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Open access

Chun-Han Lo and Ding-Ping Sun

Summary

Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism. Traditionally, inappropriately elevated levels of insulin in the face of hypoglycemia are the key to diagnosis. However, contradictory levels of insulin and C-peptide do not necessarily exclude the diagnosis. A 50-year-old female was brought to our emergency department because of conscious disturbance on the previous night. She had no history of diabetes mellitus, and was not using any medications or alcohol. Laboratory data showed low sugar, a significantly low insulin level, and elevated C-peptide. After admission, she had multiple episodes of spontaneous hypoglycemia after overnight fasts without discomfort. It was considered that a neuroendocrine tumor was the source of her hypoglycemia. CT scan of the abdomen revealed a 1.1cm hypervascular nodule in the pancreatic tail. Elective laparoscopic distal pancreatectomy was incorporated into her treatment course. A 1.2×1.0cm homogenous well-encapsulated tumor was resected. We monitored her glucose levels in the outpatient clinic every month for a period of six months. She did not have another episode of spontaneous hypoglycemia.

Learning points

  • Insulinoma causes endogenous hypoglycemia – it cannot be ruled out in patients presenting with hypoglycemia and low insulin levels; history and imaging studies should be done for further assessment

  • A 24-h fast test has the same clinical significance as that of 72-h fast test

  • C-peptide is a useful biochemical marker in addition to serum insulin, which can be used to diagnose insulinomas

  • CT scan is used to measure the tumor size and localize the tumor. However, definitive diagnosis is only achieved through histopathologic evaluation of diseased tissue

Open access

Benjamin G Challis, Nicolai J Wewer Albrechtsen, Vishakha Bansiya, Keith Burling, Peter Barker, Bolette Hartmann, Fiona Gribble, Stephen O'Rahilly, Jens J Holst and Helen L Simpson

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

  • PGDPs exhibit a diverse range of biological activities including critical roles in glucose and amino acid metabolism, energy homeostasis and gastrointestinal physiology.

  • The clinical manifestations of proglucagon-expressing tumours may exhibit marked phenotypic variation due to the biochemical heterogeneity of their secreted peptide repertoire.

  • Specific and precise biochemical assessment of individuals with proglucagon-expressing tumours may provide opportunities for improved diagnosis and clinical management.

Open access

G K Dimitriadis, K Gopalakrishnan, R Rao, D K Grammatopoulos, H S Randeva, M O Weickert and N Murthy

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

  • NICTH can be a rare complication of GISTs that may manifest with severe hypoglycaemia and neuroglucopenic symptoms.

  • NICTH can masquerade as other pathologies thus causing diagnostic confusion.

  • Histological confirmation of GIST induced NICTH and exclusion of other conditions causing hypoglycaemia is essential.

  • Mutational analysis of GISTs should be carried out in all cases as it guides treatment decision.

  • Tailored management of hypoglycaemia, in this case using growth hormone and targeted cyto-reductive therapy, minimizes the risk of possible life-threatening complications.

Open access

Avital Nahmias, Simona Grozinsky-Glasberg, Asher Salmon and David J Gross

Summary

Approximately 35% of the pancreatic neuroendocrine tumors (pNETs) are functional, the most common of which is an insulinoma. Rarely can initially nonfunctioning tumor undergo biological transformation to a hormone-secreting tumor with subsequent changes in the clinical picture. We present here three unique patients with long-standing pNETs who developed life-threatening hyperinsulinemic hypoglycemia along with tumor progression. In two of the patients, everolimus (Afinitor) was administered in an attempt to control both tumor growth and hypoglycemia. In two cases everolimus therapy resulted in the abolishment of hypoglycemia and induced significant tumor regression; however these beneficial responses were transient. These cases highlight the exceptional ability of pNETs to change biological behavior in parallel with disease progression. Our experience concurs with recently published studies demonstrating the utility of everolimus for the control of both hypoglycemia and tumor progression.

Learning points

  • Nonfunctional pNET can gain new features such as insulin secretion with related morbidity.

  • Gain of function in a previously nonfunctional pNET signifies tumor progression and is usually associated with poor prognosis.

  • Everolimus proved to be a viable treatment for hypoglycemia in insulinoma patients and was also proven highly effective in the patients presented here.

  • As disease progresses, the effect of everolimus on hypoglycemia wanes. We report for the first time the development of hypoglycemia during everolimus treatment.

Open access

Mauro Boronat, Rosa M Sánchez-Hernández, Julia Rodríguez-Cordero, Angelines Jiménez-Ortega and Francisco J Nóvoa

Summary

Treatment with continuous s.c. insulin infusion (CSII) provides better glycemic control and lower risk of hypoglycemia than conventional therapy with multiple daily insulin injections. These benefits have been related to a more reliable absorption and an improved pharmacokinetic profile of insulin delivered through CSII therapy. However, even for patients treated with CSII, exaggerated postmeal hyperglycemic excursions and late postabsorptive hypoglycemia can still constitute a therapeutic challenge. Two female patients with type 1 diabetes who began treatment with CSII required to increase their previous breakfast insulin-to-carbohydrate ratio in order to achieve postprandial glycemic goals. However, they simultaneously presented recurrent episodes of late hypoglycemia several hours after breakfast bolus. Advancing the timing of the bolus was ineffective and bothersome for patients. In both cases, the best therapeutic option was to set a basal insulin rate of zero units per hour during 6 h after breakfast. Even so, they need to routinely take a midmorning snack with 10–20 g of carbohydrates to avoid late postabsorptive hypoglycemia. They have been using this insulin schedule for about 3 years without complications. The action of prandial insulin delivered through insulin pumps can be inappropriately delayed for the requirements of some patients. Although suspension of basal rate can be an acceptable therapeutic alternative for them, these cases demonstrate that new strategies to improve the bioavailability of prandial insulin infused through CSII are still needed.

Learning points

  • CSII remains the most physiologically suitable system of insulin delivery available today.

  • Additionally, the duration of action of prandial insulin delivered through insulin pumps can be excessively prolonged in some patients with type 1 diabetes.

  • These patients can present recurrent late episodes of hypoglycemia several hours after the administration of insulin boluses.

  • The routine suspension of basal insulin for several hours, leaving meal bolus to cover both prandial and basal insulin requirements, can be a therapeutic option for these subjects.

Open access

Betty Korljan Jelaska, Sanja Baršić Ostojić, Nina Berović and Višnja Kokić

Summary

Glycogen storage disease (GSD) type I is characterized by impaired production of glucose from glycogenolysis and gluconeogenesis resulting in severe hypoglycaemia and increased production of lactic acid, triglyceride and uric acid. The most common type, glycogenosis type Ia, demands a balanced, sufficient carbohydrate intake to preserve normal 24-h glycaemia. Insufficient intake of carbohydrates can cause hypoglycaemia, as the missing glucose-6-phosphatase enzyme cannot free the glucose stored as liver glycogen and nor is gluconeogenesis possible. The principle means of handling this disorder is to avoid starving by taking regular meals during the day and night. Such a dietary regimen could lead to obesity. Herein, we present the case of an adult patient with glycogenosis type Ia suffering from hyperuricaemia, dyslipidaemia and arterial hypertension. The accumulation of these cardiovascular risk factors could lead to the early onset of atherosclerosis, which should be postponed by contemporary methods of surveillance and treatment.

Learning points

  • Continuous subcutaneous glucose monitoring may be of value in every adult patient with GSD type I to evaluate the actual prevalence of eventual hypoglycaemic and hyperglycaemic episodes.

  • Good dietary management minimizes the metabolic abnormalities of the disease and decreases the risk of long-term complications.

  • Treatment of obesity in patients with GSD reduces the risk of earlier atherosclerosis and cardiovascular disease.

Open access

M Nwokolo and J Fletcher

Summary

A 46-year-old woman presented multiple times in a 4-month period with hypotension, sepsis, hypoglycaemia and psychosis. A low random cortisol in combination with her presenting complaint made adrenal insufficiency the likely diagnosis. Fluid resuscitation and i.v. steroid therapy led to clinical improvement; however, a short synacthen test (SST) demonstrated an apparently satisfactory cortisol response. The test was repeated on a later admission and revealed a peak cortisol level of 25 nmol/l (>550 nmol/l). Concurrent treatment with i.v. hydrocortisone had led to a false-negative SST. ACTH was <5 ng/l (>10 ng/l), indicating secondary adrenal failure. We discuss the challenges surrounding the diagnosis of adrenal insufficiency and hypopituitarism, the rare complication of psychosis and a presumptive diagnosis of autoimmune lymphocytic hypophysitis (ALH).

Learning points

  • Adrenocortical insufficiency must be considered in the shocked, hypovolaemic and hypoglycaemic patient with electrolyte imbalance. Rapid treatment with fluid resuscitation and i.v. corticosteroids is vital.

  • Polymorphic presentations to multiple specialities are common. Generalised myalgia, abdominal pain and delirium are well recognised, psychosis is rare.

  • A random cortisol can be taken with baseline bloods. Once the patient is stable, meticulous dynamic testing must follow to confirm the clinical diagnosis.

  • The chronic disease progression of ALH is hypothesised to be expansion then atrophy of the pituitary gland resulting in empty sella turcica and hypopituitarism.

  • If hypopituitarism is suspected, an ACTH deficiency should be treated prior to commencing thyroxine (T4) therapy as unopposed T4 may worsen features of cortisol deficiency.