Primary aldosteronism (PA) results from excess production of mineralocorticoid hormone aldosterone by the adrenal cortex. It is normally caused either by unilateral aldosterone-producing adenoma (APA) or by bilateral aldosterone excess as a result of bilateral adrenal hyperplasia. PA is the most common cause of secondary hypertension and associated morbidity and mortality. While most cases of PA are sporadic, an important insight into this debilitating disease has been derived through investigating the familial forms of the disease that affect only a minor fraction of PA patients. The advent of gene expression profiling has shed light on the genes and intracellular signaling pathways that may play a role in the pathogenesis of these tumors. The genetic basis for several forms of familial PA has been uncovered in recent years although the list is likely to expand. Recently, the work from several laboratories provided evidence for the involvement of mammalian target of rapamycin pathway and inflammatory cytokines in APAs; however, their mechanism of action in tumor development and pathophysiology remains to be understood.
Adenoma ; Adrenal Cortex ; Aldosterone ; Cytokines ; Gene Expression Profiling ; Humans ; Hyperaldosteronism ; Hyperplasia ; Hypertension ; Mineralocorticoids ; Mortality ; Sirolimus

Congenital adrenal hyperplasia (CAH), an autosomal recessive disorder, is due to deficiency of the enzymes involved in adrenal steroidogenesis. Phenotypic manifestations vary as a result of the degree of glucocorticoid or mineralocorticoid deficiency and androgen excess present. Among Filipinos, the estimated crude incidence of CAH is approximately 1 in 7,000, which is higher than what is reported in most populations. More than 90% of all cases result from a 21-hydroxylase (21-OH) (cytochrome P450c21) enzyme deficiency involving two 21-OH genes, the active gene (CYP21) and a pseudogene (CYP21P). Studies have shown that mutations result from unequal crossover during meiosis which leads to complete deletion of the gene, gene conversion events or to point mutations. To date, there are no published data on the types of mutations present among Filipinos diagnosed with congenital adrenal hyperplasia. The objective of this study is to describe the profile of Filipino patients diagnosed with CAH and to determine the disease-causing alleles in the 21-OH gene of these patients. Using a method of combined differential polymerase chain reaction and amplification created restriction site approach, direct probing for the presence of known mutations in exons 1,3,4,6,7,8 and intron 2 of the CYP21 and CYP21P genes among Filipino patients with CAH was performed. A total of 12 unrelated CAH patients were examined. A majority of these cases had a premature splicing error mutation at nucleotide 656 of intron 2. The determination of the most frequent alleles in our population can facilitate rapid screening for mutations in the 21-OH gene and lead to a definitive diagnosis of CAH.

Human ; Male ; Female ; Steroid 21-hydroxylase ; Adrenal Hyperplasia, Congenital ; Introns ; Glucocorticoids ; Mineralocorticoids ; Alleles ; Pseudogenes ; Rna Splicing ; Nucleotides

Secondary hypertension can account for 15% of hypertension cases. The causes of secondary hypertension mostly come from renal diseases, such as renal parenchymal or renovascular disease, and endocrine diseases. The importance of diagnosing secondary hypertension lies in the fact that it may convert an incurable disease into a potentially curable disease. Even if the underlying disease may not be curable, being able to offer disease specific treatments may often make blood pressure control much easier. The causes of endocrine hypertension include primary aldosteronism, pheochromocytoma, Cushing's syndrome, acromegaly, hyper- or hypothyroidism, hyperparathyroidism and other mineralocorticoid hypertension (e.g. apparent mineralocorticoid excess syndrome, Liddle's syndrome). Primary aldosteronsim, pheochromocytoma, and Cushing's syndrome are among the common causes of endocrine hypertension. The first step in evaluating a patient with suspected endocrine-related hypertension is to exclude other secondary causes, particularly renal disorders. An accurate diagnosis of endocrine hypertension provides the clinician a unique treatment opportunity. This topic review will summarize rare causes of endocrine hypertension except primary aldosteronism and pheochromocytoma.
Acromegaly ; Blood Pressure ; Cushing Syndrome ; Endocrine System Diseases ; Humans ; Hyperaldosteronism ; Hyperparathyroidism ; Hypertension ; Hypothyroidism ; Mineralocorticoid Excess Syndrome, Apparent ; Mineralocorticoids ; Pheochromocytoma ; Resin Cements

17alpha-hydroxylase and 17,20-lyase are enzymes encoded by the CYP17A1 gene and are required for the synthesis of sex steroids and cortisol. In 17alpha-hydroxylase deficiency, there are low blood levels of estrogens, androgens, and cortisol, and resultant compensatory increases in adrenocorticotrophic hormone that stimulate the production of 11-deoxycorticosterone and corticosterone. In turn, the excessive levels of mineralocorticoids lead to volume expansion and hypertension. Females with 17alpha-hydroxylase deficiency are characterized by primary amenorrhea and delayed puberty, with accompanying hypertension. Affected males usually have female external genitalia, a blind vagina, and intra-abdominal testes. The treatment of this disorder is centered on glucocorticoid and sex steroid replacement. In patients with 17alpha-hydroxylase deficiency who are being raised as females, estrogen should be supplemented, while genetically female patients with a uterus should also receive progesterone supplementation. Here, we report a case of a 21-year-old female with 17alpha-hydroxylase deficiency who had received inadequate treatment for a prolonged period of time. We also include a brief review of the recent literature on this disorder.
Adrenocorticotropic Hormone ; Amenorrhea ; Androgens ; Corticosterone ; Estrogens ; Female ; Genitalia ; Humans ; Hydrocortisone ; Hypertension ; Male ; Mineralocorticoids ; Progesterone ; Puberty, Delayed ; Steroid 17-alpha-Hydroxylase* ; Steroids ; Testis ; Uterus ; Vagina ; Young Adult

Mineralocorticoids influences on acid-base homeostasis by the regulation of urine acidification. But its mechanism of acion is not well known in human. This study compared the acid-base status and the indices of urine acidification before and after mineralocorticoid administration in human, and analyzed the effect of mineralocorticoids on human acid-base homeostasis. We administered 9a-fludrocortisone in 6 chronic renal failure patients and 6 normal controls 0.5mg daily for 7 days. The results were as following: 1) After administration of 9a-fludrocortisone in patients group, serum aldosterone level changed from 120.2+/-71.0pg/mL to 44.8+/-32.2pg/mL(mean+/-SD, p< 0.05). Serum HCO- level was not changed. Urine ammonium excretion was incresed from 24.6+/-12.3 mmol/day to 43.7+/-19.0 (p<0.05), but there were no change in urine pH and urine anion gap, Serum potassium level decreased from 5.5+/-0.7mBq/L to 4.1+/-0.5mEq/L (p<0.05), and TTKG increased from 3.9 to 8.9(p<0.05). 2) After administration of 9a-fludrocortisone in control group, serum aldosterone level changed from 99.7+/-44.5pg/mL to 25.1+/-3 mL(p<0.05). Serum HCO- level was not changed. Urine ammonium excretion was incresed from 44.3+/-21.6mmoVday to 76.3+/-19.6(p<0.05), but there were no change in urine pH and urine anion gap. Serum potassium level decreased from 4.8+/-0.5mEq/L to 3.9+/-0.2mHq/L(p< 0.05), but there was no change in TTKG. 3) No patient or control showed any discomfort after 9-fludrocortisone administration, and there was no elevation in diastolic blood pressure, increase in body weight, electrolyte abnormality. In summary, after 9alpha-fludrocortisane administration, urinary ammonium excretion increased in both patients and control group, and this phenomenon occured with correction of hyperkalemia without urine pH change. This result implies urinary ammonium excretion increase by mineralocorticoid. In human increase in renal distal acidification by mineralocorticoid is due to increase in renal ammoniagenesis rather than stimulation on proton excretion.
Acid-Base Equilibrium ; Aldosterone ; Ammonium Compounds* ; Blood Pressure ; Body Weight ; Homeostasis ; Humans ; Hydrogen-Ion Concentration ; Hyperkalemia ; Kidney Failure, Chronic ; Mineralocorticoids ; Potassium* ; Protons

Glycyrrhizin, the main ingredient of licorice, may evoke severe hypokalemia and muscle paralysis by its mineralocorticoid effects. We present a 78-year-old man who developed subacute flaccid quadriparesis with a high creatine kinase (CK) level, hypokalemia, metabolic alkalosis, and low plasma renin activity after ingesting licorice daily for two years. A muscle biopsy revealed vacuolar degeneration of myofibers. This case suggests that glycyrrhizin (licorice)-induced hypokalemic myopathy must be included in the differential diagnosis of a patient with generalized muscle weakness and hypokalemia.
Aged ; Alkalosis ; Biopsy ; Creatine Kinase ; Diagnosis, Differential ; Glycyrrhiza ; Glycyrrhizic Acid* ; Humans ; Hypokalemia ; Mineralocorticoids ; Muscle Weakness ; Muscular Diseases* ; Paralysis ; Plasma ; Quadriplegia ; Renin

Hypokalemia is a common clinical problem. The kidney is responsible for long term potassium homoeostasis, as well as the serum potassium concentration. The main nephron site where K secretion is regulated is the cortical collecting duct, mainly via the effects of aldosterone. Aldosterone interacts with the mineralocorticoid receptor to increase sodium reabsorption and potassium secretion; the removal of cationic sodium makes the lumen relatively electronegative, thereby promoting passive potassium secretion from the tubular cell into the lumen through apical potassium channels. As a result, any condition that decreases the activity of renal potassium channels results in hyperkalemia (for example, amiloride intake or aldosterone deficiency) whereas their increased activity results in hypokalemia (for example, primary aldosteronism or Liddle's syndrome). The cause of hypokalemia can usually be determined from the history. If there is no apparent cause, the initial step is to see if hypokalemia is in associated with systemic hypertension or not. In the former group hypokalaemia is associated with a high mineralocorticoid effect or hyperactive sodium channel as in Liddle's syndrome. In hypertensive hypokalemic patients, measurement of the renin, aldosterone, and cortisol concentrations would be of help in differential diagnosis.
Aldosterone ; Amiloride ; Diagnosis, Differential ; Humans ; Hydrocortisone ; Hyperaldosteronism ; Hyperkalemia ; Hypertension ; Hypokalemia ; Kidney ; Mineralocorticoids ; Nephrons ; Potassium ; Potassium Channels ; Receptors, Mineralocorticoid ; Renin ; Sodium ; Sodium Channels

Pseudohypoaldosteronism (PHA), a rare syndrome of systemic or renal mineralocorticoid resistance, is clinically characterized by hyperkalemia, metabolic acidosis, and elevated plasma aldosterone levels with either renal salt wasting or hypertension. PHA is a heterogeneous disorder both clinically and genetically and can be divided into three subgroups; PHA type 1 (PHA1), type 2 (PHA2) and type 3 (PHA3). PHA1 and PHA2 are genetic disorders, and PHA3 is a secondary disease of transient mineralocorticoid resistance mostly associated with urinary tract infections and obstructive uropathies. PHA1 includes two different forms with different severity of the disease and phenotype: a systemic type of disease with autosomal recessive inheritance (caused by mutations of the amiloride-sensitive epithelial sodium channel, ENaC) and a renal form with autosomal dominant inheritance (caused by mutations of the mineralocorticoid receptor, MR). In the kidneys, the distal nephron takes charge of the fine regulation of water absorption and ion handling under the control of aldosterone. Two major intracellular actors necessary for the action of aldosterone are the MR and the ENaC. Impairment of the intracellular aldosterone signal transduction pathway results in resistance to the action of mineralocorticoids, which leads to PHA. Herein, ion handling the distal nephron and the clinico-genetic findings of PHA are reviewed with special emphasis on PHA type 1.
Absorption ; Acidosis ; Aldosterone ; Epithelial Sodium Channels ; Hyperkalemia ; Hypertension ; Kidney ; Mineralocorticoids ; Nephrons ; Phenotype ; Plasma ; Pseudohypoaldosteronism* ; Receptors, Mineralocorticoid ; Signal Transduction ; Urinary Tract Infections ; Water ; Wills

Mineralocorticoid receptor antagonists not only are used as a diuretics to treat essential hypertension, but also protect the heart and kidney by inhibiting inflammation and fibrosis. Since the discovery of spironolactone, the first generation of mineralocorticoid receptor antagonist, two types of non-steroid mineralocorticoid receptor antagonists (finerenone and esaxerenone) approved for clinical use have been developed, which have the advantages of high affinity, high selectivity and balanced distribution in heart and kidney, and can be used in clinic as a cardiorenal protective drug. In this paper, the development history of mineralocorticoid receptor antagonists was reviewed, and the pathophysiological mechanism of inflammation and fibrosis caused by mineralocorticoid receptors and the similarities and differences of different generations of mineralocorticoid receptor antagonists were analyzed. In particular, the phase III clinical research evidence of finerenone and esaxerenone was discussed. This paper also reviews the research progress of cardiorenal protection of non-steroid mineralocorticoid receptor antagonists in patients with chronic kidney disease.
Humans ; Fibrosis ; Heart Failure ; Mineralocorticoid Receptor Antagonists/therapeutic use* ; Mineralocorticoids/therapeutic use* ; Renal Insufficiency, Chronic/drug therapy* ; Clinical Trials, Phase III as Topic

We report a very rare case of congenital adrenal agenesis presented with adrenal insufficiency in a 4-day-old female newborn. She was admitted with darkish skin color and seizure. Her external genitalia was normal. Elevated serum level of adrenocorticotropic hormone and increased plasma renin activity were observed. Plasma cortisol level and aldosterone level were decreased. Pelvic ultrasonography revealed bilateral agenesis of adrenal glands. Six exons of the steroidogenic factor-1 (SF-1, NR5A1) gene and their intronic flanking sequences were normal. Now, she is continuously receiving replacement doses of glucocorticoids and mineralocorticoids under adrenal insufficiency. Her growth and development are completely normal. We propose that when a patient presents with 46, XY disorder of sex development or normal female genitalia with adrenal insufficiency, SF-1 gene mutation study should be included in the differential diagnosis.
Adrenal Glands ; Adrenal Insufficiency ; Adrenocorticotropic Hormone ; Aldosterone ; Diagnosis, Differential ; Exons ; Female ; Genitalia ; Genitalia, Female ; Glucocorticoids ; Growth and Development ; Humans ; Hydrocortisone ; Infant, Newborn ; Introns ; Mineralocorticoids ; Plasma ; Renin ; Seizures ; Sexual Development ; Skin