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Though many patients are asymptomatic, the elevation in plasma calcium can cause some or all of the following“stones,” “bones,” “groans,” and “moans”: kidney stones fromcalcium-phosphate and calcium-oxalate formation in urine, bonepain from excessive resorption, groans from constipation due toreduced fecal calcium, and moans from generally not feeling welland fatigue. Treatment is surgical removal of the tumor.CLINICAL CORRELATECalcium-Related Pathophysiology: HyperparathyroidismHyperparathyroidism is associated with excessive PTH secretionand results in hypercalcemia (high plasma calcium) and hypophosphatemia (low plasma phosphate).Primary hyperparathyroidism is usually caused by parathyroidtumors that produce PTH but do not have feedback regulation.The elevated PTH increases the renal activation of vitamin D;increases plasma calcium through increasing intestinal absorption, kidney reabsorption, and bone resorption; and decreasesplasma phosphate by reducing renal phosphate reabsorption.Although renal calcium reabsorption is elevated, the significantlyincreased filtered calcium load results in elevated urinary calciumand phosphate excretion, increasing the chance of kidney stoneSecondary hyperparathyroidism is caused in response to theprimary problem of low plasma calcium levels.
In secondaryhyperparathyroidism, the low plasma calcium levels are usuallycaused by vitamin D deficiency and/or chronic renal failure, andthe parathyroid glands secrete PTH to correct this problem. Thus,PTH levels will be high, but plasma calcium will be low or normal.Treatment is with vitamin D, when indicated.Adenoma(~85% of cases)Hyperplasia(~15% of cases)Carcinoma(rare)SkinGutCa2+PiVit.
DLiverParathyroid hormone(PTH) elevated25(OH)DCa2+PiRenal tubuleSerum andextracellular fluidHigh 1,25(OH)2D promotesabsorption of Ca2+ from gut2+Ca 2+Ca2+Ca filtrationincreasedPiSerum Ca2+increased;fails to suppressPTH secretionPiPiSerum Pi lowor normal25(OH)D normal1,25(OH)2D elevatedPTHCa2+PiCa2+PiCa2+PiNephrocalcinosisCalculiUrineCa2+ elevatedHigh PTH promotes Ca2+reabsorption, inhibits Pireabsorption. Alsopromotes conversion of25(OH)D to active metabolite 1,25(OH)2DLarger amount ofCa2+ filtered intotubule exceeds itsresorptive capacityand results inhypercalciuriaCa2+PiCa2+PiCa2+ PiCompensatoryincrease inosteoblasticactivity withvariable rise inserum alkalinephosphataseHigh PTH stimulatesosteoclastic resorptionof bone (Ca2+, Pi,and matrix)Variable reduction in bone density.
In rare, severe cases, cysts andbrown tumors (due to osteitis fibrosa cystica) and subperiosteal resorptionPathophysiology of Hyperparathyroidism Most cases of hyperparathyroidism arise from parathyroid tumors that cause hypersecretionof parathyroid hormone (PTH). The elevated PTH increases bone resorption, renal calcium reabsorption, and active vitamin D production (whichincreases intestinal calcium absorption).
This causes hypercalcemia, which can result in multiple symptoms (“stones,” “bones,” “groans,” and“moans”).Calcium-Regulating Hormones353D. Untreated, chronic hypoparathyroidism can result in cataracts,alopecia (hair loss), and weakened tooth enamel, in addition tothe muscle spasms and seizures. Although rare, sustained low(4 mg/dL) plasma calcium concentrations can lead to coma anddeath. If life-threatening, treatment is with intravenous calcium;otherwise, active vitamin D and oral calcium is effective in maintaining plasma calcium levels.CLINICAL CORRELATECalcium-Related Pathophysiology: HypoparathyroidismHypoparathyroidism is a deficiency of PTH, and results in hypocalcemia (low plasma calcium) and hyperphosphatemia (highplasma phosphate).
This is a fairly common occurrence followingthyroid or parathyroid surgery, and the decreased extracellularfluid calcium increases the excitability of sensory and motorneurons and muscle cells. This excitability can cause sensoryeffects such as tingling or numbness in the lips and fingers, as wellas motor effects including cramping and twitching. Severe hypocalcemia can lead to tetanic muscle spasms and seizures, so treatment is initiated when first symptoms are noted. Initial treatmentcan include intravenous calcium (if plasma levels are dangerouslylow), followed by oral calcium supplements with active vitaminPseudohypoparathyroidism has the same overall effect as hypoparathyroidism, reducing plasma calcium and increasing plasmaphosphate—however, the cause is a primary defect in the Gsprotein of the PTH receptors in bone and kidney.
Although PTHcan bind, the cAMP-pathway cannot be activated, and thus whilePTH levels are elevated, renal and bone calcium transport is notactivated.Pathologic Physiology of HypoparathyroidismPostoperative(more common)Idiopathic(rare)SkinLiverParathyroid hormone(PTH) deficient or absent25(OH)DVit.
DCa2⫹Gut PiSerum andextracellular fluidSerum Pi high due toincreased renal tubularreabsorptionPiCa2⫹PiLow 1,25(OH)2D impairsabsorption of Ca2⫹ from gutSerum Ca2⫹ belowrenal threshold2⫹CaCa2⫹Serum Ca2⫹ low dueto decreased renaltubular reabsorption,reduced absorptionfrom gut, and reducedbone resorptionPi25(OH)D normal1,25(OH)2D decreasedCa2⫹PiRenaltubuleUrineCa2+ lowAbsence or deficiency ofPTH causes diminishedreabsorption of Ca2⫹,excessive reabsorptionof Pi, and decreasedconversion of 25(OH)Dto active 1,25(OH)2DAlkalinephosphatasenormalCa2⫹PiCa2⫹PiCa2⫹PiRate of osteoblastic boneformationdecreased tomatch rate ofresorptionLittle osteoclastic boneresorption dueto lack ofPTH stimulusBone density normal or slightly increasedPathophysiology of Hypoparathyroidism Hypoparathyroidism is usually a result of thyroid or parathyroid surgery, and the lack ofparathyroid hormone reduces the formation of active vitamin D, decreases renal calcium reabsorption, and alters bone resorption activity.Hypocalcemia develops, and the low plasma calcium levels increase neuronal and muscle cell excitation, causing twitching, cramping, and inextreme cases tetany.354Endocrine PhysiologyCLINICAL CORRELATECalcium-Related Pathophysiology: Vitamin D DeficiencyVitamin D deficiency is rarely found in areas where vitamin D issupplemented in the diet and there is regular exposure to sunlight.Rickets is a disease caused by insufficient vitamin D during childhood.
The lack of vitamin D prevents adequate calcium and phosphate for bone mineralization, resulting in stunted growth andmalformed bones. In adults, prolonged vitamin D deficiency willdecrease new bone mineralization, resulting in bone deformation(osteomalacia). This is especially evident in weight-bearing bones,and can cause severe bow-legged stance. Although it is rare to seethis in adults, it can result from chronic steatorrhea, becausevitamin D is fat-soluble, and most will be lost in the feces.Renal rickets is a specific form of osteomalacia caused bychronic renal damage.
This limits the production of vitaminD, because the kidney tissue is either damaged or absent, andPTH cannot convert 25-hydroxycholecalciferol to active1,25-dihydroxycholecalciferol.Impaired growthChildhood RicketsCraniotabesFrontal bossingDental defectsChronic coughPigeon breast (tunnel chest)KyphosisRachitic rosaryHarrison grooveFlaring of ribsEnlarged ends of long bonesEnlarged abdomenCoxa varaBowleg (genu varum)Flaring of metaphyseal ends oftibia and femur. Growth platesthickened, irregular, cupped, andaxially widened. Zones of provisional calcification fuzzy andindistinct.
Bone cortices thinnedand medullae rarefiedRadiographic findingsClinical findings(all or some presentin variable degree)Radiograph shows variegated rarefaction of pelvic bones, coxa vara,deepened acetabula, and subtrochanteric pseudofracture of rightfemurRadiograph of rachitic hand shows decreased bone density,irregular trabeculation,and thin cortices ofmetacarpal and proximalphalanges.
Note increasedaxial width of epiphysealline, especially in radiusand ulnaSection of rachitic bone shows sparse,thin trabeculae surrounded by muchuncalcified osteoid (osteoid seams) andcavities caused by increased resorptionRickets The main manifestation of vitamin D deficiency is in bone mineralization.
As depicted in theillustration, in children, this results in rickets. In adults, vitamin D deficiency leads to osteomalacia.355CHAPTER31Hormones of theReproductive SystemSex hormones are involved in fetal development and sexualdifferentiation, pubertal somatic changes, and reproductivephysiology. Although the term sex hormone refers to sex steroids (primarily estrogen, progesterone, testosterone, andadrenal androgens), a wider array of hypothalamic, pituitary,gonadal, and placental hormones have important roles in thereproductive system.
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