Primary hyperparathyroidism is the unregulated overproduction of PTH resulting in abnormal calcium homeostasis.

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1 Hyperparathyridism Thrugh their secretin f parathyrid hrmne (PTH), the parathyrid glands are primarily respnsible fr maintaining extracellular calcium cncentratins. Hyperparathyridism is a disease characterized by excessive secretin f PTH, an 84 amin acid plypeptide hrmne. The secretin f PTH is regulated directly by the plasma cncentratin f inized calcium. The main effects f PTH are t increase the cncentratin f plasma calcium by increasing the release f calcium and phsphate frm bne matrix, increasing calcium reabsrptin by the kidney, and increasing renal prductin f 1,25- dihydrxyvitamin D-3 (calcitril), which increases intestinal absrptin f calcium. Thus, verprductin f PTH results in elevated levels f plasma calcium. PTH als causes phsphaturia, thereby decreasing serum phsphate levels. Hyperparathyridism is usually subdivided int primary, secndary, and tertiary hyperparathyridism. Usually, 4 parathyrid glands are situated psterir t the thyrid gland. A small number f patients have 3, 5, r ccasinally, mre glands. The glands are identified based n their lcatin as right r left and superir r inferir. The inferir glands are derived frm the third pharyngeal puch. This structure is als the embrylgic rigin f the thymus. Therefre, the inferir glands riginate mre cephalad than the superir glands, but they migrate alng with the thymus t finally becme situated mre inferirly than the superir glands. Because f their embrylgic assciatin with the thymus, the inferir glands are ften fund adjacent t r within the thymus. They are usually lcated near the inferir ple f the thyrid. The superir glands are mre cnsistent in lcatin, usually fund just superir t the intersectin f the inferir thyrid artery and the recurrent laryngeal nerve. The superir glands are derived embrylgically frm the furth pharyngeal puch. This structure als gives rise t the C cells f the thyrid gland. Because f their embrylgic rigin, the superir glands are ccasinally fund within the substance f the thyrid gland. Ectpic lcatins f parathyrid glands are discussed in mre detail in "Primary Hyperparathyridism," under surgical care. Definitin f the prblem Primary hyperparathyridism is the unregulated verprductin f PTH resulting in abnrmal calcium hmestasis. Frequency The prevalence f primary hyperparathyridism is slwly decreasing. Mst recently, the prevalence is reprted t be apprximately 4 cases in 100,000 persns. Primary hyperparathyridism affects wmen apprximately twice as frequently as men. Prevalence increases with age, but hyperparathyridism can affect persns f all ages, including children. ١

2 Etilgy In apprximately 85% f cases, primary hyperparathyridism is caused by a single adenma. In 15% f cases, multiple glands are invlved (ie, either multiple adenmas r hyperplasia). Rarely, primary hyperparathyridism is caused by parathyrid carcinma. The etilgy f adenmas r hyperplasia remains unknwn in mst cases. Familial cases can ccur either as part f the multiple endcrine neplasia syndrmes (MEN 1 r MEN 2a), hyperparathyrid-jaw tumr (HPT-JT) syndrme, r familial islated hyperparathyridism (FIHPT). Familial hypcalciuric hypercalcemia and nenatal severe hyperparathyridism als belng t this categry. The mlecular genetic basis f MEN 1 is an inactivating mutatin f the MEN1 gene, lcated n chrmsme band 11q13. MEN 2a is caused by a germline mutatin f the Ret prt-ncgene n chrmsme 10. Germline mutatin f HRPT2 lcalized n chrmsme arm 1q is respnsible fr HPT-JT, while FIHPT is genetically hetergeneus. Pathphysilgy In primary hyperparathyridism due t adenmas, the nrmal feedback n PTH prductin by extracellular calcium seems t be lst, resulting in a change in the set pint. Hwever, this is nt the case in primary hyperparathyridism frm parathyrid hyperplasia. An increase in the cell numbers is prbably the cause. The chrnic excessive resrptin f calcium frm bne caused by excessive PTH can result in stepenia. In severe cases, this may result in steitis fibrsa cystica, which is characterized by subperisteal resrptin f the distal phalanges, tapering f the distal clavicles, salt-and-pepper appearance f the skull, and brwn tumrs f the lng bnes. This is nt cmmnly seen nw. In additin, the chrnically increased excretin f calcium in the urine can predispse t the frmatin f renal stnes. The ther symptms f hyperparathyridism are due t the hypercalcemia itself and are nt specific t hyperparathyridism. These can include muscle weakness, fatigue, vlume depletin, nausea and vmiting, and in severe cases, cma and death. Neurpsychiatric manifestatins are particularly cmmn and may include depressin, cnfusin, r subtle deficits that are ften characterized prly and may nt be nted by the patient. Increased calcium can increase gastric acid secretin, and persns with hyperparathyridism may have a higher prevalence f peptic ulcer disease. Rare cases f pancreatitis have als been attributed t hypercalcemia. ٢

3 Clinical presentatin Histry Symptms related t hyperparathyridism may include bne pain, pathlgic fractures, and nephrlithiasis. Symptms related t hypercalcemia may include muscle weakness, vlume depletin, plyuria and plydipsia, neurpsychiatric symptms, peptic ulcer disease, and pancreatitis. Physical Examinatin Physical examinatin findings are usually nncntributry. Examinatin may reveal muscle weakness and depressin. A palpable neck mass is nt usually expected with hyperparathyridism, althugh in rare cases, it may indicate parathyrid cancer. Differential diagnsis The causes f hypercalcemia that result in a cncmitantly elevated PTH level are few. These include familial benign (hypcalciuric) hypercalcemia (FHH) lithium-induced hypercalcemia, and tertiary hyperparathyridism. A cautinary nte is that a minrity f patients (i.e., 10-15%) with hyperparathyridism have PTH levels at the high end f the reference range, which is inapprpriately high in the presence f elevated calcium. A subset f patients has calcium levels within the reference range with elevated PTH, which is called nrmcalcemic hyperparathyridism. Hwever, fr cnsidering this diagnsis, all ptential causes f secndary hyperparathyridism (eg, lw calcium intake, GI disrders, renal insufficiency, vitamin D deficiency, hypercalciuria f renal rigin) shuld be excluded. Secndary and tertiary hyperparathyridism are typically diagnsed n the basis f their clinical cntext. Cancer-induced hypercalcemia is usually assciated with a lw PTH level but pssibly a high PTH-related peptide level. Labratry studies Ttal serum calcium and albumin levels r inized calcium levels shuld be measured. Hypercalcemia shuld be dcumented n mre than ne ccasin befre a diagnstic wrkup is undertaken. Testing f the intact PTH level is the cre f the diagnsis. An elevated intact PTH level with an elevated inized serum calcium level is diagnstic f primary hyperparathyridism. Older assays measured prtins f the PTH mlecule, such as the C-terminal r N-terminal. These lder assays shuld n lnger be used in rutine clinical practice. The current assay uses 2 different antibdies t 2 different epitpes; therefre, nly the intact mlecules are detected. A secnd-generatin assay that measures the full-length mlecule ٣

4 shuld be used. This is imprtant in detecting nly active PTH, particularly when PTH levels are lw. A 24-hur urine calcium measurement is necessary t rule ut FHH. A markedly elevated level is an indicatin fr surgery. Imaging studies Imaging studies are nt used t make the diagnsis f primary hyperparathyridism (which is based n labratry data) r t decide n surgical therapy (which is based n clinical criteria). Imaging studies are used t guide the surgen nce surgical therapy has been decided. If a limited parathyrid explratin is t be attempted, a lcalizing study is necessary. Other uses f imaging studies in the initial evaluatin f a patient with primary hyperparathyridism are cntrversial. Fr many patients, the recmmendatin remains fr cmplete parathyrid explratin with resectin f all invlved glands. Many surgens agree that imaging studies are nt required when this surgical treatment is chsen. Hwever, in patients wh have recurrent r persistent hyperparathyridism after a previus surgical explratin, an imaging test t lcalize invlved glands is definitely indicated. As mre experience is gained with technetium Tc 99 sestamibi scanning, use f this mdality t guide surgical therapy and even t cnfirm the diagnsis itself is becming rutine. The best initial test is sestamibi nuclear medicine scanning. This radinuclide is cncentrated in parathyrid tissue. The scan is highly specific fr abnrmal parathyrid tissue. It als has a sensitivity f greater than 90% in the case f slitary adenmas. The main weakness f this test is in diagnsing multiglandular disease. In this case, sensitivity drps t apprximately 55%. When cmbined with single-phtn emissin cmputed tmgraphy scanning, it can be used effectively t lcalize ectpic and usual parathyrid adenmas and, therefre, is the imaging study f chice. Ultrasngraphy f the neck may be equivalent r superir t sestamibi scanning. Hwever, it is peratr-dependent and has been reprted t have widely varying degrees f accuracy. One advantage f neck ultrasngraphy is that it can be perfrmed rapidly by the clinician at the time f the initial evaluatin. CT scanning and MRI have als been used, althugh they have nw largely been replaced by sestamibi scanning. CT scanning has inadequate sensitivity. MRI can be useful, particularly in the case f recurrent r persistent disease and in ectpic lcatins such as the mediastinum. A bne mineral density test is a useful tl t dcument stepenia. Nte that hyperparathyridism preferentially affects the crtical bne at the radius (distal third). ٤

5 Prcedures Bilateral internal jugular vein sampling is used t help lcalize ectpic parathyrid adenmas; hwever, this technique shuld generally be reserved fr centers with specialists and fr selected patients. Treatment Medical care The diet f individuals with primary hyperparathyridism shuld include arund mg f calcium per day. Als, 400 IU f vitamin D per day is reasnable. Estrgen therapy in pstmenpausal wmen has been shwn t cause a small reductin in serum calcium and increases in BMD, with stable PTH. Hwever, risks are assciated with estrgen replacement. Ralxifene may be an alternative. Alendrnate has als been shwn t increase the spine BMD in patients with primary hyperparathyridism. Calcimimetic drugs may be an alternative in the future. Other medical therapy is limited t the treatment f hypercalcemia itself. In the acute setting, this can be accmplished by the use f intravascular vlume expansin with sdium chlride and lp diuretics such as fursemide nce the intravascular vlume is restred. In rare cases, hypercalcemia has been treated with bisphsphnate therapy as a temprary measure prir t surgical treatment. Surgical care Indicatins fr surgery Symptmatic hyperparathyridism shuld be treated by surgical excisin f the abnrmal glands. Sme clinicians advcate surgical therapy in all patients with primary hyperparathyridism, mdified nly fr thse patients wh are nt able t tlerate surgery. They argue that the peratin is generally well tlerated and such treatment prevents cmplicatins (eg, steprsis) and may reverse symptms that patients ften d nt realize they have (eg, fatigue, depressin). Others advcate a nnsurgical apprach whenever pssible, such as in patients with a calcium level less than 11.5 mg/dl, patients with n apparent symptms, and patients wh have nrmal 24-hur urine calcium excretin and n steprsis. A Natinal Institutes f Health (NIH) Wrkshp n Asymptmatic Primary Hyperparathyridism in 2002 revisited the key management issues addressed at the 1990 NIH Cnsensus Develpment Cnference. They recmmended new guidelines fr surgery and the cnservative apprach f mnitring patients ٥

6 wh d nt meet the criteria fr surgery. The indicatins fr surgery as per the 2002 guidelines are as fllws: 1.0 mg/dl abve the upper limit f the reference range fr serum calcium 24-hur urinary calcium excretin greater than 400 mg A 30% reductin in creatinine clearance Bne mineral density T-scre belw -2.5 at any site Age less than 50 years Fr mnitring f patients with asymptmatic hyperparathyridism wh d nt underg surgery, the fllwing are recmmended: serum calcium and creatinine levels every 6 mnths and annual bne mineral density (all 3 sites). Chice f surgical treatment The standard perative apprach is cmplete neck explratin with identificatin f all parathyrid glands and remval f all abnrmal glands. In the case f 4-gland hyperplasia, a 3.5-gland (subttal) parathyridectmy is perfrmed. Apprximately mg f the mst nrmal-appearing tissue is left behind. A nnabsrbable suture is left as a tag t identify the gland shuld reperatin be necessary. Apprximately 85% f cases f primary hyperparathyridism are caused by a single adenma. Therefre, mst patients wh underg full neck explratin t evaluate all parathyrids endure sme unnecessary dissectin. Rather than explre all parathyrid glands, a newer technique, directed parathyridectmy, has evlved. This technique relies n preperative imaging studies t lcalize the abnrmal gland. The surgen then remves nly that gland, withut visualizing the ther glands. With either sestamibi scanning r ultrasngraphy, an abnrmal parathyrid may be detected preperatively in 70-80% f cases. Hwever, neither technique is reliable fr detecting multiple abnrmal glands. Therefre, an additinal methd is required t cnfirm that n ther abnrmal glands are present after excisin f the imaged lesin. Fr this purpse, many centers have begun t use the intraperative PTH assay. Because the plasma half-life f PTH is nly apprximately 4 minutes, the level falls quickly after resectin f the surce. If the level fails t fall after resectin f the identified abnrmal gland, the prcedure is extended t allw fr further explratin. Hwever, the intraperative PTH ٦

7 assay is expensive and is usually available nly in centers that perfrm a high vlume f parathyridectmies. A few authrs have advcated radi-guided parathyridectmy, detecting the labeled sestamibi in the abnrmal gland using a handheld prbe. The excised radiactivity in the abnrmal parathyrid is then cmpared with the remaining backgrund t cnfirm excisin f all affected glands. Hwever, mst centers have abandned this technique because (1) if the gland labels well with sestamibi, use f the handheld prbe intraperatively is unnecessary in mst cases and (2) the use f backgrund cunts t cnfirm cmplete excisin f all abnrmal tissue has nt been well validated. Use f directed parathyridectmy results in a mre limited peratin fr mst patients, resulting in a mre rapid recvery. Hwever, it may yield a higher persistence rate than cmplete neck explratin, and it prbably shuld be perfrmed nly in centers with the capability t perfrm the intraperative PTH assay. Fr familial disease, such as MEN 1, ttal parathyridectmy is perfrmed with auttransplantatin t the frearm and crypreservatin f sme parathyrid tissue. Preperative care Parathyridectmy is usually well tlerated. The main risks are thse assciated with anesthesia. Althugh lcal anesthesia has been used successfully fr this prcedure, especially in the directed appraches where a single adenma is lcalized preperatively, general anesthesia is used mst cmmnly. In patients in whm hypercalcemia (and, therefre, dehydratin) has been severe, special attentin must be directed t periperatively restring the fluid balance. Neck mbility must be assessed t ensure prper psitining in the perating rm. If the patient's vice is nrmal, preperative dcumentatin f vcal crd functin is nt necessary. Intraperative details Cmplete parathyrid explratin The mst critical aspect t ensure success in this peratin is identificatin f all 4 parathyrid glands and remval f all abnrmal glands. ٧

8 The patient is placed in the lawn-chair psitin with the neck extended ver a transversely placed shulder rll. This psitin allws full expsure f anterir neck structures and imprves venus drainage. A lw transverse incisin placed within the skin creases prvides the best csmetic result. The length f the incisin must be adequate t allw thrugh explratin f all ptential lcatins f the parathyrid glands; hwever, given the elasticity f the neck skin flaps, a 3- t 5-cm incisin allws safe identificatin f imprtant structures. After hemstasis f the skin incisin is btained, subplatysmal flaps are develped superirly t the ntch f the thyrid cartilage and inferirly t the flat prtin f the manubrium. The sternhyid and sternthyrid (strap) muscles are separated in the midline t expse the thyrid gland. If preperative lcalizatin studies suggest a parathyrid adenma, that side is apprached first. Frequently, a middle thyrid vein may require ligatin t ensure adequate mbilizatin f the thyrid lbe. The thyrid lbe is elevated ff the cmmn cartid artery and retracted medially. The inferir thyrid artery is identified after blunt and sharp dissectin f the arelar tissue anterirly and medially t the cmmn cartid artery and pstermedially t the thyrid lbe. The recurrent laryngeal nerve is identified next, inferir and lateral t the lwer lbe f the thyrid gland. The intersectin f the inferir thyrid artery and the recurrent laryngeal nerve is an imprtant landmark because mst parathyrid glands, superir and inferir, are lcated within 2 cm f this area. The superir parathyrid glands are lcated drsal t the upper tw thirds f the thyrid lbe and psterir t the recurrent laryngeal nerve. The inferir glands, which are less cnsistent in lcatin, can usually be fund inferir t the inferir thyrid artery and ventral t the recurrent laryngeal nerve. They are usually within 1 cm f the inferir lbe f the thyrid gland. Abnrmally enlarged glands are excised after cnfirmatin f the nrmal size f ther glands. During excisin, aviding capsular rupture f the abnrmal gland is imprtant because this may be assciated with implantatin f parathyrid cells in the perative site and subsequent parathyrmatsis. Parathyrids may be identified by highly experienced surgens based n appearance and lcatin. In mst cases, identificatin f ٨

9 the parathyrid glands shuld be cnfirmed histlgically by frzen sectin examinatin. In all cases f subttal r ttal parathyridectmy with auttransplantatin, parathyrid tissue must be crypreserved fr future auttransplantatin if the initial transplants are nt functinal. Directed parathyridectmy In many respects, the perative technique is similar t that described abve fr a cmplete parathyrid explratin. Differences are nted belw. Adequate imaging f the abnrmal gland prir t surgery is essential. In additin, arrangements fr intraperative measurement f PTH shuld be cnfirmed. A line fr sampling f peripheral venus bld shuld be established. Often the distal saphenus vein prvides the mst cnvenient access. Sme surgens mdify the lcatin f the incisin based n the preperative lcatin f the adenma. This authr prefers a small incisin (ie, ~2 cm) in the standard lcatin fr a cllar incisin. This incisin can be readily extended shuld a cmplete explratin prve necessary. A baseline PTH level is drawn immediately prir t skin incisin. Fllwing identificatin and dissectin f the adenma, a preexcisin level is drawn. Manipulatin f the gland ccasinally causes significant increases in the PTH level. Fllwing excisin f the gland, PTH levels are drawn at 5 minutes and 10 minutes pstexcisin. Criteria fr adequate excisin are either: a 50% drp in PTH frm the baseline level t the 10-minute pstexcisin level r a 50% drp in PTH frm the preexcisin level at 10 minutes and a pstexcisin level belw the baseline level. The incisin may be clsed while the last PTH levels are being prcessed, but the patient shuld remain under anesthesia and the sterile field maintained until the PTH assay results are knwn. Ectpic parathyrid glands Occasinally, all parathyrid glands cannt be identified. In such instances, the usual lcatins are reexamined first because mst parathyrid glands are lcated in typical areas. If parathyrid glands are nt identified in thse lcatins, then a systematic search is perfrmed, taking int cnsideratin the path f descent f superir and inferir parathyrid glands. ٩

10 Inferir glands may be lcated in the thyrthymic ligament. They may be difficult t identify, especially after divisin f the inferir thyrid vein, a maneuver that allws the gland t retract int the superir mediastinum. Anther lcatin fr ectpic inferir parathyrid glands is the thymus. The thymus can be visualized thrugh a transverse cervical incisin by retracting the innminate vein drsally with a spnge-stick while elevating the manubrium anterirly. Divisin f the interclavicular ligament imprves visualizatin in the superir mediastinum. Superir parathyrid glands are usually drsal t the upper tw thirds f the thyrid gland. Occasinally, these glands are adjacent t the superir thyrid vessels. Other lcatins include the cartid sheath r psterir t the esphagus r pharynx (retresphageal). Finally, bth superir and inferir parathyrid glands may be lcated aberrantly within the capsule f the thyrid gland. Sme surgens perfrm a thyrid lbectmy n the side harbring the abnrmal gland after an exhaustive search is made in the afrementined lcatins. Median sterntmy is rarely required during the initial neck explratin fr hyperparathyridism. Pstperative care If a directed parathyridectmy is perfrmed successfully, mst f these patients may be safely discharged the day f surgery. Sme practitiners rutinely supplement with ral calcium pstperatively. Fr a full parathyrid explratin, calcium levels must be mnitred pstperatively every 12 hurs until stabilizatin. The nadir f serum calcium usually ccurs hurs pstperatively. Many patients becme hypcalcemic, but few becme symptmatic. Reserve treatment fr hypcalcemia unless it is severe r the patient becmes symptmatic. Hypcalcemia after parathyrid surgery may be due t hungry bne syndrme where calcium and phsphrus are rapidly depsited in the bne. This is characterized by hypparathyridism and transient, but ccasinally severe, hypcalcemia until the nrmal glands regain sensitivity. If hypparathyridism persists, ral supplementatin with calcium and vitamin D is required. Calcium citrate r calcium carbnate may be started at 2 tablets 4 times per day. Sme patients require mre r less. Calcitril is started at 1 mcg/d fr 1 day, 0.5 mcg/d fr 2 days, and then 0.25 mcg/d thereafter. Patients in whm an auttransplantatin is perfrmed require temprary calcium supplementatin. If a recurrent nerve injury is suggested because the patient has develped new harseness, immediate laryngscpy is ١٠

11 indicated. If vcal crd paralysis is bserved, immediate reperatin may be warranted t repair a transected nerve because a few f these may regain functin. Reexplratin after hurs is nt generally indicated because the risks f perating in an inflamed field utweigh the relatively lw likelihd f a benefit. A ptential life-threatening emergency in the pstperative perid is the develpment f an expanding hematma in the pretracheal space. This cmplicatin must be recgnized and treated immediately by pening the wund and evacuating the hematma. If untreated, laryngeal edema may prgress rapidly, causing airway bstructin. Mst small hematmas d nt require treatment. A subplatysmal fluid cllectin may ccasinally frm, and these are usually treated adequately with a single aspiratin. In a few cases, aspiratin may need t be repeated. Rarely, a drain may need t be placed fr recurrent fluid cllectins. Fllw-up Patients are seen 1-2 weeks pstperatively, and serum calcium and PTH levels are btained. PTH levels may be elevated pstperatively in sme patients, but if the serum calcium remains within the reference range it des nt indicate persistent disease in mst patients. After the immediate pstperative perid, fllw-up is limited t peridic determinatins f serum calcium levels t detect the persistence r recurrence f disease r hypparathyridism. Secndary hyperparathyridism Secndary hyperparathyridism is the verprductin f PTH secndary t a chrnic abnrmal stimulus fr its prductin. Typically, this is due t chrnic renal failure. Anther cmmn cause is vitamin D deficiency. Frequency Secndary hyperparathyridism ccurs t sme degree in virtually all patients with dialysis-dependent chrnic renal failure. Vitamin D deficiency is cmmn and is underdiagnsed. Etilgy In renal failure, the stimuli fr verprductin f PTH are multifactrial. Factrs include hypcalcemia, impaired 1,25-dihydrxyvitamin D prductin by the diseased kidneys, and hyperphsphatemia. Hyperphsphatemia appears t be particularly imprtant in the develpment f parathyrid ١١

12 hyperplasia. These stimuli cause multigland hyperplasia, resulting in increased PTH prductin. Pathphysilgy Chrnic verprductin f PTH in patients with renal failure cntributes t the spectrum f bne disease bserved in patients n dialysis. In mst patients n dialysis, the primary bne disease is steitis fibrsa cystica, a disease f increased bne resrptin caused by elevated PTH levels. Skeletal lesins include subperisteal bne ersins, usually bserved best in the distal phalanges. Likewise, the skull has a classic salt-and-pepper r grund-glass appearance. Other bne diseases are cmmn in patients n dialysis, but these d nt appear directly attributable t hyperparathyridism. Clinical presentatin Because virtually all patients with renal failure have hyperparathyridism t sme degree, the clinical presentatin is ften that f renal failure. In patients with secndary hyperparathyridism due t vitamin D deficiency, the symptms are mainly due t the vitamin deficiency (e.g., stemalacia with increased fracture risk, mypathy [rarely]). In advanced cases f secndary hyperparathyridism, sme patients may have bne pain. Labratry studies All patients with renal failure shuld be mnitred regularly with serum calcium, phsphrus, and PTH levels. Patients with secndary hyperparathyridism usually have a lw-nrmal calcium and elevated PTH. The phsphate level may vary based n the etilgy, trending twards high values in renal insufficiency and lw values in vitamin D deficiency. Imaging studies Radigraphic evaluatin is limited t assessments f the bne disease. Obtain radigraphs f sites f bne pain. Hand radigraphs may shw characteristic subperisteal ersins. Imaging f the parathyrid glands is nt indicated unless primary hyperparathyridism is suggested. Treatment Medical care Unlike primary hyperparathyridism, medical management is the mainstay f treatment fr secndary hyperparathyridism. Treatment with calcitril and calcium can either prevent r minimize secndary hyperparathyridism. Cntrl f the serum phsphate levels with a lw-phsphate diet and phsphate-binding agents is essential. ١٢

13 Patients with predialysis renal failure, ie, thse with early-t-mderate renal failure, usually have a mdest elevatin f PTH levels. Suppressin f PTH secretin with lw-dse calcitril (i.e., mcg/d) may prevent subsequent parathyrid gland hyperplasia and secndary hyperparathyridism; hwever, calcitril therapy must be mnitred carefully t ensure that hypercalcemia is nt induced. Patients with dialysis-dependent chrnic renal failure require calcitril, ral calcium supplementatin, calcium in the dialysate, aluminum-free phsphate binders, and cinacalcet (Sensipar) t maintain levels f serum calcium and phsphate within their reference ranges. Because patients n dialysis are relatively resistant t the actins f PTH, a PTH level within the reference range is nt necessarily desirable. A recent survey f patients n dialysis using this therapy fund that 50% had PTH levels at least 3 times the reference range. Surgical care Indicatins include bne pain r fracture, pruritus, and calciphylaxis Failure f medical therapy t cntrl hyperparathyridism is a sft indicatin fr surgery. Generally, if PTH levels f greater than pg/ml persist after crrectin f serum calcium and phsphrus levels and evidence f prgressive bne disease is present, parathyridectmy may be cnsidered. Intraperative details All 4 glands must be expsed, and bipsies are taken if needed t ensure crrect identificatin. In mst cases, diffuse hyperplasia is encuntered, althugh the size f the glands can be significantly hetergeneus. The prcedure f chice is either ttal parathyridectmy with auttransplantatin r 3.5-gland parathyridectmy. In either case, a thymectmy must be included. A 1991 article by Rthmund et al reprted a randmized cntrlled trial f ttal versus subttal parathyridectmy fr secndary hyperparathyridism. The authrs fund that 4 f 17 subjects treated with subttal parathyridectmy develped recurrent hypercalcemia, and 2 required reexplratin. Nne f the subjects treated by ttal parathyridectmy develped recurrent hypercalcemia. Therefre, several authrs prefer ttal parathyridectmy with auttransplantatin. Briefly, parathyrid tissue is cut int apprximately pieces, each f which measures 1 X 1 mm. These are inserted in pckets in the frearm musculature, and each piece is marked with a plyprpylene suture n the fascia. Parathyrid tissue als must be crypreserved in case the primary auttransplant fails. Pstperative details Pstperative care fllws the rutine described abve in Pstperative care fr primary hyperparathyridism. ١٣

14 If ttal parathyridectmy and auttransplantatin are perfrmed, the patient requires a perid f maintenance with calcium and calcitril supplementatin. Outcme and prgnsis Medical treatment f secndary hyperparathyridism is successful in mst patients. Patients wh require parathyridectmy have apprximately a 10% risk f recurrent r persistent disease. This may be due t a hyperfunctining r missed neck gland r hyperplasia f the autgraft. Occasinally, a patient has persistent hypparathyridism after peratin. If tissue has been crypreserved, transplantatin may reverse hypparathyridism. If hypparathyridism is permanent, lifelng calcium and calcitril supplementatin is necessary. Tertiary hyperparathyridism Tertiary hyperparathyridism is secndary t lng-standing secndary hyperparathyridism. Tertiary disease is characterized by the develpment f autnmus hypersecretin f PTH causing hypercalcemia. Etilgy The etilgy is unknwn. A change may ccur in the set pint f the calciumsensing mechanism t hypercalcemic levels. Pathphysilgy Tertiary hyperparathyridism is bserved mst cmmnly in patients with chrnic secndary hyperparathyridism and ften after renal transplantatin. The hypertrphied parathyrid glands fail t return t nrmal and cntinue t versecrete PTH, despite serum calcium levels that are within the reference range r even elevated. In these cases, the hypertrphied glands becme autnmic and cause hypercalcemia, even after withdrawal f calcium and calcitril therapy. This type f tertiary disease is particularly dangerus because the phsphate level is ften elevated. If the calcium value multiplied by the phsphate value yields a high prduct, diffuse calcinsis may ccur. Clinical presentatin The clinical manifestatins f tertiary hyperparathyridism include persistent hyperparathyridism after renal transplantatin r new hypercalcemia in the setting f chrnic secndary hyperparathyridism. Treatment Ttal parathyridectmy with auttransplantatin r subttal parathyridectmy is indicated. ١٤

15 Familial benign (hypcalciuric) hypercalcemia FHH is caused by a lss-f-functin mutatin f ne allele f the gene fr the calcium-sensing receptr (CaR). It causes hypercalcemia, hypphsphatemia, and hypermagnesemia. The PTH level is usually within the reference range r is mildly elevated. It can be distinguished frm primary hyperparathyridism by lw 24-hur urinary calcium excretin. Persns with FHH are asymptmatic. Parathyridectmy is nt indicated. Hypercalcemia f malignancy This disrder is usually caused by tumr release f a hrmne called PTHrelated peptide. Less cmmnly, hypercalcemia f malignancy is caused by lcal stelytic lesins and, rarely, by verprductin f 1,25-dihydrxyvitamin D. This disrder is the mst cmmn cause f hypercalcemia in hspitalized patients. The hypercalcemia f malignancy results in a lw r undetectable intact PTH level. Usually, it is easily distinguished frm hyperparathyridism. Only a few cases f ectpic prductin f true PTH are reprted in the literature. ١٥