Ectopic ACTH syndrome of different origin-Diagnostic approach and clinical outcome. Experience of one Clinical Centre.

PURPOSE: Ectopic Cushing Syndrome (EAS) is a rare condition responsible for about 5-20% of all Cushing syndrome cases. It increases the mortality of affected patients thus finding and removal of the ACTH-producing source allows for curing or reduction of symptoms and serum cortisol levels. The aim of this study is to present a 20-year experience in the diagnosis and clinical course of patients with EAS in a single Clinical Centre in Southern Poland as well as a comparison of clinical course and outcomes depending on the source of ectopic ACTH production-especially neuroendocrine tumors with other neoplasms. METHODS: Twenty-four patients were involved in the clinical study with EAS diagnosed at the Department of Endocrinology between years 2000 and 2018. The diagnosis of EAS was based on the clinical presentation, hypercortisolemia with high ACTH levels, high dose dexamethasone suppression test and/or corticotropin-releasing hormone tests. To find the source of ACTH various imaging studies were performed. RESULTS: Half of the patients were diagnosed with neuroendocrine tumors, whereby muscle weakness was the leading symptom. Typical cushingoid appearance was seen in merely a few patients, and weight loss was more common than weight gain. Patients with neuroendocrine tumors had significantly higher midnight cortisol levels than the rest of the group. Among patients with infections, we observed a significantly higher concentrations of cortisol 2400 levels in gastroenteropancreatic neuroendocrine tumors. Chromogranin A correlated significantly with potassium in patients with neuroendocrine tumors and there was a significant correlation between ACTH level and severity of hypokalemia. CONCLUSION: EAS is not common, but if it occurs it increases the mortality of patients; therefore, it should be taken into consideration in the case of coexistence of severe hypokalemia with hypertension and muscle weakness, especially when weight loss occurs. Because the diagnosis of gastroenteropancreatic neuroendocrine tumor worsens the prognosis-special attention should be paid to these patients.

NBCe1-A is required for the renal ammonia and K+ response to hypokalemia.

Hypokalemia increases ammonia excretion and decreases K+ excretion. The present study examined the role of the proximal tubule protein NBCe1-A in these responses. We studied mice with Na+-bicarbonate cotransporter electrogenic, isoform 1, splice variant A (NBCe1-A) deletion [knockout (KO) mice] and their wild-type (WT) littermates were provided either K+ control or K+-free diet. We also used tissue sections to determine the effect of extracellular ammonia on NaCl cotransporter (NCC) phosphorylation. The K+-free diet significantly increased proximal tubule NBCe1-A and ammonia excretion in WT mice, and NBCe1-A deletion blunted the ammonia excretion response. NBCe1-A deletion inhibited the ammoniagenic/ammonia recycling enzyme response in the cortical proximal tubule (PT), where NBCe1-A is present in WT mice. In the outer medulla, where NBCe1-A is not present, the PT ammonia metabolism response was accentuated by NBCe1-A deletion. KO mice developed more severe hypokalemia and had greater urinary K+ excretion during the K+-free diet than did WT mice. This was associated with blunting of the hypokalemia-induced change in NCC phosphorylation. NBCe1-A KO mice have systemic metabolic acidosis, but experimentally induced metabolic acidosis did not alter NCC phosphorylation. Although KO mice have impaired ammonia metabolism, experiments in tissue sections showed that lack of ammonia does impair NCC phosphorylation. Finally, urinary aldosterone was greater in KO mice than in WT mice, but neither expression of epithelial Na+ channel α-, ß-, and γ-subunits nor of H+-K+-ATPase α1- or α2-subunits correlated with changes in urinary K+. We conclude that NBCe1-A is critical for the effect of diet-induced hypokalemia to increase cortical proximal tubule ammonia generation and for the expected decrease in urinary K+ excretion.

Significance of prolonged QTc in acute exacerbations of COPD requiring hospitalization.

Background: A prolonged QT interval is associated with increased risk of Torsade de Pointes and cardiovascular death. The prevalence and clinical relevance of QT prolongation in acute exacerbations of COPD (AECOPD), with high risk for cardiac morbidity and mortality, is currently unclear. Methods: A dual cross-sectional study strategy was therefore designed. A retrospective study evaluated 140 patients with an AECOPD requiring hospitalization, half of which had prolonged QTc on the admission ECG. Univariate and multivariate analyses were conducted to determine associated factors; Kaplan-Meier and Cox regression analyses to assess prognostic significance. A prospective study evaluated 180 pulmonary patients with acute respiratory problems requiring hospitalization, to determine whether a prolonged QTc at admission represents an AECOPD-specific finding and to investigate the change in QTc-duration during hospitalization. Results: Retrospectively, hypokalemia, cardiac troponin T and conductance abnormalities on ECG were significantly and independently associated with QTc prolongation. A prolonged QTc was associated with increased all-cause mortality (HR 2.698 (95% CI 1.032-7.055), p=0.043), however, this association was no longer significant when corrected for age, FEV1 and cardiac troponin T. Prospectively, QTc prolongation was observed in 1/3 of the patients diagnosed with either an AECOPD, lung cancer, pulmonary infection or miscellaneous acute pulmonary disease, and was not more prevalent in AECOPD. The QTc-duration decreased significantly during hospitalization in patients with and without COPD. Conclusion: A prolonged QTc is a marker of underlying cardiovascular disease during an AECOPD. It is not COPD-specific, but a common finding during the acute phase of a pulmonary disease requiring urgent hospital admission.

An Unlikely Cause of Hypokalemia.

BACKGROUND: Hypokalemia is a common clinical disorder caused by a variety of different mechanisms. Although the most common causes are diuretic use and gastrointestinal losses, elevated cortisol levels can also cause hypokalemia through its effects on the renin-angiotensin-aldosterone system. Cushing's syndrome refers to this general state of hypercortisolemia, which often manifests with symptoms of generalized weakness, high blood pressure, diabetes mellitus, menstrual disorders, and psychiatric changes. This syndrome is most commonly caused by exogenous steroid use, but other etiologies have also been reported in the literature. Ectopic adrenocorticotropic hormone production by small-cell lung cancer is one rare cause of Cushing's syndrome, and may be associated with significant hypokalemia. CASE REPORT: We describe the case of a 62-year-old man who presented to the emergency department with weakness and hypokalemia. The patient was initially misdiagnosed with furosemide toxicity. Despite having a 30-pack-year smoking history, this patient's lack of respiratory complaints allowed him to present for medical attention twice before being diagnosed with lung cancer. It was later determined that this patient's hypokalemia was due to Cushing's syndrome caused by ectopic adrenocorticotropic hormone production from small-cell lung cancer. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case reminds emergency physicians to consider a broad differential when treating patients with hypokalemia. More importantly, it prompts emergency physicians to recognize comorbid conditions and secondary, less common etiologies in patients with repeated visits for the same complaint.

Hypokalemia and hyperkalemia in infants and children: pathophysiology and treatment.

Potassium is the second most abundant cation in the body. About 98% of potassium is intracellular and that is particularly in the skeletal muscle. Electrical disturbances associated with disorders of potassium homeostasis are a function of both the extracellular and intracellular potassium concentrations. Clinical disorders of potassium homeostasis occur with some regularity, especially in hospitalized patients receiving many medications. This article will review the pathophysiology of potassium homeostasis, symptoms, causes, and treatment of hypo- and hyperkalemia.

Expression of glutamine synthetase in the mouse kidney: localization in multiple epithelial cell types and differential regulation by hypokalemia.

Renal glutamine synthetase catalyzes the reaction of NH4+ with glutamate, forming glutamine and decreasing the ammonia available for net acid excretion. The purpose of the present study was to determine glutamine synthetase's specific cellular expression in the mouse kidney and its regulation by hypokalemia, a common cause of altered renal ammonia metabolism. Glutamine synthetase mRNA and protein were present in the renal cortex and in both the outer and inner stripes of the outer medulla. Immunohistochemistry showed glutamine synthetase expression throughout the entire proximal tubule and in nonproximal tubule cells. Double immunolabel with cell-specific markers demonstrated glutamine synthetase expression in type A intercalated cells, non-A, non-B intercalated cells, and distal convoluted tubule cells, but not in principal cells, type B intercalated cells, or connecting segment cells. Hypokalemia induced by feeding a nominally K+ -free diet for 12 days decreased glutamine synthetase expression throughout the entire proximal tubule and in the distal convoluted tubule and simultaneously increased glutamine synthetase expression in type A intercalated cells in both the cortical and outer medullary collecting duct. We conclude that glutamine synthetase is widely and specifically expressed in renal epithelial cells and that the regulation of expression differs in specific cell populations. Glutamine synthetase is likely to mediate an important role in renal ammonia metabolism.

Effects of hypokalemia on transmural dispersion of ventricular repolarization in left ventricular myocardium.

OBJECTIVE: To observe effects of hypokalemia on transmural heterogeneity of ventricular repolarization in left ventricular myocardium of rabbit, and explore the role of hypokalemia in malignant ventricular arrhythmia (MVA). METHODS: A total of 20 rabbits were randomly divided into control group and hypokalemic group. Isolated hearts in the control group were simply perfused with modified Tyrode's solution, and were perfused with hypokalemic Tyrode's solution in hypokalemic group. Ventricular fibrillation threshold (VFT), 90% monophasic action potential repolarization duration (APD90) of subepicardial, midmyocardial and subendocardial myocardium, transmural dispersion of repolarization (TDR) and C×43 protein expression in three layers of myocardium were measured in both groups. RESULTS: VFT in the control group and the hypokalemic group were (13.40 ± 2.95) V, and (7.00 ± 1.49) V, respectively. There was a significant difference between two groups (P<0.01). APD90 of three myocardial layers in the hypokalemic group were significantly prolonged than those in the control group (P<0.01). ΔAPD90 in the hypokalemic group and the control group were (38.10 ± 10.29) ms and (23.70 ± 5.68) ms, and TDR were (52.90 ± 14.55) ms and (36.10 ± 12.44) ms, respectively. ΔAPD90 and TDR in the hypokalemic group were significantly higher than those in the control group (P<0.05), and the increase in APD90 of midmyocardium was more significant in the hypokalemic group. Cx43 protein expression of all three myocardial layers were decreased significantly in the hypokalemic group (P<0.01), and ΔCx43 was significantly increased (P<0.05). Reduction of Cx43 protein expression was more significant in the midmyocardium. CONCLUSIONS: Hypokalemic can increase transmural heterogeneity of C×43 expression and repolarization in left ventricular myocardium of rabbit, and decrease VFT and can induce MVA more easily.

Inherited secondary nephrogenic diabetes insipidus: concentrating on humans.

The study of human physiology is paramount to understanding disease and developing rational and targeted treatments. Conversely, the study of human disease can teach us a lot about physiology. Investigations into primary inherited nephrogenic diabetes insipidus (NDI) have contributed enormously to our understanding of the mechanisms of urinary concentration and identified the vasopressin receptor AVPR2, as well as the water channel aquaporin-2 (AQP2), as key players in water reabsorption in the collecting duct. Yet, there are also secondary forms of NDI, for instance as a complication of lithium treatment. The focus of this review is secondary NDI associated with inherited human diseases, such as Bartter syndrome or apparent mineralocorticoid excess. Currently, the underlying pathophysiology of this inherited secondary NDI is unclear, but there appears to be true AQP2 deficiency. To better understand the underlying mechanism(s), collaboration between clinical and experimental physiologists is essential to further investigate these observations in appropriate experimental models.

Effect of combined fluoroquinolone and azole use on QT prolongation in hematology patients.

QTc prolongation is a risk factor for development of torsades de pointes (TdP). Combination therapy with fluoroquinolones and azoles is used in patients with hematologic malignancies for prophylaxis and treatment of infection. Both drug classes are implicated as risk factors for QTc prolongation. The cumulative effect on and incidence of QTc prolongation for this combination have not been previously described. A retrospective chart review was performed with hospitalized inpatients from 1 September 2008 to 31 January 2010 comparing QTc interval data from electrocardiogram (ECG) assessment at baseline and after the initiation of combination therapy. Ninety-four patients were eligible for inclusion. The majority, 88 patients (93.6%), received quinolone therapy with levofloxacin. Fifty-three patients (56.4%) received voriconazole; 40 (42.6%) received fluconazole. The overall mean QTc change from baseline was 6.1 (95% confidence interval [CI], 0.2 to 11.9) ms. Twenty-one (22.3%) of the studied patients had clinically significant changes in the QTc while receiving combination fluoroquinolone-azole therapy. Statistically significant risk factors for clinically significant changes in QTc were hypokalemia (P = 0.03) and a left-ventricular ejection fraction of <55% (P = 0.02). Low magnesium (P = 0.11), exposure to 2 or more drugs with the potential to prolong the QTc interval (P = 0.17), and female sex (P = 0.21) trended toward significance. Combination therapy with fluoroquinolone and azole antifungals is associated with increased QTc from baseline in hospitalized patients with hematologic malignancies. One in five patients had a clinically significant change in the QTc, warranting close monitoring and risk factor modification to prevent the possibility of further QTc prolongation and risk of TdP.

Acute pituitary insufficiency and hypokalaemia following envenoming by Russell's viper (Daboia russelii) in Sri Lanka: Exploring the pathophysiological mechanisms.

Russell's viper envenoming is associated with a high incidence of morbidity and mortality. Hypopituitarism following envenoming by Russell's vipers is a well recognized sequel in Burma and parts of India but has been reported only once in Sri Lanka. Hypokalaemia following envenoming by Russell's viper has not been described. Here we describe the association of acute pituitary insufficiency and hypokalaemia following Russell's viper envenoming in Sri Lanka and review the literature in order to understand its pathophysiological basis. A previously healthy 21-year-old man was envenomed by a Russell's viper and treated with antivenom. Ten hours after the bite, he developed persistent hypotension, which responded promptly to intravenous dexamethasone. His hormone profiles were consistent with hypocortisolism secondary to acute pituitary insufficiency. He also developed hypokalaemia. Analysis of urine and serum electrolytes suggested redistribution of potassium in to the cells rather than renal loss. Hypotension and hypoglycaemic coma are life-threatening manifestations of acute pituitary insufficiency. Therefore prompt steroid administration in these setting is life saving. Awareness of these complications among physicians would help to make prompt diagnosis and initiate immediate life saving treatment.

[Simultaneous presentation of Brugada syndrome and primary aldosteronism]. / Brugada-szindróma és primer aldosteronismus együttes elofordulása.

The authors present a case of a 42-year-old male patient, who was referred for evaluation for tachycardia. Detailed studies revealed Brugada syndrome and hypokalaemia due to primary aldosteronism. With this case report the authors draw attention to the risk of malignant ventricular tachycardia in a patient with low potassium level, especially in case of coexisting Brugada syndrome.

Complications of apheresis.

In general, therapeutic apheresis is a relatively safe procedure with the most commonly seen complications caused by citrate-induced hypocalcemia and urticarial reactions to the protein-containing replacement fluid. Depletion coagulopathy and immunoglobulin depletion must be anticipated when albumin is used as the replacement fluid and becomes more profound as the number of treatment increases. The most serious complications are seen when there is an anaphylactoid reaction to the multiple units of fresh frozen plasma required when used as the replacement fluid. The overall incidence of death is 0.05%, but many of these deaths were in patients with severe preexisting conditions in which the apheresis procedure, itself, may not have been the precipitating cause. As with all extracorporeal treatments requiring large bore vascular access, catheter-related trauma, clotting, infection, and bleeding may also occur.

Resistant hypertension in an aged woman presenting with clinical features simulating ectopic ACTH syndrome--response to spironolactone--.

A 91-year-old depressed woman had resistant hypertension despite a triple combination of anti-hypertensives, including a Ca-antagonist, an angiotensin receptor blocker, and a thiazide diuretic at optimal doses. She had hypokalemic metabolic alkalosis, elevated plasma cortisol and ACTH, and elevated urinary cortisol. The high-dose dexamethasone did not suppress the elevated ACTH and cortisol. The addition of spironolactone to her previous medications controlled and normalized hypertension, hypokalemia, and hormonal abnormalities within 4 months. Her blood pressure, serum electrolytes, and the hormonal states remained normalized for more than a year thereafter. Her depressed mental state also improved after spironolactone.

Hormonal and pharmacological modification of plasma potassium homeostasis.

Human skeletal muscles contain the largest single pool of K+ in the body (2600 mmol, 46 times the total K+ content of the extracellular space). Intense exercise may double arterial plasma K+ in one min. This is because of excitation-induced release of K+ from the working muscle cells via K+ channels. This hyperkalemia is rapidly corrected by reaccumulation of K+ into the muscle cells via Na+,K+ pumps, often leading to hypokalemia. Hyperkalemia may also arise from muscle cell damage, excessive oral or intravenous administration of K+, acidosis, renal failure, depolarization of muscle cells with succinyl choline, activation of K+ channels by fluoride poisoning, hyperkalemic periodic paralysis, malignant hyperthermia, inhibition of the Na+,K+ pumps by digitalis glycosides or treatment with nonselective beta blockers. Hyperkalemia may cause arrhythmia and can be treated with beta2 agonists, insulin or hemodialysis. Hypokalemia may be induced by the stimulation of the Na+,K+ pumps in skeletal muscles seen postexercise, or by catecholamines, beta2 agonists, pheochromocytoma, theophylline, caffeine or insulin, by sepsis, myocardial infarction, trauma, burns and heart failure. Rare causes are hypokalemic periodic paralysis, inhibition of K+ channels by barium, chloroquine or barbiturates. Hypokalemia often reflects dietary K+ deficiency, alkalosis, renal or gastrointestinal loss of K+. Hypokalemia is more likely to cause arrhythmia than hyperkalemia and can be treated by oral or intravenous administration of K+ under frequent control of electrocardiogram and plasma K+. Because of their size and high contents of K+, Na+,K+ pumps and K+ channels, the skeletal muscles play a central role in the acute, from min-to-min ongoing regulation of plasma K+. This is decisive for the maintenance of muscle contractility and heart function.

Profound hypokalaemia due to Nurofen Plus and Red Bull misuse.

We report an unusual and emerging cause of profound hypokalaemia associated with a severe myopathy, attributable to misuse of Nurofen Plus, a readily available over-the-counter medication containing ibuprofen and codeine, and excessive ingestion of the caffeine-containing energy drink, Red Bull. The mechanism of the hypokalaemia may be ascribed to ibuprofen-mediated type 2 renal tubular acidosis, and caffeine-mediated antagonism of adenosine receptors or intercompartmental shift of potassium into the intracellular space. Practitioners should be aware that patients with codeine addiction who misuse Nurofen Plus may present with severe hypokalaemia complicated by myopathy.

The myotonias and susceptibility to malignant hyperthermia.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle in which volatile anesthetics trigger a sustained increase in intramyoplasmic Ca(2+) via release from sarcoplasmic reticulum and, possibly, entry from the extracellular milieu that leads to hypermetabolism, muscle rigidity, rhabdomyolysis, and death. Myotonias are a class of myopathies that result from gene mutations in various channels involved in skeletal muscle excitation-contraction coupling and sarcolemmal excitability, and unusual DNA sequence repeats that result in the inability of many proteins, including skeletal muscle channels that affect excitability, to undergo proper splicing. The suggestion has often been made that myotonic patients have an increased risk of developing MH. In this article, we review the physiology of muscle excitability and excitation-contraction coupling, the pathophysiology of MH and the myotonias, and review the clinical literature upon which the claims of MH susceptibility are based. We conclude that patients with these myopathies have a risk of developing MH that is equivalent to that of the general population with one potential exception, hypokalemic periodic paralysis. Despite the fact that there are no clinical reports of MH developing in patients with hypokalemic periodic paralysis, for theoretical reasons we cannot be as certain in estimating their risk of developing MH, even though we believe it is low.