Biochemical Testing After Pheochromocytoma Removal: How Early?

Pheochromocytomas are catecholamine-producing tumors with typical clinical presentation. Tumor resection is considered as an appropriate treatment strategy. Due to its unpredictable clinical behavior, biochemical testing is mandatory to confirm the success of tumor removal after surgery. The aim of the study was to investigate the feasibility of a shorter interval of postoperative testing (earlier than the recommended 2-4 weeks according to recently published Guidelines). We investigated 81 patients with pheochromocytoma before and after surgery. Postoperative examination was performed of stable subjects after their transport from the surgical to the internal ward (7.1±2.2 days after surgery). Plasma metanephrines were used for the diagnosis of pheochromocytoma and confirmation of successful tumor removal. All subjects with pheochromocytoma had markedly elevated plasma metanephrines before surgery. No correlation between postoperative interval (the shortest being 3 days) and plasma metanephrine levels was found. Postoperative plasma metanephrine levels did not differ significantly from those taken at the one-year follow-up. In conclusion, we have shown that early postoperative diagnostic workup of subjects with pheochromocytoma is possible and may thus simplify early postoperative management of this clinical condition.

High incidence of cardiovascular complications in pheochromocytoma.

Excess of catecholamines in pheochromocytoma is usually accompanied with classical symptoms and signs. In some cases, severe cardiovascular complications (e. g., heart failure, myocardial infarction) may occur. We performed a retrospective analysis focused on the incidence of cardiovascular complications (classified as follows: arrhythmias, myocardial involvement or ischemia and atherosclerosis, cerebrovascular impairment) before the establishment of diagnosis of pheochromocytoma among 145 subjects treated in our hospital. Cardiovascular complications occurred in 28 subjects, but these subjects did not differ significantly from subjects without complications in age, gender, body mass index, paroxysmal symptoms, symptom duration, tumor dimension, catecholamine secretory phenotype, and incidence of hypertension or diabetes mellitus. Arrhythmias occurred in 15 subjects (2 arrhythmia types in 2 subjects): atrial fibrillation in 9 subjects, supraventricular tachycardia in 3 cases, and ventricular tachycardia in 2 patients. Significant bradycardia was noted in 3 cases. Five subjects presented with heart failure with decreased systolic function (takotsubo-like cardiomyopathy found in 2 cases). One subject suffered from hypertrophic obstructive cardiomyopathy. Seven subjects presented with non-ST-segment elevation myocardial infarction, 2 patients with ST-segment myocardial infarction, and 1 subject underwent coronary artery bypass grafting. Two subjects suffered from significant peripheral atherosclerosis. Among cerebrovascular complications, transient ischemic attack was found in 3 cases, 2 subjects suffered from stroke, and subarachnoidal bleeding occurred in 1 patient. One subject suffered from diffuse neurological impairment due to multiple ischemic white matter lesions. These data show relatively high incidence of cardiovascular complications (19.3%) in subjects with pheochromocytoma. Early diagnosis is mandatory to prevent severe complications in pheochromocytoma.

Vascular disturbances in primary aldosteronism: clinical evidence.

Primary aldosteronism (PA) is a common form of arterial hypertension with a high prevalence of cardiovascular complications. In patients with PA, complex mechanisms may lead to functional and/or structural abnormalities of the blood vessel wall. Clinical evidence indicates that patients with PA may have immune cell activation, increased oxidative stress, impaired endothelial function and vascular remodeling. Activation of fibroproliferation has been found in resistant arteries of patients with PA. Subjects with PA compared to essential hypertensives with similar blood pressure levels have increased intima-media thickness and arterial stiffness as measured by pulse wave velocity. These functional and morphological changes can be modified by an increased sodium intake. Vascular remodeling in PA may indicate a poor response to specific therapy with lower probability of cure and/or normalization of blood pressure. Early diagnosis of PA before blood vessel wall disturbances develop is of utmost importance.

The conversion process of hydrocarbon hydrates into CO2 hydrates and vice versa: thermodynamic considerations.

Microscopy, confocal Raman spectroscopy and powder X-ray diffraction (PXRD) were used for in situ investigations of the CO(2)-hydrocarbon exchange process in gas hydrates and its driving forces. The study comprises the exposure of simple structure I CH(4) hydrate and mixed structure II CH(4)-C(2)H(6) and CH(4)-C(3)H(8) hydrates to gaseous CO(2) as well as the reverse reaction, i.e., the conversion of CO(2)-rich structure I hydrate into structure II mixed hydrate. In the case of CH(4)-C(3)H(8) hydrates, a conversion in the presence of gaseous CO(2) from a supposedly more stable structure II hydrate to a less stable structure I CO(2)-rich hydrate was observed. PXRD data show that the reverse process requires longer initiation times, and structural changes seem to be less complete. Generally, the exchange process can be described as a decomposition and reformation process, in terms of a rearrangement of molecules, and is primarily induced by the chemical potential gradient between hydrate phase and the provided gas phase. The results show furthermore the dependency of the conversion rate on the surface area of the hydrate phase, the thermodynamic stability of the original and resulting hydrate phase, as well as the mobility of guest molecules and formation kinetics of the resulting hydrate phase.

[Diagnostic of secondary hypertension in clinical practice]. / Diagnostika sekundární hypertenze v ambulantní praxi.

Arterial hypertension is a common worldwide disease with a prevalence of approximately 26%. Secondary cause is known in 5-10% of patients with hypertension. We should think of secondary hypertension in all patients with resistant hypertension, in patients with sudden deterioration in the control of hypertension and in patients with laboratory and clinical signs of diseases associated with secondary hypertension. It is important to distinguish between secondary hypertension and pseudo-resistance (noncompliance to treatment, white coat syndrome). Secondary causes of hypertension can be divided into endocrine (primary aldosteronism, pheochromocytoma, hypercortisolism, hyperparathyreoidism), renal - renovascular and renal parenchymal hypertension, and other causes as sleep apnoe syndrome, hypertension in pregnancy, coarctation of the aorta and intracranial tumors.

[Pheochromocytoma: diagnosis and treatment]. / Feochromocytom: diagnostika a lécba.

Pheochromocytoma (pheo) is adrenal or less frequently extraadrenal tumour of chromafine tissue. Pheos are rare, but cardiovascular and metabolic abnormalities are common. Unrecognised pheo may lead to fatal hypertensive crisis during anesthesia or other stresses. Proper diagnosis of pheo is thus of utmost importance. 24-h blood pressure (BP) monitoring may contribute to the diagnosis of pheo due to increased BP variability and absence of night BP decline. Pheo contains large amount of enzyme catechol-O-methyl transpherase (COMT) with subsequent excessive production of COMT metabolites like metanephrines. Measurement of plasma free metanephrines or urinary fraccionated metanephrines has usually higher sensivitivity and specificity compared with plasma or urinary catecholamines. Morphological diagnosis of adrenal/extraadrenal pheo is based on CT/MR visualisation and 123I-metaiodobenzylguanidin (MIBG) or PET 18F-fluorodeoxyglucose scan. Genetic analysis should be performed in all confirmed pheo cases, especially in younger subjects below 50 years of age in order to detect mutations of following genes: von Hippel-Lindau (VHL), RET- protooncogen, genes encoding B, C and D subunit of mitochondrial sukcinat dehydrogenaze (SDHB, SDHC, SDHD) and neurofibromatosis type I gene. Pharmacological treatment is based on alpha blockers with subsequent (after 24-48 hours) administration of beta-blockers/especially in patients with tendency to tachycardia/. Following this therapy normalisation of BP is common and laparoscopic excision of pheo tumour can be realised. Malignant pheos are difficult to treat due to early occurrence of metastasis and lack of response to chemotherapy or iradiation in most cases.

Relationship between clinical, 24-hour, average day-time and night-time blood pressure and measures of arterial stiffness in essential hypertension.

Arterial wall stiffness is considered an independent cardiovascular risk factor. Aim of this study was to evaluate relationship between clinical, 24-hour, average day-time and night-time blood pressure (BP) and measures of arterial stiffness assessed by pulse wave velocity (PWV) (using SphygmoCor applanation tonometer) in essential hypertension (severe-resistant (RH, n=29) and moderate hypertension (EH, n=35)) and in normotensive control subjects (n-29) (NCS) matched by age. After multiple regression analysis, PWV remains significantly correlated mainly with night-time pulse pressure and to a lesser extent with age. PWV was significantly higher in RH compared to moderate EH and NCS.

The effect of adrenalectomy on exercise response of the renin-angiotensin-aldosterone system and exercise tolerance in primary aldosteronism.

Primary aldosteronism (PA) is associated with objectively measured lower physical fitness and blunted response of the renin-angiotensin-aldosterone system to exercise. The purpose of this pilot study was to objectively measure exercise response of the renin-angiotensin-aldosterone system and cardiopulmonary fitness changes after laparoscopic adrenalectomy (ADE) in patients with unilateral PA. We examined a total of 14 patients with confirmed PA before and after ADE, by means of spiroergometry and hormonal evaluation. As expected, after adrenalectomy basal aldosterone (Aldo) levels before exercise decreased significantly, with a concomitant increase in plasma renin (PR). The increase in Aldo (285.9+/-171.3 to 434.1+/-278.2 ng/l; p=0.02) and blunted increase in PR (7.1+/-0.4 to 8.9+/-10.4 pg/ml; NS) post-exercise before ADE became significant after ADE Aldo post-ADE (46.8+/-18.8 to 106.5+/-68.1 ng/l; p<0.0001) and PR post-ADE (20.1+/-14.5 to 33.9+/-30.7 pg/ml; p=0.014). After adrenalectomy, the patients had a non-significant increase in peak workload and VO(2peak). We found normalization of the renin-angiotensin-aldosterone system response to exercise with little changes in cardiopulmonary fitness six months after ADE.

[Diagnostic and therapeutic procedures in pheochromocytoma: current trends]. / Diagnostické a terapeutické postupy u feochromocytomu: soucasné trendy.

Pheochromacytoma is a relatively rare cause of arterial hypertension. Untreated pheochromacytoma may however lead to a fatal hypertensive crisis during anaesthesia or another form of stress. It is therefore important to correctly diagnose this disease. 24-hour monitoring of blood pressure (BP) can already contribute to the diagnosis of pheochromacytoma based on the frequent occurrence of BP variability and the absence of a night-time fall in BP. 5 gene mutations have so far been identified that may be responsible for the familial form of pheochromacytoma: mutation of the von Hippel-Lindau (VHL) gene, leading to the onset of VHL syndrome, mutation of the RET-proto-oncogene in multiple endocrine adenomatosis type 2, mutation of the type 1 gene for neurofibromatosis, which is associated with von Recklinghausen's disease and finally mutation of the genes encoding the B and D subunits of succinated hydrogenase (SDHB, SDHD), which are associated with familial paragangliomas and pheochromacytoma. Genetic analysis should therefore be carried out for all confirmed cases of pheochromacytoma, especially for young people under 50 years of age. Biochemical diagnostics relies mainly on measurements of free metanephrines in plasma or urine, which usually has greater diagnostic weight than plasma, or catecholamines in urine. The diagnosis of extraadrenal or multiple forms can use not only CT/MR but also imaging using the radiopharmaceutical 123I-Metaiodobenzylguanidine (MIBG) or 18F-fluorodopamine PET (only available in the USA). Pharmacological treatment using alpha or beta receptor blockers with subsequent laparoscopic excision of the tumor is usually successful in benign forms of pheochromocytoma. Unfortunately, there are still no convincingly effective therapeutic procedures available for malign forms.

Lower physical fitness in patients with primary aldosteronism is linked to the severity of hypertension and kalemia.

Hypokalemia as a typical feature of primary aldosteronism (PA) is associated with muscle weakness and could contribute to lower cardiopulmonary fitness. The aim of this study was to describe cardiopulmonary fitness and exercise blood pressure and their determinants during a symptom-limited exercise stress test in patients with PA. We performed a cross-sectional study of patients with confirmed PA who were included before adrenal vein sampling on whom a symptom-limited exercise stress test with expired gas analysis was performed. Patients were switched to the treatment with doxazosin and verapamil at least two weeks before the study. In 27 patients (17 male) the VO(2peak) was 25.4+/-6.0 ml/kg/min which corresponds to 80.8+/-18.9 % of Czech national norm. Linear regression analysis shows that VO(2peak) depends on doxazosin dose (DX) (p=0.001) and kalemia (p=0.02): VO(2peak) = 4.2 - 1.0 * DX + 7.6 * Kalemia. Patients with higher doxazosin doses had a longer history of hypertension and had used more antihypertensives before examination, thus indicating that VO(2peak) also depends on the severity of hypertension. In patients with PA, lower cardiopulmonary fitness depends inversely on the severity of hypertension and on lower plasma potassium level.

Biochemical markers of endothelial dysfunction in patients with endocrine and essential hypertension.

The aim of our study was to evaluate potential differences in the concentration of biochemical markers of endothelial dysfunction between essential hypertension, endocrine hypertension (pheochromocytoma, primary hyperaldosteronism) and control healthy group and to assess a potential relationship between these markers of endothelial dysfunction and vasopressor substances overproduced in endocrine hypertension. We have investigated 21 patients with moderate essential hypertension, 29 patients with primary hyperaldosteronism, 24 subjects with pheochromocytoma and 26 healthy volunteers. Following parameters of endothelial dysfunction were measured, von Willebrand factor (vWf), plasminogen activator (t-PA) and E-selectin (E-sel). Clinical blood pressure was measured according to the European Society of Hypertension recommendations. We found significantly higher levels of the von Willebrand factor in patients with essential hypertension in comparison with a control group (114+/-20 IU/dl vs 90+/-47 IU/dl; P=0.04) and patients with primary hyperaldosteronism (114+/-20 IU/dl vs 99+/-11 IU/dl; P=0.01). Patients with endocrine hypertension revealed increased levels of vWF compared to the control group, but these differences did not reach statistical significance. Levels of t-PA were increased in patients with pheochromocytoma in comparison with the control group (4.6+/-1.9 ng/ml vs 3.4+/-0.9 ng/ml; P=0.01) and with primary hyperaldosteronism (4.6+/-1.9 ng/ml vs 3.4+/-1.1 ng/ml; P<0.01). In case of E-selectin we found lower levels in patients with pheochromocytoma in comparison with other groups, but they differed significantly only with primary hyperaldosteronism (40.2+/-15.0 ng/ml vs 51.3+/-23.0 ng/ml; P=0.05). Our study did not reveal any convincing evidence of differences in the levels of biochemical markers of endothelial dysfunction between essential and endocrine hypertension. No correlation between the biochemical markers of endothelial dysfunction and vasopressor substances activated in endocrine hypertension was found.

Combination antihypertensive therapy in clinical practice. The analysis of 1254 consecutive patients with uncontrolled hypertension.

The aim of the study was to analyze the clinical use of different types of combination therapy in a large sample of consecutive patients with uncontrolled hypertension referred to Hypertension Centre. We performed a retrospective analysis of combination antihypertensive therapy in 1254 consecutive patients with uncontrolled hypertension receiving at least triple-combination antihypertensive therapy. Among the most prescribed antihypertensive classes were renin-angiotensin blockers (96.8%), calcium channel blockers (82.5%), diuretics (82.0%), beta-blockers (73.0%), centrally acting drugs (56.0%) and urapidil (24.1%). Least prescribed were spironolactone (22.2%) and alpha-1-blockers (17.1%). Thiazide/thiazide-like diuretics were underdosed in more than two-thirds of patients. Furosemide was prescribed in 14.3% of patients treated with diuretics, while only indicated in 3.9%. Inappropriate combination therapy was found in 40.4% of patients. Controversial dual and higher blockade of renin-angiotensin system occurred in 25.2%. Incorrect use of a combination of two antihypertensive drugs with the similar mechanism of action was found in 28.1%, most commonly a combination of two drugs with central mechanism (13.5%). In conclusion, use of controversial or incorrect combinations of drugs in uncontrolled hypertension is common. Diuretics are frequently underdosed and spironolactone remains neglected in general practice. The improper combination of antihypertensive drugs may contribute to uncontrolled hypertension.

Inflammatory markers in primary aldosteronism.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension with a high frequency of cardiovascular complications. The unfavorable cardiometabolic profile may be due to aldosterone-mediated activation of inflammatory cells, circulatory cytokines and activation of collagen synthesis in the vessel wall. Aim of our study was to evaluate differences in the levels of hsCRP, IL-6, TNF-alpha and N-terminal propeptide of collagen I (PINP) in patients with PA and essential hypertension (EH) as a control group, and between the subtypes of PA (aldosterone producing adenoma - APA, idiopathic hyperaldosteronism - IHA). We studied 28 patients with PA (IHA - 10 patients, APA - 12 patients, 6 unclassified) and 28 matched patients with EH. There were no differences in the levels of inflammatory markers between the followed groups [EH vs. PA: TNF-alpha (5.09 [3.68-6.32] vs. 4.84 [3.62-6.50] pg/ml), IL-6 (0.94 [0.70-1.13] vs. 0.97 [0.71-1.28] pg/ml), hsCRP (0.53 [0.25-1.54] vs. 0.37 [0.31-0.61] mg/l), leukocytes (6.35+/-1.42 vs. 5.97+/-1.29 10(9) l); APA vs. IHA: TNF-alpha (4.54 [3.62-7.03] vs. 5.19 [4.23-5.27] pg/ml), IL-6 (0.96 [0.63-1.21] vs. 0.90 [0.65-1.06] pg/ml), hsCRP (0.34 [0.29-0.47] vs. 0.75 [0.36-1.11] mg/l), leukocytes (6.37+/-1.41 vs. 5.71+/-1.21 10(9) l)]. Significant differences in the levels of PINP between PA and EH group were observed (35.18 [28.46-41.16] vs. 45.21 [36.95-62.81] microg/l, p

Detection of circulating T-activating enzyme in the serum of a patient having hemolytic-uremic syndrome and disseminated intravascular coagulation.

A three-and-a-half-year old boy suffering from streptococcal pneumonia developed hemolytic-uremic syndrome and disseminated intravascular coagulation (DIC). His red blood cells (RBC) were shown to be T- and Tk-activated; serial testing showed his mature RBCs as well as neocytes remained T-activated at 40 days. Anti-T was detected in his serum, with only one of two T-activated RBC samples. T-activating enzyme was shown to be present in his serum.

Management of necrotic neck wounds with a "sandwich" pectoralis myocutaneous flap.

A modified pectoralis major myocutaneous flap was used to stabilize necrotic neck wounds rapidly in irradiated patients. The flap was a "sandwich" flap that included an overlying "parasternal" pectoral skin paddle for pharyngeal reconstruction, the pectoralis muscle for carotid protection, and a meshed skin graft applied to the undersurface of the muscle to replace cervical skin. This flap has been used to reconstruct seven patients with severe wound necrosis from pharyngeal fistula and infection. All patients had carotid exposure in the infected wound. Reconstruction in all patients accomplished restoration of pharyngeal continuity, carotid protection, and cervical skin replacement. Some patients required more than one procedure for closure. There were no carotid "blowouts" in any of the patients. This technique enables the head and neck surgeon to stabilize these contaminated wounds rapidly and to reconstruct complex defects of the pharynx and cervical skin.

Diurnal blood pressure variation in pheochromocytoma, primary aldosteronism and Cushing's syndrome.

We examined circadian blood pressure (BP) variation (expressed as a relative night-time BP decline) in subjects with primary aldosteronism (78 patients), pheochromocytoma (n=45) and Cushing's syndrome (n=18). Subjects with aldosterone-producing adenoma (n=21) and pheochromocytoma (n=27) were also investigated after the tumour removal. In all, 65 patients with essential hypertension served as a control group. The night-time BP decline was significantly attenuated in all three forms of endocrine hypertension compared to the control group (primary aldosteronism P<0.0001, pheochromocytoma P<0.0001 for systolic and diastolic BP and Cushing's syndrome P<0.0001/<0.001 vs essential hypertension). In the case of pheochromocytoma, the absence of the night-time BP decrease was more prominent compared to the primary aldosteronism group (P=0.003/0.001) and for the diastolic BP also in comparison with the Cushing's syndrome group (P=0.03). Tumour removal led in both groups to the restoration of the previously altered circadian rhythm (aldosterone-producing adenoma: P=0.0005/0.0009; pheochromocytoma: P=0.001/0.0007). Our study demonstrates a blunted circadian BP variation in all forms of adrenal hypertension in comparison with essential hypertension. This reduction of the night-time BP decrease was more prominent in pheochromocytoma than in primary aldosteronism or Cushing's syndrome.

Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region.

Recently published studies from different parts of the world report significantly higher prevalence of primary hyperaldosteronism (PH) in hypertensives (ranging from 5 to 25%) than the previously accepted figures. There have been no data so far about the prevalence of PH in Central Europe. Therefore, we have undertaken this study to evaluate the prevalence of PH in patients with moderate to severe hypertension referred to a hypertension unit in the Czech Republic, together with the determination of the percentage of different subtypes of PH including familial forms. In addition to that, we have evaluated the prevalence of other types of secondary forms of hypertension.A total of 402 consecutive patients (230 females and 172 males) with hypertension, referred to our hypertension unit, were studied. Positive aldosterone/renin ratio (ARR, (ng/100 ml)/(ng/ml/h)) >/=50 as a more strict marker of PH was found in 87 patients (21.6%), 30% of them were normokalaemic. The diagnosis of PH was later confirmed in 77 cases (89%); the total prevalence of PH was thus 19%. PH consisted of the following forms: idiopathic hyperaldosteronism 42%, unilateral aldosterone-producing adenoma 36%, unilateral hyperplasia 7%, nonclassifiable PH (refused operation/adrenal venous sampling) 13%, familial hyperaldosteronism type 1.2%. The prevalence of other types of secondary hypertension was as follows: pheochromocytoma 5%, renovascular 4.5%, hypercortisolism 2%, renal 0.75%. In conclusion, we have noted that PH in the Central Europe region (Czech Republic) is the most frequent form of endocrine hypertension with a considerably high prevalence in moderate to severe hypertension. Application of more strict criteria raises the probability of correct diagnosis of PH including the early normokalaemic stages of PH.

Congenital anomaly of the thumb: absent intrinsics and flexor pollicis longus.

Congenital absence of the median-innervated intrinsic muscles and flexor pollicis longus was seen in varying degrees of severity in eleven hands of eight patients. Three members were involved in one family in which the anomaly was probably an autosomal dominant. There were no chromosomal abnormalities. Surgical treatment of seven hands, including release of the adduction contracture and transfer of the ring-finger superficialis tendon to provide opposition and to reinforce the ulnar collateral ligament of the metacarpophalangeal joint, resulted in significant improvement in pinch and grasp.

Replacement of upper esophagus: results with myocutaneous flap and with gastric transposition.

The authors reviewed 25 cases of pharyngoesophageal replacement. A tubed pectoralis major myocutaneous flap was employed in ten cases where an adequate distal resection margin could be obtained above the thoracic inlet. Total gastric transposition was used in 15 cases where resection extended into the mediastinum. The overall rates of complications (52%), postoperative mortality (20%), and satisfactory deglutition (80%) were similar for both operations and were superior to those achieved with reconstructive procedures previously used by the authors. The choice of method is influenced by the length of the pharyngoesophagus to be replaced and the general condition of the patient. Gastric transposition is a more versatile operation and is adaptable to replacement of the entire esophagus if necessary, while the tubed pectoralis major myocutaneous flap has proven particularly effective for the rehabilitation of elderly and severely debilitated patients.

Sensations from surgically transferred glabrous skin; central versus peripheral factors.

In reinnervated skin transferred from the foot to the hand, sensory thresholds approach normal values--an observation not predicted by the theoretical relationship between innervation density and tactile acuity. Therefore, we suggest that innervation density is not the major factor determining tactile acuity. Rather, the hand region of the central somesthetic map may be specialized to provide a calibre of function unavailable to other regions.