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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Primary hyperparathyroidism &#40;HP&#41; is a disease characterized by autonomous production of parathyroid hormone &#40;PTH&#41;&#44; in which there is hypercalcemia&#44; or high-normal serum calcium with elevated serum PTH or inappropriately &#8220;normal&#8221; calcium&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">HP occurs in about 1&#37; of the adult population&#44; but affects more than 2&#37; of it after 55 years&#44; being 2&#8211;3 times more common in women than in men&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The most common cause is a parathyroid adenoma &#40;80&#37;&#8211;85&#37; single and double in about 4&#37;&#41;&#46; The remaining cases are due to hyperplasia of the parathyroid glands&#44; or&#44; more rarely&#44; a parathyroid carcinoma&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Familiar forms of HP are uncommon&#44; manifesting usually as part of multiple endocrine neoplasia &#40;MEN&#41;&#44; with very rare forms of presentation&#44; primary hyperparathyroidism and familial neonatal hyperparathyroidism&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Clinical Manifestations</span><p id="par0025" class="elsevierStylePara elsevierViewall">From the description of the disease in the 1930s by Albright and Reifenstein&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> clinical expression has changed considerably<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The first clinical descriptions regarded it as an uncommon disease with significant morbidity&#44; which usually involved bone or renal disease&#44; or both&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Currently&#44; due to increased use of biochemical markers&#44; the most frequent clinical form &#40;88&#37;&#41; is a mild and asymptomatic hypercalcemia with serum calcium about 1<span class="elsevierStyleHsp" style=""></span>mg&#47;dL above normal&#46; However&#44; HP may present more floridly or as asymptomatic subclinical forms&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Skeletal Manifestations</span><p id="par0040" class="elsevierStylePara elsevierViewall">Due to its predominantly cortical bone expression&#44; PTH excess can lead to osteitis fibrosa cystica &#40;2&#37; of cases&#41;&#44; manifested as bone pain and fractures&#46; The typical radiographic signs include subperiosteal resorption of the middle and distal phalanges&#44; thinning of the distal clavicles&#44; a mottled or &#8220;salt and pepper&#8221; skull pattern&#44; bone cysts and brown tumors in the long bones and pelvis&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#8211;7</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Renal Manifestations</span><p id="par0045" class="elsevierStylePara elsevierViewall">Nephrolithiasis or nephrocalcinosis can be observed in approximately 20&#37; of patients with HP&#46; About 5&#37; of nephrolithiasis are secondary to HP&#44; while the majority are due to calcium oxalate by hipercalciuria&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The most frequent finding&#44; however&#44; is hypercalciuria &#40;35&#37;&#8211;40&#37; of cases&#41; due to an increased filtered load of calcium&#44; which exceeds the reabsorption capacity&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Some patients will only have decreased creatinine clearance and renal impairment&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Gastrointestinal Manifestations</span><p id="par0060" class="elsevierStylePara elsevierViewall">May present as anorexia&#44; nausea&#44; vomiting and constipation&#46; Peptic ulcer is rare &#40;unless it occurs in the context of a MEN 1&#41;&#46; Likewise&#44; acute pancreatitis is rarely seen due to hypercalcemia associated with HP&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Neuromuscular Manifestations</span><p id="par0065" class="elsevierStylePara elsevierViewall">Muscle weakness and fatigue&#44; intellectual fatigue&#44; mental disturbances&#44; and in rare cases that present with severe hypercalcemia&#44; coma&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Cardiovascular Manifestations</span><p id="par0070" class="elsevierStylePara elsevierViewall">HP has been associated with hypertension&#46; Hypercalcemia can also cause ECG changes such as shortening of the QT&#44; blockages or increased sensitivity to digitalis&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In the classical forms&#44; myocardial&#44; valvular and vascular calcifications were described in HP&#46; Today&#44; stiffness and a decreased vascular ventricular<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> index can be seen&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Diagnosis</span><p id="par0080" class="elsevierStylePara elsevierViewall">Given the nonspecific clinical and practical absence of symptoms&#44; 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and metabolic acidosis with hyperchloremia secondary to an inhibition of bicarbonate reabsorption by PTH&#44; as well as increased markers of bone turnover&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Differential Diagnosis</span><p id="par0095" class="elsevierStylePara elsevierViewall">Differential diagnosis should be established with the following entities&#46;</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Malignancy</span><p id="par0100" class="elsevierStylePara elsevierViewall">It is important to note that HP and malignancies are the 2 most common causes of hypercalcemia &#40;90&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">In addition&#44; malignancy-associated hypercalcemia is the most prevalent cause of hypercalcemia in hospitalized patients&#44; being serious and rapidly evolving&#44; as it is often linked to advanced stage malignancies&#44; and therefore a poor prognosis&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In hypercalcemia of malignancy&#44; PTH is suppressed &#40;except in the rare cases of PTH-producing tumors where it is elevated&#41;&#44; and along with the clinical data&#44; points at the diagnosis<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;16</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Familial Hypocalciuric Hypercalcemia</span><p id="par0115" class="elsevierStylePara elsevierViewall">It is a familial syndrome with autosomal dominant inheritance&#44; a consequence of a mutation that inactivates one allele of the calcium sensing receptor in parathyroid glands in the renal<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> tubule&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">It is asymptomatic young adults&#44; with mild hypercalcemia and PTH in the normal range or slightly elevated being the only laboratory findings&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">There is no need for its treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The way to differentiate this clinical entity of HP consists of documenting a low urinary calcium in 24<span class="elsevierStyleHsp" style=""></span>h urine&#44; and decreased calcium&#47;creatinine clearance ratio<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15&#44;19&#8211;21</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Drugs</span><p id="par0135" class="elsevierStylePara elsevierViewall">Two drugs that deserve special consideration when evaluating a patient with hyperparathyroidism are thiazide diuretics and lithium&#46;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0140" class="elsevierStylePara elsevierViewall">Hypercalcemia due to thiazide diuretics<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;22</span></a>&#58; they reduce renal calcium excretion and may cause some mild hypercalcemia&#46; Should be removed whenever possible because can mask an HP&#59; reassess the patient at 3 months&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0145" class="elsevierStylePara elsevierViewall">Hypercalcaemia due to Lithium&#58; Lithium may also reduce urinary calcium excretion&#44; leading to hypocalciuria and hypercalcemia&#44; and in a small percentage of patients&#44; elevation of PTH&#46;</p></li></ul></p><p id="par0150" class="elsevierStylePara elsevierViewall">The pattern to be followed is the same way&#44; stop treatment if possible and reassess at 3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Normocalcemic Primary Hyperparathyroidism</span><p id="par0155" class="elsevierStylePara elsevierViewall">It has been hypothesized whether this entity represents the first phase of HP or if it is a different disease characterized by an alteration in the regulation of PTH secretion&#44; or a state of relative resistance to the action of PTH&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">It represents an incidental finding in a patient studied for decreased bone mineral density &#40;BMD&#41;&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Must be differentiated from secondary &#40;SH&#41;&#44; and essential hyperparathyroidism to determine the values of vitamin D&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">It requires close monitoring in order to detect symptomatic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Secondary Hyperparathyroidism</span><p id="par0175" class="elsevierStylePara elsevierViewall">Clinical situation in which the parathyroid glands respond well to low extracellular calcium concentration &#40;renal failure&#44; poor intake&#44; malabsorption&#44; etc&#46;&#41;&#46; However&#44; if the increase in PTH cannot correct the plasma calcium&#44; either due to a disorder in the organs responsible for transportation or deficiencies&#44; hypocalcemia develops&#46; Therefore&#44; HS may be associated with calcium concentrations that are within or below the reference range&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Laboratory findings show high or normal PTH with low calcium levels or within normal limits&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">It is very important to measure levels of vitamin D and 24-h urinary calcium&#44; in order to make the differential diagnosis of vitamin D deficiency leading to HP&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">HS treatment is to correct the primary abnormality that caused hypocalcemia&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> details the root causes of HS&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Diagnosis Tree and Differential Diagnostic Table</span><p id="par0200" class="elsevierStylePara elsevierViewall">Faced with an elevation of PTH&#44; measurement of serum calcium&#44; and subsequently&#44; calciuria in 24<span class="elsevierStyleHsp" style=""></span>h urine is required&#46; If the latter is normal&#44; this suggests a normocalcemic HP&#46; If&#44; however&#44; it is elevated&#44; HP will be very likely&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">In cases where calciuria is reduced&#44; reposition of vitamin D should be carried out before levels of serum calcium and PTH are measured&#46; If these values are normalized&#44; the picture is compatible with hypovitaminosis D&#46; HS If&#44; however&#44; they remain high&#44; this points to an HP with vitamin D deficiency &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> and <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Requirements of Vitamin D</span><p id="par0210" class="elsevierStylePara elsevierViewall">The daily requirement for vitamin D is 800&#8211;1000<span class="elsevierStyleHsp" style=""></span>U&#47;day&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">It is noteworthy that about 90&#37; of patients with HP have&#44; at least&#44; insufficient vitamin D levels&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Treatment consists in supplementing and maintaining vitamin D levels above 30<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#44; strictly controlling the values of calcemia&#44; calciuria&#44; and phosphatemia and to monitor the numbers of vitamin D every 3&#8211;6 months&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15&#44;19&#44;20</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Treatment of Primary Hyperparathyroidism</span><p id="par0225" class="elsevierStylePara elsevierViewall">If symptomatic&#44; surgery is the treatment of choice&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">If the patient is asymptomatic&#44; management is more controversial&#44; and in any case&#44; should be monitored to detect any disease progression&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Current recommendations are established as the annual measurement of serum calcium and creatinine&#44; as well as performing a bone density test every 1&#8211;2 years&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p></span></span>"
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          "identificador" => "xpalclavsec113176"
          "titulo" => "Keywords"
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        2 => array:2 [
          "identificador" => "xres125881"
          "titulo" => "Resumen"
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          "titulo" => "Palabras clave"
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          "titulo" => "Introduction"
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        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Clinical Manifestations"
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            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Skeletal Manifestations"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Renal Manifestations"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Gastrointestinal Manifestations"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Neuromuscular Manifestations"
            ]
            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Cardiovascular Manifestations"
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        6 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Diagnosis"
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          "titulo" => "Differential Diagnosis"
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            0 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Malignancy"
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            1 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Familial Hypocalciuric Hypercalcemia"
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            2 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Drugs"
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            3 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Normocalcemic Primary Hyperparathyroidism"
            ]
            4 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Secondary Hyperparathyroidism"
            ]
          ]
        ]
        8 => array:2 [
          "identificador" => "sec0075"
          "titulo" => "Diagnosis Tree and Differential Diagnostic Table"
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        9 => array:2 [
          "identificador" => "sec0080"
          "titulo" => "Requirements of Vitamin D"
        ]
        10 => array:2 [
          "identificador" => "sec0085"
          "titulo" => "Treatment of Primary Hyperparathyroidism"
        ]
        11 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2011-05-06"
    "fechaAceptado" => "2011-06-17"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec113176"
          "palabras" => array:8 [
            0 => "Primary hyperparathyroidism"
            1 => "Secondary hyperparathyroidism"
            2 => "Hypercalcemia"
            3 => "Familial hypocalciuria hypercalcemia"
            4 => "25-hydroxy vitamin D"
            5 => "1&#44;25-dihydroxy vitamin D"
            6 => "Osteoporosis"
            7 => "Osteopenia"
          ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec113177"
          "palabras" => array:8 [
            0 => "Hiperparatiroidismo primario"
            1 => "Hiperparatiroidismo secundario"
            2 => "Hipercalcemia"
            3 => "Hipercalcemia hipocalci&#250;rica familiar"
            4 => "25-hidroxivitamina D"
            5 => "1&#44;25-dihidroxivitamina D"
            6 => "Osteoporosis"
            7 => "Osteopenia"
          ]
        ]
      ]
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Primary hyperparathyroidism &#40;PHPT&#41; is characterized by the autonomous production of parathyroid hormone &#40;PTH&#41;&#44; in which there is hypercalcemia or normal-high serum calcium levels in the presence of elevated or inappropriately normal serum PTH concentrations&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Exceptionally in symptomatic patients&#44; a diagnosis can be established on the basis of clinical data&#46; PHPT must always be evaluated in patients with clinical histories of nephrolithiasis&#44; nephrocalcinosis&#44; osseous pain&#44; subperiosteal resorption&#44; and pathologic fractures&#44; as well as in those with osteoporosis&#8211;osteopenia&#44; a personal history of neck irradiation&#44; or a family history of multiple endocrine neoplasia syndrome &#40;types 1 or 2&#41;&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Diagnosis of PHPT is biochemical&#46; Asymptomatic hypercalcemia without guiding signs or symptoms is the most frequent manifestation of the disease&#46; For differential diagnosis&#44; PTH must be measured&#44; as well as phosphate&#44; chloride&#44; 25-hydroxyvitamin D&#44; 1&#44;25 dyhidroxyvitamin D and calcium-to-creatinine clearance&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The diagnosis and differential diagnosis of primary hyperparathyroidism will be discussed here&#46;</p>"
      ]
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        "titulo" => "Resumen"
        "resumen" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El hiperparatiroidismo primario &#40;HP&#41; es una entidad cl&#237;nica que se caracteriza por la producci&#243;n aut&#243;noma de parathormona &#40;PTH&#41;&#44; en la cual hay hipercalcemia o calcio s&#233;rico normal-alto&#44; con valores de PTH elevados o inapropiadamente normales&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">De forma excepcional&#44; el diagn&#243;stico puede establecerse a partir de la cl&#237;nica en pacientes sintom&#225;ticos&#46; El HP siempre debe ser tenido en cuenta en pacientes con historia de c&#225;lculos renales&#44; nefrocalcinosis&#44; dolor &#243;seo&#44; fracturas patol&#243;gicas&#44; resorci&#243;n subperi&#243;stica o en aqu&#233;llos que presenten osteoporosis-osteopenia&#44; antecedentes de irradiaci&#243;n en cuello o historia familiar de neoplasia endocrina m&#250;ltiple tipo 1 o 2&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El diagn&#243;stico del HP es bioqu&#237;mico&#44; siendo la hipercalcemia asintom&#225;tica la manifestaci&#243;n m&#225;s frecuente de la enfermedad&#46; Para el diagn&#243;stico diferencial&#44; adem&#225;s de la PTH&#44; debe medirse el f&#243;sforo&#44; cloro&#44; 25 hidroxivitamina D&#44; 1&#44;25 dihidroxivitamina D y calciuria&#46;A continuaci&#243;n&#44; se revisa el diagn&#243;stico y se detallan los cuadros cl&#237;nicos con los que se deber&#237;a plantear el diagn&#243;stico diferencial&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara">Please&#44; cite this article as&#58; Mart&#237;nez Cordellat I&#46; Hiperparatiroidismo&#58; &#191;primario o secundario&#63; Reumatol Clin&#46; 2011&#46; <span class="elsevierStyleInterRef" href="doi:10.1016/j.reuma.2011.06.001">doi&#58;10&#46;1016&#47;j&#46;reuma&#46;2011&#46;06&#46;001</span>&#46;</p>"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Changes in the clinical presentation of HP&#46;</p>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">HP&#44; primary hyperparathyroidims&#59; PTH&#44; parathyroid hormone&#46;</p>"
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                  \t\t\t\t" style="border-bottom: 2px solid black">PTH&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">HP 1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Suggestive variable&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Malignant disease&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8595;Rare &#8593; &#40;T production of PTH&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">HHF&#44; familial hypocalciuric hypercalcemia&#59; HP&#44; primary hyperparathyroidism&#46;</p>"
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                  \t\t\t\t" style="border-bottom: 2px solid black">Cl Ca&#47;Cr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8593; &#40;&#62;200<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#62;0&#46;02&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">HHF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8595; &#40;&#60;100<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8804;0&#46;01&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">PTH&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Blood Calcium&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">High&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Normal or high&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Normal&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">HP with vitamin D deficiency&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">High&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Normal-low or low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Low &#40;&#60;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HS with vitamin D deficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                    0 => array:2 [
                      "titulo" => "The parathyroid glands and metabolic bone disease"
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                        0 => array:2 [
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                          "autores" => array:2 [
                            0 => "F&#46; Albright"
                            1 => "E&#46;C&#46; Reifenstein"
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                    0 => array:1 [
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                        "fecha" => "1984"
                        "editorial" => "Williams &#38; Wilkins"
                        "editorialLocalizacion" => "Baltimore"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Time to reconsider current clinical decision paradigms&#63;"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "G&#46; El-Hajj Fuleihan"
                            1 => "Hyperparathyroidism&#58;"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2008-1305"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2008"
                        "volumen" => "93"
                        "paginaInicial" => "3302"
                        "paginaFinal" => "3304"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18772461"
                            "web" => "Medline"
                          ]
                        ]
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              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Primary hyperparathyroidism&#58; incidence&#44; morbidity&#44; and potential economic impact in a community"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46; Heath III"
                            1 => "S&#46;F&#46; Hodgson"
                            2 => "M&#46;A&#46; Kennedy"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM198001243020402"
                      "Revista" => array:7 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "1980"
                        "volumen" => "302"
                        "paginaInicial" => "189"
                        "paginaFinal" => "193"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7350459"
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                0 => array:1 [
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                    0 => array:1 [
                      "Revista" => array:8 [
                        "titulo" => "Proceedings of the NIH consensus development conference on diagnosis and management of asymptomatic primary hyperparathyroidism"
                        "tituloSerie" => "J Bone Miner Res"
                        "fecha" => "1991"
                        "volumen" => "6"
                        "numero" => "Suppl&#46; 2"
                        "paginaInicial" => "2"
                        "editores" => "J&#46;T&#46;PottsJr&#46;J&#46;E&#46;FradkinG&#46;D&#46;AurbachJ&#46;P&#46;BilezikianL&#46;G&#46;Raisz"
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                      "titulo" => "Skeletal disease in primary hyperparathyroidism"
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                          "autores" => array:6 [
                            0 => "S&#46;J&#46; Silverberg"
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Vol. 8. Issue 5.
Pages 287-291 (September - October 2012)
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Vol. 8. Issue 5.
Pages 287-291 (September - October 2012)
Continuing Medical Education
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Hyperparathiroidism: Primary or Secondary Disease?
Hiperparatiroidismo: ¿primario o secundario?
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22542
Isabel Martínez Cordellat
Servicio de Reumatología, Hospital Universitario Doctor Peset, Valencia, Spain
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Figures (2)
Tables (4)
Table 1. HP Differential Diagnosis/Malignant Disease.
Table 2. HP Differential Diagnosis/HHF.
Table 3. Causes of Secondary Hyperparathyroidism.
Table 4. Normocalcemic HP/HP With Vitamin D Deficiency/HS Due to Hypovitaminosis D.
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Abstract

Primary hyperparathyroidism (PHPT) is characterized by the autonomous production of parathyroid hormone (PTH), in which there is hypercalcemia or normal-high serum calcium levels in the presence of elevated or inappropriately normal serum PTH concentrations.

Exceptionally in symptomatic patients, a diagnosis can be established on the basis of clinical data. PHPT must always be evaluated in patients with clinical histories of nephrolithiasis, nephrocalcinosis, osseous pain, subperiosteal resorption, and pathologic fractures, as well as in those with osteoporosis–osteopenia, a personal history of neck irradiation, or a family history of multiple endocrine neoplasia syndrome (types 1 or 2).

Diagnosis of PHPT is biochemical. Asymptomatic hypercalcemia without guiding signs or symptoms is the most frequent manifestation of the disease. For differential diagnosis, PTH must be measured, as well as phosphate, chloride, 25-hydroxyvitamin D, 1,25 dyhidroxyvitamin D and calcium-to-creatinine clearance.

The diagnosis and differential diagnosis of primary hyperparathyroidism will be discussed here.

Keywords:
Primary hyperparathyroidism
Secondary hyperparathyroidism
Hypercalcemia
Familial hypocalciuria hypercalcemia
25-hydroxy vitamin D
1,25-dihydroxy vitamin D
Osteoporosis
Osteopenia
Resumen

El hiperparatiroidismo primario (HP) es una entidad clínica que se caracteriza por la producción autónoma de parathormona (PTH), en la cual hay hipercalcemia o calcio sérico normal-alto, con valores de PTH elevados o inapropiadamente normales.

De forma excepcional, el diagnóstico puede establecerse a partir de la clínica en pacientes sintomáticos. El HP siempre debe ser tenido en cuenta en pacientes con historia de cálculos renales, nefrocalcinosis, dolor óseo, fracturas patológicas, resorción subperióstica o en aquéllos que presenten osteoporosis-osteopenia, antecedentes de irradiación en cuello o historia familiar de neoplasia endocrina múltiple tipo 1 o 2.

El diagnóstico del HP es bioquímico, siendo la hipercalcemia asintomática la manifestación más frecuente de la enfermedad. Para el diagnóstico diferencial, además de la PTH, debe medirse el fósforo, cloro, 25 hidroxivitamina D, 1,25 dihidroxivitamina D y calciuria.A continuación, se revisa el diagnóstico y se detallan los cuadros clínicos con los que se debería plantear el diagnóstico diferencial.

Palabras clave:
Hiperparatiroidismo primario
Hiperparatiroidismo secundario
Hipercalcemia
Hipercalcemia hipocalciúrica familiar
25-hidroxivitamina D
1,25-dihidroxivitamina D
Osteoporosis
Osteopenia
Full Text
Introduction

Primary hyperparathyroidism (HP) is a disease characterized by autonomous production of parathyroid hormone (PTH), in which there is hypercalcemia, or high-normal serum calcium with elevated serum PTH or inappropriately “normal” calcium.

HP occurs in about 1% of the adult population, but affects more than 2% of it after 55 years, being 2–3 times more common in women than in men.

The most common cause is a parathyroid adenoma (80%–85% single and double in about 4%). The remaining cases are due to hyperplasia of the parathyroid glands, or, more rarely, a parathyroid carcinoma.

Familiar forms of HP are uncommon, manifesting usually as part of multiple endocrine neoplasia (MEN), with very rare forms of presentation, primary hyperparathyroidism and familial neonatal hyperparathyroidism.

Clinical Manifestations

From the description of the disease in the 1930s by Albright and Reifenstein,1 clinical expression has changed considerably2 (Fig. 1).

Fig. 1.

Changes in the clinical presentation of HP.

(0.1MB).

The first clinical descriptions regarded it as an uncommon disease with significant morbidity, which usually involved bone or renal disease, or both.3

Currently, due to increased use of biochemical markers, the most frequent clinical form (88%) is a mild and asymptomatic hypercalcemia with serum calcium about 1mg/dL above normal. However, HP may present more floridly or as asymptomatic subclinical forms.1,4

Skeletal Manifestations

Due to its predominantly cortical bone expression, PTH excess can lead to osteitis fibrosa cystica (2% of cases), manifested as bone pain and fractures. The typical radiographic signs include subperiosteal resorption of the middle and distal phalanges, thinning of the distal clavicles, a mottled or “salt and pepper” skull pattern, bone cysts and brown tumors in the long bones and pelvis.5–7

Renal Manifestations

Nephrolithiasis or nephrocalcinosis can be observed in approximately 20% of patients with HP. About 5% of nephrolithiasis are secondary to HP, while the majority are due to calcium oxalate by hipercalciuria.8,9

The most frequent finding, however, is hypercalciuria (35%–40% of cases) due to an increased filtered load of calcium, which exceeds the reabsorption capacity.

Some patients will only have decreased creatinine clearance and renal impairment.

Gastrointestinal Manifestations

May present as anorexia, nausea, vomiting and constipation. Peptic ulcer is rare (unless it occurs in the context of a MEN 1). Likewise, acute pancreatitis is rarely seen due to hypercalcemia associated with HP.10

Neuromuscular Manifestations

Muscle weakness and fatigue, intellectual fatigue, mental disturbances, and in rare cases that present with severe hypercalcemia, coma.11,12

Cardiovascular Manifestations

HP has been associated with hypertension. Hypercalcemia can also cause ECG changes such as shortening of the QT, blockages or increased sensitivity to digitalis.

In the classical forms, myocardial, valvular and vascular calcifications were described in HP. Today, stiffness and a decreased vascular ventricular13 index can be seen.

Diagnosis

Given the nonspecific clinical and practical absence of symptoms, the diagnosis is established by laboratory studies.

In the differential diagnosis screening, apart from calcium and PTH, the values of phosphorus, chlorine, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and creatinine corrected urinary calcium in 24h urine 10 should be determined.

The diagnosis of HP is confirmed when hypercalcemia or corrected calcium is in the high-normal range in the presence of elevated or inappropriately normal PTH.14,15 Other laboratory data to consider are: serum phosphorus, which tends to be low or in the lower limits of normal, calciuria, which is elevated in 40% of patients, 25-hydroxyvitamin D, which is usually lower than normal and may be associated with severe disease, and metabolic acidosis with hyperchloremia secondary to an inhibition of bicarbonate reabsorption by PTH, as well as increased markers of bone turnover.14,15

Differential Diagnosis

Differential diagnosis should be established with the following entities.

Malignancy

It is important to note that HP and malignancies are the 2 most common causes of hypercalcemia (90%).10

In addition, malignancy-associated hypercalcemia is the most prevalent cause of hypercalcemia in hospitalized patients, being serious and rapidly evolving, as it is often linked to advanced stage malignancies, and therefore a poor prognosis.

In hypercalcemia of malignancy, PTH is suppressed (except in the rare cases of PTH-producing tumors where it is elevated), and along with the clinical data, points at the diagnosis10,16 (Table 1).

Table 1.

HP Differential Diagnosis/Malignant Disease.

  PTH  Ca  Clinical Data 
HP 1  ↑  ↑  Suggestive variable 
Malignant disease  ↓Rare ↑ (T production of PTH)  ↑↑   

HP, primary hyperparathyroidims; PTH, parathyroid hormone.

Familial Hypocalciuric Hypercalcemia

It is a familial syndrome with autosomal dominant inheritance, a consequence of a mutation that inactivates one allele of the calcium sensing receptor in parathyroid glands in the renal17 tubule.

It is asymptomatic young adults, with mild hypercalcemia and PTH in the normal range or slightly elevated being the only laboratory findings.

There is no need for its treatment.17,18

The way to differentiate this clinical entity of HP consists of documenting a low urinary calcium in 24h urine, and decreased calcium/creatinine clearance ratio14,15,19–21 (Table 2).

Table 2.

HP Differential Diagnosis/HHF.

  24h Urine Ca  Cl Ca/Cr 
HP  ↑ (>200mg/day)  >0.02 
HHF  ↓ (<100mg/day)  ≤0.01 

HHF, familial hypocalciuric hypercalcemia; HP, primary hyperparathyroidism.

Drugs

Two drugs that deserve special consideration when evaluating a patient with hyperparathyroidism are thiazide diuretics and lithium.

  • -

    Hypercalcemia due to thiazide diuretics10,22: they reduce renal calcium excretion and may cause some mild hypercalcemia. Should be removed whenever possible because can mask an HP; reassess the patient at 3 months.

  • -

    Hypercalcaemia due to Lithium: Lithium may also reduce urinary calcium excretion, leading to hypocalciuria and hypercalcemia, and in a small percentage of patients, elevation of PTH.

The pattern to be followed is the same way, stop treatment if possible and reassess at 3 months.16

Normocalcemic Primary Hyperparathyroidism

It has been hypothesized whether this entity represents the first phase of HP or if it is a different disease characterized by an alteration in the regulation of PTH secretion, or a state of relative resistance to the action of PTH.23,24

It represents an incidental finding in a patient studied for decreased bone mineral density (BMD).

Must be differentiated from secondary (SH), and essential hyperparathyroidism to determine the values of vitamin D.

It requires close monitoring in order to detect symptomatic disease.25

Secondary Hyperparathyroidism

Clinical situation in which the parathyroid glands respond well to low extracellular calcium concentration (renal failure, poor intake, malabsorption, etc.). However, if the increase in PTH cannot correct the plasma calcium, either due to a disorder in the organs responsible for transportation or deficiencies, hypocalcemia develops. Therefore, HS may be associated with calcium concentrations that are within or below the reference range.

Laboratory findings show high or normal PTH with low calcium levels or within normal limits.

It is very important to measure levels of vitamin D and 24-h urinary calcium, in order to make the differential diagnosis of vitamin D deficiency leading to HP.26

HS treatment is to correct the primary abnormality that caused hypocalcemia.

Table 3 details the root causes of HS.

Table 3.

Causes of Secondary Hyperparathyroidism.

1. Renal failure 
Alteration in calcitriol production 
Hyperphosphatemia 
 
2. ↓ intake of Ca 
 
3. Ca malabsorption 
Vitamin D deficiency 
Bariatric surgery 
Celiac disease 
Pancreatic disease (fat malabsorption) 
 
4. Renal calcium loss 
Idiopathic hypercalciuria 
Loop diuretics 
 
5. Inhibition of bone resorption 
Biphosphonates 
Hungry bone syndrome 
Diagnosis Tree and Differential Diagnostic Table

Faced with an elevation of PTH, measurement of serum calcium, and subsequently, calciuria in 24h urine is required. If the latter is normal, this suggests a normocalcemic HP. If, however, it is elevated, HP will be very likely.

In cases where calciuria is reduced, reposition of vitamin D should be carried out before levels of serum calcium and PTH are measured. If these values are normalized, the picture is compatible with hypovitaminosis D. HS If, however, they remain high, this points to an HP with vitamin D deficiency (Fig. 2 and Table 4).

Fig. 2.

Diagnostic tree.

(0.28MB).
Table 4.

Normocalcemic HP/HP With Vitamin D Deficiency/HS Due to Hypovitaminosis D.

  PTH  Blood Calcium  Urine Calcium  Vitamin D 
HP normocalcemic  High  Normal or high  Normal  Normal 
HP with vitamin D deficiency  High  Normal  Normal-low or low  Low (<20) 
HS with vitamin D deficiency  High  Normal or low  Low  Low (<20) 

HP, primary hyperparathyroidism; HS, secondary hyperparathyroidism; PTH, parathyroid hormone.

Requirements of Vitamin D

The daily requirement for vitamin D is 800–1000U/day.

It is noteworthy that about 90% of patients with HP have, at least, insufficient vitamin D levels.

Treatment consists in supplementing and maintaining vitamin D levels above 30ng/ml, strictly controlling the values of calcemia, calciuria, and phosphatemia and to monitor the numbers of vitamin D every 3–6 months.14,15,19,20

Treatment of Primary Hyperparathyroidism

If symptomatic, surgery is the treatment of choice.

If the patient is asymptomatic, management is more controversial, and in any case, should be monitored to detect any disease progression.

Current recommendations are established as the annual measurement of serum calcium and creatinine, as well as performing a bone density test every 1–2 years.21

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Please, cite this article as: Martínez Cordellat I. Hiperparatiroidismo: ¿primario o secundario? Reumatol Clin. 2011. doi:10.1016/j.reuma.2011.06.001.

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