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Open access

Kieran Palmer, Scott Weerasuriya, Benjamin Whitelaw, and Rajaventhan Srirajaskanthan

Summary

We report a rare case of posterior reversible encephalopathy syndrome (PRES), precipitated by ectopic Cushing’s syndrome, in a patient with a metastatic pancreatic neuroendocrine tumour. A 55-year-old female presented as a hypertensive emergency with seizures and severe biochemical disturbance, including alkalosis, hypokalaemia and hyperglycaemia. MRI showed vasogenic oedema in the parieto-occipital region, consistent with a diagnosis of PRES. She had a significantly raised serum cortisol (>6000 nmol/L) which did not suppress with dexamethasone. Plasma adrenocorticotropic hormone (ACTH) concentrations were neither suppressed nor raised but were consistently within the normal reference range. The unexpected finding of a normal ACTH may be explained by either tumour secretion of unmeasured ACTH-related peptides, immunoassay antibody interference or episodic ACTH secretion. PRES is usually reversible with prompt and appropriate treatment. Hypercortisolism associated PRES is rare and may be associated with a worse outcome.

Learning points

  • PRES secondary to ectopic Cushing’s syndrome is very rare.
  • PRES in this context may indicate a worse prognosis.
  • In ectopic Cushing’s syndrome, if the serum ACTH level is normal, consider testing for ACTH-related peptides or interfering antibodies.
  • Further research is required to establish the best treatment approach and to improve patients’ outcomes.
Open access

Seong Keat Cheah, Chad Ramese Bisambar, Deborah Pitfield, Olivier Giger, Rogier ten Hoopen, Jose-Ezequiel Martin, Graeme R Clark, Soo-Mi Park, Craig Parkinson, Benjamin G Challis, and Ruth T Casey

Summary

A 38-year-old female was identified as carrying a heterozygous pathogenic MEN1 variant (c.1304delG) through predictive genetic testing, following a diagnosis of familial hyperparathyroidism. Routine screening for parathyroid and pituitary disease was negative. However, cross-sectional imaging by CT revealed a 41 mm pancreatic tail mass. Biopsy via endoscopic ultrasound confirmed the lesion to be a well-differentiated (grade 1) pancreatic neuroendocrine tumour (pNET) with MIB1<1%. Biochemically, hyperinsulinaemic hypoglycaemia was confirmed following an overnight fast, which was subsequently managed by diet alone prior to definitive surgery. Pre-operative work-up with octreotide SPECT CT demonstrated avid tracer uptake in the pancreatic lesion and, unexpectedly, a focal area of uptake in the left breast. Further investigation, and subsequent mastectomy, confirmed ductal carcinoma in situ pT2 (23 mm) grade 1, N0 (ER positive; HER2 negative). Following mastectomy, our patient underwent a successful distal pancreatectomy to resect the pNET. Loss of heterozygosity (LOH) at the MEN1 locus was found in both the breast tumour and pNET, thereby in keeping with a 'two-hit' hypothesis of oncogenesis, a suggestive but non-definitive clue for causation. To obtain further support for a causative relationship between MEN1 and breast cancer, we undertook a detailed review of the published literature which overall supports the notion that breast cancer is a MEN1-related malignancy that presents at a younger age and histologically, is typically of ductal subtype. Currently, clinical guidance regarding breast cancer surveillance in MEN1 does not exist and further research is required to establish a clinical and cost-effective surveillance strategy).

Learning points

  • We describe a case of pNET and breast cancer diagnosed at a young age of 38 years in a patient who is heterozygous for a pathogenic MEN1 variant. Loss of the wild-type allele was seen in both breast tissue and pNET specimen.
  • Breast cancer may be an under-recognised MEN1-associated malignancy that presents at a younger age than in the general population with a relative risk of 2–3.
  • Further research is required to determine the cost-effectiveness of breast cancer surveillance approach at a younger age in MEN1 patients relative to the general population .
Open access

Carolina Chaves, Mariana Chaves, João Anselmo, and Rui César

Summary

Berardinelli–Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive disease, characterized by the absence of subcutaneous adipose tissue, leptin deficiency and severe metabolic complications, such as insulin resistance, diabetes mellitus, and dyslipidemia. The most common mutation occurs in BCSL2 which encodes seipin, a protein involved in adipogenesis. We report a patient with BSCL who was diagnosed with diabetes at 11 years old. He was started on metformin 1000 mg twice daily, which lowered glycated hemoglobin (HbA1c) to less than 7%. Four months later, HbA1c raised above 7.5%, indicating secondary failure to metformin. Therefore, we added the peroxisome proliferator-activated receptor-gamma (PPARG) agonist, pioglitazone. Since then and for the last 5 years his HbA1c has been within the normal range. These findings indicate that pioglitazone should be considered as a valid alternative in the treatment of diabetes in BSCL patients. To the best of our knowledge, this is the first specific report of successful long-term treatment with pioglitazone in a patient with BSCL.

Learning points

  • Berardinelli–Seip congenital lipodystrophy (BSCL) is a recessive genetic disorder associated with severe insulin resistance and early onset diabetes, usually around puberty. Failure of oral antidiabetic medication occurs within the first years of treatment in BSCL patients.
  • When failure to achieve metabolic control with metformin occurs, pioglitazone may be a safe option, lowering insulin resistance and improving both the metabolic control and lipodystrophic phenotype.
  • Herein we show that pioglitazone can be a safe and efficient alternative in the long-term treatment of BSCL patients with diabetes.
Open access

Antonella Corcillo, Zoe Kleinaki, Stella Kapnisi, Nikolaos Fountoulakis, Giuseppe Maltese, Stephen M Thomas, and Janaka Karalliedde

Summary

A 26-year-old Caucasian female with no past medical history or family history of auto-immune disease presented to the emergency department with new onset painless left foot drop. A panel of blood tests revealed blood glucose of 49.9 mmol/L and raised blood ketone levels. The patient was referred to the diabetes team who made a clinical diagnosis of type 1 diabetes (T1DM) and insulin treatment was initiated. Elevated levels of diabetes auto-antibodies were subsequently detected. Nerve conduction studies demonstrated a left common peroneal nerve lesion with conduction block at the fibular head. After 2 weeks of insulin treatment, a significant improvement of her foot drop was observed and after 8 weeks she was walking normally. The most probable cause of her foot drop was acute diabetic mononeuropathy. To our knowledge, there are no similar cases in adult patients reported in the literature. Our case highlights the importance of physicians being aware of atypical presentation of new onset T1DM.

Learning points:

  • There is an increasing incidence of T1DM with more than half of patients presenting after the age of 20.
  • Diabetic peripheral neuropathy can present both acutely and as a mononeuropathy.
  • Although rare, clinicians should be aware of mononeuropathy as a presenting symptom of T1DM to avoid delay in the treatment initiation.
  • This case highlights an unusual presentation of T1DM and illustrates the importance of the early diagnosis and management of T1DM.
Open access

Anthony Ramos-Yataco, Kelly Meza, Reyna Cecilia Farfán-García, Solange Ortega-Rojas, Isaac Salinas-Mamani, Ivonne Silva-Arrieta Ontaneda, and Ricardo Correa

Summary

The first case of the novel coronavirus infection (COVID-19) in Peru was reported on March 6, 2020. As of September 7, 2020, about 700 000 cases of COVID-19 resulting in 29,976 deaths have been confirmed by the Ministry of Health. Among COVID-19 patients with co-morbidities, type 2 diabetes mellitus (T2DM) has been recognized as a risk factor for severe disease. Patients with T2DM may experience diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic (HHS) if infected with the coronavirus 2 (SARS-CoV-2). Regular blood analysis including arterial blood gas is essential in monitoring the care of patients with T2DM infected with COVID-19. We report five cases of DKA in patients with underlying T2DM that presented with severe COVID-19 infection.

Learning points:

  • COVID-19 may cause acute metabolic dysregulations in patients with T2DM.
  • It is important to monitor basic metabolic panel (BMP) and arterial blood gases (ABGs) in patients with COVID-19 since metabolic complications can develop unexpectedly.
  • Patients with T2DM develop an inflammatory syndrome characterized by severe insulin resistance and B cell dysfunction that can lead to DKA.
Open access

Ana M Lopes and Sofia Teixeira

Summary

Molecular alterations of the transcription factor hepatocyte nuclear factor 1B (HNF1B) are associated with systemic disease, with kidney disease and maturity-onset diabetes of the young (MODY) as the most characteristic manifestations. Other features comprise pancreatic exocrine insufficiency, liver and biliary anomalies, and genital tract malformations. HNF1B-associated disease is clinically heterogeneous, and therefore the diagnosis is challenging. The authors describe the case of a 19-year-old man with new-onset diabetes after kidney transplantation (NODAT). The kidney disease presented during fetal life as bilateral hyperechogenic kidneys. Renal function progressively deteriorated during childhood, and at the age of 19, the patient was submitted to a living-kidney transplant. Two weeks after transplant, NODAT developed. Given the young age and normal body weight, NODAT was unexpected, and the possibility of HNF1B-associated disease was considered. Screening for mutations in HNF1B was undertaken, and a known mutation was found. As this case highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive renal disease.

Learning points:

  • HNF1B anomalies are associated with systemic disease, including kidney disease, diabetes mellitus, pancreatic exocrine insufficiency, liver test abnormalities and genital tract malformations.
  • Phenotype is variable and there are no pathognomonic manifestations, but kidney disease appears to be the most common feature and diabetes the most frequent extra-renal phenotype.
  • Spontaneous gene alterations are common, and the lack of family history should not exclude the diagnosis.
  • HNF1B defects should be considered when NODAT develops in a young adult kidney transplant recipient with a suggestive kidney disease and without extensive risk factors for diabetes.
  • The most appropriate treatment for HNF1B-associated diabetes is not established, but immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period.
  • Immunosupressive regimens free of calcineurin inhibitors should be considered in patients with HNF1B-associated disease to minimize the risk of developing NODAT.
Open access

Ellada Sotiridou, Henrike Hoermann, Sommayya Aftab, Antonia Dastamani, Eva Thimm, Louise Doodson, Spyros Batzios, Sebastian Kummer, and Pratik Shah

Summary

Tyrosinaemia type 1 (TT1) is a rare inherited disorder of amino acid metabolism typically presenting with liver failure and renal tubular dysfunction. We describe three individuals with TT1 and transient hyperinsulinaemic hypoglycaemia (HH). Two siblings with TT1 and acute liver dysfunction were diagnosed with hyperinsulinaemic hypoglycaemia in the neonatal period. Both siblings were successfully treated with diazoxide/chlorthiazide and treatment was gradually weaned and stopped after 8 and 6 months of age respectively. The third patient presented with a neonatal liver failure with mild cholestasis, coagulopathy, fundus haemorrhages, vitamin A and E deficiency and hyperinsulinaemic hypoglycaemia. He maintained euglycaemia on high dose diazoxide (5–12 mg/kg/day) but developed pulmonary hypertension at 12 weeks of age. After discontinuation of diazoxide, he continued maintaining his blood glucose (BG) within the normal range. Although histological abnormalities of the pancreas including beta-cell hyperplasia are well documented, the exact mechanism of excessive insulin secretion in TT1 is not well understood. It may be related to the accumulation of toxic metabolites in the target organs including pancreas. Therefore, in patients with TT1 and persistent hypoglycaemia beyond the recovery of the acute liver failure, it is important to exclude hyperinsulinism which is usually transient and can be successfully treated with diazoxide and chlorothiazide. Further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.

Learning points:

  • Every child with TT1 should be monitored for signs and symptoms of hypoglycaemia and screened for HH at the time of real hypoglycaemia.
  • If hypoglycaemic episodes persist even after improvement of liver function, hyperinsulinism should be suspected.
  • Treatment with diazoxide is effective, however, children need to be monitored closely for possible side effects.
  • The pathophysiological mechanism of hyperinsulinism in children with TT1 is not elucidated yet and further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.
Open access

Jennifer R Snaith, Duncan McLeod, Arthur Richardson, and David Chipps

Summary

Insulinomatosis is a rare cause of hyperinsulinaemic hypoglycaemia. The ideal management approach is not known. A 40-year-old woman with recurrent symptomatic hyperinsulinaemic hypoglycaemia was diagnosed with an insulinoma. A benign 12 mm pancreatic head insulinoma was resected but hypoglycaemia recurred 7 years later. A benign 10 mm pancreatic head insulinoma was then resected but hypoglycaemia recurred within 2 months. Octreotide injections were trialled but exacerbated hypoglycaemia. After a 2-year interval, she underwent total pancreatectomy. A benign 28 mm pancreatic head insulinoma was found alongside insulin-expressing monohormonal endocrine cell clusters (IMECCs) and islet cell hyperplasia, consistent with a diagnosis of insulinomatosis. Hypoglycaemia recurred within 6 weeks. There was no identifiable lesion on MRI pancreas, Ga-68 PET or FDG PET. Diazoxide and everolimus were not tolerated. MEN-1 testing was negative. Insulinomatosis should be suspected in insulinomas with early recurrence or multifocality. De novo lesions can arise throughout the pancreas. Extensive surgery will assist diagnosis but may not provide cure.

Learning points:

  • Insulinomas are usually benign and managed surgically.
  • Insulinomatosis is characterised by multifocal benign insulinomas with a tendency to recur early. It is rare.
  • Multifocal or recurrent insulinomas should raise suspicion of MEN-1 syndrome, or insulinomatosis.
  • Insulinomatosis is distinguished histologically by insulin-expressing monohormonal endocrine cell clusters (IMECCs) and tumour staining only for insulin, whereas MEN-1 associated insulinomas stain for multiple hormones.
  • The ideal treatment strategy is unknown. Total pancreatectomy may not offer cure.
Open access

Marcio José Concepción-Zavaleta, Sofía Pilar Ildefonso-Najarro, Esteban Alberto Plasencia-Dueñas, María Alejandra Quispe-Flores, Cristian David Armas-Flórez, and Laura Esther Luna-Victorio

Summary

Type B insulin resistance syndrome (TBIR) is a rare autoimmune disease caused by antibodies against the insulin receptor. It should be considered in patients with dysglycaemia and severe insulin resistance when other more common causes have been ruled out. We report a case of a 72-year-old male with a 4-year history of type 2 diabetes who presented with hypercatabolism, vitiligo, acanthosis nigricans, and hyperglycaemia resistant to massive doses of insulin (up to 1000 U/day). Detection of anti-insulin receptor antibodies confirmed TBIR. The patient received six pulses of methylprednisolone and daily treatment with cyclophosphamide for 6 months. Response to treatment was evident after the fourth pulse of methylprednisolone, as indicated by weight gain, decreased glycosylated haemoglobin and decreased requirement of exogenous insulin that was later discontinued due to episodes of hypoglycaemia. Remission was eventually achieved and the patient is currently asymptomatic, does not require insulin therapy, has normal glycaemia and is awaiting initiation of maintenance therapy with azathioprine. Thus, TBIR remitted without the use of rituximab. This case highlights the importance of diagnosis and treatment in a timely fashion, as well as the significance of clinical features, available laboratory findings and medication. Large controlled studies are required to standardise a therapeutic protocol, particularly in resource-constrained settings where access to rituximab is limited.

Learning points:

  • Type B insulin resistance syndrome is a rare autoimmune disorder that should be considered in patients with dysglycaemia, severe insulin resistance and a concomitant autoimmune disease.
  • Serological confirmation of antibodies against the insulin receptor is not necessary in all cases due to the high associated mortality without timely treatment.
  • Although there is no standardised immunosuppressive treatment, a protocol containing rituximab, cyclophosphamide and steroids has shown a significant reduction in previously reported mortality rates.
  • The present case, reports successful remission in an atypical patient using cyclophosphamide and methylprednisolone, which is an effective therapy in countries in which rituximab is not covered by health insurance.
  • When there is improvement in the hypercatabolic phase, the insulin dose should be reduced and/or discontinued to prevent hypoglycaemia; a mild postprandial hyperglycaemic state should be acceptable.
Open access

Annabelle M Warren, Duncan J Topliss, and Peter Shane Hamblin

Summary

Despite improvements in localisation techniques and surgical advances, some patients with insulinoma will not be cured by surgery or may not be suitable for surgery. Medical management with diazoxide is an option for such cases. This case report details 27 years of successful management of insulinoma using diazoxide. It has been effective and safe, with only minor adverse effects.

Learning points:

  • Long term diazoxide use can be a safe, effective option for insulinoma when it cannot be localised or removed surgically.
  • Common adverse effects include peripheral oedema, hyperuricaemia, and hirsutism.
  • 68Ga-NOTA-exendin-4 PET/CT scan should be considered for insulinoma localisation when other modalities have been unhelpful.