Related Disciplines > Gastroenterology
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Search for other papers by Cristina Alvarez-Escola in
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Search for other papers by Jersy Cardenas-Salas in
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Summary
In patients with active acromegaly after pituitary surgery, somatostatin analogues are effective in controlling the disease and can even be curative in some cases. After treatment discontinuation, the likelihood of disease recurrence is high. However, a small subset of patients remains symptom-free after discontinuation, with normalized growth hormone (GH) and insulin-like growth factor (IGF1) levels. The characteristics of patients most likely to achieve sustained remission after treatment discontinuation are not well understood, although limited evidence suggests that sustained remission is more likely in patients with lower GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on an MRI scan and/or in patients who receive long-term treatment. In this report, we describe the case of a 56-year-old female patient treated with lanreotide Autogel for 11 years. Treatment was successfully discontinued, and the patient is currently disease-free on all relevant parameters (clinical, biochemical and tumour status). The successful outcome in this case adds to the small body of literature suggesting that some well-selected patients who receive long-term treatment with somatostatin analogues may achieve sustained remission.
Learning points:
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The probability of disease recurrence is high after discontinuation of treatment with somatostatin analogues.
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Current data indicate that remission after treatment discontinuation may be more likely in patients with low GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on MRI, and/or in patients receiving prolonged treatment.
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This case report suggests that prolonged treatment with somatostatin analogues can be curative in carefully selected patients.
Search for other papers by Etienne Larger in
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Search for other papers by Nicolai J Wewer Albrechtsen in
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Search for other papers by Lars H Hansen in
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Search for other papers by Richard W Gelling in
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Sorbonne University, UPMC, University of Paris 6, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
Search for other papers by Jacqueline Capeau in
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Search for other papers by Carolyn F Deacon in
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Search for other papers by Ole D Madsen in
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Department of Education Planning and Development, Faculty of Medicine, Toho University, Tokyo, Japan
Search for other papers by Fumiatsu Yakushiji in
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Search for other papers by Pierre De Meyts in
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Search for other papers by Jens J Holst in
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Search for other papers by Erica Nishimura in
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Summary
Glucagon stimulates hepatic glucose production by activating specific glucagon receptors in the liver, which in turn increase hepatic glycogenolysis as well as gluconeogenesis and ureagenesis from amino acids. Conversely, glucagon secretion is regulated by concentrations of glucose and amino acids. Disruption of glucagon signaling in rodents results in grossly elevated circulating glucagon levels but no hypoglycemia. Here, we describe a patient carrying a homozygous G to A substitution in the invariant AG dinucleotide found in a 3′ mRNA splice junction of the glucagon receptor gene. Loss of the splice site acceptor consensus sequence results in the deletion of 70 nucleotides encoded by exon 9, which introduces a frame shift and an early termination signal in the receptor mRNA sequence. The mutated receptor neither bound 125I-labeled glucagon nor induced cAMP production upon stimulation with up to 1 µM glucagon. Despite the mutation, the only obvious pathophysiological trait was hyperglucagonemia, hyperaminoacidemia and massive hyperplasia of the pancreatic α-cells assessed by histology. Our case supports the notion of a hepato–pancreatic feedback system, which upon disruption leads to hyperglucagonemia and α-cell hyperplasia, as well as elevated plasma amino acid levels. Together with the glucagon-induced hypoaminoacidemia in glucagonoma patients, our case supports recent suggestions that amino acids may provide the feedback link between the liver and the pancreatic α-cells.
Learning points:
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Loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis.
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Loss of function of the glucagon receptor causes hyperaminoacidemia, hyperglucagonemia and α-cell hyperplasia and sometimes other pancreatic abnormalities.
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A hepato–pancreatic feedback regulation of the α-cells, possibly involving amino acids, may exist in humans.
Search for other papers by Pooja Sahni in
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Search for other papers by Nitin Trivedi in
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Search for other papers by Abdulkadir Omer in
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Summary
A 65-year-old obese Caucasian woman presented with symptomatic postprandial hypoglycemic episodes, resolution of symptoms with carbohydrate intake and significantly elevated anti-insulin antibody levels. She did not have any evidence for the use of oral antidiabetic medications, insulin, herbal substances, performing strenuous exercise or history of bariatric surgery. Fingerstick blood glucose readings revealed blood sugar of 35 mg/dL and 48 mg/dL, when she had these symptoms. Her medical history was significant for morbid obesity, hypothyroidism and gastro esophageal reflux disease. Her home medications included levothyroxine, propranolol and omeprazole. A blood sample obtained during the symptoms revealed the following: fingerstick blood sugar 38 mg/dL, venous blood glucose 60 mg/dL (normal (n): 70–99 mg/dL), serum insulin 202 IU/mL (n: <21), proinsulin 31.3 pmol/L (n: <28.9), C-peptide 8 ng/mL (n: 0.9–7), beta-hydroxybutyrate 0.12 mmol/L (n: 0.02–0.27) anti-insulin antibody >45.4 U/mL (n: <0.4). The result obtained while screening for serum sulfonylurea and meglitinides was negative. The repeated episodes of postprandial hypoglycemia associated with significantly elevated anti-insulin antibodies led to a diagnosis of insulin antibody syndrome (IAS). Significant improvement of hypoglycemic symptoms and lower anti-insulin antibody levels (33 U/mL) was noted on nutritional management during the following 6 months. Based on a report of pantoprazole-related IAS cases, her omeprazole was switched to a H2 receptor blocker. She reported only two episodes of hypoglycemia, and anti-insulin antibody levels were significantly lower at 10 U/mL after the following 12-month follow-up.
Learning points:
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Initial assessment of the Whipple criteria is critical to establish the clinical diagnosis of hypoglycemia accurately.
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Blood sugar monitoring with fingerstick blood glucose method can provide important information during hypoglycemia workup.
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Autoimmune hypoglycemia is a rare cause of hypoglycemia, which can be diagnosed on high index of clinical suspicion and systematic evaluation.
Search for other papers by Laila Ennazk in
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Search for other papers by Ghizlane El Mghari in
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Search for other papers by Nawal El Ansari in
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Summary
Autoimmune pancreatitis is a new nosological entity in which a lymphocytic infiltration of the exocrine pancreas is involved. The concomitant onset of autoimmune pancreatitis and type 1 diabetes has been recently described suggesting a unique immune disturbance that compromises the pancreatic endocrine and exocrine functions. We report a case of type1 diabetes onset associated with an autoimmune pancreatitis in a young patient who seemed to present a type 2 autoimmune polyglandular syndrome. This rare association offers the opportunity to better understand pancreatic autoimmune disorders in type 1 diabetes.
Learning points:
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The case makes it possible to understand the possibility of a simultaneous disturbance of the endocrine and exocrine function of the same organ by one autoimmune process.
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The diagnosis of type 1 diabetes should make practitioner seek other autoimmune diseases. It is recommended to screen for autoimmune thyroiditis and celiac diseases. We draw attention to consider the autoimmune origin of a pancreatitis associated to type1 diabetes.
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Autoimmune pancreatitis is a novel rare entity that should be known as it is part of the IgG4-related disease spectrum.
Search for other papers by Elise Flynn in
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University of Melbourne, Parkville, Victoria, Australia
Search for other papers by Sara Baqar in
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Search for other papers by Dorothy Liu in
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University of Melbourne, Parkville, Victoria, Australia
Search for other papers by Elif I Ekinci in
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Search for other papers by Stephen Farrell in
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University of Melbourne, Parkville, Victoria, Australia
Search for other papers by Jeffrey D Zajac in
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Search for other papers by Mario De Luise in
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University of Melbourne, Parkville, Victoria, Australia
Search for other papers by Ego Seeman in
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Summary
ACTH-secreting phaeochromocytoma (ASP) is a rare cause of ACTH-dependent Cushing’s syndrome (CS). We report the case of a 63-year-old female presenting with CS secondary to an ASP complicated by bowel perforation. This case report highlights ASP as an uncommon but important cause of ectopic ACTH secretion (EAS). There have been 29 cases of ASP, all of which were unilateral and benign, but associated with significant complications. Patients presenting with ASP have the potential for cure with unilateral adrenalectomy. Given this promising prognosis if recognised, ASP should be considered in the diagnostic workup of ACTH-dependent CS. As this case demonstrates, gastrointestinal complications can arise from severe hypercortisolaemia associated with CS. Early medical and surgical intervention is imperative as mortality approaches 50% once bowel perforation occurs.
Learning points
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Consider phaeochromocytoma in the diagnostic workup of ACTH-dependent CS; screen with plasma metanephrines or urinary catecholamines.
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Serial screening may be required if ACTH-secreting phaeochromocytoma is suspected, as absolute levels can be misleading.
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Early catecholamine receptor blockade and adrenal synthesis blockade may avoid the need for rescue bilateral adrenalectomy in ACTH-secreting phaeochromocytoma.
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Consider early medical or surgical management when gastrointestinal features are present in patients with CS, as bowel perforation due to severe hypercortisolaemia can occur and is associated with significant mortality.
Search for other papers by Benjamin G Challis in
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Search for other papers by Chung Thong Lim in
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Search for other papers by Alison Cluroe in
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Search for other papers by Ewen Cameron in
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Search for other papers by Stephen O’Rahilly in
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Summary
McKittrick–Wheelock syndrome (MWS) is a rare consequence of severe dehydration and electrolyte depletion due to mucinous diarrhoea secondary to a rectosigmoid villous adenoma. Reported cases of MWS commonly describe hypersecretion of mucinous diarrhoea in association with dehydration, hypokalaemia, hyponatraemia, hypochloraemia and pre-renal azotemia. Hyperglycaemia and diabetes are rarely reported manifestations of MWS. Herein we describe the case of a 59-year-old woman who presented with new-onset diabetes and severe electrolyte derangement due to a giant rectal villous adenoma. Subsequent endoscopic resection of the tumour cured her diabetes and normalised electrolytes. This case describes a rare cause of ‘curable diabetes’ and indicates hyperaldosteronism and/or whole-body potassium stores as important regulators of insulin secretion and glucose homeostasis.
Learning points
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McKittrick–Wheelock syndrome (MWS) is typically characterised by the triad of pre-renal failure, electrolyte derangement and chronic diarrhoea resulting from a secretory colonic neoplasm.
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Hyperglycaemia and new-onset diabetes are rare clinical manifestations of MWS.
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Hyperaldosteronism and/or hypokalaemia may worsen glucose tolerance in MWS.
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Aggressive replacement of fluid and electrolytes is the mainstay of acute management, with definitive treatment and complete reversal of the metabolic abnormalities being achieved by endoscopic or surgical resection of the neoplasm.
Search for other papers by Jerena Manoharan in
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Search for other papers by Caroline L Lopez in
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German Cancer Consortium (DKTK), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany, National Center for Tumor Diseases (NCT), Dresden, Germany
Search for other papers by Karl Hackmann in
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Search for other papers by Max B Albers in
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Search for other papers by Anika Pehl in
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Search for other papers by Peter H Kann in
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Search for other papers by Emily P Slater in
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German Cancer Consortium (DKTK), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany, National Center for Tumor Diseases (NCT), Dresden, Germany
Search for other papers by Evelin Schröck in
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Search for other papers by Detlef K Bartsch in
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Summary
We report about a young female who developed an unusual and an aggressive phenotype of the MEN1 syndrome characterized by the development of a pHPT, malignant non-functioning pancreatic and duodenal neuroendocrine neoplasias, a pituitary adenoma, a non-functioning adrenal adenoma and also a malignant jejunal NET at the age of 37 years. Initial Sanger sequencing could not detect a germline mutation of the MEN1 gene, but next generation sequencing and MPLA revealed a deletion of the MEN1 gene ranging between 7.6 and 25.9 kb. Small intestine neuroendocrine neoplasias (SI-NENs) are currently not considered to be a part of the phenotype of the MEN1-syndrome. In our patient the SI-NENs were detected during follow-up imaging on Ga68-Dotatoc PET/CT and could be completely resected. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients. Whether an aggressive phenotype or the occurrence of SI-NENs in MEN1 are more likely associated with large deletions of the gene warrants further investigation.
Learning points
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Our patient presents an extraordinary course of disease.
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Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients, besides the typical MEN1 associated tumors.
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This case reports indicate that in some cases conventional mutation analysis of MEN1 patients should be supplemented by the search for larger gene deletions with modern techniques, if no germline mutation could be identified by Sanger sequencing.
Search for other papers by Taiba Zornitzki in
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Sackler School of Medicine, Tel-Aviv University, Tel Aviv, 69978, Israel
Search for other papers by Hadara Rubinfeld in
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Search for other papers by Lyudmila Lysyy in
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Search for other papers by Tal Schiller in
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Search for other papers by Véronique Raverot in
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Sackler School of Medicine, Tel-Aviv University, Tel Aviv, 69978, Israel
Search for other papers by Ilan Shimon in
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Search for other papers by Hilla Knobler in
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Summary
Acromegaly due to ectopic GHRH secretion from a neuroendocrine tumor (NET) is rare and comprises <1% of all acromegaly cases. Herein we present a 57-year-old woman with clinical and biochemical features of acromegaly and a 6 cm pancreatic NET (pNET), secreting GHRH and calcitonin. Following surgical resection of the pancreatic tumor, IGF1, GH and calcitonin normalized, and the clinical features of acromegaly improved. In vitro studies confirmed that the tumor secreted large amounts of both GHRH and calcitonin, and incubation of pNET culture-derived conditioned media stimulated GH release from a cultured human pituitary adenoma. This is a unique case of pNET secreting both GHRH and calcitonin. The ability of the pNET-derived medium to stimulate in vitro GH release from a human pituitary-cell culture, combined with the clinical and hormonal remission following tumor resection, confirmed the ectopic source of acromegaly in this patient.
Learning points
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Signs, symptoms and initial work-up of acromegaly due to ectopic GHRH secretion are similar to pituitary-dependent acromegaly. However, if no identifiable pituitary lesion is found, somatostatin receptor scan and further imaging (CT, MRI) should be performed.
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Detection of GHRH in the blood and in the tumor-derived medium supports the diagnosis of ectopic GHRH secretion.
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Functional bioactivity of pNET-secreted GHRH can be proved in vitro by releasing GH from human pituitary cells.
Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK
Search for other papers by Benjamin G Challis in
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Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
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Search for other papers by Vishakha Bansiya in
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Search for other papers by Keith Burling in
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Search for other papers by Peter Barker in
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Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Search for other papers by Bolette Hartmann in
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Search for other papers by Fiona Gribble in
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Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK
Search for other papers by Stephen O'Rahilly in
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Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Search for other papers by Jens J Holst in
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Search for other papers by Helen L Simpson in
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Summary
Pancreatic neuroendocrine tumours (pNETs) secreting proglucagon are associated with phenotypic heterogeneity. Here, we describe two patients with pNETs and varied clinical phenotypes due to differential processing and secretion of proglucagon-derived peptides (PGDPs). Case 1, a 57-year-old woman presented with necrolytic migratory erythema, anorexia, constipation and hyperinsulinaemic hypoglycaemia. She was found to have a grade 1 pNET, small bowel mucosal thickening and hyperglucagonaemia. Somatostatin analogue (SSA) therapy improved appetite, abolished hypoglycaemia and improved the rash. Case 2, a 48-year-old male presented with diabetes mellitus, diarrhoea, weight loss, nausea, vomiting and perineal rash due to a grade 1 metastatic pNET and hyperglucagonaemia. In both cases, plasma levels of all measured PGDPs were elevated and attenuated following SSA therapy. In case 1, there was increased production of intact glucagon-like peptide 1 (GLP-1) and GLP-2, similar to that of the enteroendocrine L cell. In case 2, pancreatic glucagon was elevated due to a pancreatic α-cell-like proglucagon processing profile. In summary, we describe two patients with pNETs and heterogeneous clinical phenotypes due to differential processing and secretion of PGDPs. This is the first description of a patient with symptomatic hyperinsulinaemic hypoglycaemia and marked gastrointestinal dysfunction due to, in part, a proglucagon-expressing pNET.
Learning points
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PGDPs exhibit a diverse range of biological activities including critical roles in glucose and amino acid metabolism, energy homeostasis and gastrointestinal physiology.
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The clinical manifestations of proglucagon-expressing tumours may exhibit marked phenotypic variation due to the biochemical heterogeneity of their secreted peptide repertoire.
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Specific and precise biochemical assessment of individuals with proglucagon-expressing tumours may provide opportunities for improved diagnosis and clinical management.
Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, London, UK
Division of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry, UK
Search for other papers by G K Dimitriadis in
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Search for other papers by K Gopalakrishnan in
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Department of Clinical Biochemistry and Histopathology, Coventry and Warwickshire, Pathology Service, UHCW NHS Trust, Coventry, UK
Search for other papers by D K Grammatopoulos in
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Division of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry, UK
Search for other papers by H S Randeva in
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Search for other papers by M O Weickert in
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Search for other papers by N Murthy in
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Summary
We report the case of a 70-year-old previously healthy female who presented acutely to the Accident and Emergency department with left-sided vasomotor symptoms including reduced muscle tone, weakness upon walking and slurred speech. Physical examination confirmed hemiparesis with VIIth nerve palsy and profound hepatomegaly. A random glucose was low at 1.7 mmol/l, which upon correction resolved her symptoms. In hindsight, the patient recalled having had similar episodes periodically over the past 3 months to which she did not give much attention. While hospitalized, she continued having episodes of symptomatic hypoglycaemia during most nights, requiring treatment with i.v. dextrose and/or glucagon. Blood tests including insulin and C-peptide were invariably suppressed, in correlation with low glucose. A Synacthen stimulation test was normal (Cort (0′) 390 nmol/l, Cort (30′) 773 nmol/l). A computed tomography scan showed multiple lobulated masses in the abdomen, liver and pelvis. An ultrasound guided biopsy of one of the pelvic masses was performed. Immunohistochemistry supported the diagnosis of a gastrointestinal stromal tumour (GIST) positive for CD34 and CD117. A diagnosis of a non islet cell tumour hypoglycaemia (NICTH) secondary to an IGF2 secreting GIST was confirmed with further biochemical investigations (IGF2=96.5 nmol/l; IGF2:IGF1 ratio 18.9, ULN <10). Treatment with growth hormone resolved the patient's hypoglycaemic symptoms and subsequent targeted therapy with Imatinib was successful in controlling disease progression over an 8-year observation period.
Learning points
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NICTH can be a rare complication of GISTs that may manifest with severe hypoglycaemia and neuroglucopenic symptoms.
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NICTH can masquerade as other pathologies thus causing diagnostic confusion.
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Histological confirmation of GIST induced NICTH and exclusion of other conditions causing hypoglycaemia is essential.
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Mutational analysis of GISTs should be carried out in all cases as it guides treatment decision.
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Tailored management of hypoglycaemia, in this case using growth hormone and targeted cyto-reductive therapy, minimizes the risk of possible life-threatening complications.
