Ramaswami Nalini

Ectopic corticotropin-releasing hormone (CRH) syndrome from metastatic small cell carcinoma: a case report and review of the literature.

BackgroundCushings Syndrome (CS) which is caused by isolated Corticotropin-releasing hormone (CRH) production, rather than adrenocorticotropin (ACTH) production, is extremely rare.MethodsWe describe the clinical presentation, course, laboratory values and pathologic findings of a patient with isolated ectopic CRH causing CS. We review the literature of the types of tumors associated with this unusual syndrome and the behavior of these tumors by endocrine testing.ResultsA 56 year old woman presented with clinical and laboratory features consistent with ACTH-dependent CS. Pituitary imaging was normal and cortisol did not suppress with a high dose dexamethasone test, consistent with a diagnosis of ectopic ACTH. CT imaging did not reveal any discrete lung lesions but there were mediastinal and abdominal lymphadenopathy and multiple liver lesions suspicious for metastatic disease. Laboratory testing was positive for elevated serum carcinoembryonic antigen and the neuroendocrine marker chromogranin A. Serum markers of carcinoid, medullary thyroid carcinoma, and pheochromocytoma were in the normal range. Because the primary tumor could not be identified by imaging, biopsy of the presumed metastatic liver lesions was performed. Immunohistochemistry was consistent with a neuroendocrine tumor, specifically small cell carcinoma. Immunostaining for ACTH was negative but was strongly positive for CRH and laboratory testing revealed a plasma CRH of 10 pg/ml (normal 0 to 10 pg/ml) which should have been suppressed in the presence of high cortisol.ConclusionsThis case illustrates the importance of considering the ectopic production of CRH in the differential diagnosis for presentations of ACTH-dependent Cushings Syndrome.

Pathogenesis of A−β+ Ketosis-Prone Diabetes

A−β+ ketosis-prone diabetes (KPD) is an emerging syndrome of obesity, unprovoked ketoacidosis, reversible β-cell dysfunction, and near-normoglycemic remission. We combined metabolomics with targeted kinetic measurements to investigate its pathophysiology. Fasting plasma fatty acids, acylcarnitines, and amino acids were quantified in 20 KPD patients compared with 19 nondiabetic control subjects. Unique signatures in KPD—higher glutamate but lower glutamine and citrulline concentrations, increased β-hydroxybutyryl-carnitine, decreased isovaleryl-carnitine (a leucine catabolite), and decreased tricarboxylic acid (TCA) cycle intermediates—generated hypotheses that were tested through stable isotope/mass spectrometry protocols in nine new-onset, stable KPD patients compared with seven nondiabetic control subjects. Free fatty acid flux and acetyl CoA flux and oxidation were similar, but KPD had slower acetyl CoA conversion to β-hydroxybutyrate; higher fasting β-hydroxybutyrate concentration; slower β-hydroxybutyrate oxidation; faster leucine oxidative decarboxylation; accelerated glutamine conversion to glutamate without increase in glutamate carbon oxidation; and slower citrulline flux, with diminished glutamine amide–nitrogen transfer to citrulline. The confluence of metabolomic and kinetic data indicate a distinctive pathogenic sequence: impaired ketone oxidation and fatty acid utilization for energy, leading to accelerated leucine catabolism and transamination of α-ketoglutarate to glutamate, with impaired TCA anaplerosis of glutamate carbon. They highlight a novel process of defective energy production and ketosis in A−β+ KPD.

A−β− Subtype of Ketosis-Prone Diabetes Is Not Predominantly a Monogenic Diabetic Syndrome

OBJECTIVE Ketosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the A−β− subgroup of KPD, characterized by complete insulin dependence, absent β-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes. RESEARCH DESIGN AND METHODS Over 8 years, 37 patients with an A−β− phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects. RESULTS The majority (70%) of the A−β− KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low-frequency, heterozygous sequence variants in HNF-1α (A174V or G574S), PDX1 (putative 5′–untranslated region CCAAT box, P33T, or P239Q), or PAX4 (R133W) were found in 27% (10/37) of patients, with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported. CONCLUSIONS Despite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated β-cell dysfunction, A−β− KPD is most likely not a predominantly monogenic diabetic syndrome. Several A−β− KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.

Islet-Specific T-Cell Responses and Proinflammatory Monocytes Define Subtypes of Autoantibody-Negative Ketosis-Prone Diabetes

OBJECTIVE Ketosis-prone diabetes (KPD) is characterized by diabetic ketoacidosis (DKA) in patients lacking typical features of type 1 diabetes. A validated classification scheme for KPD includes two autoantibody-negative (“A−”) phenotypic forms: “A−β−” (lean, early onset, lacking β-cell functional reserve) and “A−β+” (obese, late onset, with substantial β-cell functional reserve after the index episode of DKA). Recent longitudinal analysis of a large KPD cohort revealed that the A−β+ phenotype includes two distinct subtypes distinguished by the index DKA episode having a defined precipitant (“provoked,” with progressive β-cell function loss over time) or no precipitant (“unprovoked,” with sustained β-cell functional reserve). These three A− KPD subtypes are characterized by absence of humoral islet autoimmune markers, but a role for cellular islet autoimmunity is unknown. RESEARCH DESIGN AND METHODS Islet-specific T-cell responses and the percentage of proinflammatory (CD14+CD16+) blood monocytes were measured in A−β− (n = 7), provoked A−β+ (n = 15), and unprovoked A−β+ (n = 13) KPD patients. Genotyping was performed for type 1 diabetes–associated HLA class II alleles. RESULTS Provoked A−β+ and A−β− KPD patients manifested stronger islet-specific T-cell responses (P < 0.03) and higher percentages of proinflammatory CD14+CD16+ monocytes (P < 0.01) than unprovoked A−β+ KPD patients. A significant relationship between type 1 diabetes HLA class II protective alleles and negative T-cell responses was observed. CONCLUSIONS Provoked A−β+ KPD and A−β− KPD are associated with a high frequency of cellular islet autoimmunity and proinflammatory monocyte populations. In contrast, unprovoked A−β+ KPD lacks both humoral and cellular islet autoimmunity.

Surviving the storm: two cases of thyroid storm successfully treated with plasmapheresis.

Thyroid storm is a rare, but critical, illness that can lead to multiorgan failure and carries a high death rate. The following case series describes two adult men with Graves’ disease who presented in thyroid storm and either failed or could not tolerate conventional medical management. However, both patients responded well to plasmapheresis, which resulted in clinical and biochemical stabilisation of their disease processes. The treatment option of plasmapheresis should be considered as a stabilising measure, especially when patients have failed or cannot tolerate conventional therapy. Plasmapheresis leads to amelioration of symptoms and a significant decline in thyroid hormone levels, providing a window to treat definitively with thyroidectomy.

Surviving the storm

Thyroid storm is a rare, but critical, illness that can lead to multiorgan failure and carries a high death rate. The following case series describes two adult men with Graves’ disease who presented in thyroid storm and either failed or could not tolerate conventional medical management. However, both patients responded well to plasmapheresis, which resulted in clinical and biochemical stabilisation of their disease processes. The treatment option of plasmapheresis should be considered as a stabilising measure, especially when patients have failed or cannot tolerate conventional therapy. Plasmapheresis leads to amelioration of symptoms and a significant decline in thyroid hormone levels, providing a window to treat definitively with thyroidectomy.

Unusual presentation of more common disease/injury: Surviving the storm: two cases of thyroid storm successfully treated with plasmapheresis

Thyroid storm is a rare, but critical, illness that can lead to multiorgan failure and carries a high death rate. The following case series describes two adult men with Graves’ disease who presented in thyroid storm and either failed or could not tolerate conventional medical management. However, both patients responded well to plasmapheresis, which resulted in clinical and biochemical stabilisation of their disease processes. The treatment option of plasmapheresis should be considered as a stabilising measure, especially when patients have failed or cannot tolerate conventional therapy. Plasmapheresis leads to amelioration of symptoms and a significant decline in thyroid hormone levels, providing a window to treat definitively with thyroidectomy.