Gitelman syndrome with hiponatremia, a rare presentation
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The mutation is found in the <span class="elsevierStyleItalic">SLC12A3 </span>gene, but there are also others. Its prevalence is estimated to range 25 cases per 1 million.<span class="elsevierStyleSup">1</span> Acquired GS is rarer and usually associated with autoimmune diseases or after renal transplantation.<span class="elsevierStyleSup">2</span></p><p class="elsevierStylePara">GS phenotype is characterized by hypokalemic alkalosis, hypomagnesemia, hypocalciuria, and secondary aldosteronism without hypertension. Hyponatraemia is not a recognised feature of GS.<span class="elsevierStyleSup">3</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">CASE REPORT</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">A 34 year old caucasian woman with no prior medical presented with severe hypokalemia; hypomagnesemia and mild hyponatremia. Her past medical and family history were unremarkable. She was on no medication and denied any symptoms, unless for occasionally muscle cramps. Water intake ≥3L/day. She was normotensive, no edemas and normal urine output. The review of systems was otherwise negative.</p><p class="elsevierStylePara">Table 1 summarizes laboratory investigation.</p><p class="elsevierStylePara">Patient was managed with oral magnesium and spironolactone 50mg/day. Her condition improved significantly and her last routine lab control showed serum potassium 3.78mmol/L, magnesium 0.79mmol/L and sodium 136.0mmol/L, without any other changes.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Potassium excretion is mostly derived from secretion in the distal nephron, driven by an electrochemical gradient increased by aldosterone-induced sodium reabsorption; and by an electroneutral K<span class="elsevierStyleSup">+ </span>Cl<span class="elsevierStyleSup">- </span>secretory mechanism.<span class="elsevierStyleSup">4</span></p><p class="elsevierStylePara">Hypokalemia may result from decreased intake, increased translocation into the cells, or, most often, increased losses in the urine, gastrointestinal tract, or sweat.</p><p class="elsevierStylePara">Although these causes were sought by history taking and clinical examination, we needed to exclude surreptitious vomiting or drugs abuse because high urinary potassium, metabolic alkalosis and alkaline urine can also be present in these two disorders. Differential diagnosis with vomiting was made through urinary chloride which is low in hypovolemia due to hyperaldosteronism, opposing to patient normal values poiting to a renal disorder. Diuretic abuse was excluded through a negative urinary screen.</p><p class="elsevierStylePara">Because the patient was normotensive, we stood with Gitelman or Bartter’s.</p><p class="elsevierStylePara">Magnesium excretion rate is regulated by distal reabsorption that depends on epithelial TRPM6 channels, which gene suffers a downregulation mutation in GS, inducing urinary magnesium wasting leading to hypomagnesemia,<span class="elsevierStyleSup">5</span> opposing to Bartter syndrome.</p><p class="elsevierStylePara">Calcium is absorbed in proximal nephron driven by an electronegative transcellular gradient induced by chloride-sodium transport; and in DCT driven by parathyroid hormone and Vitamin D. Hypocalciuria pathogenesis still remains debated but an important role is played by metabolic alkalosis.<span class="elsevierStyleSup">6</span></p><p class="elsevierStylePara">At the end, our patient fulfilled the diagnostic criteria for GS, although few unusual aspects. First, the inappropriately high urine pH and pCO2 (directly proportional to bicarbonate (HCO<span class="elsevierStyleInf">3</span><span class="elsevierStyleSup">-</span>) concentration) could be explain through high chloride delivery that enhances HCO<span class="elsevierStyleInf">3</span><span class="elsevierStyleSup">-</span> secretion in type A intercalated cells (to maintain electroneutrality). Adding to this, hypokalemia suppresses aldosterone secretion, which reduces sodium reabsorption (no hypovolemia) increasing back-diffusion of hydrogen, allowing the urine to become more alkaline than plasma.<span class="elsevierStyleSup">6</span> Aldosterone activity degree could be accessed through tubular fluid potassium concentration at distal cortical collecting tubule, estimated from transtubular potassium gradient but this would only be usefull in hyperkalemia settings. Additionaly, recente publications found that its assumptions were not valid.<span class="elsevierStyleSup">7</span> Finally, patients with metabolic alkalosis have a respiratory compensation but the beneficial pH effect is blunted when arterial pCO<span class="elsevierStyleInf">2 </span>elevation increases renal acid excretion stimulating renal ammoniagenesis, raising urine pH.<span class="elsevierStyleSup">6</span></p><p class="elsevierStylePara">Mild hyponatraemia was present and, opposing to diuretic use (excluded), is not a typical feature of GS. After excluding hypothyroidism, adrenal insufficiency and renal failure, hyponatraemia associated to normal volemia, inappropriately high urine osmolality and urinary sodium concentration suggested the presence of a syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The stimulus for this secretion is unclear. Although chronic hypokalemia could be characterized by some resistance of tube collector cells to ADH, GS has a urinary diluting capacity disturbed creating a <span class="elsevierStyleItalic">SIADH like effect</span>. Opposing to Bartters, GS has a preserved concentrating ability,<span class="elsevierStyleSup">6</span> because medullary thick ascending limb is intact. Since there is no hypovolemia, urinary sodium excretion is high to maintain electroneutrality as HCO<span class="elsevierStyleInf">3</span><span class="elsevierStyleSup">-</span> is being excreted. Adding to this, in severe hypokalemia, via unknown mechanism, distal chloride excretion is increased causing a paralell sodium waste.</p><p class="elsevierStylePara">There are only a few cases of GS with hyponatraemia reported and in two of them a combination of high water intake with an impaired urinary dilution capacity caused by GS was described as a possible explanation for <span class="elsevierStyleItalic">SIADH-like</span> biochemical features.<span class="elsevierStyleSup">8,9</span> Adding to water, our patient must had a high intake of salt which raised the sodium delivery to the collecting duct and could explain both sodium and HCO<span class="elsevierStyleInf">3</span><span class="elsevierStyleSup">-</span> excretion increase, with water free of electrolytes retention. To the best of our knowledge it was what happened to our patient.</p><p class="elsevierStylePara">A genetical study would confirm the diagnosis and clarify about additional anomalies but we didn’t performe it because of economic issues. However, we still don’t have many doubts about the diagnosis because there is a large phenotype variability without relationship between the clinical severity and type of mutations. Furthermore, heterozygotes have a higher rate of sodium excretion than wild-type individuals, probably due to higher salt intake.<span class="elsevierStyleSup">10</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The authors declare that they have no conflicts of interest related to the contents of this article.</p><p class="elsevierStylePara"><a href="grande/12224_16025_52538_en_t1_12224.jpg" class="elsevierStyleCrossRefs"><img src="12224_16025_52538_en_t1_12224.jpg" alt="Results of the laboratory investigation."></img></a></p><p class="elsevierStylePara">Table 1. Results of the laboratory investigation.</p>" "pdfFichero" => "P1-E567-S4570-A12224-EN.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:4 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438956" "palabras" => array:1 [ 0 => "Urinary electrolytes" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438958" "palabras" => array:1 [ 0 => "Transporte tubular" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438960" "palabras" => array:1 [ 0 => "Hyponatraemia" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438962" "palabras" => array:1 [ 0 => "Hypokalemia" ] ] ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12224_16025_52538_en_t1_12224.jpg" "Alto" => 2287 "Ancho" => 1423 "Tamanyo" => 950452 ] ] "descripcion" => array:1 [ "en" => "Results of the laboratory investigation." ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Knoers NV, Levtchenko EN. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 9 | 11 | 20 |
| 2024 October | 57 | 45 | 102 |
| 2024 September | 59 | 26 | 85 |
| 2024 August | 78 | 73 | 151 |
| 2024 July | 43 | 29 | 72 |
| 2024 June | 64 | 39 | 103 |
| 2024 May | 66 | 30 | 96 |
| 2024 April | 73 | 36 | 109 |
| 2024 March | 70 | 32 | 102 |
| 2024 February | 53 | 44 | 97 |
| 2024 January | 43 | 27 | 70 |
| 2023 December | 42 | 24 | 66 |
| 2023 November | 63 | 35 | 98 |
| 2023 October | 64 | 34 | 98 |
| 2023 September | 79 | 35 | 114 |
| 2023 August | 34 | 29 | 63 |
| 2023 July | 43 | 36 | 79 |
| 2023 June | 40 | 21 | 61 |
| 2023 May | 57 | 43 | 100 |
| 2023 April | 34 | 19 | 53 |
| 2023 March | 43 | 21 | 64 |
| 2023 February | 34 | 23 | 57 |
| 2023 January | 51 | 25 | 76 |
| 2022 December | 53 | 27 | 80 |
| 2022 November | 37 | 29 | 66 |
| 2022 October | 53 | 59 | 112 |
| 2022 September | 47 | 37 | 84 |
| 2022 August | 63 | 48 | 111 |
| 2022 July | 37 | 54 | 91 |
| 2022 June | 39 | 39 | 78 |
| 2022 May | 46 | 41 | 87 |
| 2022 April | 45 | 42 | 87 |
| 2022 March | 52 | 58 | 110 |
| 2022 February | 49 | 38 | 87 |
| 2022 January | 39 | 34 | 73 |
| 2021 December | 33 | 37 | 70 |
| 2021 November | 25 | 32 | 57 |
| 2021 October | 33 | 46 | 79 |
| 2021 September | 42 | 39 | 81 |
| 2021 August | 53 | 35 | 88 |
| 2021 July | 45 | 34 | 79 |
| 2021 June | 41 | 33 | 74 |
| 2021 May | 63 | 38 | 101 |
| 2021 April | 110 | 50 | 160 |
| 2021 March | 101 | 40 | 141 |
| 2021 February | 63 | 13 | 76 |
| 2021 January | 29 | 16 | 45 |
| 2020 December | 48 | 17 | 65 |
| 2020 November | 30 | 14 | 44 |
| 2020 October | 24 | 17 | 41 |
| 2020 September | 29 | 9 | 38 |
| 2020 August | 29 | 14 | 43 |
| 2020 July | 45 | 8 | 53 |
| 2020 June | 51 | 16 | 67 |
| 2020 May | 50 | 13 | 63 |
| 2020 April | 41 | 14 | 55 |
| 2020 March | 38 | 10 | 48 |
| 2020 February | 48 | 13 | 61 |
| 2020 January | 41 | 17 | 58 |
| 2019 December | 45 | 18 | 63 |
| 2019 November | 28 | 17 | 45 |
| 2019 October | 26 | 10 | 36 |
| 2019 September | 29 | 15 | 44 |
| 2019 August | 31 | 16 | 47 |
| 2019 July | 35 | 21 | 56 |
| 2019 June | 36 | 27 | 63 |
| 2019 May | 30 | 22 | 52 |
| 2019 April | 78 | 34 | 112 |
| 2019 March | 51 | 28 | 79 |
| 2019 February | 35 | 24 | 59 |
| 2019 January | 39 | 31 | 70 |
| 2018 December | 93 | 45 | 138 |
| 2018 November | 120 | 27 | 147 |
| 2018 October | 83 | 23 | 106 |
| 2018 September | 86 | 18 | 104 |
| 2018 August | 59 | 22 | 81 |
| 2018 July | 57 | 22 | 79 |
| 2018 June | 55 | 18 | 73 |
| 2018 May | 72 | 18 | 90 |
| 2018 April | 85 | 14 | 99 |
| 2018 March | 60 | 16 | 76 |
| 2018 February | 54 | 7 | 61 |
| 2018 January | 48 | 10 | 58 |
| 2017 December | 71 | 12 | 83 |
| 2017 November | 66 | 19 | 85 |
| 2017 October | 50 | 9 | 59 |
| 2017 September | 47 | 19 | 66 |
| 2017 August | 43 | 11 | 54 |
| 2017 July | 37 | 16 | 53 |
| 2017 June | 41 | 11 | 52 |
| 2017 May | 45 | 21 | 66 |
| 2017 April | 55 | 12 | 67 |
| 2017 March | 39 | 10 | 49 |
| 2017 February | 37 | 15 | 52 |
| 2017 January | 22 | 14 | 36 |
| 2016 December | 94 | 8 | 102 |
| 2016 November | 106 | 12 | 118 |
| 2016 October | 110 | 14 | 124 |
| 2016 September | 158 | 2 | 160 |
| 2016 August | 238 | 7 | 245 |
| 2016 July | 218 | 8 | 226 |
| 2016 June | 148 | 0 | 148 |
| 2016 May | 150 | 0 | 150 |
| 2016 April | 129 | 0 | 129 |
| 2016 March | 107 | 0 | 107 |
| 2016 February | 115 | 0 | 115 |
| 2016 January | 110 | 0 | 110 |
| 2015 December | 145 | 0 | 145 |
| 2015 November | 115 | 0 | 115 |
| 2015 October | 112 | 0 | 112 |
| 2015 September | 96 | 0 | 96 |
| 2015 August | 75 | 0 | 75 |
| 2015 July | 81 | 0 | 81 |
| 2015 June | 40 | 0 | 40 |
| 2015 May | 62 | 0 | 62 |
| 2015 April | 16 | 0 | 16 |
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