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Open access

Baris Akinci, Rasimcan Meral, Diana Rus, Rita Hench, Adam H Neidert, Frank DiPaola, Maria Westerhoff, Simeon I Taylor, and Elif A Oral

Summary

A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients.

Learning points:

  • A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years.
  • Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed.
  • The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin.
  • Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite.
  • Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.
Open access

Diana Catarino, Cristina Ribeiro, Leonor Gomes, and Isabel Paiva

Summary

Pituitary infections, particularly with fungus, are rare disorders that usually occur in immunocompromised patients. Cushing’s syndrome predisposes patients to infectious diseases due to their immunosuppression status. We report the case of a 55-year-old woman, working as a poultry farmer, who developed intense headache, palpebral ptosis, anisocoria, prostration and psychomotor agitation 9 months after initial diabetes mellitus diagnosis. Cranioencephalic CT scan showed a pituitary lesion with bleeding, suggesting pituitary apoplexy. Patient underwent transsphenoidal surgery and the neuropathologic study indicated a corticotroph adenoma with apoplexy and fungal infection. Patient had no preoperative Cushing’s syndrome diagnosis. She was evaluated by a multidisciplinary team who decided not to administer anti-fungal treatment. The reported case shows a rare association between a corticotroph adenoma and a pituitary fungal infection. The possible contributing factors were hypercortisolism, uncontrolled diabetes and professional activity. Transsphenoidal surgery is advocated in these infections; however, anti-fungal therapy is still controversial.

Learning points:

  • Pituitary infections are rare disorders caused by bacterial, viral, fungal and parasitic infections.
  • Pituitary fungal infections usually occur in immunocompromised patients.
  • Cushing’s syndrome, as immunosuppression factor, predisposes patients to infectious diseases, including fungal infections.
  • Diagnosis of pituitary fungal infection is often achieved during histopathological investigation.
  • Treatment with systemic anti-fungal drugs is controversial.
  • Endocrine evaluation is recommended at the time of initial presentation of pituitary manifestations.
Open access

Alessandro Rossini, Francesca Perticone, Laura Frosio, Marco Schiavo Lena, and Roberto Lanzi

Summary

ACTH-secreting pheochromocytoma is a very rare cause of Cushing’s syndrome, with a high morbidity and mortality risk due to both cortisol and catecholamines excess. We report the case of a 45-year-old female patient with a 3 cm, high-density, left adrenal mass, diagnosed as an ACTH-secreting pheochromocytoma. The biochemical sensitivity of the tumor to somatostatin analogues was tested by a 100 μg s.c. octreotide administration, which led to an ACTH and cortisol reduction of 50 and 25% respectively. In addition to alpha and beta blockers, preoperative approach to laparoscopic adrenalectomy included octreotide, a somatostatin analogue, together with ketoconazole, in order to achieve an adequate pre-surgical control of cortisol release. Histopathological assessment confirmed an ACTH-secreting pheochromocytoma expressing type 2 and 5 somatostatin receptors (SSTR-2 and -5).

Learning points:

  • ACTH-secreting pheochromocytomas represent a rare and severe condition, characterized by high morbidity and mortality risk.
  • Surgical removal of the adrenal mass is the gold standard treatment, but adequate medical therapy is required preoperatively to improve the surgical outcome and to avoid major complications.
  • Somatostatin analogs, in addition to other medications, may represent a useful therapeutic option for the presurgical management of selected patients.
  • In this sense, the octreotide challenge test is a useful tool to predict favorable therapeutic response to the treatment.
Open access

Katta Sai, Amos Lal, Jhansi Lakshmi Maradana, Pruthvi Raj Velamala, and Trivedi Nitin

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.

Learning points:

Open access

Khaled Aljenaee, Osamah Hakami, Colin Davenport, Gemma Farrell, Tommy Kyaw Tun, Agnieszka Pazderska, Niamh Phelan, Marie-Louise Healy, Seamus Sreenan, and John H McDermott

Summary

Measurement of glycated haemoglobin (HbA1c) has been utilised in assessing long-term control of blood glucose in patients with diabetes, as well as diagnosing diabetes and identifying patients at increased risk of developing diabetes in the future. HbA1c reflects the level of blood glucose to which the erythrocyte has been exposed during its lifespan, and there are a number of clinical situations affecting the erythrocyte life span in which HbA1c values may be spuriously high or low and therefore not reflective of the true level of glucose control. In the present case series, we describe the particulars of three patients with diabetes who had spuriously low HbA1c levels as a result of dapsone usage. Furthermore, we discuss the limitations of HbA1c testing and the mechanisms by which it may be affected by dapsone in particular.

Learning points:

  • Various conditions and medications can result in falsely low HbA1c.
  • Dapsone can lead to falsely low HbA1c by inducing haemolysis and by forming methaemoglobin.
  • Capillary glucose measurement, urine glucose measurements and fructosamine levels should be used as alternatives to HbA1c for monitoring glycaemic control if it was falsely low or high.
Open access

Punith Kempegowda, Lauren Quinn, Lisa Shepherd, Samina Kauser, Briony Johnson, Alex Lawson, and Andrew Bates

Summary

A 62-year-old Asian British female presented with increasing tiredness. She had multiple co-morbidities and was prescribed steroid inhalers for asthma. She had also received short courses of oral prednisolone for acute asthma exacerbations in the last 2 years. Unfortunately, the frequency and dose of steroids for asthma was unclear from history. Her type 2 diabetes mellitus (DM) control had deteriorated over a short period of time (HbA1c: 48–85 mmol/mol). Blood tests revealed undetectable cortisol and ACTH (<28 mmol/L, <5.0 ng/L). Renin, electrolytes and thyroid function were within normal limits. A diagnosis of secondary adrenal insufficiency, likely due to long-term steroid inhaler and recurrent short courses of oral steroids for asthma exacerbations was made. Patient was commenced on hydrocortisone 10 mg, 5 mg and 5 mg regimen. Steroid inhaler was discontinued following consultation with respiratory physicians. Despite discontinuation of inhaled steroids, patient continued not to mount a response to Synacthen®. Upon further detailed history, patient admitted taking a ‘herbal’ preparation for chronic osteoarthritic knee pain. Toxicology analysis showed presence of dexamethasone, ciprofloxacin, paracetamol, diclofenac, ibuprofen and cimetidine in the herbal medication. Patient was advised to discontinue her herbal preparation. We believe the cause of secondary adrenal insufficiency in our patient was the herbal remedy containing dexamethasone, explaining persistent adrenal suppression despite discontinuation of all prescribed steroids, further possibly contributing to obesity, hypertension and suboptimal control of DM. In conclusion, a comprehensive drug history including herbal and over-the-counter preparations should be elucidated. Investigation for the presence of steroids in these preparations should be considered when patients persist to have secondary adrenal insufficiency despite discontinuation of prescribed steroid medications.

Learning points:

  • The likelihood of complementary and alternative medicines (CAMs) in medication-induced secondary adrenal insufficiency should be considered in any patient presenting with potential symptoms of adrenal insufficiency.
  • If the contents of CAM preparation cannot be ascertained, toxicology screening should be considered.
  • Patients should be advised to stop taking CAM preparation when it contains steroids and hydrocortisone replacement therapy commenced, with periodic reassessment of adrenal function, and then if indicated weaned accordingly.
  • Patients should be informed about the contents of CAM therapies, so they can make a truly informed choice regarding the risks and benefits.
  • This case also highlights a need to increase regulatory processes over CAM therapies, given their propensity to contain a number of undisclosed medications and potent steroids.
Open access

Marcela Rodríguez Flores, Ruth Carmina Cruz Soto, Verónica Vázquez Velázquez, Reina Ruth Soriano Cortés, Carlos Aguilar Salinas, and Eduardo García García

Summary

In patients with gastric bypass (GB), high glucose variability (GV) and hypoglycemia have been demonstrated, which could impact the metabolic status and eating behavior. We describe the glucose patterns determined through continuous glucose monitoring (CGM) in two patients with >5 years follow-up after GB and significant weight recovery, who reported hypoglycemic symptoms that interfered with daily activities, and their response to a nutritional and psycho-educative prescription. Case 1: A 40-year-old woman without pre-surgical type 2 diabetes (T2DM) and normal HbA1c, in whom CGM showed high GV and hypoglycemic episodes that did not correlate with the time of hypoglycemic symptoms. Her GV reduced after prescription of a diet with low glycemic index and modification of meal patterns. Case 2: A 48-year-old male with pre-surgical diagnosis of T2DM and current normal HbA1c, reported skipping meals. The CGM showed high GV, 15% of time in hypoglycemia and hyperglycemic spikes. After prescription of a low glycemic index diet, his GV increased and time in hypoglycemia decreased. Through the detailed self-monitoring needed for CGM, we discovered severe anxiety symptoms, consumption of simple carbohydrates and lack of meal structure. He was referred for more intensive psychological counseling. In conclusion, CGM can detect disorders in glucose homeostasis derived both from the mechanisms of bariatric surgery, as well as the patient’s behaviors and mental health, improving decision-making during follow-up.

Learning points:

  • High glycemic variability is frequent in patients operated with gastric bypass.
  • Diverse eating patterns, such as prolonged fasting and simple carbohydrate ingestion, and mental health disorders, including anxiety, can promote and be confused with worsened hypoglycemia.
  • CGM requires a detailed record of food ingested that can be accompanied by associated factors (circumstances, eating patterns, emotional symptoms). This allows the detection of particular behaviors and amount of dietary simple carbohydrates to guide recommendations provided within clinical care of these patients.
Open access

Wei Yang, David Pham, Aren T Vierra, Sarah Azam, Dorina Gui, and John C Yoon

Summary

Ectopic ACTH-secreting pulmonary neuroendocrine tumors are rare and account for less than 5% of endogenous Cushing’s syndrome cases. We describe an unusual case of metastatic bronchial carcinoid tumor in a young woman presenting with unprovoked pulmonary emboli, which initially prevented the detection of the primary tumor on imaging. The source of ectopic ACTH was ultimately localized by a Gallium-DOTATATE scan, which demonstrated increased tracer uptake in a right middle lobe lung nodule and multiple liver nodules. The histological diagnosis was established based on a core biopsy of a hepatic lesion and the patient was started on a glucocorticoid receptor antagonist and a somatostatin analog. This case illustrates that hypercogulability can further aggravate the diagnostic challenges in ectopic ACTH syndrome. We discuss the literature on the current diagnosis and management strategies for ectopic ACTH syndrome.

Learning points:

  • In a young patient with concurrent hypokalemia and uncontrolled hypertension on multiple antihypertensive agents, secondary causes of hypertension should be evaluated.
  • Patients with Cushing’s syndrome can develop an acquired hypercoagulable state leading to spontaneous and postoperative venous thromboembolism.
  • Pulmonary emboli may complicate the imaging of the bronchial carcinoid tumor in ectopic ACTH syndrome.
  • Imaging with Gallium-68 DOTATATE PET/CT scan has the highest sensitivity and specificity in detecting ectopic ACTH-secreting tumors.
  • A combination of various noninvasive biochemical tests can enhance the diagnostic accuracy in differentiating Cushing’s disease from ectopic ACTH syndrome provided they have concordant results. Bilateral inferior petrosal sinus sampling remains the gold standard.
Open access

Aoife Garrahy, Matilde Bettina Mijares Zamuner, and Maria M Byrne

Summary

Coexistence of autoimmune diabetes and maturity-onset diabetes of the young (MODY) is rare. We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and glucokinase (GCK) MODY. A 32-year-old woman was treated with insulin for gestational diabetes at age 32 years; post-partum, her fasting blood glucose was 6.0 mmol/L and 2-h glucose was 11.8 mmol/L following an oral glucose tolerance test, and she was maintained on diet alone. Five years later, a diagnosis of LADA was made when she presented with fasting blood glucose of 20.3 mmol/L and HbA1C 125 mmol/mol (13.6%). GCK-MODY was identified 14 years later when genetic testing was prompted by identification of a mutation in her cousin. Despite multiple daily insulin injections her glycaemic control remained above target and her clinical course has been complicated by multiple episodes of hypoglycaemia with unawareness. Although rare, coexistence of latent autoimmune diabetes of adulthood and monogenic diabetes should be considered if there is a strong clinical suspicion, for example, family history. Hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA. This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA.

Learning points:

  • We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and GCK-MODY.
  • It has been suggested that mutations in GCK may lead to altered counter-regulation and recognition of hypoglycaemia at higher blood glucose levels than patients without such mutation. However, in our case, hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA.
  • This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA to avoid hypoglycaemia.
Open access

Peter Novodvorsky, Emma Walkinshaw, Waliur Rahman, Valerie Gordon, Karen Towse, Sarah Mitchell, Dinesh Selvarajah, Priya Madhuvrata, and Alia Munir

Summary

Bariatric surgery is an effective therapy for obesity but is associated with long-term complications such as dumping syndromes and nutritional deficiencies. We report a case of a 26-year-old caucasian female, with history of morbid obesity and gestational diabetes (GDM), who became pregnant 4 months after Roux-en-Y bypass surgery. She developed GDM during subsequent pregnancy, which was initially managed with metformin and insulin. Nocturnal hypoglycaemia causing sleep disturbance and daytime somnolence occured at 19 weeks of pregnancy (19/40). Treatment with rapid-acting carbohydrates precipitated further hypoglycaemia. Laboratory investigations confirmed hypoglycaemia at 2.2 mmol/L with appropriately low insulin and C-peptide, intact HPA axis and negative IgG insulin antibodies. The patient was seen regularly by the bariatric dietetic team but concerns about compliance persisted. A FreeStyle Libre system was used from 21/40 enabling the patient a real-time feedback of changes in interstitial glucose following high or low GI index food intake. The patient declined a trial of acarbose but consented to an intraveneous dextrose infusion overnight resulting in improvement but not complete abolishment of nocturnal hypoglycaemia. Hypoglycaemias subsided at 34/40 and metformin and insulin had to be re-introduced due to high post-prandial blood glucose readings. An emergency C-section was indicated at 35 + 1/40 and a small-for-gestational-age female was delivered. There have been no further episodes of hypoglycaemia following delivery. This case illustrates challenges in the management of pregnancy following bariatric surgery. To our knowledge, this is the first use of FreeStyle Libre in dumping syndrome in pregnancy following bariatric surgery with troublesome nocturnal hypoglycaemia.

Learning points:

  • Bariatric surgery represents the most effective treatment modality in cases of severe obesity. With increasing prevalence of obesity, more people are likely to undergo bariatric procedures, many of which are women of childbearing age.
  • Fertility generally improves after bariatric surgery due to weight reduction, but pregnancy is not recommended for at least 12–24 months after surgery. If pregnancy occurs, there are currently little evidence-based guidelines available on how to manage complications such as dumping syndromes or gestational diabetes (GDM) in women with history of bariatric surgery.
  • Diagnosis of GDM relies on the use of a 75 g oral glucose tolerance test (OGTT). The use of this test in pregnant women is not recommended due to its potential to precipitate dumping syndrome. Capillary glucose monitoring profiles or continuous glucose monitoring (CGM) is being currently discussed as alternative testing modalities.
  • As the CGM technology becomes more available, including the recently introduced FreeStyle Libre Flash glucose monitoring system, more pregnant women, including those after bariatric surgery, will have access to this technology. We suggest urgent development of guidelines regarding the use of CGM and flash glucose monitoring tools in these circumstances and in the interim recommend careful consideration of their use on a case-to-case basis.