eMedicine Specialties > Pediatrics: General Medicine > Endocrinology
Pseudohypoaldosteronism
Updated: Jul 11, 2008
Introduction
Background
Pseudohypoaldosteronism (PHA) refers to a heterogeneous group of disorders of electrolyte metabolism characterized by an apparent state of renal tubular unresponsiveness or resistance to the action of aldosterone. The condition is characterized by hyperkalemia, metabolic acidosis, and normal glomerular filtration rate (GFR). Volume depletion or hypervolemia; renal salt wasting or retention; hypotension or hypertension; and elevated, normal, or low levels of renin and aldosterone may be observed in the various conditions that result in this syndrome.
Since primary PHA was first described, it has been further classified into a classic form of PHA (PHA type I [PH-I]) and PHA type II (PHA-II), which is also referred to as chloride shunt syndrome. Recently, PHA-I has been recognized as a heterogeneous syndrome that includes at least 2 clinically distinguishable entities with either renal or multiple target organ defects (MTOD). Early childhood hyperkalemia, or renal tubular acidosis (RTA) IV subtype 5, is a variant of the renal form of PHA-I.
PHA-II (also known as Gordon syndrome or chloride shunt syndrome) is a rare familial renal tubular defect characterized by hypertension and hyperkalemic metabolic acidosis in the presence of low renin and aldosterone levels. Paver and Pauline first reported PHA-II in 1964,1 although Gordon described it as a new clinical entity in 1970.2
The molecular basis for most individuals who have PHA-II was linked to loss-of-function mutations in WNK1 or WNK4.3,4,5,6,7 WNKs comprise a family of serine-threonine protein kinases with unusual placement of the catalytic lysine compared with all other protein kinases. WNK1 or WNK4 regulate chloride cotransporters of the distal nephron and other epithelia.
An acquired or secondary form of PHA has also been described.
A summary of the forms of PHA is as follows:
- Primary pseudohypoaldosteronism
- Type I (PHA-I)
- Renal type I (renal PHA-I)
- Multiple target organ defect type I (MTOD PHA-I)
- Early childhood hyperkalemia
- Type II (PHA-II)
- Gordon syndrome
- Adolescent hyperkalemic syndrome
- Type I (PHA-I)
- Secondary pseudohypoaldosteronism
Pathophysiology
Renal pseudohypoaldosteronism type I
Renal PHA-I, or early childhood hyperkalemia, is probably due to a maturation disorder in the number or function of aldosterone receptors. This autosomal dominant disorder has been associated with mutations in the human mineralocorticoid receptor gene (MLR) in numerous kindreds and also in sporadic cases.
Multiple target organ defect pseudohypoaldosteronism type I
In this variant, other organs are involved, such as the sweat glands, salivary glands, and colon. The fundamental abnormality in MTOD PHA-I is a loss-of-function mutation in the alpha or beta subunits of the epithelial sodium channel (ENaC), resulting in defective sodium transport in many organs containing the ENaC (eg, kidney, lung, colon, sweat and salivary glands). This amiloride-sensitive member of the degenerin/epithelial sodium channel (Deg/ENaC) superfamily of ion channels is comprised of 3 homologous units (alpha, beta, gamma) and is expressed in the apical membrane of epithelial cells lining the airway, colon, and distal nephron. ENaC plays an essential role in transepithelial Na+ and fluid balance.
The state of hyper-reninism and hyperaldosteronism in these children is the result of sustained extracellular fluid (ECF) volume depletion and is not due to peripheral resistance to mineralocorticoids.
Pseudohypoaldosteronism type II
As first reported in 2003 and confirmed with molecular studies, the defect for PHA-II involves absent WNK1 or WNK4 kinase function in the distal nephron.3,5,6,7 WNK4 is exclusively expressed in the distal nephron, whereas WNK1 functions in most polarized epithelia (cells that line the lumen of hepatic biliary ducts, gallbladder, pancreatic ducts, epididymis, sweat ducts, and colonic crypts). These kinases regulate the thiazide-sensitive Na-Cl cotransporter (NCCT) in the distal nephron. Specifically, loss-of-function mutations in WNK1 or WNK4 abolish WNK regulation of NCCT, resulting in the uninhibited NCCT activity that causes PHA-II.
Prior studies had implicated both proximal and tubular defects. Enhanced chloride absorption in the distal nephron had been suggested as the primary abnormality; thus, the name chloride shunt syndrome was proposed. This increased reabsorptive avidity of the distal nephron for chloride, in turn, limits the sodium-dependent and mineralocorticoid-dependent voltage that is the driving force for potassium and hydrogen ion secretion, resulting in hyperkalemia and acidosis. The increased reabsorption of sodium chloride results in hyperchloremia with ensuing volume expansion and hypertension. Volume expansion results in secondary hypoaldosteronism and, consequently, in hyporeninemia.
Evidence suggests that enhanced sodium chloride reabsorption takes place in several nephron segments proximal to the potassium-secreting sites (proximal to the proximal tubule and thick ascending limb of the loop of Henle). An alternative mechanism to explain the renal tubular defect in this syndrome is abnormally low levels of urinary prostaglandin metabolites, a product of renal prostaglandin synthesis. Mutations in the thiazide-sensitive Na+/Cl- cotransporter gene have been excluded as a cause.
Other authors still speculate that Gordon syndrome could result from a generalized increase in the activity of the bumetanide-sensitive Na+ -K+ -2Cl- cotransporter; however, this has not been studied. Based on lack of response to the infusion of atrial natriuretic peptide (ANP), an increased proximal tubular reabsorption caused by inherited insensitivity to the action of the natriuretic factor has been proposed. However, other authors have not demonstrated this.
Summary of Pseudohypoaldosteronism
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Table
| Details | Pseudohypoaldosteronism Type I | Pseudohypoaldosteronism Type II | |||
|---|---|---|---|---|---|
| Renal PHA-I | MTOD PHA-I | Early Childhood Hyperkalemia | PHA-II | ||
| Synonyms | Classic PHA of infancy, Cheek and Perry syndrome, autosomal dominant PHA-I, subtype 4 RTA IV | Autosomal recessive PHA-I | Subtype 5 RTA IV | Adolescent hyperkalemic syndrome, Spitzer-Weinstein syndrome, subtype 3 RTA IV | Gordon syndrome, mineralocorticoid-resistant hyperkalemia, chloride shunt syndrome |
| Age | Newborn period, infancy | Newborn period, infancy | Infancy, childhood | Childhood | Adulthood |
| Organs | Kidney | Kidney, sweat glands, salivary glands, colon | Kidney | Kidney | Kidney |
| Genetics | Autosomal dominant, sporadic | Autosomal recessive, sporadic | Unknown | Unknown | Autosomal dominant, sporadic |
| Mechanism | Heterozygous MLR mutations (possible) | Defective Na transport in organs that contain ENaC | Maturation disorder in the number or function of aldosterone receptors | Chloride shunt | Chloride shunt |
| Serum potassium | High | High | High | High | High |
| Acidosis | Present | Present | Present | Present | Present |
| Serum sodium | Normal or low | Normal or low | Normal | Normal | Normal |
| PRA* | High | High | Normal or high | Normal or low | Low |
| Aldosterone | High | High | Normal or high | Normal or low | Low |
| Blood volume | Normovolemia, hypovolemia | Normovolemia, hypovolemia | Normovolemia | Hypervolemia | Hypervolemia |
| Blood pressure | Normal or low | Normal or low | Normal or low | Normal or low | Normal or low |
| GFR | Normal | Normal | Normal | Normal | Normal |
| Salt wasting | Renal | Renal, sweat or salivary glands, colon | Absent | Absent | Absent |
| Hypercalciuria | Present or absent | Absent | Absent | Present | Present |
| Therapy | Na supplementation, K-binding resins | High-Na, low-K diet, K-binding resins, hydrochlorothiazide | Na bicarbonate, K-binding resins | Dietary Na restriction, hydrochlorothiazide | Dietary Na restriction, hydrochlorothiazide |
| Prognosis | Outgrow by age 2 y | Lifelong therapy | Outgrow by age 5 y | Lifelong therapy | Lifelong therapy |
| Details | Pseudohypoaldosteronism Type I | Pseudohypoaldosteronism Type II | |||
|---|---|---|---|---|---|
| Renal PHA-I | MTOD PHA-I | Early Childhood Hyperkalemia | PHA-II | ||
| Synonyms | Classic PHA of infancy, Cheek and Perry syndrome, autosomal dominant PHA-I, subtype 4 RTA IV | Autosomal recessive PHA-I | Subtype 5 RTA IV | Adolescent hyperkalemic syndrome, Spitzer-Weinstein syndrome, subtype 3 RTA IV | Gordon syndrome, mineralocorticoid-resistant hyperkalemia, chloride shunt syndrome |
| Age | Newborn period, infancy | Newborn period, infancy | Infancy, childhood | Childhood | Adulthood |
| Organs | Kidney | Kidney, sweat glands, salivary glands, colon | Kidney | Kidney | Kidney |
| Genetics | Autosomal dominant, sporadic | Autosomal recessive, sporadic | Unknown | Unknown | Autosomal dominant, sporadic |
| Mechanism | Heterozygous MLR mutations (possible) | Defective Na transport in organs that contain ENaC | Maturation disorder in the number or function of aldosterone receptors | Chloride shunt | Chloride shunt |
| Serum potassium | High | High | High | High | High |
| Acidosis | Present | Present | Present | Present | Present |
| Serum sodium | Normal or low | Normal or low | Normal | Normal | Normal |
| PRA* | High | High | Normal or high | Normal or low | Low |
| Aldosterone | High | High | Normal or high | Normal or low | Low |
| Blood volume | Normovolemia, hypovolemia | Normovolemia, hypovolemia | Normovolemia | Hypervolemia | Hypervolemia |
| Blood pressure | Normal or low | Normal or low | Normal or low | Normal or low | Normal or low |
| GFR | Normal | Normal | Normal | Normal | Normal |
| Salt wasting | Renal | Renal, sweat or salivary glands, colon | Absent | Absent | Absent |
| Hypercalciuria | Present or absent | Absent | Absent | Present | Present |
| Therapy | Na supplementation, K-binding resins | High-Na, low-K diet, K-binding resins, hydrochlorothiazide | Na bicarbonate, K-binding resins | Dietary Na restriction, hydrochlorothiazide | Dietary Na restriction, hydrochlorothiazide |
| Prognosis | Outgrow by age 2 y | Lifelong therapy | Outgrow by age 5 y | Lifelong therapy | Lifelong therapy |
*Plasma renin activity
Frequency
International
- Renal PHA-I: More than 70 cases of this salt-wasting syndrome have been reported in the literature since the first description in 1958.8 Renal PHA-I, also called Cheek and Perry syndrome or classic PHA of infancy, represents the most common form of PHA-I. The early childhood hyperkalemia variant of renal PHA-I is the most common subtype of type IV RTA in children and is found with equal frequency in males and females. Occasionally, several siblings are affected.
- MTOD PHA-I: Multiple target organ resistance has been reported in several kindreds.
- PHA-II: This is a rare form of PHA.
- Secondary PHA: An acquired form of PHA has been rarely reported but may occur more frequently in clinical practice.
Mortality/Morbidity
- Renal PHA-I: Individuals may present with severe symptoms early after birth and throughout the first two weeks of life or may be asymptomatic.
- MTOD PHA-I: Individuals are prone to developing respiratory symptoms; death may ensue during the neonatal period.
- PHA-II: Most individuals are asymptomatic until adolescence when hypertension develops.
Sex
The early childhood hyperkalemia variant of renal PHA-I is found with equal frequency in males and females.
Age
- Renal PHA-I only occurs in newborns and infants and usually improves with age.
- Early childhood hyperkalemia occurs in infants and young children.
- MTOD PHA-I occurs in newborns and infants but persists into adulthood.
- PHA-II occurs in older children and adults. Although the defect is present at birth, the disease is not usually diagnosed until adolescence.
- Secondary PHA may occur at any age.
Clinical
History
- Renal pseudohypoaldosteronism type I
- The clinical expression of renal pseudohypoaldosteronism type I (PHA-I) widely varies, even among members of the same family and with the same gene defect. Affected children may have severe symptoms in early infancy (first 2 wk of life) or may be essentially asymptomatic.
- Salt wasting and polyuria may be present in utero and result in polyhydramnios.
- Anorexia and vomiting generally develop immediately after birth.
- Symptoms are similar to those observed in mineralocorticoid deficiency.
- Salt craving is observed in older children.
- Vomiting is usually the only symptom in those with early childhood hyperkalemia.
- Multiple target organ defects pseudohypoaldosteronism type I
- Salt-wasting episodes develop soon after birth and usually are more severe than in renal PHA-I.
- These individuals have a high incidence of lower respiratory tract involvement secondary to impaired bacterial killing, resulting from increased sodium chloride concentration in airway surface fluid, which can mimic cystic fibrosis.
- Pseudohypoaldosteronism type II
- A similar condition has been described in children (Spitzer-Weinstein syndrome) that is characterized by short stature, hyperkalemic metabolic acidosis, blood pressure within the reference range, and reference range aldosterone levels.
- Urolithiasis may be present.
Physical
- Renal pseudohypoaldosteronism type I
- Symptomatic individuals have failure to thrive, weight loss, vomiting, and dehydration appearing as early as the first 2 weeks of life.
- Affected individuals have repeated episodes of dehydration and may appear to be in shock and comatose.
- Weight loss may occur. If therapy is delayed, these individuals may become severely undernourished, and failure to thrive becomes evident during infancy.
- Affected individuals have a marked tendency to develop low blood volume and hypotension just like those with true hypoaldosteronism.
- Failure to thrive or growth retardation is the only physical finding in children with early childhood hyperkalemia. Hypertension is absent.
- Multiple target organ defects pseudohypoaldosteronism type I
- The clinical picture is similar to that seen with renal PHA-I, but symptoms may be more severe.
- These individuals may have recurrent episodes of dyspnea, cyanosis, fever, tachypnea, and intercostal retractions. Crackles may be auscultated over pulmonary fields.
- Pseudohypoaldosteronism type II
- These individuals, in contrast to those with PHA-I, are usually volume expanded and hypertensive.
- Hypertension is limited to adolescent or adult individuals and is the cardinal feature of adults with this syndrome.
- Short stature is the cardinal feature in children, who are usually asymptomatic, and hypertension during adolescence or young adulthood has usually been the initial sign. For this reason, this syndrome is often called adolescent hyperkalemic syndrome.
- Children with the chloride shunt syndrome have blood pressure within the reference range (Spitzer-Weinstein syndrome). A finding of 2 affected normotensive children (aged 4 and 11 y) and an older affected sibling (aged 21 y) in the same family suggests that Gordon syndrome and Spitzer-Weinstein syndrome are the same genetic entity. In fact, hypertension may be absent in adults and present in children.
- Muscular weakness and periodic paralysis has been described in children with Gordon syndrome.
Causes
- Renal pseudohypoaldosteronism type I
- The renal limited form appears to be inherited in an autosomal dominant pattern with variable expression. Many children have been found to have a loss-of-function mutation in the human mineralocorticoid receptor gene (MLR).
- Even though many cases appear to be sporadic, elevated plasma aldosterone levels were found in some of the apparently asymptomatic parents.
- Multiple target organ defects pseudohypoaldosteronism type I
- Multiple target organ defects (MTOD) PHA-I is most likely inherited as an autosomal recessive disorder and has a high incidence of consanguinity among parents. The degree of penetrance varies. Most studied kindreds have had a loss-of-function mutation in one of the subunits of the epithelial Na+ channel (ENaC).
- Sporadic cases have also been suggested.
- Pseudohypoaldosteronism type II
- An autosomal dominant form of inheritance has been suggested. Analysis of 8 affected families showed linkage to chromosome arms 1q31-42 and 17p11-q21.9 The genetic defect has not yet been characterized.
- Sporadic instances also occur.
- Secondary pseudohypoaldosteronism
- Secondary PHA is limited to the kidneys and has been described in infants and children with obstructive uropathy, urinary tract infection, tubulointerstitial nephritis, sickle cell nephropathy, systemic lupus erythematosus, amyloidosis, neonatal medullary necrosis, and, in some infants, after unilateral renal vein thrombosis. Cases have also been reported in patients with multiple myeloma and renal transplantation. Tubular injury is presumed responsible for the diminished response to aldosterone in these disorders.
- Drugs can impair renin or aldosterone synthesis or cause mineralocorticoid resistance. Drugs that can cause PHA include cyclooxygenase inhibitors (NSAIDs), beta-adrenergic antagonists, heparin, ACE inhibitors, potassium-sparing diuretics (ie, amiloride, triamterene, spironolactone), trimethoprim, and cyclosporine A.
- Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause hyperkalemia and metabolic acidosis as a result of inhibition of renin release.
- Beta-adrenergic antagonists alter potassium distribution and interfere with the renin-aldosterone system, resulting in hyperkalemia.
- Heparin inhibits aldosterone synthetase and causes hyperkalemia because of impaired aldosterone synthesis.
- ACE inhibitors can result in hypoaldosteronism with hyperkalemic acidosis by inhibiting angiotensin II formation.
- Potassium-sparing diuretics impair distal potassium secretion; spironolactone antagonizes the effects of aldosterone, amiloride, and triamterene by directly closing the sodium channel in the luminal membrane of the collecting tubular cell.
- Cyclosporine inhibits basolateral sodium-activated and potassium-activated adenosine triphosphatase, thereby decreasing intracellular potassium. These drugs should be used with caution in patients with tubulointerstitial nephritis, mild-to-moderate renal function impairment, and diabetic nephropathy because of the risk of hyperkalemia.
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| References |
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Further Reading
Keywords
pseudohypoaldosteronism, PHA, pseudohypoaldosteronism type I, PHA-I, Cheek and Perry syndrome, renal pseudohypoaldosteronism type I, AD renal PHA-I, multiple target organ pseudohypoaldosteronism, MTOD PHA-I, autosomal recessive PHA-I, AR PHA-I, early childhood hyperkalemia, renal tubular acidosis subtypes 4 and 5, RTA, pseudohypoaldosteronism type II, PHA-II, Gordon syndrome, adolescent hyperkalemic syndrome, Spitzer-Weinstein syndrome, mineralocorticoid-resistant hyperkalemia, renal tubular acidosis type IV subtype 3, metabolic acidosis, hypervolemia, renal salt wasting, hypotension, hypertension, chloride shunt syndrome, renal tube defects, short stature, urolithiasis, obstructive uropathy, urinary tract infection, tubulointerstitial nephritis, sickle cell nephropathy, systemic lupus erythematosus, amyloidosis, neonatal medullary necrosis, unilateral renal vein thrombosis, failure to thrive, adolescent hyperkalemic syndrome
