Wikipedia

Pseudohypoaldosteronism

(Redirected from Hypertensive hyperkalemia, familial)

Pseudohypoaldosteronism (PHA) is a condition that mimics hypoaldosteronism (presenting hyperkalemia).[1] Two major types of primary pseudohypoaldosteronism are recognized and these have major differences in etiology and presentation.[2]

Pseudohypoaldosteronism type 1 (PHA1)

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Pseudohypoaldosteronism Type 1
 
In pseudohypoaldosteronism type 1, aldosterone is elevated (hyperaldosteronism), but because the body fails to respond to it, it appears similar to hypoaldosteronism.
SpecialtyNephrology  
SymptomsFailure to thrive, dehydration, hyponatremia, metabolic acidosis, hyperkalemia, and other non-specific symptoms including nausea, vomiting, extreme fatigue, and muscle weakness.
CausesMutations in the NR3C2, SCNN1A, SCNN1B, or SCNN1G genes

Pseudohypoaldosteronism type 1 (PHA1) is characterized by the body's inability to respond adequately to aldosterone, a hormone crucial for regulating electrolyte levels. This condition often manifests with dehydration as the kidneys struggle to retain sufficient salt, leading to symptoms like increased thirst and dry mouth. Additionally, PHA1 disrupts electrolyte balance, resulting in low levels of sodium and high levels of potassium in the blood.

Mechanism

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PHA1 is an heterogeneous disease, which can be caused by mutations in different genes. On one hand, mutations on the gene NR3C2 (coding the mineralocorticoid receptor) cause the synthesis of a non-functional receptor which is unable to bind aldosterone or function correctly. In the kidney, aldosterone plays an important role of regulating sodium and potassium homeostasis by its actions on distal nephron cells.[3]

On the other hand, autosomal recessive PHA1 is caused by mutations in both alleles of either SCNN1A, SCNN1B or SCNN1G. These genes code the different subunits of the epithelial sodium channel, ENaC, which is located in the collecting duct of the nephron, and is responsible for sodium reabsorption and potassium secretion (by generating the electrochemical gradient necessary for potassium efflux by ROMK channel).[3]

Onset

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Symptoms

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Types

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Type OMIM Gene Inheritance Age of Onset Description
PHA1A 177735 NR3C2 (Mineralocorticoid receptor, MLR) Autosomal dominant Neonatal but improves with age. Adults are usually asymptomatic without treatment.[4] Salt wasting caused by renal unresponsiveness to mineralocorticoids. Patients often present with hyperkalaemic acidosis despite high aldosterone levels. Not all individuals with the mutation develop PHA1A suggesting that illness and volume depletion may play a role in the development of the clinically recognized PHA1A.
PHA1B 264350 SCNN1A, SCNN1B, SCNN1G (encoding epithelial sodium channel subunits) Autosomal recessive Neonatal, persists into adulthood.[5] Renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder often involves multiple organ systems and can be life threatening in the neonatal period. Patients usually present with hyponatremia, hyperkalemia, and increased plasma renin activity with high serum aldosterone concentrations. PHA1B is often mistaken for cystic fibrosis.

Treatment

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Treatment of severe forms of PHA1 requires relatively large amounts of sodium chloride.[6] Potassium restriction in the diet might also contribute to decrease urinary sodium wasting.[7]

Risks

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Individuals with PHA1B can have additional symptoms such as cardiac arrhythmia, shock, recurrent lung infections, or lesions on the skin due to imbalanced salts in the body especially in infancy.

A stop mutation in the SCNN1A gene has been shown to be associated with female infertility.[8]

Pseudohypoaldosteronism type 2 (PHA2)

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PHA2 also known as Familial hyperkalemic hypertension or Gordon syndrome is a rare disorder characterized by abnormalities in how the body regulates sodium and potassium levels. This condition stems from mutations in specific genes involved in the regulation of sodium transport within the kidneys.

Unlike in PHA1 in which aldosterone resistance is present, in PHA2 blood volume increases occur regardless of normal or low aldosterone levels due to the enhanced activity of sodium transporters in the kidney.[9]

Mechanism

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PHA2 is associated with mutations in the WNK4, WNK1, KLHL3 and CUL3 genes. These genes regulate the Sodium-chloride symporter (NCC) transporter, which is involved in controlling the levels of sodium and chloride in the body. Normally, the NCC transporter reabsorbs sodium and chloride in a part of the kidney called the distal convoluted tubule (DCT), however in PHA2 this process is dysregulated. Mutations in these genes lead to overactivity of NCC, causing excessive sodium and chloride reabsorption.

The hyperkalemia found in PHA2 is proposed to be a function of diminished sodium delivery to the cortical collecting tubule (potassium excretion is mediated by the renal outer medullary potassium channel (ROMK) in which sodium reabsorption plays a role). Alternatively, WNK4 mutations that result in a gain of function of the Na-Cl co-transporter may inhibit ROMK activity resulting in hyperkalemia.[10]

Onset

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The age of onset is difficult to pinpoint and can range from infancy to adulthood.[citation needed]

Symptoms

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People with PHA2 have hypertension and hyperkalemia despite having normal kidney function. Many individuals with PHA2 will develop hyperkalemia first, and will not present with hypertension until later in life. They also commonly experience both hyperchloremia and metabolic acidosis together, a condition called hyperchloremic metabolic acidosis.

People with PHA2 may experience other nonspecific symptoms including nausea, vomiting, extreme fatigue, muscle weakness, and hypercalcuria.

Some PHA2E patients present with dental abnormalities.[11] Patients with recessive KLHL3 mutations and dominant CUL3 mutations tend to have more severe phenotypes.[12]

A study in 2024 linked PHA2 to epilepsy. Epileptic seizures were seen in 3 of the 44 affected subjects. Two of the subjects had Generalized tonic–clonic seizure and one subject had migraine seizures. All three subjects had WNK4 mutations. It's speculated that the epilepsy may be caused by potassium spikes resulting in abnormal CNS neuron activity. The study also linked PHA2 to proximal renal tubular acidosis.[13] Metabolic acidosis is also known to cause epileptic seizures.

Types

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Type OMIM Gene Inheritance Age Of Onset Description
PHA2A 145260 mapped to chromosome 1q31-q42[14] Autosomal dominant Varies Does not involve salt wasting.
PHA2B 614491 WNK4 Autosomal dominant 10+ with a mean age of 28[15] May involve salt wasting.[16] Patients typically do not experience hypertension until adulthood.[15] Bicarbonate is higher than other PHA2 types. Aldosterone concentrations are often normal.[17] TRPV6 may be involved.[18]
PHA2C 614492 WNK1 Autosomal dominant 15+ with a mean age of 36[15] Does not involve salt wasting.[16] Significantly less severely affected than other PHA2 types.[15] Affected patients have hypertension together with long-term hyperkalemia, hyperchloremia, normal plasma creatinine, reduced bicarbonate, and low renin levels. Aldestrone levels may be normal or elevated.
PHA2D 614495 KLHL3 Autosomal dominant or autosomal recessive Mean age at diagnosis was found to be around 24 to 26, but it varies widely.[15] May involve salt wasting.[16] Individuals with the autosomal dominant mutations typically show higher potassium levels than those with autosomal recessive mutations. Hypertension usually develops in adulthood. Patients often present with low bicarbonate (17-18).[15]
PHA2E 614496 CUL3 Autosomal dominant 3-15 years old[15] Most severe manifestations of PHA2 compared to patients with other mutations. Almost all individuals present with hypertension before age 18.[15]

Treatment

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PHA2 requires salt restriction and use of thiazide diuretics to block sodium chloride reabsorption and normalise blood pressure and serum potassium.[citation needed]

Risks

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Pregnancy risks

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As of 2018, at least seven reported cases of severe metabolic acidosis occurring during pregnancy have been reported in PHA2 patients.[19]

A study in 2023 also described a patient with severe preeclampsia later being diagnosed with PHA2D associated with chronic hyperkalemia and hyperchloremic metabolic acidosis. The twin babies were born healthy and discharged from the hospital.[20]

Other risks

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One study noted that severe hypercalciuria from untreated PHA2 resulted in kidney stones, and osteoporosis in some patients.[21]

History

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PHA1 was first described by Cheek and Perry in 1958.[22] Later pediatric endocrinologist Aaron Hanukoglu reported that there are two independent forms of PHA with different inheritance patterns: A renal form with autosomal dominant inheritance exhibiting salt loss mainly from the kidneys, and a multi-system form with autosomal recessive form exhibiting salt loss from kidney, lung, and sweat and salivary glands.[23][24]

The hereditary lack of responsiveness to aldosterone could be due to at least two possibilities: 1. A mutation in the mineralocorticoid receptor that binds aldosterone, or 2. A mutation in a gene that is regulated by aldosterone. Linkage analysis on patients with the severe form of PHA excluded the possibility of linkage of the disease with the mineralocorticoid receptor gene region.[25] Later, the severe form of PHA was discovered to be due to mutations in the genes SCNN1A, SCNN1B, and SCNN1G that code for the epithelial sodium channel subunits, α, β, and γ, respectively.[26]

On the other hand, PHA2 was initially described by Dr. Richard Gordon.[27] Mutations in WNK1 and WNK4 as a cause for PHA2 were first described in 2001 by Richard Lifton´s laboratory.[28] Later, mutations in KLHL3 and CUL3 were also found in different PHA2 patients in 2012.[29]

See also

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References

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  1. ^ "Pseudohypoaldosteronism: Overview - eMedicine Pediatrics: General Medicine". Retrieved 2009-03-06.
  2. ^ Diaz-Thomas A, Pascual-Y-Baralt JF (5 August 2022). Hoffman RP (ed.). "Pseudohypoaldosteronism". MedScape. WebMD LLC. Retrieved 6 June 2024.
  3. ^ a b Riepe FG, Finkeldei J, de Sanctis L, Einaudi S, Testa A, Karges B, et al. (November 2006). "Elucidating the underlying molecular pathogenesis of NR3C2 mutants causing autosomal dominant pseudohypoaldosteronism type 1". The Journal of Clinical Endocrinology and Metabolism. 91 (11): 4552–4561. doi:10.1210/jc.2006-1161. PMID 16954160.
  4. ^ Amin N, Alvi NS, Barth JH, Field HP, Finlay E, Tyerman K, et al. (2013-08-01). "Pseudohypoaldosteronism type 1: clinical features and management in infancy". Endocrinology, Diabetes & Metabolism Case Reports. 2013: 130010. doi:10.1530/EDM-13-0010. PMC 3922296. PMID 24616761.
  5. ^ Bandhakavi M, Kirk J, Hogler W, Barrett T, Shaw N (November 2008). "Long-term outcome of autosomal recessive pseudohypoaldosteronism". Endocrine Abstracts. 17. ISSN 1470-3947.
  6. ^ Hanukoglu A, Hanukoglu I (October 2010). "Clinical improvement in patients with autosomal recessive pseudohypoaldosteronism and the necessity for salt supplementation". Clinical and Experimental Nephrology. 14 (5): 518–519. doi:10.1007/s10157-010-0326-8. PMID 20661616. S2CID 9764720.
  7. ^ Adachi M, Tajima T, Muroya K (2020). "Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1". CEN Case Reports. 9 (2): 133–137. doi:10.1007/s13730-019-00441-0. ISSN 2192-4449. PMC 7148393. PMID 31900739.
  8. ^ Boggula VR, Hanukoglu I, Sagiv R, Enuka Y, Hanukoglu A (October 2018). "Expression of the epithelial sodium channel (ENaC) in the endometrium - Implications for fertility in a patient with pseudohypoaldosteronism". The Journal of Steroid Biochemistry and Molecular Biology. 183: 137–141. doi:10.1016/j.jsbmb.2018.06.007. PMID 29885352. S2CID 47010706.
  9. ^ O'Shaughnessy KM (November 2015). "Gordon Syndrome: a continuing story". Pediatric Nephrology. 30 (11): 1903–1908. doi:10.1007/s00467-014-2956-7. PMID 25503323. S2CID 195676310.
  10. ^ Garovic VD, Hilliard AA, Turner ST (November 2006). "Monogenic forms of low-renin hypertension". Nature Clinical Practice. Nephrology. 2 (11). Nature Clinical Practice Nephrology: 624–630. doi:10.1038/ncpneph0309. PMID 17066054. S2CID 27864633.
  11. ^ Perrier R, Boscardin E, Malsure S, Sergi C, Maillard MP, Loffing J, et al. (August 2016). "Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit". Journal of the American Society of Nephrology. 27 (8): 2309–2318. doi:10.1681/ASN.2015020154. PMC 4978035. PMID 26701978.
  12. ^ Fernandez CJ (2023). Monogenic hypertension with hyperkalemic acidosis, low renin, and variable aldosterone. pp. 1–117. doi:10.1016/C2021-0-01825-3. ISBN 978-0-323-96120-2.
  13. ^ Shirin N, Rabinowitz G, Blatt I, Karlish SJ, Farfel Z, Mayan H (2024). "Association of Familial Hyperkalemia and Hypertension with Proximal Renal Tubular Acidosis and Epileptic Seizures". Nephron. 148 (3): 179–184. doi:10.1159/000531868. PMID 37666233.
  14. ^ Mansfield TA, Simon DB, Farfel Z, Bia M, Tucci JR, Lebel M, et al. (June 1997). "Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21". Nature Genetics. 16 (2): 202–205. doi:10.1038/ng0697-202. PMID 9171836.
  15. ^ a b c d e f g h Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, et al. (January 2012). "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities". Nature. 482 (7383): 98–102. Bibcode:2012Natur.482...98B. doi:10.1038/nature10814. PMC 3278668. PMID 22266938.
  16. ^ a b c Susa K, Sohara E, Rai T, Zeniya M, Mori Y, Mori T, et al. (October 2014). "Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice". Human Molecular Genetics. 23 (19): 5052–5060. doi:10.1093/hmg/ddu217. PMID 24821705.
  17. ^ Farfel Z, Iaina A, Levi J, Gafni J (December 1978). "Proximal renal tubular acidosis: association with familial normaldosteronemic hyperpotassemia and hypertension". Archives of Internal Medicine. 138 (12): 1837–1840. doi:10.1001/archinte.1978.03630370047021. PMID 718349.
  18. ^ Yang SS, Hsu YJ, Chiga M, Rai T, Sasaki S, Uchida S, et al. (April 2010). "Mechanisms for hypercalciuria in pseudohypoaldosteronism type II-causing WNK4 knock-in mice". Endocrinology. 151 (4): 1829–1836. doi:10.1210/en.2009-0951. PMID 20181799.
  19. ^ Awad S, Keely E, Abujrad H (2018). "Resolution of Metabolic Abnormalities During Pregnancy in a Patient with Gordon Syndrome and KLHL3 Mutation". AACE Clinical Case Reports. 4 (3): 235–239. doi:10.4158/AACR-2017-0006.
  20. ^ Cater TL, Espinosa LB (2023). "THU598 Pseudohypoaldosteronism Type 2: A New Variant Of A Rare Disease". Journal of the Endocrine Society. 7 (S1): A322–A323. doi:10.1210/jendso/bvad114.595. PMC 10555376.
  21. ^ D'ambrosio V, Mcknight O, Wan E, Speller R, Moss R, Siew K, et al. (June 2023). "#6875 Complications and Treatment of Hypercalciuria in Familial Hyperkalaemic Hypertension (FHHT)". Nephrology Dialysis Transplantation. 38 (S1): i241–i242. doi:10.1093/ndt/gfad063c_6875. S2CID 259396958.
  22. ^ Cheek DB, Perry JW (June 1958). "A salt wasting syndrome in infancy". Archives of Disease in Childhood. 33 (169): 252–256. doi:10.1136/adc.33.169.252. PMC 2012226. PMID 13545877.
  23. ^ Hanukoglu A (November 1991). "Type I pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects". The Journal of Clinical Endocrinology and Metabolism. 73 (5): 936–944. doi:10.1210/jcem-73-5-936. PMID 1939532.
  24. ^ Hanukoglu I, Hanukoglu A (April 2016). "Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases". Gene. 579 (2): 95–132. doi:10.1016/j.gene.2015.12.061. PMC 4756657. PMID 26772908.
  25. ^ Chung E, Hanukoglu A, Rees M, Thompson R, Dillon M, Hanukoglu I, et al. (November 1995). "Exclusion of the locus for autosomal recessive pseudohypoaldosteronism type 1 from the mineralocorticoid receptor gene region on human chromosome 4q by linkage analysis". The Journal of Clinical Endocrinology and Metabolism. 80 (11): 3341–3345. doi:10.1210/jcem.80.11.7593448. PMID 7593448.
  26. ^ Chang SS, Grunder S, Hanukoglu A, Rösler A, Mathew PM, Hanukoglu I, et al. (March 1996). "Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1". Nature Genetics. 12 (3): 248–253. doi:10.1038/ng0396-248. PMID 8589714. S2CID 8185511.
  27. ^ Gordon RD, Geddes RA, Pawsey CG, O'Halloran MW (November 1970). "Hypertension and severe hyperkalaemia associated with suppression of renin and aldosterone and completely reversed by dietary sodium restriction". Australasian Annals of Medicine. 19 (4): 287–294. doi:10.1111/imj.1970.19.4.287. PMID 5490655.
  28. ^ Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, et al. (August 2001). "Human hypertension caused by mutations in WNK kinases". Science. 293 (5532): 1107–1112. doi:10.1126/science.1062844. PMID 11498583.
  29. ^ Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, et al. (January 2012). "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities". Nature. 482 (7383): 98–102. Bibcode:2012Natur.482...98B. doi:10.1038/nature10814. PMC 3278668. PMID 22266938.
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