy after conventional systemic chemotherapy. Acute-onset hyperglycaemia was detected after 7 weeks on weekly blood glucose monitoring, with no glucocorticoid use or prior history of diabetes. On presentation, there was no evidence of DKA, and her glycated haemoglobin level was within the normal non-diabetic range at 5.3%, reflecting the acuity of her presentation. Initial serum C-peptide was preserved; however, it became undetectable a few weeks later, confirming insulin deficiency. We describe a case of atypical presentation of immunotherapy-induced diabetes, review the existing literature on this emerging clinical entity and discuss the differential diagnosis for new-onset diabetes mellitus in patients with metastatic cancer.

Learning points

• Regular proactive glycaemic monitoring in patients receiving immunotherapy, particularly antibodies against programmed death ligand 1 and PD1, can facilitate very early detection of immunotherapy-induced diabetes, prompting insulin commencement and avoiding life-threatening presentations of diabetic ketoacidosis.

• Glycated haemoglobin can be within the normal range in patients diagnosed acutely with immunotherapy-induced diabetes.

• Serum C-peptide can be preserved initially in patients diagnosed with immunotherapy-induced diabetes but is likely to become undetectable during their illness.

• New-onset diabetes in patients with metastatic cancer carries a broad differential diagnosis.

Summary

A 52-year-old female presented with recurrent episodes of fasting or post-absorptive hypoglycemia. A 72-h fasting test confirmed endogenous hyperinsulinemia. Conventional imaging was unremarkable. Selective pancreatic arterial calcium stimulation and hepatic venous sampling showed a maximum calcium-stimulated insulin concentration from several pancreatic areas, mainly the proximal splenic artery and the proximal gastroduodenal artery, suggesting the presence of one or more occult insulinoma(s) in the region of the pancreatic body. ⁶⁸Ga-DOTA-exendin-4 PET/CT showed however generalized increased uptake in the pancreas and a diagnosis of nesidioblastosis was therefore suspected. The patient has been since successfully treated with dietetic measures and diazoxide. Treatment efficacy was confirmed by a flash glucose monitoring system with a follow-up of 7 months.

Learning points

• Adult nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia.

• The distinction between insulinoma and nesidioblastosis is essential since the therapeutic strategies are different.

• ⁶⁸Ga-DOTA-exendin-4 PET/CT emerges as a new noninvasive diagnostic tool for the localization of an endogenous source of hyperinsulinemic hypoglycemia.

• Medical management with dietetic measures and diazoxide need to be considered as a valuable option to treat patients with adult nesidioblastosis.

• Flash glucose monitoring system is helpful for the evaluation of treatment efficacy.

Summary

Sarcoidosis is an inflammatory, multisystem disease with an undetermined etiology. The presence of noncaseating granulomas in involved organs is a characteristic pathomorphological feature. Sarcoidosis, like a chameleon, can mimic different medical conditions. Although the lungs are most commonly involved, extrapulmonary manifestations can influence any system. The clinical course of the disease may differ. Immediate initiation of glucocorticosteroid therapy is important when critical organs are impaired. A case of a patient with sarcoidosis whose first clinical symptoms were related to diabetes insipidus (DI) was presented. The diagnosis of multiple organ sarcoidosis was delayed because of an adequate response to treatment with vasopressin. The multidisciplinary diagnostic approach validated the involvement of the pituitary gland, lungs, lymph nodes, bones, and subcutaneous tissue. The presented case emphasizes the critical importance of the multifaceted differential diagnosis of patients with DI.

Learning points

• Sarcoidosis usually affects the lung but can also be a multisystemic disease.

• The assessment of the extension of sarcoidosis remains complex.

• A multidisciplinary approach must identify all-organ involvement and initiate appropriate sarcoidosis treatment.

• Diabetes insipidus (DI) can be the first symptom of a systemic granulomatous disorder.

• In the differential diagnosis of DI, a comprehensive assessment of rare causes of endocrine disorders, including extrapulmonary sarcoidosis, should be considered.

Summary

Myopathy caused by thyrotoxicosis is not uncommon. Skeletal muscles are commonly involved, but dysphagia is a rare manifestation of thyrotoxicosis. We aim to raise awareness of dysphagia caused by hyperthyroidism and review similar cases in the literature. We present a case of severe dysphagia caused by hyperthyroidism. We also summarize similar case reports in the literature. Our patient is a 77-year-old man who presented with thyrotoxicosis related to Graves’ disease (GD), dysphagia to both liquid and solid food, and weight loss. Further investigations revealed severe esophageal dysphagia and a high risk for aspiration. He required the placement of a G-tube for feeding. After 8 weeks of methimazole treatment, his thyroid function normalized and his dysphagia improved significantly, leading to the removal of the feeding G-tube. We summarize 19 case reports published in the literature of hyperthyroidism leading to dysphagia. Patients with thyrotoxicosis and dysphagia are at higher risk for aspiration pneumonia and thyroid storm. Based on previous case reports, on average, approximately 3 weeks of treatment with anti-thyroidal drugs and beta-blockers is needed before patients can eat normally. We report a case of dysphagia associated with GD, which is rare and needs prompt recognition to restore euthyroid status. Dysphagia generally resolved with normalization of thyroid function.

Learning points

• Myopathy caused by thyrotoxicosis is not uncommon.

• Skeletal muscles are commonly involved, but dysphagia is a rare manifestation of thyrotoxicosis.

• Dysphagia due to hyperthyroidism resolves with normalization of thyroid function.

• Early recognition of dysphagia related to hyperthyroidism and early initiation of therapy may help reverse the dysphagia and prevent complications.

Summary

Osilodrostat is a novel, orally administered cortisol synthesis inhibitor, approved in 2020 by the European Medicines Agency (EMA) for the treatment of Cushing’s syndrome in adults. A significant amount of the studies currently available in the literature focus on treatment in patients with Cushing’s disease. However, data collected from patients treated with osilodrostat in real-life settings still represents a small entity. For this reason, in this article, we will discuss two real-life cases of patients with Cushing’s disease treated with this drug. The first report is about a 35-year-old woman with an adrenocorticotrophic hormone (ACTH)-secreting adenoma. After non-curative trans-nasal-sphenoidal (TNS) surgery, due to a small remnant of the adenoma, medical therapy with osilodrostat achieved fast and effective biochemical and clinical response. During treatment, progressive increase of ACTH levels and an enlargement of the pituitary remnant were documented, with planned radiosurgical treatment. The second case reports a 32-year-old man diagnosed with Cushing’s disease in 2020, who, after surgery refusal, started osilodrostat at progressively up-titrated doses, according to 24 h urinary free cortisol levels, up to 5 mg twice a day. With osilodrostat, the patient reached biochemical and clinical control of disease until TNS surgery in October 2021, with complete remission. The first post-surgical biochemical assessment was equivocal in spite of a transient clinical hypoadrenalism, reverted after 2 months with the restoration of physiological hypothalamic-pituitary-adrenal axis (HPA) function.

Learning points

• Osilodrostat is a potent oral drug viable for Cushing’s disease as medical therapy when surgery is not feasible or remission cannot be reached.

• Osilodrostat proves to be a safe drug and its main adverse effect is hypoadrenalism, due to the adrenolytic action of the compound.

• Osilodrostat needs a very tailored approach in its clinical use because there is no correlation between the level of hypercortisolism pre-treatment and the dose required to reach disease control.

Summary

The Covid-19 vaccination has been rapidly implemented among patients with cancer. We present two cases of patients with endocrine tumours who developed lymphadenopathy following a Covid-19 vaccination. In the case of a patient with multiple endocrine neoplasia (MEN) 1 syndrome, an 18-fluorodeoxyglucose (18FDG)-PET/CT showed positive axillary lymph nodes. Further work-up with fine needle aspiration showed a reactive pattern following a Covid-19 vaccination in the ipsilateral arm shortly before the 18FDG-PET/CT. A second patient, in follow-up for thyroid cancer, developed clinical supraclavicular lymphadenopathy after a Covid-19 vaccination. Follow-up ultrasound proved the lesion to be transient. These cases demonstrate lymphadenopathy in response to a Covid-19 vaccination in two patients susceptible to endocrine tumours and metastatic disease. With growing evidence about the pattern and occurrence of lymphadenopathy after mRNA Covid-19 vaccination, recommendations for scheduling and interpretation of imaging among cancer patients should be implemented to reduce equivocal findings, overdiagnosis, and overtreatment, while maintaining a good standard of care in oncological follow-up.

Learning points

• Reactive lymphadenopathy is very common after an mRNA vaccination against Covid-19 and should be part of the differential diagnosis in patients with endocrine tumours who recently received a Covid-19 mRNA vaccination and present with an ipsilateral lymphadenopathy.

• A good vaccine history is essential in assessing the risk for lymphadenopathy and if possible, screening imaging in patients with endocrine tumours should be postponed at least 6 weeks after the previous vaccination.

• For now, a multidisciplinary care approach is recommended to determine the necessary steps in the diagnostic evaluation of lymphadenopathy in the proximity of a Covid-19 vaccination.