Biomedical subjects

U Kuhnle

Publications and source records attributed to U Kuhnle.

At least 55 records · Page 3Linked to original sources

PubMed1990

Pseudohypoaldosteronism in eight families: different forms of inheritance are evidence for various genetic defects.

Pseudohypoaldosteronism is a rare hereditary disorder presenting in early infancy with renal salt loss leading to hyponatremia and hyperkalemia despite high levels of plasma aldosterone. The patients are insensitive to mineralocorticoids; however, sodium supplementation is able to correct electrolyte abnormalities. Absent or greatly diminished type I aldosterone receptors in peripheral mononuclear leucocytes have been recently demonstrated and explain the lack of response to mineralocorticoids. We have studied the mode of inheritance in eight families with a total of nine patients. There was evidence for an autosomal recessive form of inheritance in four families, while the other four families appeared to have an autosomal dominant mode of transmission. In three families the autosomal recessive form was characterized by normal receptor as well as hormone data in both parents, while in one family receptor levels in both parents were greatly reduced, but hormone levels were normal. In the four families with an autosomal dominant mode of transmission there was always one parent with reduced receptor binding in peripheral mononuclear leucocytes and elevated serum hormone levels. These parents were entirely asymptomatic. In an extended family we were able to study an aunt and her newborn daughter, who were both also biochemically affected but clinically asymptomatic. It, therefore, appears that this dual pattern of genetic transmission may indicate differing genetic defects which cause the same clinical picture of pseudohypoaldosteronism.

Adolescent↗

PubMed1989

Inheritance of mineralocorticoid effector abnormalities of human mononuclear leucocytes in families with pseudohypoaldosteronism.

In-vitro effects of aldosterone on intracellular sodium and potassium concentrations have been described for normal human mononuclear leucocytes (HML). After incubation for 1 h at 37 degrees C, intracellular sodium and potassium in HML are significantly higher in the presence of 1.4 nM aldosterone than after incubation without aldosterone. As published earlier, these effects were absent in patients with pseudohypoaldosteronism. In the present paper, the families of seven patients with pseudohypoaldosteronism (index cases) were studied. In the first family, two siblings were affected by the disease and had a reduced number of mineralocorticoid (MC) receptors on HML. Intracellular sodium and potassium in HML from these patients did not show a response to 1.4 nM aldosterone. The parents, who were first cousins, had no history of disease and normal receptor data, but in the mother, the response of HML electrolytes to aldosterone was abnormal. In the second family, the mother of a child with pseudohypoaldosteronism, the mother's sister, and her son, had low numbers of MC receptors. Only the aunt of the index case had an uncertain history of the disease. The MC effector mechanism was abnormal in both children and both mothers studied. In a third family, the effector defect was present only in HML of the father. In three further families the abnormality of the effector mechanism was detected in HML of the patient's mother. These data suggest an autosomal dominant inheritance of pseudohypoaldosteronism with variable expression of the gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗

PubMed1988

Lack of effect of aldosterone on intracellular sodium and potassium in mononuclear leucocytes from patients with pseudohypoaldosteronism.

In three patients with pseudohypoaldosteronism the effects of aldosterone on intracellular sodium and potassium were studied and compared with normal controls in whom aldosterone prevents the loss of sodium and potassium in vitro. Mononuclear leukocytes were incubated with or without aldosterone (1.4 nM) in RPMI-1640 for 1 h at 37 degrees C. After two washes in isotonic MgCl2 the wet cell pellets were weighted and intracellular sodium and potassium determined by flame photometry, results are expressed as mmol/kg wet cells. In the patients intracellular sodium fell from 18, 23 and 29 mmol/kg to 14, 18 and 11 mmol/kg, respectively, in the absence of aldosterone. With aldosterone added to the incubation medium sodium was not different from values obtained without aldosterone (15, 20 and 13 mmol/kg). Corresponding values for potassium were 89, 48 and 75 mmol/kg before and 68, 32 and 51 mmol/kg after incubation without and 69, 36 and 54 mmol/kg after incubation with aldosterone. Thus, incubation with aldosterone did not show an effect on intracellular sodium and potassium as seen in normals. Baseline values of sodium and potassium before the incubation were within the normal range. From these results it is concluded that in patients with pseudohypoaldosteronism the absent or decreased number of mineralocorticoid receptors in mononuclear leucocytes are accompanied by a lack of response of intracellular sodium and potassium to aldosterone in vitro. However, normal baseline intracellular electrolyte concentrations in these patients may indicate that mineralocorticoids are not involved in the maintenance of normal levels of intracellular sodium and potassium.

Adult↗

PubMed1988

Parallel determination of mineralocorticoid and glucocorticoid receptors in T- and B-lymphocytes of human spleen.

The binding characteristics of glucocorticoid and mineralocorticoid receptors were determined in T- and B-lymphocytes from the spleen of four deceased kidney donors. The number of glucocorticoid and mineralocorticoid receptors was equivalent in T- and B-cells (respectively, 1308 +/- 364 and 1335 +/- 520 glucocorticoid receptors per cell, and 174 +/- 29 and 164 +/- 24 mineralocorticoid receptors per cell). The number of binding sites per cell was 5- to 10-fold higher for dexamethasone than for aldosterone. The apparent dissociation constant of dexamethasone for glucocorticoid receptors was 2-fold higher than that of aldosterone for mineralocorticoid receptors. In conclusion, subpopulations of human lymphocytes have an equal number of glucocorticoid and mineralocorticoid receptors.

B-Lymphocytes↗

PubMed1987

Dexamethasone-suppressible hyperaldosteronism: pathophysiology, clinical aspects, and new insights into the pathogenesis.

A profile of dexamethasone-suppressible hyperaldosteronism (DSH), a variant of primary aldosteronism, is drawn by reviewing its pathophysiological and clinical aspects. Genetic studies show no HLA linkage and point to an autosomal dominant mode of inheritance, suggesting that the prevalence of this disease has been underestimated in the past. Hypertension, hypokalemia, suppressed renin, and high aldosterone values characterize DSH in the basal state, similar to the other forms of primary aldosteronism, i.e., aldosterone-producing adenoma (APA) or bilateral idiopathic adrenal hyperplasia (IAH). Biochemically DSH and APA can be differentiated from IAH since in both aldosterone does not respond to upright posture, to angiotensin II infusion, and to angiotensin-converting enzyme (ACE) captopril. In contrast, morphologically DSH is similar to IAH, since neither macroscopic nor histologic examinations of the adrenals give evidence of any unilateral abnormality. However, DSH is differentiated from APA and IAH by the hyperresponsiveness of aldosterone to acute ACTH administration as well as by the failure of aldosterone to escape from prolonged ACTH stimulation. The final diagnosis of DSH rests upon the prompt reversal of the features of mineralocorticoid excess by glucocorticoid therapy. In some cases hypertension is unresponsive to dexamethasone and needs alternative treatment. The main pathogenetic hypotheses point to a pituitary and/or an adrenal abnormality, but the intrinsic nature of the disease remains to be elucidated.

Adenoma↗

PubMed1987

Aldosterone receptors in different types of primary hyperaldosteronism.

The number of mineralocorticoid-binding sites on mononuclear leukocytes and plasma aldosterone (aldo) concentrations were measured in patients with different types of primary hyperaldosteronism. Patients with unilateral adenoma and patients with bilateral adrenal hyperplasia had a significantly lower (P less than 0.001) mean number of binding sites for aldo [144 +/- 36 (+/- SD; n = 6) and 140 +/- 28 sites/cell (n = 4), respectively] compared with normal subjects (292 +/- 110 sites/cell; n = 25). In four patients with dexamethasone-suppressible hyperaldosteronism, mineralocorticoid-binding sites in mononuclear leukocytes were normal (291 +/- 108 sites/cell). In all patients undergoing surgery for unilateral adenoma, the receptors normalized 3 months after the operation. In two patients the reduction in receptors persisted for a short time after surgery even though the plasma aldo level had already normalized. We conclude that mineralocorticoid excess produces down-regulation of mineralocorticoid receptors, which, in turn, might contribute to the genesis of the aldo escape phenomenon.

Adult↗

PubMed1987

Effects of aldosterone on intralymphocytic sodium and potassium in patients with primary aldosteronism.

In vitro effects of aldosterone have been described with regard to the intracellular sodium and potassium concentrations of human mononuclear leukocytes. In the present paper the in vitro effect of aldosterone on the intracellular sodium and potassium of human mononuclear leukocytes in 6 patients with primary aldosteronism was investigated. Except for one patient with elevated intracellular electrolytes, sodium and potassium in mononuclear leukocytes of patients with aldosteronism without incubation were within the range for normals. In the patients, no significant change of intracellular sodium or potassium was observed during incubation with or without aldosterone (1.4 nmol/l), whereas in normals, the loss of sodium and potassium during incubation without aldosterone was prevented by 1.4 nmol/l aldosterone. This insensitivity to aldosterone indicates that intracellular electrolytes in mononuclear leukocytes of patients with primary aldosteronism are kept in normal ranges by mechanism which are independent of mineralocorticoids and may represent the cellular correlate to the renal 'escape' phenomenon in aldosteronism.

Adult↗

PubMed1986

Dermatitis herpetiformis and growth retardation.

We report a juvenile patient with dermatitis herpetiformis, growth retardation and delayed onset of puberty. All symptoms reversed on gluten withdrawal and drug therapy was not required. It is suggested that dermatitis herpetiformis in this patient is the result of long-standing coeliac disease.

Adolescent↗

PubMed1986

Is salt-wasting in congenital adrenal hyperplasia due to the same gene as the fasciculata defect?

Clinical studies in patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) were designed to ascertain the genetics of the salt-wasting component of the disorder. The gene controlling aldosterone biosynthesis may not be the same gene that controls 21-hydroxylase in the adrenal zona fasciculata. This we infer from the following clinical observations: (1) concordance for salt-wasting is not observed in all HLA-identical sibs with CAH; (2) the defect in aldosterone biosynthesis does not persist throughout life as does the fasciculata defect; (3) there is a significantly increased gene frequency of B40 and Bw47 in salt-wasting CAH; (4) obligate heterozygote parents of patients with salt-wasting CAH do not express a partial defect in aldosterone biosynthesis, as they do in the fasciculata. These observations cast doubt on the accepted concept of the autosomal recessive transmission of the glomerulosa 21-hydroxylase deficiency.

17-alpha-Hydroxyprogesterone↗

PubMed1986

Comparison of plasma atrial natriuretic peptide levels in healthy children from birth to adolescence and in children with cardiac diseases.

An age-related dependence of plasma ANP levels was studied in 163 healthy children (94 boys, 69 girls) between the ages of day 1 and 16 yr. In neonates during the first 2-4 days of life, significantly higher plasma ANP plasma levels (range 129-356 pg/ml, mean 227) were found compared with older infants and children (p less than 0.001). Beyond the neonatal period through adolescence no significant difference in ANP concentrations could be found between the various age groups. Plasma ANP levels ranged between 2 and 109 pg/ml (mean 47) for all age groups after the newborn period. ANP levels were also determined in 15 adult volunteers and in arterial and venous cord blood of 16 healthy newborns, and concentrations were similar to those found in children. In addition, plasma ANP levels were measured in 40 children with various cardiac diseases; 22 of 40 patients exhibited ANP levels above the upper normal range seen in control children. Of these 22 patients all except two children revealed clinical signs of heart failure. In contrast 15 of 17 children without heart failure showed plasma ANP levels within the range of control children. ANP plasma levels ranged between 93 and 967 pg/ml (mean 284) in patients with heart failure and between 15 and 118 pg/ml (mean 57) in patients without heart failure, respectively. Increased ANP levels in neonates and cardiac patients may result from increased atrial distention and reflect a compensatory mechanism to improve cardiac function by reducing pre- and afterload.

Adolescent↗

PubMed1986

Contribution of the adrenal gland to the production of androstenedione and testosterone during the first two years of life.

Androstenedione and testosterone were measured in whole adrenal glands of 56 previously healthy boys who died suddenly between birth and 2 yr of age. In each adrenal gland, the concentration of androstenedione considerably exceeded that of testosterone. The highest concentrations were found during the first week of life (median, 295 ng/g; range, 98-320 ng/g). Thereafter, values decreased rapidly until the end of the first year of life (median, 10 ng/g; range, 4.4-22.7 ng/g). Adrenal testosterone concentrations averaged 15% of those of androstenedione in the same gland and similarly decreased until the end of the first year. The decrease of adrenal androgen concentrations paralleled the involution of the fetal adrenal zone. A close correlation existed between the concentration of androstenedione in adrenal tissue and plasma. However, no correlation existed between adrenal and plasma testosterone. When the adrenals and testes of the same infant were compared, there was 10 times more androstenedione in the adrenals than in the testes during the first 2 yr of life. The testes contained more testosterone than the adrenals only during the first 4 months. Thus, in infant boys the adrenals are the main source of androstenedione during the first 2 yr. After the sixth month of life, they also are the main source of testosterone.

Adrenal Glands↗

PubMed1986

Evidence for the secretion of an antimineralocorticoid in congenital adrenal hyperplasia.

Plasma extracts from patients with congenital adrenal hyperplasia were found to contain substances that competed with aldosterone for mineralocorticoid receptor-binding sites in a rat kidney cytosol system. In normal subjects and patients with other disorders, the mineralocorticoid receptor-binding activity in such extracts could be entirely accounted for by the sum of the contributions of the steroids known to bind to the mineralocorticoid receptor. The secretion of these binding substances in patients with the C-21 hydroxylation defect was ACTH dependent. While these substances could be either mineralocorticoid agonists or antagonists, the latter is more likely. Production of mineralocorticoid antagonists would account for the compensatory hyperaldosteronism that occurs in the simple virilizing form, in which there is minimal impairment of aldosterone secretory reserve, and for the tendency to Addisonian crisis in patients with the salt-losing form, who have a more severe defect in aldosterone biosynthesis.

Adolescent↗

PubMed1986

Is heterozygosity for the steroid 21-hydroxylase deficiency responsible for hirsutism, premature pubarche, early puberty, and precocious puberty in children?

We applied the ACTH-stimulation test developed in our laboratory for the detection of heterozygous carriers of the 21-hydroxylase deficiency gene to patients suffering from hirsutism (n = 89), premature pubarche (n = 75), early puberty (n = 37), and precocious puberty (n = 22). While, in the general population, this test is positive in less than 2%, we found in 33% of hirsute patients, in 41% of patients with premature pubarche, and in 33% of patients with early puberty a hormonal response similar to the one seen in heterozygous carriers for the 21-hydroxylase defect. In contrast, only 18% of patients with precocious puberty responded abnormally. Thus we speculate that, at least in some patients with hirsutism, premature pubarche, and early puberty, heterozygosity for the 21-hydroxylase defect plays a major role in the pathogenesis of these disorders.

17-alpha-Hydroxyprogesterone↗

PubMed1986

Generalized unresponsiveness to mineralocorticoid hormones: familial recessive pseudohypoaldosteronism due to aldosterone-receptor deficiency.

The present report describes two sibs--born from consanguineous parents--presenting with severe salt wasting. Generalized pseudohypoaldosteronism (PHA) was diagnosed on the basis of markedly elevated sodium concentration in urine (84 & 63 mmol/L respectively), sweat (181 & 196), saliva (- & 120) and stool (- & 189), hyponatremia (112 & 132) and hyperkalemia (10.7 & 7.3) in the presence of increased plasma aldosterone (greater than 8.5 & 5.4 ng/ml), plasma renin activity (40 & 18.9 ng/ml/hr) and urinary aldosterone (greater than 32 & 11.6 micrograms/day). Both parents investigated under basal conditions (sodium ad libitum) and under sodium restricted diet appeared to be normal. Aldosterone binding studies performed on mononuclear leukocytes showed no type I receptors in the investigated child whereas low amounts were found in both parents (90 sites/cell and 63 sites/cell in the mother and the father, respectively). Isolated renal unresponsiveness to mineralocorticoid hormones is thought to be an autosomal dominant inherited disease. In contrast, the results obtained in these two new cases of generalized PHA, as well as the fact that four of five yet reported cases were born from consanguineous parents, suggest an autosomal recessive mode of inheritance for generalized PHA.

Aldosterone↗

PubMed1986

The determination of mineralocorticoid receptors in human mononuclear leukocytes from patients with mineralocorticoid excess: physiological and pathological implications.

The affinity and the capacity of mineralocorticoid receptors (MR) in human mononuclear leukocytes (HML) were determined in 9 patients with Conn's syndrome (PA) and in 3 patients with pseudohypoaldosteronism (PHA). The number of binding sites per cell was 136 +/- 39 (mean +/- SD) in PA. One case with PHA had no MR, and of the other 2 patients, one had 50 and the other 55 receptors per cell. The capacity of normal controls ranged from 200 to 400 receptors per cell (n = 20). We conclude that the etiology of PHA is due to a lack of MR in the target tissues and that a down regulation of MR may exist in PA.

Adult↗

PubMed1986

[Pseudohypoaldosteronism--renal salt loss syndrome. Therapy and course exemplified by 2 siblings].

In 2 sibs pseudohypoaldosteronism was diagnosed by measurements of high serum aldosterone and elevated plasma renin activity. During their first week of life the first born girl, phenotypically normal, went through a severe salt-losing crisis with hyponatremia and hyperkalemia. Steroids given because of suspected congenital adrenal hyperplasia had no effect. High parenteral and later oral substitution of sodium normalized the serum electrolytes. The younger brother had milder symptoms. His salt-losing crisis developing during the first week of life was treated immediately with salt substitution. Both children developed normally with high oral sodium chloride supplementation, as regulated by the parents, using daily body weight measurements. Both children frequently suffer salt-losing crises, generally preceded by simple upper respiratory tract infections, which have to be treated in the hospital by infusion with a hyperosmolar sodium chloride solution.

Acidosis↗

PubMed1985

Aldosterone-receptor deficiency in pseudohypoaldosteronism.

Pseudohypoaldosteronism, a syndrome characterized by salt wasting and failure to thrive, usually presents in infancy as high urinary levels of sodium despite hyponatremia, hyperkalemia, hyperreninemia, and elevated aldosterone levels. We have investigated this syndrome for the possibility of abnormal Type I or "mineralocorticoid-like" receptors, which have intrinsic steroid specificity indistinguishable from that of renal mineralocorticoid receptors and are found in many tissues and cells, including mononuclear leukocytes. We have studied three patients with pseudohypoaldosteronism: the 28-year-old index case in Melbourne (Patient 1) and two siblings in Munich, eight and two years of age (Patients 2 and 3); clinically, Patient 3 had a less severe case than his sister. Percoll-separated control monocytes bound [3H]aldosterone with high affinity (Kd approximately 3 nM) and limited capacity (150 to 600 sites per cell). On repeated examination, no [3H]aldosterone binding was found in monocytes from Patients 1 and 2; in Patient 3, the levels were 62 sites per cell, more than 2 S.D. below those of the control. Levels in the parents of the Munich patients (first cousins) were normal. It appears that pseudohypoaldosteronism is caused by a Type I receptor defect, that the defect may be complete or partial, that transmission may be autosomal recessive, and that the study of patients with pseudohypoaldosteronism may indicate physiologic roles for Type I receptors in nonepithelial tissues.

Adult↗

PubMed1984

Etomidate: a selective adrenocortical 11 beta-hydroxylase inhibitor.

To investigate the adrenocortical suppression caused by the anesthetic etomidate, plasma levels of progesterone (P), 17-hydroxyprogesterone (17-OHP), 11-deoxycorticosterone (DOC), corticosterone (B), aldosterone (Aldo), 11-deoxycortisol (S), cortisol (F), and cortisone (E) were measured simultaneously before and after a short-term ACTH stimulation test in a 6.5-year-old boy whose convulsions could be kept under control only with constant etomidate infusions. During etomidate therapy, plasma levels of DOC and S were extremely elevated, the progestins P and 17-OHP were slightly elevated, whereas B and Aldo were in the lower normal range, and F and E were markedly decreased. A short-term ACTH stimulation test during etomidate infusion gave a blunted response of B, Aldo, F and E, whereas the level of DOC remained high and S even further increased. P and 17-OHP showed a positive response to ACTH. The ratios of B/DOC and F/S, which reflect adrenocortical 11 beta-hydroxylase activity, were extremely decreased during etomidate and did not change after ACTH stimulation. In contrast, the ratios of DOC/P and S/17-OHP, which reflect 21-hydroxylase activity, were elevated and remained elevated after ACTH stimulation. After discontinuation of etomidate therapy, all the baseline steroid levels were somewhat elevated, but responded normally to ACTH. These results demonstrate that etomidate causes a specific and reversible blockade of the 11 beta-hydroxylation of adrenal steroid synthesis.

17-alpha-Hydroxyprogesterone↗