for mealtime contol, because they effectively lower peandil hyperglycemia. Ifexenatide i used, then additional injections will be requied atthe two major meals ofthe day. I using an inezetin- enhancer drug such as sitagliptin, injections are not required. This approach is useful with incretin agonists exenatide o hiraglutide in patients who need to lose weight, who gain considerable weight ‘with meal insulin, or who ‘experience poor control. despite attempts to regulate meal glycemia with short-acting insulins. [Recent studies suggest possible benefit of combining long acting basal insulins with ineretin receptor agonists "Not BDA approved for this indication References [Acord Study Group, Efe of intensive blood presureconirl in type 2 dats St eng) 0 sisting Pn NEB "2015 January 2015 Volume 38, Supplement 1, 1-593 American Dabetr Acton FaitasngBebamor Change. Key Sete for Tmpowerng Yous Pooers, hn clngnarorsange oy Dishes Pevenion Program Rerarch Group. The Diabetes Prevention Progam {DIP Deception ot enyl trrenton Diabetes Cave 2002.5.2165-71 Fou CSctal Upaae on Peveion of Carnarealae Duce in Adu Wa ype 2 Diabetes Mites in Light of Recent Erne. A Scie Statement From the ‘Anencin Heart Arocnion andthe America Dishes Ausotion Dsbles ‘Gusber A} Abeabonvon 0, Baraiy J etal. Amescen aocaion of lca edo ‘cinco’ comprehensive dibees tusapeneat gotta 2013 conan GGeandy SM, Clean jl, Dass SR et a. Detgnoss ab ranagement of he atibol tndcome, At Aransas Heart AvsoiyNaional Hea, Lang nd Blood Tnarue Skate Stement Exceve vuany, Ciclten Soosntaa7sses Has E: Lard, Sloe. An ana of charac of sbjet examined for ihstinetet on pace ptbogy. Diabetes Tec Ther 20181 5:09—18, Kan Bue) Peano, Sem M, The metabolic sdeomes Tine fora crcl pera jit sateen om te Americas Babes Asoiaon sd the Ear pet Auocation forthe Seay of DiabiesDabees Care 005,8.2269-508, Kabler We, Bare Connor y Fowler cra Redaceon he incene of ype 2 “Gates wherein or melvin N El] Med 200234693 003, Lpska, Buy Cj iauce SF Ureatmttormn onthe etang old to morc eval elie, Date Care 20114151 Mount Lapin H, Cole € Coniston effing and postranda lama (doce inctment othe ove ral hyperemia’ pea abet pats Npnatone wath incesnng level of HoAe- Diabetes Cae 2095,2686155 [Nest Bul, Sonow RG, cha. Thaeliie donee stton, snd on ‘uve her fare Acoma atemes em the Aenean Hert Avecson Sed Americar Dbets Asvoxaton, Dbees Care 20082725683, Stone NJ al 2013 ACCIAHLA guide ofthe eaten of blo coer Te dace alberonlrauc arioaselar ea inal teprt ofthe Aces ee of Ctaaigyfanenean Heart Asean Task Foe on Pree Guide Sn4sa908 Sup S48 osensoc Gee) The eatto‘are til Randomied addon of ian NPH isn tool therapy of ype 2 abet potent. Diabe reread GOUT AND HYPERURICEMIA Method of Salma Chohan, MD + Gout is the most commen inflammatory atbits in men and is Increasing in prevalence + Adefiitve diagnosis of gout requires demonstration of mono sodium urate crystals in synovial fuid of tophi + Gouty arthitis often begins inthe lower extremity joints Septic arthritis, rheurnatoid arthritis, and calcium pyrophosphate disease (pseudogout) can mimic gout and should be rulee out [CURRENT THERAPY + The goals of successful gout treatment include terminating the acute attack, preventing intermittent attacks, and undertaking Tong-term therapy to avoid chronic arthritis + Indications for chronie treatment of gout include frequent attacks, recurrent arthritis, and kidney disease + A serum urate level of less than 6.0 mg/dl. is the goal when Using urate-lowering therapy + Nonpharmacologic treatment includes lifestyle modification and dietary changes. += The mainstay of urateowering therapies remains xanthine ox dase inhibition Epidemiology ‘Gout, or monosodium urate crystal deposition disease, isthe most common inflammatory arthetis of men and is an inceeasingly common problem among postmenopausal women. Its a chronic disorder, affecting over 3 mallion people inthe United States and increasing in both prevalence and incidence, especially n persons colder than 68 years. Gout is often accompanied hy serious comor bid disorders (hypertension, cardiovascular disease, cheonie kid ney disease, and all of the component features of the metabolic syndrome) ‘and is managed in primary care practice in about 90% of affected persons. Therefore identifying risk factors, opt= ‘mizing diagnosis, and choosing the appropriate treatment for gout are important skills for a wide array of caregivers. Pathoph ‘and Risk Factors Cee ee an Rete et prte mebotm in homens Hyperuricemia, a serum urate concentration exceeding urate s0l- ubilty (6.8 mg/dL}, is an invariable accompaniment of gout, though serum uric acid levels might not be elevaced daring an acute attack. Hyperuricemia predisposes affected persons to ura rystal formation and deposition, which lead to the inflammatory responses underlying the symptoms of gout. Thus, treatment of gout is aimed at reducing and maintaining serum urate concentra- thon at subsaturating levels, usually set at less than 6.0 mg/dL. Hyperuricernia Risk factors for hyperuricemia include obesity, hypertension, hyperlipidemia, insulin resistance, renal insuflieiency, and vse of diuretics. Diets rich in certain foods are also associated with increased risk for gout. Many studies with large patient cohorts have demonstrated a relationship herween hyperuricemia and hypertension, catdiovascular and peripheral vascular disease, chronie kidney disease, and diabetes mellitus. The association of hyperuricemia and metabolic syndrome has also been shown in children and adolescents, Interventional trials of asymptomatic patients with hyperuricemia and high cardiovascular risk must be performed before sich treatment ean be advocated, Diagnosis Acate gout is characterized by an abrupt onset of joint pain, ery- ‘hema, and swelling, usually of one joint, but less commonly of more than one. The arthritis most often occurs first in a lower extcemity joint, especially the fist metatarsophalangeal (MTP) joint at the base of the great toe, The predilection for ths ste is thought to be secondary to cooler actal temperature or repeated trauma and pressure on this joint. “The gold seandard for diagnosis of gout is the demonstration of monosodium urate crystals by polarized light microscopy, ether in Join fluid aspirated during an acute attack or between attacks, of from material aspirated from suspected tophi. To aspirate the frst MTP joint, the joine is first idencitied by palpating the space at the base of the metacarpal on the dorsal aspect while flexing and extending the toe, The needle is then inserved perpendicularly into the joint space ro avoid the extensor hallucis tendon. Synovial fluid 751 Gout and Hyperuricemia11 Endocrine and Metabolic Disorders 752 {rom affected joints should immediately be examined under polar ied microscopy to confirm the diagnosis of needle-shaped crystals with negative birefringence, If polarized microscopy is unavail- able, then fluid should be promptly sent ina sterile tube for crystal confirmation to an appropriate laboratory. ‘Unfortunately, the equipment and analytical expertise necessary to make this diagnosis are not widely available to primary care physicians. As a result, the diagnosis of acute gout is commonly nade on clinical grounds, often using clinical and laboratory cri teria established by organizations such as the American College of| Rheumatology and the European League Against Rheumatism. These diagnostic guidelines emphasize the presence of signs of inflammation (ewelling, warmth, redness, tenderness, and loss fof joint function), abrupt onset, monoarticular involvement, ‘occurrence in the frst MTP joint, and presence of tophi, ‘The initial symptoms and signs of gout often occur after many’ years of asymptomatic hyperuricemia. In untreated or inade- ‘uately treated patients, the course of the disease often involves acute attacks at increasing frequency, with shortening of asymp. tomatic periods (called intercritical gout) and, ultimately, develop- ment of chronic joint disease (gouty arthropathy) and tophi {masses of urate crystals in a chronic inflammatory matrix) in bone, joints, skin, and even solid organs (Figure I) Indications for Treatment Early n gout, patients might have attacks that are separated by years and manageable over the course of few days with ant-inflammatery ‘medications and adjuncts such as joint rest and application of ice. ‘Over time, the attacks usually become more frequent, prolonged, and disabling, eventually requiring long-term urate-lowering treat ‘ment aimed at preventing urate crystal deposition and eventually abolishing acute flares and resolving tophi. Indications for urate- Towering (antibyperuricemic) therapy ate listed in Box | Figure 1. Inadermal urate deposit(tophus). (Reprinced with permission fom Mandell BF: Gout and crystal deposition disase. In Weisman MEL ‘Weindlatt ME, Losie J Van Vollenhoven R leds. Targeted Treatment of the Rheumatie Disest, Piladelphi, Saunders, 2010, 295-302) FREIETIN icstons or Ute anerin Tey + Frequent and eisabling gouty stacks, often defined a: ‘wo of three flares armualy, though this is not evidence dased; the decision to reat is based on both number of flares and the consequent disability resulting fromm flares + Chronie gouty disease: clinical oF radiographically evider joint erosions + Tophaceous deposits: subcutaneous or intraosseous * Gout with renal insufficiency 1 Recurrent kidney stones Urate nephropathy Uninary ure acid excretion exceeding 1100 mg/d (6.5 mene), When determined in men younger than 25 years or in preme- hepausal wornen Treatment Acute Gout Gouty arthritis occurs suddenly and attacks are often very painful and disabling. Patients describe acute onset of exquisite Pain, swelling, erythema, and inability to bear weight on the afflicted joint. Occasionally, patients have constitutional symptoms inelud- ing fever and chills, with an elevation of sedimentation rate and white blood cell count. To terminate an attack, nonsteroidal antiinflammatory drugs (NSAIDs), colehicine (Colerys) of cort- costeroids can be offered. I given 3 full antiinflammatory dos fge, NSAIDs have a rapid onser and are quite efficacious in relieving pain and shortening the duration ofan attack, The utility ofthis class of drugs may be limited by renal insufficiency, cardio- vascular risk factors, and gastoincestinal bleeding. While indo methacin (Indocin),sulindae (Clinorill, and naproxen (Naprosyn) ate all FDA approved for treating acute attacks of out, nearly every drug in this class and the selective eyclooxygen- Sse (COX) 2 inhibitors also have considerable efficacy. High-dose Salicylate therapy lowers serum uric acid by interfering im renal trate transport; low-dose aspirin has the opposite effec, but it soften continued in gout patients because ofits overriding impor tance in managing coronary artery disease ‘Oral colchicine has been used to teat gout for many years as an ‘unproven drug withno FDA dosage recommendations or presenib- ing information, In July 2009, however, the FDA-approved Col- crys, a singlesingredient colchicine product, for the fist day of treatment of acute gout attacks ata low-dose regimen of 1.2 mg followed by 0.6 mg in 1 hour (total 1.8 mg). With this regimen, colchicine can be used to abort an attack iftaken immediately after the development ofthe frst symptom of gout flare. Higher colchi: cine doses (0.6 mg every hot, until symptoms improve oF until gastrointestinal symptoms of diarrhea, nausea, oF vomiting Aevelop, for a total of 4.8 mg over 6 5)" have traditionally been recommended, A randomized, placebo-conteolled wal comparing the low-dose and high-dose regimens showed both approaches had equivalent efficacy n pain relief at 24 hours (compared with pla- cbo). However, adverse gastrointestinal events were significantly less common with the low-dose regimen, In subjects warranting auditional flare treatment, continued use of colchicine 0.6 mg twice daily (reducing to once daily asthe flare subsides) is appro= priate in persons with normal renal and hepatic function ‘Gastrointestinal symptoms are generally the frst clinial signs of colchicine toxicity in patients with normal renal and hepatic function. More serious toxicities do occur and include neuro- myopathy, aplastic anemia, and worsening renal and hepatic function. Care should be used in patients with renal or hepatic ‘impairment, and because of potentially serious drug-drug interac- tions, colchicine should be avoided in patients receiving cyclo- sporine (Neoral), clarithromyein (Biaxin), verapamil (Calan), Not vA approved for this indication lake inthe United Sate.and amlodipine (Noevasc. Imeavenous colchicine” isnot available in Europe. The FDA has stopped the marketing of unapproved dnjectable colchicine prodvetsin the United States and discourages the compounding of 1V colchicines because of eports of prepa tion eerors causing deaths Corticosteroids provide a safe alternative for patients with con: traindications to NSAIDs or colchicine. For isolated monoaricd- lar attack, capecall of medivim or lage joints, aspiration of joint fluid and ineraarvular injection with triamcinolone acetonide (Kenalog) 20 co 40 mg can quickly terminate an attack. For poly- ariclar attacks oF attacks in smaller joints, systemic corticoste- roids (oral or intramuscular) may be employed. Oral prednisone ‘tartinga¢20 mg tvce daily with taper over 10 0 ld days is very cifective, Patients can have rebound attacks if oral steroids are ter inated too quickly, snd thes methylprednisolone (Medrol) dose packs shouldbe avoided. ineamuselar injections used, a single Alose of iameinolone 40:mg may be employed "There is interest in agent blocking the action of interleukin 1 {IL-1}, aeytokine thought o play amajor role i isiating and sus taining acute gouty inflammation, Anakinea (Kineret) and cana- Kinal lari)" ate potent injectable IL-1 snhibstors and staies are ongoing to astess the vty ofthese agents to mitigate acute attacks, In. 2013 canakinumab became the fist biologic agent approved for acute gout in Europe. It was approved by the Euro- pean. Medicines Ageney for symptomatic treatment of adult patients with frequent gouty antris attacks in whom NSAIDs And colchicine ate contraindicated, are not tolerated, oF do not provide an adequate response, and'in whom repeated courses of Corticosteroid are not appropriate, Rilonacepe (Accalyt) which is also i this class, was declined approval for gout by the EDA in 2012 because of concerns about long-teem sat. Interertical Gout After an attack subsides, management is directed at preventing recurrentattacks. During acute attacks of gout, normal serum urate concentration sreported in upto 40% of afected patients, andthus it isnot an accurate reflection of the true urate pool. Confirmation ‘of hyperuricemia i best achieved either before the resolution of at attack or2 to4 weeks after it, in order to achieve an accurate serum urate concentration. There isa generalizable correlation between, the serum urate level and rick for recurrent attack, Prophylaxis of furure attacks during early urate-lowering thet= apy can consist of calchicine (Colerys) at doses of 0.6 mg once or twice a day (based on renal function) or NSAIDs. If chronic NSAIDs are used, acid-reducing medications such as proton pump inhibitors or histamine-2 blockers may be employed for patients at risk for gastrointestinal bleeding. Long-Term Urate-Lowering (Antihyperuricemic) Therapy ‘The aim of urate-lowering therapy iso reduce and maintain serum urate at concenteations below those at which extracellular Tide fare saturated with monosodium urate. In general, an ultimate Serum urate conceneration of less than 6.0 midi advised. Urate lowering can be achieved ether by increasing urinary excretion or by decreasing production of urate 'Nonpharmacologie urate-lowering treatment begins with lif style changes. Diet and weight lost must be addressed. Obesity and weight gan are risk factors for gout, and weight Toss hasbeen ‘Shown to decrease the risk of gout. A purine restricted dict has foften been recommended to patients but is often unpalatable fd impractical. Reduction in alcohol intake, namely beer and Tiguor ean effectively reduce urate levels Similarly, reduced intake of red meat and shelish also lowers the risk of recurrent gouty Stacks, Studies have shoyin an increased frequency of atacke in patients who consume [uit juices and soft drinks containing Iighsfractase corn syrup, an ingredient not found in det drinks "Not FDA approved for this indication Deacceds doage te ‘Once the decision is made to institute serum urate-lowering ther apy, the duration of treatment is indefinite and must be long-term t0 be effective, The majority of patients with gout and tophaceous dis- case will continue to have attacks if therapy is discontinued, and thus education isa key pate of the treatment plan. Patients should be instructed that, with initiation of any urate-lowering therapy, they will be at increased isk for a flareup and thus must continue regular use of prophylactic agents as outlined above. At least 80% {0.95% of cases of hyperuricemia and gout are attributable £0 impaired urate excretion, which is reflected in diminished urate clearance of fractional excretion of uric acid but not ustally in low daily urine uri acid excretion. In practice, 24-hous urine col Iections are rarely performed. Patients are preferentially treated with xanthine oxidase inhibitors because ofthe easier dosing sched- ale and because many patients have contraindications to uricosurics such as renal insufficiency and kidney stones Uricosuries Relative to medications aimed at urate synthesis, uricosurics are relegated to second-line treatment of patients with elevated urate bburden or tophaceous disease. The most commonly used urico- suric agent inthe United States is probenecid. This isa very effec- tive drug that concentrates and promotes urinary excretion of arate. Tes utility is limited in patients with renal insufficiency, and probenecid is not recommended a8 firsvline therapy in patients with nephrolithiasis or urie acid overexcretion, The main- tenance dose of probenecid required to achieve and maintain serum urate concentration at les than 6.0mp/dL is 0.5 to 3 giday,” administered in 2 or 3 daily doses, Once goal serum urate concentration is achieved with a uricoruric agent, the risk of uric acid calculi is diminished, because urinary urie acid excretion becomes normal ‘Other drugs found to have uricosuric effects include fenofibrate Tricor)’, a fibrie acid derivative used to treat hyperlipidemia, and the antibypertensives losartan (Cozaar) and amlodipine (Nor vase)! These agents have mild uricosuric properties and may be useful adjuncts 2o urate-lowering therapy. Skim mille ingestion has been shown to lower serum urate levels through uricosurie cffects, Lower urate levels have also been secn in patients who consume coffee, but the mechanism of action is unknown, Xanthine Oxidase Inhibitors Allopazinol (Zyloprim) and febuxostat(Uloric) are the only FDA- approved xanthine oxidase inhibitors for the treatment of gout Allopurinol, introduced in 1966, is approved in doses of 100 to 800 mglday. More than 90% of patients with gout treated with arate-lowering medication in the United States are given allopuri- nol, but dosages of more than 300 mg/day are infrequently employed, and often patients do not achieve serum urate concen trations of 6.0 mg/dl. of less. Appropriate use of allopurinol is lrn= ited for several reasons. There are genuine concerns about allopurinol drug interactions, gastrointestinal intolerance, rashes ranging from mild to life-threatening), and the are but sometimes fatal hypersensitivity syndrome. Allopurinol should be avoided with the immunosuppressives azathioprine (Imuran) and 6- mercaptopurine (Purinethol) because it can increaze the risk of bbone marrow toxicity, as these medications are partially metabo- lized by xanthine oxidase. Allopurino! should not be taken with ampicillin owing to increased risk of rash Effective dosing of allopurinol is often not achieved because of compliance with published bur recently dispured recommenda- tions for allopurinol dose reduction in states of renal impairment. Allopurinol should be initiated at 100 mg daily in patients with creatinine clearance of 40 mL/min or greater, and it should be titrated in 100-mg increments every 2 t0 4 week, with the end- point of dosing determined by achievement of serum urate cone tration of 6.0 mg/dL. or less "Not EDA approved for thi indication, “Not yet approved fr we im the United State, Gout and Hyperuricemia 75311 Endocrine and Metabolic Disorders 154 ‘The FDA approved febuxostat (Ulric) in 2009, Unlike allopus nol, this i a nonpurine analogue and sslestive xanthine oxidase Inhibitor thats not sncoxporated ito purine nucleotides and does not appear to afec pyrimidine metabolism. Febuxostat is primarily Inetabolized by oxidation andglucuronidation inthe iver with ile zenal excretion of drug; this contrasts with the ena elimination of ‘oxyparinol, the main allopurinol metabolite. The recommended Staring dose of febuxostatis 40 mg daily, with an increase to 80 mg daly if secum wrate concentrations do not reach goal urate levesin 2 weeks in patients with normal reba function. In Europe higher dosages($0-120 mgdaify)"havereceived approval, andstad. ieshaveallrmedche efficacy and safety of dosnginthistange Inthe FOCUS tial, aS-year study ofelficacy and saery, eDuxostat was shown to have durable matenance of secum arate concentration 3t 6.0 mg/dl. oF less, nearly complete elimination of gouty fares, nd resolution ofbascinetophsin subjers An advantage of ebuxo. ‘at over allopurinol is thats can salely be taken by patients with éreatinin clearance greater than 30 mL/min Pegloticase Pegloticase (pegylated porcine recombinant urcass, Krystexxa was granted FDA approval in 2010 for ueatnent of reactory out. Humans lack the enzyme uricase, which converts uric acd {oallantoin, a more soluble purine degradation product. Replace- ‘ment ofthis missing enzyme allows direct conversion of urate allantoin, with eventual depletion of increased body urate pools and contol of disease, including resolution of tophi- Recombinant lviease therapy profoundly lowers serum urate concentration, a8 was demonstrated in two large wal. Peglotcase is approved st 2 dosage of $ mg intravenously every 2 weeks. Potential New Therapies Arnuimber of other novel agents with new therapeutic target for the treatment of acute and chzonic gout are under investigation Stnventgational drug inthe United Sates References Becker MA, Chban . We can mae gout munigeneat moe sucess ow: Cee “Gpin Rhema! 20082016" 72 Dalbeh 8 Stamp 1, Ap Seneen acer rate lowering and aves vets Seo Dil 2007209913 Sctumaches HR Becker MA, Liat Pebuxomat nse testen of got $year Samp 10 Devnel J, Zhang Mesa Ving slope stone the dose sed on Sandy], Becker MA Barat IS, ea Redacon of plasma rate level flowing ‘restment eth maleple doses of pelos pasetilenesipcl-onjated rt ‘heim patents wt treatment are gout Rel of phase I snomied {Pedy thes Rheum 2008 58.2882-91 Teck sob Fare DE, Senne High verilow dong of oral clcicine for ‘col act gou face Arts Roum 2010562 1000-5, “ZaangW Doheny M Pucca etal EULAR evidence buedcommenatnefr gu ‘as Dingo Report af sak fovea te sandngconmaee enon neal staring Seepetn ESCIT- Aan Rtas 200668 1001-1 {Zsa Pandy 8), Cho Hk. Comobiderof ou snd yperaicemsa nthe US ge ‘sal poulauem NHANES 20072008, An] Med 207135107997 ol dosing in ren mpl HYPERALDOSTERONISM Method of Jongoh Kim, MD; and Lawrence Chan, MD + Hyperaldosteronism may be suspected in patients with severe, resistant, or early-onset hypertension and hypertensive patents with family history, hypokalemia, metabolic alkalsis, and adre- nal mass. Evaluation begins with measurement of moming plasma aldosterone concentration (PAC in ng/dl) and plasma Fenin actviy (PRA in nj) in a sodium and potassur repleted state and off of significantly interfering medications {epironolactone Aldactone, eplerenone [Inspr], arnlorde [Midamor, tiamterere [Dyrerium,petassiumovasting thrts, tnd tance dred produce} fo et west + Elevated PRA and PAC suggest secondary hypealdesteronism suppressed PRA and PAC suggest conditions mimicking hype. Aldosternism; suppressed PRA but elevated PAC suggest pri rary hyperaldosteronism (screening positive f PAC[PRA ratio 320-40 and PAC >15 mg/dl} + Postve screening of primary hyperaldesteronism should be confirmed with one af he allowing tests 1V saline suppression, eral salt loading, furecortsone (Florine)! suppression, of captopril (Capoten) challenge test + Once primary hyperadesteronism is biochemically confirmed, computed tomography (CI) of the adrenal glands ls recom mended to excl adrenocortical ercinoma and help subype primary hyperaldesteronism + If suglal treatment is considered, adrenal vein sampling is indicated to fferertate unilateral vs. blaterallesions (may skip ifthe patients <40 years of age and has a T-confrmes unit. eral adrenal nodule > 1c). A cortsol-corrected aldosterone ‘ato from the high tthe low side™ 41 wth cosyrtrapin (Car. teosyn) stimulation confens unilateral aldosterone excess Tet FA seed sna ‘hale day sper + Laparoscopic adrenalectomy is recommended for unilateral ds fase. Otherwise, medical Weatrment with 2 rineralcortcoid Feeeptor antagonist (MRA: spronelactone [Aldactone] or eple tnone[lnspra)] is recommended. + Spironolactone: 12.5 to 25 mg/day trated to a maximum dose (of 400 g/day to acheve normal blood pressure and normoks lemia Side effects include increased serum creatinine, hypeka lem, gynecomastia, and menstrual regularities + Eplerenane: 25 mg ance or twice daily trated to 2 maximum ose of 100 mg/cay to achieve norma blood pressure ané nor. motalemia, Side eects include increased retnine, yperiale tia, hypertigycerideri, increase liver enzymes, headache, Sind fatigue + Arilrde (Midamor)' or tamterene (Dytenium)’ (epithelial sodium channel antagonists) can be used in those who carnat tolerate MRAS of are sil hypertensive hypokalemic while on MRAs. Other antihypertensive agents are also added i neces sary to contol hypertension. Introduction Hiyperaldosteronism is a state of excessive aldosterone secretion, Primary hyperaldosteronism occurs due to autonomous hyperse- cretion of aldosterone, whereas secondary hyperaldosteronism ‘occurs due to activation of the renin angiotensin aldosterone sys- tem (RAAS}. Primary hyperaldosteronism is the most common cause of secondary hypertension, and recent reports suggest that 5% to 20% of hypertensive patients have primary hyperaldoster- ‘onism (as opposed to less than 1%, as previously reported). Sec- ondary hyperaldosteronism includes two different categories; fone is compensatory activation of the RAAS due to decreased effective circulating volume, asin congestive heat failure and liver cirthosis; the other is overactivity of the RAAS accompanied by hypertension, as in renovascular hypertension. There are also sev- zal conditions that mimic aldosterone excess through vatious‘mechanisms that present with hypertension and other metabolic perturbations. Except for che compensatory activation of the AAS, these conditions cause secondary hypertension with of without other metabolic consequences, such as hypokalemia and metabolic alkalosis, which bring them to medical attention ‘This chapter covers the current approaches to hyperaldosteronism for patients suspected of having hypertension secondary to excess aldosterone production. Pathophysiology ‘Aldosterone isa steroid hormone produced by the zona glomerw fsa i the adrenal gland and contriutes to volume and potassium homeostasis via st action primarily on the principal cells in the collecting tubule of the kidney. The main stimuli of aldosterone Secretion are angiotensin ILand hyperkalemia, which increase symthesis and activity of aldosterone synthase. Aldosterone and Angiotensin I are part of the RAS; plasma renin from the juxta- slomeralar apparatus converts angiotensinogen to angiotensin I, and angiotensin-converting enzyme (ACE) converts angiotensin 1 to angiotensin IL. Subsequently, angiotensin Il stimulates secre tion of aldosterone. Renin secretion is controlled by renal artery pressure, sodium delivery to the distal nephron, and sympathevc activation (via Bt). Increased effective arterial circulating volume from the action of aldosterone decreases tenin secretion by negative feedback (Figure 1). Other minor factors involved in aldosterone secretion are_adrenacortcottopie hormone and hyponatremia (which increase aldosterone secretion), and atrial natriuretic peptide (which decreases aldosterone scerction) ‘Aldosterone binds to the nuclear mineralocorticoid receptors Activation of the minetalocorticoid receptors up-regulates the basolateral Na”/K™ pumps and the epithelial sodiur channels (ENaC), leading to increased reabsorption of Na” and Cr” and scctetion of K” and HT", The mineralocorticoid receptors can also rivated by other hormones with mineralocorticoid activity Cortisol i able to bind to the mineralocorticoid receptors with similar affinity as aldosterone but normally is converted to inactive cortisone by 1p hydroxysteroid dehydrogenase 2 (11 HSD2 Mutationsinbibition of 11 T1SD2 or very high cortisol levels above the capacity of 11 HSD2, as in Cushing's syndrome (par ticularly ectopic Cushing's syndgomel, and glucocorticoid resi tance can ease activation of the mineralocorticoid receptors. ‘Angiotensinogen Angiotensin ¥ Angiotensin I Aldosterone AACE from the lang Zona glomerslosa of the astenal gland Aldosterone precursors such as deoxycorticosterone have a weak rmineralocortcoid effect but can cause features of hyperaldoster fonism when they aze present at very high levels asin some forms ff congenital adrenal hyperplasias (11 hydroxylase deficiency or 17a hydroxylase deficiency) of deoxycorticosteroid-secteting tumors. Additionally, activating mutations of the ENaCs also ‘ause increased sodium absorption and hypertension mimicking hyperaldosteronism (Liddle's syndrome) Clinical Manifestations Primary hyperaldosteronism usually presents with normokalemic hypertension. Hypokalemia is present only in 9% to 37% of cases and may indicate more severe cases. Patients with primary hyper aldosteronism usually do not develop severe volume overload or edema because of aldosterone escape possibly related to acral natriuretic peptide, pressure natriuresis, or decreased sodium absorption at other nephron segments. Metabolic alkalosis, mild hypematremia (due to reset osmostat from volume expansion), and hypomagnesennia may be observed. Glomerular fileation rate dnd urinary albumin excretion can be elevated independent of sys sic hypertension, Cardiovascular morbidity and mortality are higher in primary hyperaldosteronism than in essential hyperten sion. Secondary hyperaldosteronism {when itis not from hypovo- emia) and other conditions mimicking hyperaldosteronism can present with similar features as primary hyperaldosteronism plus specific manifestations for each disease entity. Depending on the rechanism of disease, more severe volume overload and pulmo. nary edema may be found (eg, renovascular hypertension) because aldosterone escape may not work. Evaluation Screening Hiyperaldosteronism may be suspected based on severe or resistant hypertension, early onset hypertension without known risk fae 3s, and hypertension with other features such as family history of hyperaldosteronism, early-onset hypertension, cerebrovascular fccident at a young age, hypokalemia, metabolic alkalosis, and adrenal mass. Currently, there is no evidence-guided screening strategy. Some experts believe that routine screening for primary hyperaldosteronism is warranted in newly diagnosed hypertension considering its high prevalence, whereas others recommend that T__tevtemtason $1 en antaennsne Sodium delvery tothe distal tubule Sympathetic tore Kidney Ateroles Fear ‘Nat and Cr reabsorption | Vasoconstiction | BP regulaton °K" and H! excretion Inarmmation Figure 1. The reninangiotensin-aldosterone system (RAAS). Abbreviations: ACE—angiotensinconverting enzyme: BP=blood presurs; JGA™ yuxtaglomeralar appara Hyperaldosteronism 75511 Endocrine and Metabolic Disorders 156 EERIE soups with Relatively High Prevalence of Primary Hyperaldosteronismn (Reported Prevalence of Primary Hyperaldosteronism is Provided if Available) + Joint National Commission (INC) 7 stage 2 hypertension (© 160-178/ 100-108 mmHg), prevalence 8% += JNC 7 stage 3 hypertension (180/110 mm Hg), prevalence 13% + Drugeresistant hypertension (2140/90 men Hg despite 3 med ications), prevalence 17%-23% + Hyperension and hypokalemia (spontaneous or diuretic induced) «Hypertension and family history of earh-onset hypertension or cerebrovascular accident at a young age (<40 years) + Hypertension with adrenal incidentaloma, prevalence 1.1%- 10% + Hypertensive firstdegree relatives of primary hyperaldoster targeted screening is more appropriate. The recommendations of the Endocrine Society guidelines for primary hyperaldosteronism in 2008 provide helpful background information in selecting patients for screening (Box 1). ‘When a decision is made to sereen for excessive mineralocort coid effect, one should first examine the plasma renin and aldoste- one levels; that is, plasma renin activity (PRA, nplmL/hr) and plasma aldosterone concentration (PAC, ng/L). It is important to note that several factors can affect PRA and PAC, such as age, medications, time of day, diet (salt intake), posture, method of blood collection, level of potassium, and level of creatinine (Table T)-Duretics (both potassium sparing and wasting) and min~ ccalocorticoid antagonist can have a significant effect on PRA and PAC. Angiotensin converting enzyme inlbitors/angiotensin ecep- tor blockers (ACEUARB) and dihydropyridine caleium channel blockers can affect PRA and PAC modestly: Ideally, all medications and other factors that may affect PRA and PAC should be removed ‘unfortunately, it is not always practical and safe to do this because ofthe possibility of uncontrolled hypertension. Ifnecessary,anthy: pertensive agente that affect PRA and PAC only minimally such as slow-release. verapamil (Calan SR), hydralazine (Apresoline), prazosin (Minipress), doxazosin (Cardura), or terazosin (Hytrin) can be used. The Endocrine Sociery 2008 guidelines recommend certain caveats that optimize the chance for obtaining more easily interpretable PRA and PAC results (ox 2) Patterns of PRA and PAC help differentiate among primary hyperaldosteronism, secondary hyperaldosteronism, and condi- tions mimicking hyperaldosteronism. Differential diagnoses according to different patterns of PRA and PAC are listed in Sox 3. It hoth PRA and PAC are high, farther investigation for causes of secondary hyperaldosteronism should follow. If both PRA and PAC are suppressed, further investigation for conditions that mimic hyperaldosteronism ie indicated. Suppressed PRA and elevated PAC suggest primary hyperaldosteronism, and aldos rone renin ratio (ARR) should be calculated; ARR’ above 20-40 while PACisgreaterthan 15 ngldL (to avoid alse posiive from very ERD) Medical Factors That May Affect Aldosterone and Renin Measurement EFFECT ON ALDOSTERONE Medications Blocker ‘ Cental ay agonists 1 (clonidine [Catapres} cemethyldopa [Aldoret) NSAIDS KC wasting diretics eI > epating diuretics ACE inhibitors 1 Adrenergic receptor binders 1 Dihyéropyridine Cu** blockers Renin inhibitors Potassium Status Hiypekaionia 1 Potassim loading Dietary Sodium Sodium restricted Sodium loaded 1 thers Advanced age 1 Resa impatement . Pregnaney 1 Renovascular hypertension ‘Malignant hypertesion t Abbreviation: SSAIDS~Nonterodalsninfanmaony doe EFFECT ON RENIN EFFECT ON ALDOSTERONE— RENIN RATIO. m 1 u 1 1 1 1 1 1 1 1 1 1 1 plasma renin activity 1 1 direct renin concentration = 1 “1 1 1 uw t uw t t 1 t 1FETE rece to wessue PRA and PAC + Correct hypokalemia + Liberalize Sodium intake {Withdraw the fllowing agents that markedly affect PRA and PAC for at least 4 weeks: spironolactone (Aldactone), eplere none (Inspr), amiloride (Midamnor), tiamterene (Dyreriur), ppotassiurmwvasting diuretic, and products from licorice. + Hfnot diagnostic and hypertension can be controlled with rel: stively non-interfenng medications, withdraw the following agents for at least 2 weeks: p-blockers, central agonists (clo Fidine [Catapres], methyldopa [Algomet), NSAIDs, ACEIs/ ARBs, renin inhibitors, and cihydropyridine calcium’ channel antagonist. + Hecessary, start other antihypertensive agents that have fewer effets on ARR: slow-release verapamil (Calan-S2), hydralazine (Apresoline) (wth verapamil te prevent reflex tachycardia), pra zosin (Minipress), daxazosin (Cardura), and terazosin (Hytin} + Obtain blood for PRA and PAC mid-morning aftr the patient has been up for atleast 2 hours and seated for 5-15 minutes. Ties dear upon FREEEEIND iter! oeznoses According o PRA and PAC ‘Causes of Primary Hyperaldosteronism: [PRA and TPAC (>15 ng/d}; ARR > 20-40 + Most Common + Aldosterone-producing adenoma + Bilateraladrenalhyperpasia or idiopathic hyperaldosteranism + Less Commen + Unilateral hyperplasia or primary adrenal hyperplasia + Farnlialhyperaldosteronism type 1 or glucocorticoid reme- diable aldosterorism + Fall hyperaldosteronism type 2 + Aldosteroneproducing adrenocortical carcinoma + Ectopie aldosterone-secreting turnor (ovary, kidney) + Multiple endocrine neoplasia type | ‘Causes of Secondary Hyperaldesteronism: PRA and [PAC; ARR=10 + Renovaseular hypertension + Diuretic use + Renin-secreting tumor + Malignant hypertension + Coarctation of the aorta ‘Causes of Conditions Which Mimic Mineralocortcoid Excess: |PRA and [PAC Congenital adrenal hyperplasia + Exogenous mineralocorticoid + Deorycortcosterone producing turmor * Cushing's syndrome + TIBHSD2 deficiency + Altered alosterone metabolism + Lidde's syndrome Glucocorticoid resistance low PRA raising ARR) is considered sercening postive for primary hhyperaldosteronism. Confirmatory teste should follow to avoid false positives, Diagnostic flow and subsequent management of hhyperaldosteroniem are summarized in Figure 2. Of note, there is no consensus on cut-off values for PRA PAC, o ARR. In addition, PRA and PAC are often obtained in a les-than-optimal condition Therefore, its important to understand how PRA and PAC can be affected by various factors. For example, if ARRis positive while on medications that decrease PAC or inerease PRA (thus decreasing iypertension patente evaluated for hypereldosteroniam 1 ‘Sop medicalions that alfet PRA and PAG slgniieanly fo TPRA TPAC, TPRA TPAC TPRA “PAG Investigate causes of || Investigate Diagnestic work up| ‘jecondary hyperatdosteroniem || forprmary Fyperaldosteroniem || mimickere hyperalaosteronism t PACIPRA =20-40 PAC =1s avs | —T[herenal or Laparoscopic | [ Mecieal renalecomy| | management Figure 2. Evaluation ofhyperaldoneronim, Abbreviations: AVS adrenal ‘ein samplings CT computed tomograpiy; PAC. plarma aldosterone Coneensrapon” in ngldL; PRA plasma renin actty ingle Sif aungwal‘tWeatment ig pursued, May ip if 80 years old. with usilaealadzenal mass 1 em, EEZID crenal vein sampling + Alter both adrenal veins have been cannulated, draw baseline samples for PRA, PAC, ACTH, and cortisol from the IVG, right adrenal vein, and let adrenal vein. + Inject 250 meg of cosyntrapin (Cortrosyn) after cannulation, or infuse 50 mcg cosyntropin per hour beginning 30 minutes before adrenal vein canrulation. This reduces stress-related fluctuations in aldosterone and cortisl values and augments the biochemical gradients (this step is controversial) + Draw blood for aldosterone and cortisol levels at 5, 15, and 30. minutes from the peripheral site and from exch adrenal vein ARR), ARR off this medication wil be cleatly positive, Sereening tests should be repeated if results ae inconclusive Confirmatory Tests of Primary Hyperaldosteronismm ‘The positive screening test should be followed by confirmatory tests fo avoid false positives. The confirmatory tests are designed ‘physiologically suppress aldosterone levels that would normally ‘occur in the absence of primary hyperaldosteronism. However, some experts believe that some aldosterone-prodicing lesions are not completely independent of the RAS, and confirmatory Suppression tests ean give false-negative results. Other experts think that confirmatory tests are not necessary for those with obvious clinicalbiochemical features. Furthermore, there is no goldvstandard confirmatory test. Therefore, factors such a5 cost accessibility, feasibility, patient compliance, local expertise, and Accuracy of assay shotld be taken into consideration in selecting Confimatory tests. The Endocrine Society guidelines in 2008 state that any of the following four confirmatory tests can be used: oral salt loading text, saline suppression test, fudzocortisone Hyperaldosteronism11 Endocrine and Metabolic Disorders 158 REE °1otocols and interpretation of Recommended Confirmatory Tests proroco. Oral sodium loading test 1. Place the patient ons high-sodism diet {2200 mmol day) for 3 days Replace potassium co compensate forthe kaluresis induced by che high-sodium det. Golect’ 24-howr rine onthe third day for determination of Aldosterone, sodium, and seating: adequate ifthe urine dium >200 mmoV24 hr 1V alin infusion test Place the patent spine 1 hou before drawing blood for moming baseline fasting levels of rein, aldowterone, conve, and porassum, Infuse 1 of 0.9% NaCl over thous, keeping the patient fupine, Monitor blood pressure spd heart rate ‘ter 4 hous, draw blood for sieasurement of rain, aldosterone, contsa, and potas, Fludrocortisone Suppeesion test Give 0.1 mg fadrocortizone every hours for 4 days, wich che potassium level checked every Enoure tobe sure that ii greater than 4 mmol Encourage a liberal sodium diet to keep unnary sodium excretion renter than 3 munolg/day ‘Gn day 4, draw Blood for an SptigNt7 Am plasma cortisol level and 10 a3 plasma aldosterone, fenin, and cortisol level Captopni! challenge west (Give 25-50 mg captopril afer the patient hasbeen upright fort hour ‘The pasene remains upright throughout the test. Daw blood fr measurement of plasma renin, aldosterone, and fortisol atime 0, at Thur and at hours INTERPRETATION Confirmed ifthe 24-hour wrine tdonerone ie 12 meg (33:3 nmol) co 14 meg (38.8 nmol) Raled out if the 24 hour urine ldosterone is <10 meg (27.7 nmol). The tet i eguivoes! tf the valve fallen between, REMARKS Do not perform thi tet in Davents wath cevere lnconteled hypertension, renal failure, cardiae file! arrhythmias, or severe ippelalera (Confirmed ifthe PAC is >10 ngldL (277 pmol} Ruled outifthe PAC 15 1 em), mini- ‘mal unilateral adrenal limb thickening, unilateral microadenomas (tem), and bilateral macroadenomas and/or microadenomas. APAsare typically smaller than 2 cm, and BAHs exhibit either nor ‘mal ornodular changes. Aldosterone-producing adrenal carcinomas are almost always larger chan 4 cm in diameter and have imaging characteristics suspicious for malignancy. However, there are limita tions; small APAs may be missed, hyperplasia may be misread as adenomas, and nonfinetional tumors are radiologically indistin fuishable from APAs. Although several studies suggested imaging txateia for different subtypes, no study has conclusively established specific criteria that differentiate among different subtyper of pri- sary hypezaldosteronism. In fact, CT accurately lateralizes in onlyabout 50% to 70% of cases, Therefore, adrenal vein sampling is required to differentiate unilateral from bilateral lesions if surgical resection is being pursued, Some experts believe that individuals 40 years or younger with a unilateral adenoma larger than 1 em cdo not need adeenal vein sampling because nonfunctioning tumots are uncommon in this young age group. Adrenal Vein Sarnpling Aldosterone levels are measured from adrenal venous blood sam- ples obtained through adrenal vein cannulation to distinguish between unilateral and bilateral lesions. Unilateral lesions are associated with a marked increase in PAC on the side of the tumor {and suppressed PAC on the other side), whereas bilateral lesions have little diffezence between the two sides. Adrenal vein sampling (AVS) should be performed only by experienced physicians in part hhecause recognition and suecessfl cannulation of the right adre nal vein especially can be challenging. Complications of AVS include adzenal heme ‘adcenal infarction, adrenal vein per- foration, and adrenal vein thrombosis, which occur only rarely (<25% in the hands of a physician skilled in the proceduce, ‘The use of cosyntropin (Cortrosyn) stimulation to minimize stress-induced fluctuation in aldosterone level is controversial, land some believe that it has no effect on AVS accuracy. If cosyn ‘opin is not used, then AVS should be done in the morning after overnight recumbency to avoid postural aldosterone changes and reflect circadian aldosterone secretion. In reality diferent centers use different techniques, protocols, and interpretation criteria. The Endocrine Society guidelines in 2008 provide interpretation criteria with and without cosyntropit tus. The first step for interpretation isto determine whether the pro- cedure was done corcectl. The adrenal vein-to-IVC cortisol ratio should be greater than 10:1 with cosyatropin given and greaterthan 3:1 without cosyntropin. ithe ratioissignificanty lower than these values, improper cannulation is implied. Next, divide the PAC values forthe right and left adrenal veins by their cespective cortisol values to correct the dilutional effect of the inferior phrenic vein flow into the left adrenal vein thie is termed the cortitol-corrected aldosterone (A/C). Li cosyatropin is used, an A/Cratio ofthe high to the low side of greater than 4:1 indicates unilateral aldosterone hypersecretion, whereas an A/Crati of less than 3:1 suggests bilat- eral aldosterone hypersecretion. These cutoffs were reported to have sensitivity of 95% and specifieity of 100% for unilateral Iesione. Ifthe AIC ratio is between 3:1 and. rceults of AVS should be interpreted in the context of CT, clinical findings, and other tests. Without cosyntropin, an AC ratio of the high tothe low side of greater than 2 of an AVC ratio of the high side to the periphery greater than 2.5 plus an A/C ratio of the low side tothe periphery oflesethan I (suppressed contralateral aldasterone secretion} is consistent with unulateral aldosterone excess Ancillary Tests Clinical findings and other ancillary tests may help differentiate unilateral APAs from BAH. BAHe will respond with increase in plasma aldosterone to postural stimulation, whereas APAS will not, Plasma 18-hydroxycorticosterone level tende to be higher in PAs as compared with BAFls. lodocholesterol scintigraphy may the able to show functional correlation of anatomical abnormalities (butts not available at most centers). Incerpretation exiteria ofthese tests are listed in Table 5, Patients with APAs tend to be younger (€40 years), predominantly female, very hypertensive with ‘marked hypokalemia (<3 mmol/L), and they tend to have a very high PAC (>25 mg/dL as compared with those with BAHs, Treatment ‘Treatment of secondary hyperaldosteronism and conditions mim- icking hyperaldosteronism depends on thei evology. Treatment of primary hyperaldosteronism is discussed her. The goals of treat ment of primary hyperaldosteronism ate (1) normalization of the serum potassium in hypokalemic patients, (2) normalization ofthe blood pressure, and (3) reversal ofthe effects of hyperaldosteron- im on the cardiovascular system, When a small group of patients LOTED 'erprctation of Dynamic Testing Test FINDINGS Screening Test PAGIPRA ratio Confmatory Tests Positive if 20-40 with PAC >15 ngldl (Oral sodium loading test Positive if24-hr urine aldosterone ‘xeretion ¢ 212-1 me Saline infusion test Positive #PAC afterinfusionis >10 ag. Fludracortisone! Positive ifupright PACs >6ng/don day ‘at 10am Positive PAC doce not decrease by 30% "and PRA renvaine suppecssed "suppression tert Captopal! challenge test avs With cosyiropin AIC ratio the high othe low sie} >4:1— simalaton ‘lateral aldoweroneexcese, AGralio Hl to 41— unclear [AIG tatio 3st —> bilateral aldosterone Without cosyntropin A/C zatiofrom the high othe low side ‘simulation 32:1 nilateral aldonterane exces AlGrato fom te high side to the periphery S2:Sand A\Cratio from the contralateral) side to the periphery <1 — unateral ldonerone excess IF Equives! AVS Postural simslaton tet PAC fll or fail to rise by 30%: ‘consistent with APA PAC increases by a leat 33%: consistent with BAHs +100 ag is consistent with APAS Recumbent 18: Ihydraxyeortcosterone [NP-59iodocholesterol Unilateral easy uptake («5 ¢}: consistent scintigraphy ‘with unilateral aldosterone excest Binteral early peake (<5 4} content ‘with bilateral aldosterone excess Negative sean does sot rule ou either cislosy Not FDA approved for this edeason Abbrvntioe NC ratio= conolcoreted aMdostrone ati APA~aldetrene producing adscomar, WSeadeenal vein suaplog: BAHL=blaralsdsral Ejpenlna, PAC plana aldnrone coneateaon, PRA™plea renin were followed after treatment with adrenalectomy or minera- Tocorticoid teceptor antagonists (MRA), left ventricular mass was reduced (faster with adrenalectomy than MRA), glomerular filtration rate and urinary albumin secretion decreased and became similar to that in essential hypertension, and excessive car diovascular riek compared to essential hypertension disappeared. Cardiovascular complications were rather related to age, duration ‘of hypertension, and smoking. Therefore, timely diagnosis and treatment is essential, For unilateral lesions, surgical resection of 1 affected adrenal gland i recommended mainly to obviate the need for prolonged medical treatment and side effects. For bilateral lesions, medical treatment is recommended because surgical risk outweighs benefits. MRAs are a key component of medical treatment and used as a preoperative measure or mainte nance treatment (GRA should be eteated with the lowest dose dof glucocorticoid thatcan normalize blood pressure and potassium levels rather than MRAs). A low-sodium diet (sodium <100 mEq! day=2.3 g/day or sal 6 gay) is also important, because left ven~ tricular hypertrophy is associated with urine sodium excretion in primary hyperaldosteronism but not in estential hypertension, (Other lifestyle changes include acrobic exercise, smoking cesta. sion, and weight loss Hyperaldosteronism11 Endocrine and Metabolic Disorders 3 Unilateral Hyperseeretion Adrenalecomy, usally laparoscopic, i ecommended. After adze palectomy, Blood pressure improves in all patents (maximal improvement in I-6monthe, sometime continues tofallupto I yest), ‘but 30% to 60% of patentshave persstenthypertension. Blood pe sure and potassim evel shoul be contolled befor surgery’ MRA such as spironolactone (Aldactone) and eplerenone (Insp)! can be ted to control blood presize in patents awaiting adrenalectomy land also to prevent postoperative hypoaldosternism. Postopers- tively, normal saline i given to maintain volume stats, MRA ad potassium ripplements are cscontinued, and antihypertensive med. {eations may be reduced, Toconfirm brochemicalcaze, PAC and FRA should be checked shortly after the operation. Risk factors for perss tenthypereension afer adrenalectomy include alder age, duration of hypertension (> years), se oftwo or more antihypertensive agents preoperatively blood presure higher than 165/100 mm Hi, low ARK peeopecatively low rine aldostezone, poor sponse 0 i nolactone preoperatively familyhistoryafmore than one ies degree {clative with hypertension, and elevated serum ereatiine level Bilateral Hypersecretion MRAs andor ENaC antagonists combined with other antihyper tensives are used. One study showed that spironolactone had stronger antihypertensive effect than eplerenone, but theres insuf- ficient evidence to choose one medication over another. Subtotal adrenalectomy has been tried, but only a minority of patients have responded with significant blood pressure improvement. Unilat- eral adrenalectomy, however, may help selected patients by debulking aldosterone-producing tissues Spironolactone isthe most widely used MRA. Iris very effective in decreasing blood pressure. The medication is initiated at 12.5 to 25 mplday and can be titrated to 400 mg/day, with most patients requiring at least 200 mg/day. Potassium should be maintained at normal levels withovst use of potassium supplements, Use of spirono- Tactone can be limited by side effects; antiandrogenic cause gynecomastia in men and progesterone effect can cause ‘menstrual icregulariies in women. ‘There are drug interactions ¢0 consider; spironolactone increases the halite of digoxin {Lanoxin} and salicylates, and ocher NSAIDs may decrease the effectiveness of spironolactone. Serum potassium and creatinine should be closely monitored for the first 4 to 6 weeks, in partcular for those swith renal insulficieney oF diabetes, Spironolactone is not zecom ‘mended if creatinine clearance is less than 30 mLIminte. Eplerenone' is a competitive and selective antagonist ofthe aldo- sterone receptors. Ir hat a lower binding affinity to androgen and progesterone receptors than spironolactone, This leads to fewer side clfects. Eplerenone is 25% to 50% less potent in antagonizing the aldosterone receptors than spitonolactone. Eplerenone has a short halflife and may be more effective if given twice daily. Dosing is started at 25mg once of twice daily, with a maximum dose of 100 mg/day. Again, serum potassium and creatinine should be closely monitored forthe rst‘ t06 weeks in pariculacforthose with renal insufficiency or diabetes. Other adverse effects include hyper triglyceridemia, increased liver enzymes, headache, and fatigue. Eplerenone is contraindicated sf serum potassium is greater than 5.5 mEqiL at initiation, if creatinine clearance ie less than 30 mL/ ‘minute, oF if there is concomitant use of strong CYP3.\4 inhibitors such as ketoconazole (Nizoral) and itraconzole (Speranox) ENaC antagonists, amiloride (Midamor)” and. tviamterene (Dyrenium),’ can be used in patients who cannot tolerate MRAS or are stil hypertensivefbypokalemic while on MRAs. Amiloride is prescribed at 10 to 20 mg/day in divided doses. Side effects include dizziness, fatigue, and impotence. Triamterene is dosed at 100 to 300 mplday in divided doses, and its side effects are ‘mainly dizziness and nausea. Addition of thiazide diuretics can help conteol blood pressuse by celieving volume overload. If blood pressure remains uncontrolled other antihypertensive agents such 8 ACEI/ARBs or aleium channel blockers may be used, "Not FDA approved for thi indication References Born Frotberg Rencke M Rump LC al. Cardinale nd cerebronatcae ‘tthe Genta cons regis J Ch Endocinot Meta 903,94 113520 ‘Catena C, Coluasi GL, Nadal B eal, Cardiovaselar outcomes in patients with under Carey RM, Fura © etal Cae detection, dag and went of utes with prmaryaldeterniens an eedaree sey caval races Bude Ete) Cl Endaccl Merb 200898 006-11 Garden RD, Gon Seater CE. Hamlet SM, et al Angiotensin responsive ‘ieanerone producing aeoma masguerdes 2 iopattehyperaldonteronos IBA tear hyperpana) or lowestain ema hypertension} Hpprene Th dela abet net, SMS SSSR Ret kta hl cn comgted i dedi oe idan ity ee ‘hig taeea S e racy Mend RL a laid nd dy SOE REIS SL a a ise ei) or ening the major types af primary aldosteronism, J Clin Endo- ‘Rossi GP, Berini G, Cabumi G ea. A prospective study ofthe prevalence of pe ag tte iS le Mea Sel ‘Ross GP, Secia TM, Pessina AC. Adrenal gland: a diagnostic algorithm - the holy ale pnt has Sy ats ae soc pe yf el ge pny rn ScoVLLSEMICHE pc Leg od agcomtn pi th ont dora Sosa ee HYPERLIPIDEMIA Method of Jongoh Kim, MD; and Lawrence Chan, MD + Hyperlipidemia diagnosed basee onthe fasting lipid profile in ‘the context of global cardiovascular risk. The exception is when the triglyceride level is greater than 500 mg/dl because of sub. stantial risk of pancreatitis + Secondary causes of hyperlipidemia, such as hypothyroidism, slcohalsm, uncontrolled diabetes melitus, kicney disorders, pregnancy, and medications, should be thoroughly investigated Sand treated if found. + Possibly of fanlal hyperlipiderna based on family history and physical findings should be considered because cardiovascular Fisk can be underestimated and treatment can be challenging, + Therapy should be guided by goals of treatment based on est rated cardiovascular risk unless triglyceride level >500 m/l, in which case lowering tighcerides to prevent pancreatitis i a priority.+ Low-density lipoprotein (LOL) cholesterol isa primary goal fl- lowed by non-high-density ipepratein (HDL) cholesterol as 2 secondary goal Therapeutic Ifestyle changes should be initiated in everyone With LDL cholesterel above their target. Therapeutic lifestyle changes are also recommended for those with very high, high, ‘or moderately high cardiovascular risk Pharmacologic agents should be added if therapeutic lifestyle changes are not successful, Pharmacologic agents can be con- sidered from the beginning for those with very high, high, or ‘moderately high cardiovascular risk + Statin therapy Is preferred if tolerated, and the intensity of ther- apy should be strong enough tolower LDL cholesteral atleast by 30% to 40% Statins are the treatment of choice for their proven effects on cardiovascular outcomes. Other agents can be added based fon response to statins and other targets such as high tighcer- Ides of loveHDL.cholesterel All other cardiovascular risk factors should be treated aggres- sively at the same time Hyperlipidemia is condition of elevated serum lipids and lipo. proteins. Hyperlipidemia is associated with an increased risk of cardiovascular disease and, ifthe triglyceride level is greater than 500 mg/dL, pancreatitis. Unless the triglyceride level is greater than 500 mgidL, the primary goal of management of hyperlipid- cemia is to decrease the risk of cardiovascular disease. In this regard, appropriate treatment of hyperlipidemia is essential in patients with established cardiovascular disease (secondary pre vention), whereas detection and treatment of hyperlipidemia are guided by the risk of cardiovascular disease in asymptomatic patients (primary prevention) "The prevalence of hyperlipidemia varies with the definition of hyperlipidemia and the population studied. The percentage of US. adults with a total cholesterol level of 240 mg/dl. oF higher declined érom 19% to 14% in men and from 21% to 15% in ‘women from 1988 to 2008. This may be in part due to increased use of lipid-lowering medications, from 3.4% to 15.5%. However, major risk factors for cardiovascular disease actually have become more common: the prevalence of obesity (BMI >30 kg/m“) increased from 19.9% t0 31.6% in men and from 25.2% 10 in women, and the prevalence of diabetes increased from to 11.1% in men and from 4.6% to 6.3% in women over this period. Therefore, optimal treatment of hyperlipidemia to reduce cardiovascular risk is of paramount importance. Various societies and professional organizations have published clinical guidelines for bypeslipidemia. The approach used in this chapter is mostly based on The Third Report of the Expert Panel ‘on Detection, Evaluation, and Treatment of High Blood Choles- terol in Adults (Adult Treatment Panel IIL) published in 2002 and updated in 2004 by National Heart Blood Lung Institute (NHBLI). Recommendations from other recent guidelines are also integzated in this chapter. These guidelines include The Lipo: protem Management in Patients with Cardiometabolic Risk, Consensus Statement from the American College of Cardiology Foundation and the American Diabetes. Association (ACC! ADA) (2008), The European Society of Cardiology and European Atherosclerosis Society (ESCIEAS) Guidelines for the Manage- ‘ment of Dyslipidaemias (2011), and the American Association of Clinical Endocrinologists’ (AACE) Guidelines for Management lof Dyslipidemia and Prevention of Atherosclerosis (2012) In November, 2013, the American College of Cardiology (ACC) and American Heart Association (ATTA) released a new guideline in collaboration with National Heart Blood Lung Institute (NHBLI): 2013 ACCIAHA Guideline on the Treatment of Blood Cholesterolto Reduce Atherosclerotic Cardiovascalar Rsk ne Adults A Report of the American College of Cardiology/American Heart Association Task Force om Practice Guidelines. This now guideline represents a substantial departure from previous Diet ms et aaa wot q vast toe | Hou en > fParerel Gut cM tissues Figure 1. Overview of exogtous ad edogeous pti of Iii nfalka, alison Checigloniien, HOLS igh dent pn tence east Spepettas DL ies lipoproteins; VLDL ~very-low-density lipoproteins. guidelines in that it emphasizes the use of statins of appropriate srength according to the estimated cardiovascular rik without specific low-density lipoprotein (LDL) cholesterol targets. Sims- ilarties and differences of this new guideline compared with the others will be discussed later in the chapter. Pathophysiology Lipids have two main point of entry into the circulation: the gut {exogenous pathway) and the liver fendogenous pathway). The exogenous and endogenous pathways are interconnected by inter mediate pathways (reverse cholesterol transport pathway and others). These pathways are outlined in Figore | Exogenous Pathway Lipids in food are emulsified by bile acids and then hydrolyzed into fatty acide and cholesterl by pancreatic lipases in the intestinal lumen. Inside the intestinal cells, fatty acids and cholesterol are reesterified and then packaged with apolipoprotein (Apo) B48 into chylomicrons. Chylomiceonsaze secreted into the intestinal lymph and delivered to the systemic circulation. At peripheral tissues, tr- lyeerides are hydrolyzed by lipoprotein lipase with Apo Cl acting asa cofactor. Released free fatty acids are then taken up for further ‘metabolism or storage. Chylomicron remnants are aken up by the liver via the chylomicron remnant receptors Endogenous Pathway The endogenous pathtvay begins inthe liver with the synthesis of triglyceride-rich very-low-density lipoproteins (VLDLs). Micro. somal triglyceride transfer protein facilitates the transfer of lipids fonto Apo B100 and stabilizes the protein for secretion as VLDLs. VLDLs, as chylomicrons, undergo lipolysis by lipoprotein lipase, releasing free fatty acids, generating. smaller particles called intermediate-densty lipoproteins (IDLs, also known ae VLDL remnants). IDLs are either removed by the liver or further pro- cessed into cholesterol-rich LDLs. LDL¢ are taken up into the liver for other cells via LDL receptors, a process regulated by cellular cholesterol requirement. Macrophages can also take up LDLs via the scavenger receptors and become foam cells. Foam cells play a key role in the development of atherosclerosis, Reverse Cholesterol Transport High-density hpoproteins (HDI) are the major lipoproteins involved in the transport of cholesterol from peripheral tissues back to the liver. HDL are synthesized by both the hepatocytes and the enterocytes in the form of small diseoidal particles con: taining Apo AI and phospholipids. HDL acquire adeitional lipids and apolipoproteins from trglyceride-depleted chylomicrons and VLDL remnants. HIDLs remove free cholesterol from tissues with the help of Apo AI and esterify it with lecithin cholesterol acyl- ransferase. Cholesteryl esters are then transferred to Apo B. 100-containing lipoproteins (VLDLs, IDLs, and LDLs) by choles- teryl ester transfer protein (CETP). HDLs can also be talen up dlixectly by the liver class B type I scavenger receptors (SR-BI}11 Endocrine and Metabolic Disorders 3 Plasma Lipids and Atherosclerosis ‘Multiple studies have shown that total cholesterol and LDL cho, lesterol levels contribute to cardiovascular disease risk and that lowering of total cholesterol and LDL cholesterol levels reduces the risk. Non-IIDL cholesterol (ve. total cholesterol ~ HDL cho- lesterol VLDL +IDL+LDL cholesterol), reflects total athero: genic lipoprotein burden and may be a better risk indicator than EDL cholesterol, especialy in people with combined hyperlipid- cmia, diabetes, metabolic syndrome, and chronic kidney disease. Blevated triglycerides, in particular nonfasting levels, also may bbe an independent cardiovascular risk factor. Even mildly elevated triglycerides (>150 mg/dL) can indicate metabolic syndrome, which isa strong risk factor for cardiovascular disease. Elevated triglycerides are often associated with low-HDL. cholesterol and high levels of small, dense LDL particles (hyperlipidemia trad) HDL particles are considered protective against the formation of atherosclerotic plaque through reverse cholesterol transport and also possibly antiinflammatory and antioxidative activities HDL cholesterol levels have been shown to be inversely associated with cardiovascular risk. However, the benefits of using druge to lower triglycerides only and/or raising HDL cholesterol in redue- ing cardiovascular risk have not been proved. Table | shows the ATP II classification of lipid profile. Evaluation Global Cardiovascular Risk Assessment ‘The first step in assessing risk is to stratify global cardiovascular tisk scores. Global risk scores estimate 10-year cardiovascular risk, which combines the effects of well-known risk factors, using ‘one of several risk-calculation tools. Individeal tools have devel- oped based on large epidemiology studies examining a limited number of available risk factors. Traditional risk factors such as age, sex, cigarette smoking, cholesterol, diabetes, and blood pres sure are able o predict 80% to 90% of the cardiovascular events in people 40 years or older. However, these tools may not ae rately estimate cardiovascular risk in individuals with different demographics or unaccounted risk factors. The Framingham risk score, one of the most commonly used tools, provides several co LDL Cholestral mg/dl) ‘The NCEP ATP Ill Classifietion of LDL, Total, and HDL Cholesterol and Triglycerides (mg/dl) <100 Optimal 100-129 [Near optimal/above optimal 130-159 Borderline high 160-189 High 2190 Very high Total Chelestrl (mg/dl) <200 Desirable 200-259 Borderline high 2240 High HDL Cholesterol (mg/dl) <40 Low 260 High “Trgiycerides (mg/d) <150 150-199 200-499 High 2500 Very high Panel! sidelines HDL high-dsstypoprtein, LDL-iow-densty different risk assessment tools for different outcome measures Uhitps/framinghamriskscore.com). The hard coronary heart dis- ease (CHD) tool, used in the ATP Ill, incozporates age, sex, total cholesterol, HDL cholesterol, smoking, systolic blood pressure, and antilypertensive medications, and i predicts coronary death for myocardial infarction (http/fhp2010.nblbihin.net/atpiicaleu latonasprusertype=prof). The SCORE, used in the ESCIEAS guidelines forthe management of dyslipidemsias, incorporates sim lar risk factors and predicts fatal cardiovascular events (wwe: hheartscore.org). The Reynolds risk score incorporates high: sensitivity CRP and parental premature myocardial infarction, inaddition co the risk factors mentioned above, and predits major cardiovascular events (wwrw-reynoldsrskscore.org) In the ATP I, risk assessment begins with identifying the fol- lowing cardiovascular risk factors: cigarette smoking, hyperten- sion (BP >140/90 mm Hg) or use of antihypertensive agents, HDL cholesterol less than 40 mg/dL. (> 60 mg/dL isa negative risk factor), age >45 years in men and >55 yeatein women, family ise fry of premature CHD (male first-degree relatives <55 years, female first-degree relatives <65 years). The presence of zer0 of fonly one risk factor is considered as low risk (almost always, the risk for hard CHD over 10 years is <10%|. Iftwo ot more risk factors are present without CHD or CHD equivalents, the Bra ringham risk score for the hard CIID over 10 years needs to be talculated, A risk of less than 10% is considered as moderate risk, W the risk is between 10% and 20%, itis considered as moderately high esk, Ifthe risk i higher than 20%, wis considered as a CHD risk eguivalent, Diabetes and clinical forms of atherosclerotic dis fase (abdominal aortic ancurysm, carotid artery disease— transient ischemic attack, stroke of carotid origin, greater than 50% obstruction of carotid artery, and peripheral vascular dis- tase) are also considered 3 CHD equivalents, CHD and CHD equivalents belong to the high-risk group. Recent, chronic kid- rey disease with glomerular filsation rate less than 60 mL rinute/1.73 mis also recognized as a CHD equivalent by some societies. The very-high-risk gyoup was introduced in the ATP Ml update and more recent guidelines. The ATP II update defined the very-high-rsk group as established cardiovasculae disease plus multiple major risk factors (especially diabetes), severe and poorly controlled risk factors (especially continued smoking), multiple risk factors of the metabolic syndrome, and acute coronary syn drome. The therapeutic approach is determined by this risk strat- ification. Established cardiovascular disease itself and diabetes with other cardiovascular risk factor(s) are also considered as very high risk by some authorities (see the Treatment section and Tables 2 and 3) The new 2013 ACCIAHA guideline focuses on identifying four subgroups of patients for whom the benefits of statin therapy out- weigh the risk (Table 4). The new Pooled Cohort Equation is used toestimate a 10-year risk of atherosclerotic cardiovascular disease {nonfatal myocardial infarction, CHD death, and nonfatal and fatal stroke) for those aged 40 to 79 years, incorporating age, sex, race, HDL and total cholesterol, diabetes, hypertension, and smoking status (htip/tools.cardiosource org/ASCVD-Risk istimator). Statin therapy ie recommended regardless of the baze- line LDL. cholesterol level in these four subgroups (see Table 4) The new guideline provides no recommendations for individuals requiring maintenance hemodialysis or with class Ilo IV ischemic systolic heart failure Measurement of Lipid Profiles Lipid profiles should he measured as a part of global risk assess ment, and the frequeney of checkup is determined by age, sex, and eek factors for cardiovascular disease. A fasting lipid profile (fasting for 9-12 hours) is recommended to ensure the most precise ipid assessment, specifically triglycerides (subsequently LDL cho- lesterol ifcaleulated using the Friedewald equation). Nonfasting lipid profile provides an accurate measurement of other lipide, including total cholesterol, HDL cholesterol, Apo B, and Apo AL. Recent studies showed that differences in triglyceride levels According to fasting time were smal. Therefor, lipid values from rnonfasting samples should not be ignored.LETTE 101 cholesterol Goals mg/dl) and Levels for Inittating Lifestyle and Pharmacologic Interventions (The ATP Ill Update) LoL cHoLEsTEROL LEVELAT WHICH TO INITIATE DRUG, LDL CHOLESTEROL LEVEL AT WHICH TO Risk CATEGORY GOAL (mg/dl) INITIATE TLC (mg/dl) THERAPY mg/dl) High CHD or CHD rik <100 (<70 if very high >100 100 {<100 optional equivalents or 10-year risk") Fisk of heart attack >20% Moderately high 2 or more risk factors and <130 (<100 optional) >130 130 (100-129 optional) ‘odyear risk 1072-207 Moderate Lor more risk factors and <180 >130 >16o TO-year risk <10% Lower 0-1 risk factor <160 S160 >190 “Nay hgh seat corse syndroseox abled cadionasua seas ls mull major ik factors eopeclly diabetes svete ad poy consoled sk faces ong o multiple ik actors of te metabolic syndrome TE 101 chelester and Apo 8 Goals in More Recent Guidelines coat ToLcHoLEsTEROL _APOB (raya) (reg Very high risk: ertablshed 7 0 diovascular dieate or diabetes plas rajor csrdiovaralor rik actors) High ssk: 2 or more vsk 100 %0 factors andlor 10-year rae 320%" oF CHD equivalent diabetes wihouc any mayor ‘cardiovascular ss factor) Aapied from the lpopotein managements patents wih catdometabole tk, Consens sateen’ from the Ameras College of Carol Foandton nd the Asenan Dates Anocton |ACCIABAY 2008, and tae Ameri, Rusotatos of Cink Eadnesologss’ (AACE) guidelines Tor masogerent ‘of dlptdeas and prevention of sortie 2012) ‘sagen rit sselaion recomended nthe ATP IT and ANCE guidelines the inthe ACCAADA raters LDL cholesterol is calculated cither using the Friedewald equation (LDL. cholesterol ~total cholesterol HDL cholesterol — tiglycerides'S) or directly measured. The Friedewald equation should be used with appropriate caution: fasting state samples should be used, it becomes less accurate if triglycerides >200 mg/ aL, not valid if triglycerides >400 mg/dL. and LDL cholesterol can bbe underestimated at levels <70 meal. Apolipoproteins, including Apo B and Apo AL, may also be mea- sured. The Apo B level (Apo B100) reflects the number of athero, genic lipoprotein particles and appears to be a hetter measure of cardiovascular disease than the EDL cholesteral evel or the LDL ppartcle size, Apo B level and Apo B/Apo Al ratio are as good as traditional lipid profiles and are especially useful in certain situations such as combined hyperlipidemia, metabolic syndrome, diabetes, and chronic kidney disease (Other medical conditions may also affect lipid profiles. Second- ary causes include hypothyroidism, nephrotic syndeome, dyspam- maglobulinemia, use of progestin (especially those with androgenic activity), cholestasis, use of protease inhibitors, chronic kidney disease, uncontrolled diabetes, obesity, excessive aleohol intake, use of thiazide or p-blockers, use of corticosteroids, use of ora estrogen (not transdermal}, and pregnancy. These conditions should be detected and treated, if appropriate, to improve control ‘of hyperlipidemia Family history of premature cardiovascular disease and hyperlipidemia and physical findings such as xanthomas, xanthe- Jasmas, and premature arcus comcalis may suggest’ familial wo) “The Four Target Groups and Two Exceptions Statin Therapy in the 2013 ACC/AHA Guideline ‘CHARACTERISTICS. TREATMENT Clinical atheroeleroie catdiovacclae disease” £75 year: highitensity statin 375 yearsornot candidate for Aighdntensty satin moderate intensity statin igh intensity atin Moderate-iatesiy statin (may use highinensity satin if IWyear rik 275%), Moderate o high-intensity LDL cholesterol >190 mgldl. 40-75 yeats with diabetes, LDL ‘holesterol 7-189 ng/L. 40-75 years without diabetes, [LDL cholesterol 70-189 mgd, O-yest atherosclerotic cardiovaseulae tsk 27.5% Maintenance hemodialysis No recommendation Inchemie systolic heart failure, No recommendation "NYHA class ILIV “Coranary eat dete, tok, a prgheral aren dcae of renamed thro ‘o-year sk of eastal myoctril infarction covey boat ste death, sd onl snd fal stoke anng the Poled Cohort Egon (pitocl Sard rote og ASCD Risk Botte) hyperlipidemia. Familial hyperlipidemia can be associated with significantly high risk of cardiovascular disease, which could be underestimated by the global risk se Treatment Overview ‘Treatment is primarily aimed at lowering LDL. cholesterol level, which has heen shown to decrease th risk of cardiovascular dix ‘casein numerous stadiesunlees the trighycerid level ie higher than 500 mld, n which case erglycerids should be lowered immed ately to prevent pancreatitis Every reduction of LDL cholesterol by 40 mg/dL is associated with about 20% reduction in cardio- vascular risk. The absolute rk reduction by lowering LDL choles- terol is proportional tothe global cardiovascular rik. Therefore, the targeted goal of LDL cholesterol i determined by the global catdiovascolar risk “The weatment goals and approaches according tothe ATP I are summarized in Table 2. The optional goal of LDL cholerteral less than 70 mgd. was added inthe 2004 update forthe very-bigh-isk roup. Established cardhovascalardiseave itself and diabetes with bother cardiovascular risk factor(s) are also considered as very high Suleby some authorities, The goals for LDL cholesterol and Apo B in the very-highrsk and high-k groups according to more ecent sidelines are listed in Tsb'e 3. Asa fist line, therapewie hesyle 76311 Endocrine and Metabolic Disorders z changes should be initiated when LDL cholesterol i above the target range. People with very high, high, or moderately high risk should also start making therapeutic lifestyle changes regardless of theit LDL cholesterol level. Medications may be added at the same time astherapeute lifestyle changes for those withvery high high, or mod- rately high risk. If medications are indicated, statin is prefersed because of proven efficacy that has been consistently shown in mul- tiple clinical trials. The intensity of treatment should be strong ‘enougho reduce LDL cholesterol evelby atleast 30% 040%. Once the LDL cholesterol goal is achieved, then not HDL cholesterol eve should be controlled. The treatment goal for the non-HDL choles- terol is 30 mgfdL. above the LDL cholesterol goal. Specific treatment oflow-HDL cholesterol is controversial. CETP inhibitors, which spe- cifically increase HDL cholesterol by blocking tansfer of cholesterol to Apo B-containing lipoproteins, were not effective in reducing car diovascular risk. The effect of increasing HDL cholesterol with niacin Jn people taking statins has not been encouraging. Generally response to treatment can be evaluated in 6 weeks. Once under con ‘tol, lipid profiles ean be monitored every 4 to 6 months. “The ACCIAHIA Task Force on Practice Guidelines issued a new guideline in 2013. The new approach recommends treating at-risk patients with statins of appropriate strength (reflecing the design ‘of most published clinical trials, rather than titrating combina: tions of lipid-lowering medications to a preset target based on baseline cholesterol levels. Stengh of the statin (high intensity LDL cholesterol reduction >50%, moderate intensity: LDL cho- Testerol reduction 30%-50%) is determined by the global risk. ‘The Pooled Cohort Equation, anew algorithm forrisk calculation, is used to estimate the global rik in those with LDL cholesterol 70 to 189 mgldL but without clinical atherosclerotic or diabetes (see ‘Table 4}. This new approach initially faced considerable skept- cism because of the absence of LDL cholesterol targets, neglect ff nonstatin therapy, and questionable validity of the new algo- rithm for risk calculation (the Pooled Cohort Equation). Is pre- dicted that patients eligible for statin therapy may double according to the new guideline Part of the controversy over the new ACCIAHA guideline per- tains to the tsk-calculation tools, which have limitations: most of th risk calculators do not consider family history of premature cardiovascular events, which can lead toa serious underestimation ‘ofthe risk in some patients (the Reynolds Risk Score includes family history of premature myocardial infarction};some ofthe risk calew- lators donot predict risk of stroke, which is another major cardio- vascular event (the hard CHD too! in the ATP II predicts only fatal and nonfatal myocardialinfazction whereas thenew Pooled Cohort Equation predict both nonfatalifatal myocardial infarction and stroke); these risk calculators ate not always validated beyond the original cohorts from which they were developed. The new risk prediction algorithm (the Pooled Cohort Equation) was also citi cized for overestimating cardiovascular risk when applied to different cohorts. The pane] who developed the algorithm coun- tered that the criticism was largely based on data obtained from cohorts that include volunteers who tend to be healthier chan the general population, On the other hand, validity of the algorithm hhas not been established by prospective clinical trials The 2013 ACCJAHA guideline fovuses on the proven effects of, statins on cardiovascular disease. It is predicted that patients eligi ble for statin therapy may double according to the new guideline and patients who are at high risk for cardiovascular disease will benefit from wider use of statins, Efficacy of adding other choles- terol lowering medications such as fibrates or niacin to achieve previously recommended target is limited (discussed below), but management of those who are not tolerant or contraindicated to moderate-high intensity stains is not well addressed. Hovrever, recent studies suggest thatthe high efficacy of the newly developed PCSK9 inhibitors may significantly change the landscape of effec- tive cholesterol management in such individuals Therapeutic Lifestyle Changes Al patients with hyperlipidemia should be counseled on lifestyle ‘modifications. Dietary modification co limit intake of lipids is an essential component, given that the main source of lipids is cxogenous dictay fat Saturated faty acide and trans-unsaturated fatey acids increase LDL cholesterol while dietary ters decrease EDL cholesterol. Carbohydeates donor affect LDL cholesterol but snereas ighverdes and decrease HDL cholestrol, particularly if they have a high glycemic index. Intake of uctose a component of sucrose, increases triglycerides and decreases HDL cholesterol Body weight reduction and physical acuity have a small effect on LDL cholesterol but reduce triglycerides and increase HDL choles terol significantly. Alcohol intake har an’ adverse effect on triglycerides, Tnaividal patents will need different approaches based on their cardiovascular risk ad lipid profiles, Generally, total dietary fatis recommended to constitute 25-35% of the total calorie intake nainly a8 mono- or poly-unsaturated fat, haiting saturated fat £7 % and trans iat 1% ofthetotalealoric intake. Toerapeutcife- style changes include diets with emphasis on vegetables, fruits, ‘whole grais, low-fat dairy products, poultry, fs, legumes, now Tropical vegetable ol, and mute aswell a limited intake of sects, sugar sweetened beverages, anlred meats; further redaction of sat trated fat (<5-6% ofthe total caloric intake) and rane fa; weight reduction; and increased regular physical activity, The amount of cholesterol intake is not wel correlated with LDL cholesterol evel sndthere sno recommendedlint forintake. Management of other ‘isk factors suchas smoking cessation and contrlling blood pres- sure in hypertensive patients and blood glucose in diabetics is also very important. Pharmacologic Agents ‘The currently available lipid-lowering agents can be classified based on their mechanism of action into statins (3-hydroxy-3: methylglutary! coenzyme A [HMG-CoA] reductase inhibitors) fibrates, niacin, bile acid sequestrants, and cholesterol absorption inhibitors such as ezetimibe (Zetia). These classes of agents differ ard to degree and type of lipid lowering, and agents within, the same group may differin efficacy and sde effects, Conventional dosing regimens and common adverse effects ate summarized in “Table 5. Expected changes in lipid profiles are shown in Tab‘ 6, The choice of drug depends on the specific lipid abnormalities and concurrent medical conditions. In general, statins are the most tffective drugs to lower cardiovascular risk and are the treatment of choice when medications are indicated based on the global cardio. varcularrisk. Ifthe primary goal stolowertriglycerides, brates or biacin may be more effective, Ii the teatment goalis not achieved by statins or statins are not tolerated, another agent should be used, Statins Statins are usually the first drug of choice in patients with high cholesterol levels to reduce cardiovascular risk. Statine are the only class of lipid-lowering agents that has been shown in multiple ‘domized clinical trials to improve cardiovascular outcomes in pri mary and secondary prevention. Furthermore, risk reduction was apparent in a wide range of patient, including men, women, smokers, those with diabetes, and those with hypertension as well asin older popelations, Also, statins lead to the highest degree of LDL cholesterol reduction among all of the lipid-lowering agents The approximate equipotent dosages of various statine and their cholesterol-lowering effects are listed in Table 7. The 2013, ACCIAHA guideline recommends moderate or high-intensity statins (see Table 7) based on the global rsk (see Table 4). Sratins inhibit HMG-CoA reductase, the rate-limiting enzyme in choles- terol biosynthesis. By blocking cholesterol biosynthesis, statins ‘upregulate the LDL receptor on the hepatocytes and increase cle ance of IDL and LDL. In addition to their direct effects on lipid ‘metabolism, statins have been reported to have pleiotropic effects (eg, reduced formation of reactive oxygen species, inhibition of platelet reactivity, and decreased vasoconstriction), Statins are usually well tolerated. Potential common side effects include nonspecific gastrointestinal symptoms such as dyspepsia, bheadaches, fatigue, and myopathy, Hepatitis occurs in less than 1%. There is a amall increase in risk of developing diabetes. Tei secommended that the physician monitor for development ofTE v2jor Oras for Management of Hyperlipidemia STARTING DAILY AGENT DOSACE DOSAGE RANGE MECHANISM, SIDE EFFECTS. Stating Lovastatin (Mevacor) 20mg. 10-80. mg Decreased cholesterol Malas, arthralgias, Pravastatin (Pravachol) 40mg 10-80 me Synthesis, increased igh liver enzymes, Sinwastatin (Zocor)” 20-40 mp 80 me hepatie EDL receptors, dyspepaia Fluvastatin (Lescol) 40 mg 20-80m— decreased VLDL release Atorearatin (Lipitor) 10-20 mg 10-80 me Roswvasacin Crestor) 10mg. 540mg. Pravastatin (Livalo)) 2g 2ame Fibratae Fenofibrate (Thicor) 48-145 mg 48145 me. Increased LPL activity, Dyspepsia, myalgia, Gemfibronl (Lopid) 120mg 1200 me decreased VDL. filstonce, high liver Feofibeic aid (Trilipix) 45-135 mg 45-135 mg Synthesis nays Immediate release 250m 250-3000 mg Decreased VLDL synthesis Flushing, high glucose, Extended release 500mg 500-2000 mg ‘re aig high liver (iaspan) caymnes Bile Acid Sequestrante Cholestyramine S65 Ane Increased bile acid Bloating, constipation, (Questran) ‘cretion, neeased LDL. elevated erigicerdes Golestipol (Colentid) 2g 2166 receptors Golesevelam (Welehol) 3.75 g 37543756 Cholesterel Absorption Inhibitors Execimibe (Zetia) tom. tome Deceased intestinal High liver enaymes cholesterol absorption Combination Therapies (single pil) Execimibelsimvarttin —10/20mg 10110-10780 mg (Wrresa} Extended-eleae niaciny — SOO/20 mg -500/20-1000/20 mg simvastatin (Simeor) ‘See the text for the FDA wang ABrestaons IDL EEE Metabolic exfects of Each Lipid Lowering Drug Class LoL CHOLESTEROL Satine Risse, ric aide nova Niacin 025% Bile acid sequestrants yisiaasy% Cholesterol absorption iaubitors domas% low deat ipepetin: LPL ipprecn iste; TG—tigheide; VLDL =very-low-deniy Kippot HDL CHOLESTEROL ‘TRIGLYCERIDES rm-t0% 16-30% 120%-35 30% ‘Adaped som lpoproteia mangement in pata wth cardnmetabalic ith, cone ate (rm the American Cogs of Cardiology Foundation andthe Aenean ‘Diabetes Asocaton[NCCIADA) morcleone QO12) myopathy clinically and hepatotoxicity with liver function tests (baseline and within 3 months and then periodically). Myopathy is one of the most common causes for cessation of stating. Myal- gias can occur in about 10% to 20% of patients, which ie much more often than reporced inthe clinical tials. The risk of chabdo- iyolysis, however, is very low (0.10.2 per 1000 person-yeatt) Risk for myopathy is increased in patients with advanced age, female sex, small body habitus, hypothyroidism, alcoholism, medical conditions {particularly liver or kidney disease), major surgery, excessive physical activity, history of myopathy, family history of myopathy, high-dose statins, and interacting medications or food such as grapefruit juice (>1 Liday}. Simva- statin (Zocor), lovastatin (Mevacor), and atorvastatin (Lip are primarily metabolized through CYP3A\4, which is inhibited by protease inhibitors, cyclosporine (Neoral, Sandimmune), amio- darone (Cordarone, Pacerone), nondibydropyridine calcium ‘Sad American Aoistos of Cia! Eadorsalogir [AACE gues for anagem dapdenia te prevesion of channel blockers, fibrates, and other agents. Pravastatin (Prava- chol) ismetabolized by the kidney, not by the P490 system. Fluvas, tn (Lescol) and rosuvastatn (Crestor) are primarily metabolized nugh CYP2C3, Simvastatin and lovastatin should be avoided in patients receiving protease inhibitors, Statin dosage should be reduced in patients taking cyclosporine, Because of significant risk of myopathy related to simvastatin, the FDA recommends that 80 mg/day should tot be used unless the patient has been taking 80 mg safely for longer chan 12 months. The FDA further recom- sends tha the dose be limited to 20 mg ifthe patient is also taking amiodarone, amlodipine (Norvasc), oF ranolazine (Ranexa), and 0 10 mg/day if caking diltiazem (Cardizem), dronedarone (Mul- tag), or verapamil (Calan). Addition of fibrates increases the risk ‘of myopathy; in patients on a statin, fenofibrate (Tricor) is pre- ferred over gemfibrozil (Lopid), which has a much higher risk of thabdomyolysis. Symptoms of satin myopathy are heaviness,11 Endocrine and Metabolic Disorders z MOTD) Eevinotency and Percentage Reduction in Total Cholesterol According to the Different Types and Doses of Statins REDUCTION IN TOTAL PRAVASTATIN FLUVASTATIN: CHOLESTEROL (%4) (PRAVACHOL), mg—_(LESCOL), mg as s 10 17 10 20 2 20 0 uw 40° so 2 10! 37 2 - - Modified frm Pessing van Ses an clleagee 2007). ‘See the tnt forthe FDA warming {Moderate teanty tans fredaton of LDL cholenerl 30%-507), ‘igesntennty sta duct of LDL cholera 230%) stiffness, cramping associated with weakness during exertion, and tendon-associated pain, Location of symptoms can be at the thighs, at the calves, or generalized, Symptoms can be very nonspe: cific, and differentiating statin-elated myopathy from other causes is not easy. Therelore, baseline symptoms, physical exam- ination, and assessment of creatinine kinaze level Before the initi- ation of stating can be very helpful. Further decisions regarding stopping or switching medications can be made based on the sever- ity of symptoms, level of ereatnine kinase elevation, and presence of rhabdomyolysis. In patients who develop myopathy while on simvastatin or atorvastatin, ifthe decision iso continue treatment with a statin, one option is to cautiously switch them to prava: statin, fluvastatin, of rosuvastatin, which are less prone to cause myopathy. Furthermore, rostvastatin has a long doration of Action and can be taken once every other day, or weekly, if neces- sary. Theoretically, coenzyme Q1O may help statin-induced myop athy, but there is insufficient data to support its use. For patients ‘who cannot tolerate stating other agents should be used Fibrates “The effect of fibrates on cardiovascular outcomes is not as favor able as with starine or niacin. However, ibrates ean be useful in subsets of patients with high triglycerides and low-HDL choles terol, Recently, the ACCORD lipid tial showed that addition of fenofibrate to simvastatin in type 2 diabetic patients with cardio. vascular risk factors did not improve cardiovascular outcomes, though there was a rend for better outcomes in a subgcoup with triglycerides greater than 204 mg/dL. and HDL cholesterol less than 34 mg/dL. Fiaces have multiple favorable metabolic effects including activation of peroxisome _proliferator activated receptor (contributing tothe regulation of both lipid and earbo- hydrate metabolism), stimulation of lipoprotein lipase (increasing tnglyceride hydrolysis), and downregulation of Apo Cll improv= ing lipoprotein remnant clearance as Apo CI inhibit lipoprotein lipase). An enhanced VLDL-to-LDL conversion may lead to mild LDL cholesterol elevation in some patients. This effect may decrease over weeks at the LDL receptors are upregulated. Fibrates are generally wel tolerated. The most common side effect is dyspepsia, Other side effects include myopathy and hepatic enzyme elevation, particularly when fibrates are added to statins ‘As mentioned above, fenofibrate is recommended when added to statins because ofthe high risk of thabdomyolysis associated with gemfibrozil plus statins, Fibrates increase the risk of gallstones, And patients on warfarin (Coumadin) may need dose adjustment. Monitoring of liver enzymes is recommended, at baseline and within 3 months and then periodically. Creatinine level can be increased through unclear mechanisms, Niacin Niacin or nicotinic acid effectively decreases the hepatic production of VLDL and:husLDL cholesterol levels, and raises HDL cholesterol levels by reducing cholesterol transfer from HDL to Apo Bontaining lipoproteins and HDL clearance by the liver. Niacin SIMVASTATIN. ATORVASTATIN. ROSUVASTATIN (ZocoR}” mg (UPITOR), mg (ERESTOR), mg 5 2s 10 5 20 10 s 40 20) 10° (80) 40° 20 : 10° “ isthe most potent agent available to increase HDL cholesterol. Sev zal triale showed the effect of niacin in preventing cardiovascular disease. But the benefit of adding niacin to statins has not been proved. Niacin did not improve cardiovascular risk when added to simvastatin in patients with high risk for cardiovascular disease in the AIM HIGH scudy and the HPS2-Thrive study. There were excess adverse events and wends towards signs of harm among the niacin sroups. The most common side effect of niacin ie flushing. This can 5e avoided or minimized by initiating therapy with alow dose of nia- cin, taking an aspirin 1 hour before niacin, avoiding hot foods or bev terages atthe time the niacin staken, or switching to extended-release forms (Niaspan). Hepatotoxicity ean oveur at any time. Immediate release forms are les likely to cause hepatotoxicity than sustained- release forms (Slo-Niacin), Extended-release forms can minimally ele vate transaminases but significant hepatotoxicity is rare. When switching to different forms itis recommended that one should start, with low doses and titrate up to achieve desired response. Liver func- tion tests should be monitored regularly, at baseline and every 3 months forthe first year and then periodically. Other side effects include pruritus, increased uri acid levels, and hyperglycemia Bile Acid Sequestrants Bile acid equestrants have been in clinical use for many decades ‘These agents promote fecal excretion of bile acids. The liver responds with increased integration of cholesterol into bile acid synthesis to maintain a stable bile acid pool. The consequent decrease in cholesterol in the liver leads to upregulation of the LDL receptor and enhanced LDL clearance from the plasma: FIMG.CoA synthase activity ean increase, so combination therapy with statins would be synergistic, especialy in patients with a sub- ‘optimal response, Available agente are cholestyramine (Questean}, colestipol (Colestid}, and colesevelam (Welchol). Most side effects involve the gastrointestinal tact, with constipation and bloating being the most common. These agents may interfere with the absorption of warfarin, phenobarbital, levothyroxine (Synthroid), and digoxin (Lanoxin), among other medications. Patients on multiple medications should he advised to take bile acid seques- tants L hour before of 4 hou after taking the other medications ‘These agents can also cause elevation of triglyceride level. As they. are not systemically absorbed, the bile acid sequestrants may be the preferred agents when systemic absorption is to be avoided, such as during pregnancy of lactation. Cholesterol Absorption Inhibitors Ezetimibe is the first in a new class of pharmaceutical agents that Inhibit the sterol transporters in the intestine. Ezetimibe isa good add-on agent in people taking a statin if the LDL cholesterol goal 1 not achieved or high doses of statin cannot be tolerated, stimibe was shown to modestly decrease cardiovascular events when added to simvastatin in high tsk patients. Elevated liver enzymes have been reported but the risk of hepatotoxicity seems to be not different from that of placebo,Several new lipid-lowering agents are under development Among these, PCSK9 (proprotein convertase subtilsin/kexin type 9) inhibitors have shown promise in several phase 2-3 tals. The PCSK9 protein appears to control the number of LDL receptors. ‘When it binds to the LDL receptor, the later is destroyed with the LDL particle. Interference with PCSK9s LDL receptor binding capacity or silencing the gene for PCSK9 allows the LDL receptor to recycle to the cell sutlace to remove more circulating plasma cholesterol, Individuals with los-of-Function mutations of PCSK9 have very low LDL cholesterol levels and are protected from CHD. Various PCSK9 inhibitors {mostly monoclonal antibodies) have been shown to decrease LDL cholesterol levels by >40-70% with no significant side effects when used as a single agent or added to maximal dose statin. Posthoc analyses showed that addition of PCSK9 inhibitors for 12-18 months decreased cardiovascular ‘events by 50%, Larger studies with longer follow up for eardiovas- cular outcome are underway. The Endocrinologic and Metabolic Drugs Advisory Committee of the US FDA recommended approval of two human monoclonal antibodies (alirocumab [Pra Iuent], evolocumab [Repatha]} based on expected benefit espe- cially for those with familial hypercholesterolemia. PCSK9 inhibitors enable reduction of LDL cholesterol to levels previously not achievable. Ia this regard, itis important to note that LDL cho. lesterol at levels <70 mg/dL can be underestimated by the Friede- vwald equation, The initial clinical rials appear quite exciting, though the long term safety of PCSK9 inhibition by the different reatment strategies remains to be established. References {ropa JD, Davison M, Furberg CD Lipoprotein management npasenes wheat “Fenetabol tie Cosenustnfseee eprom te ADA sad he ACE fo ‘tio, J Ar CL. Coda 200651 1312-95 ‘carl Ru Bk Lace DA, eal Trad iid and popes in Sal, Tosie20i0 Jaa 2012308184534 Eckel RH, ake JM, Ard JD ea. 2013 ACCIAHA guideline on eye manage ‘pent to redo carirascelr rake A report of the American Coige of jlogyAmnercan Heart Asecton wk fre on pace codlen TA Cul doi4c3a960-48 ecg HN, Eas MB, Lovato LC Efecto combination lipid therapy pe dates melits NEagl J Med 2010862186974 in Alpe 8 ele Gh 240 ACCRA aiding ae ade A report ofthe Ar udtiges developed i elaboration withthe American Sociey of Echocardiography, American Society of Niklear Cardiology. Soe) 0 Soscry for Cardiowasslr Magnese Resonance} Am Coll Carel 2010,56 Grindy Clean J Mers NB, al. mplicaions of eer clncl ale forche liman MD, Capewel 8, Ning H, eal. Cardovsclar heh behavior and ‘health far shuoge (1948-2008) sod projections to 2020, Rese rom te ‘ional Heath aod Nursen Exanvnation Surveyr (SILANES, Circles Jelinger PS, Ssth DA, Mebts AE et Asian Avoca of Ciel Eade Seg quienes fo management of hpeipdena ad peeention of ter ‘lees. Endocs rec 2012811078 Joy Ts Hele RA, Navratve reve: Satcselated myopathy, Ann Intern Med eaney J, Gusta CD, Jasco JA. A pragmatic view of he new choetrl ts ‘pet gudnes N Engl) Med 20143702758 ‘ower J Coline D, Frednan DS, ea Low-enty ipeprotela an hghdensity “opto patie seine pdt ovary evens ad are avery cnged Dpgeiieon therpy she Veterans Alu High Dest Lipopotes Inert i Casals 200613 133665. ‘Gerch WG, ta. Adbereaee wo eviden- TEAS) rien 2011 8217692818 Relinens JO: Paice, Kestpt Mca licay and safety af algcumab nce ng lip andcardvasclsr events Nag] Med 2015.73: 149-3 sebninc MS, Cooplane RE Wine 8, cal lbeay aod ent af eolacaah in ‘sing lips and cardiovascular ents N Eng] ed 2019573 1500-9, Stone NJ, Robinson J Lishescin AH, ca. ACGIAHA guideline onthe treatment "2 Wlod cholera to rdacesthosclcobe carhoruelr ok to sda A porto the Armen Colege of CarilogyiAcurican Heart Aviation tk lowe ot pace guideline, Ain Coll Cardiol 2015652889934 The vp Elects oextenedtlete ais witht “pipran tN Eng] Med 2016 37130512 ‘ecevingnteasine satin therapy Bagh J Med 2011365 2255-6. “cto, evsuation, abd trexnentof high blood cholereol n nuh INCE HYPERPARATHYROIDISM AND HYPOPARATHYROIDISM. Method of John P. Bilezikian, MD Primary Hyperparathyroidism + Most common cause of hypercalcemia. + Diagnosis established by elevated serum calcium concentration and patathyrosé hormone level hats frankly elevated or is inthe Upper range of normal + Insome patients the parathyroid hormone level is elevated but the serum calcium concentration is normal Hypoparathyroidism + Much less commen than primary hyperparathyreidism. + Most often due to surgical rernoval of all parathyroid tissue of autoimmune destructor. + Diagnosis is established by hypocalcemia and low parathyroid hormone levels Primary Hyperparathyroidism + When symptoms are present, parathyroid surgery is indicate. Inthe absence af symptoms, surgeryisrecornmended ifany one ‘of four criteria is met (see Table 2) Preoperative localization testing prior to surgery has become routine Conservative management is reserved generally for thoze who do not meet surgical criteria, + Prudent use of calcium and vitamin D is recommended, and ambulation is encouraged, + Pharmacologic agents such as bisphosphonates show promise ‘spinerease bone density while calcimimetic therapy may be ind cated to reduce the serum calcium level. Hypoparathyroidism + Raute management of hypocalcemia is a medical emergency and requires intravenous administration of calcium + Chronietreatraents based upon adequate ealeiu, vitamin D, an, often, the actve vitamin D metabolite 1,25-dirydroxytzmnin D. + Management with parathyroid hormone is under investigation Primary Hyperparathyradism Incidence and General Characters Primary hyperparathyroidimm (PHPT) is «relatively common tndocrine divcave with an incidence as high av Lin 300\to Lin 1000, The incidence of PHPT increased withthe advent ofthe mle tichannelautoanalyzer inthe 1970s, PHT oceurs in individuals of all ages but occure most frequently in the sixth decade of lie, Women ae affected more often than men bya ratio of 31, PHPT in children i an unusual event. tight hea component of one of : i 18711 Endocrine and Metabolic Disorders LORD > erential Diagnosis of Hypercalcemia, ‘Primary bypeeparathyoidism Malignancy Other endocrinopathies Hyperthyroidism Pheochromocytoma ‘Advenalinstficiency ViPomns Medications Tithiim Thiaides Thyroid hormone Vitamin D Vimin A Granulomatous diseases anual hypocaleiurichypercalemia Inmabilizaton several endocrinopathies with a genetic basis, such as multiple endocrine neoplasia (MEN), type [or I PHPTis caused by exces- sive secretion of parathyroid hormone (PTH) from one or more parathyroid glands. A benign, solitary adenoma is found in 80% of patients, Less commonly, in 15% t0 20% of subjects, all four glands are hyperplastic. Four-gland parathyroid disease may occur sporadically or in association with the MEN ddromes. The most uncommon presentation of PHPT is parathy- roid cancer, occurring in less than 0.5% of patients with PHPI Differential Diagnosis ‘The major diagnostic distinction to be made is between PHPTand snalignanes, the other most eommon cause of hypercalcemia. These two etiologies account for more than 90% of all patients with hypercalcemia (Table 1). A much longer, complete list of potential causes of hypercalcemia is considered after there two etiologies are ruled out or if theze is reason to believe that a different caus is likely Today, PHPT presents most often as an asymptomatic disor der. In contrast, malignancy-associated hypercalcemia is usually found ata later stage of the malignant process and is associated with symptoms, Besider a major difference in clinical presentation between these ro. most common causes of hypercalcemia, the PTHimmunoassay isa helpful distinguishing point. In patients with PHP, the PTH level will be elevated or in the upper range of not smal, whereas in malignancy, the PTH levels invariably suppressed. Pathophysiology, Molecular Genetics, and Pathology TThe pathophysiology of PHPT relates tothe loss of normal feed- back control of PTH by extracellular calcium. Why the parathy- roid cell loses its normal sensitivity t0 calcium is not known. Genetic abnormalities that could be linked to sporadic parathy roid tumors have been described. A rearrangement of the cyclin. DIPRAD1) protooncogene has been seen in some patients with PHPT, The rearrangement associates the PTH gene with the growth promoter eyelin D1, Tumor suppressors, stich as the gene associated with MENA, have generated interest, as have potential abnormalities in the gene for the caleium-sensing. receptor Although the gene for the calcium receptor has been implicated in familial hypocaleiueic hypercalcemia and neonatal severe hyper parathyroidism, there i little evidence for this genetic abnormality In the sporadic form of PHPT. The typical parathyroid adenoma is an enlarged, oval shaped, smooth, red-brown gland. A visible rim of normal yellow-brown, parathyroid tissue is sometimes seen, The typical size ofthe para thyroid adenoma is smaller than it used to be, but still is much larger than a normal gland, which generally weighs 35 to SOmg. Parathyroid adenomas are generally over 150 mg and can be mich Targer. Microscopically, the parathyroid adenoma onsite of a network of celle arranged alongside a capillary net- ‘work, resembling classic endocrine microanatomy. Eat cells are reduced or absent, The form of PHPT characterized by four gland hyperplasia is seen grossly as uniformly enlarged glands, Micro- scopically, solid masses of chief cells are seen in the absence of fat cells In contrast to the adenoma, in which asim of normal tis, sue can sometimes be seen, normal tise is absent in hyperplastic disease, The histological distinctions between adenomatous and hyperplastic disease are not always so cleat, Signs and Symptoms PHPT is associated classically with skeletal and renal complica. tions, In severe cases, the skeleton can be involved in a process called osteitis ftbrosa cystica, Subperiosteal resorption of the distal phalanges, tapering of the distal clavicles, a “salt and pepper” appearance of the skull, bone eysts, and brown tumors ff the long bones arc all overt manifestations of hyperparathyr tid bone disease, This form of hyperparathyroid bone disease is now most unusual in countries where multichannel screening i routine. Skeletal involvement in PHPT is detected much more often by dual energy x-ray absorptiometry (see later). Similar to the reduced incidence of gross «keletal disease, the kidney is also involved in PHPT much less commonly than Most series place the incidence of nephrolithiasis now rho more than 15% to 20%. Nepheolithiasis, nevertheless, is still the most common complication of PHPT. Other renal fea- tures of PHPT include diffuse deposition of calcium- phosphate complexes in the parenchyma {nephrocalcinosis), ‘The frequency of this complication is unknown, Hyperealeiaria, (daily calcium excretion of >250 mg in women of >300 mg in ren} is sen in 30% to 40% of patients, PHPT may be associ- ated with a reduction in creatinine clearance, in the absence of ny other cause, Classic associations exist between PIIPT and other organs, such a8 the neuromuscular system, the gasteoin- testinal tract, and the cardiovascular and articular systems, but such panopleistic features of PHPT are rarely seen today. More vexing are nonspecific elements associated with PHPT, such as easy fatigability, a sense of weakness, and a feeling that the aging process is advancing faster than it should be. This is sometimes accompanied by an intellectual weariness and a sense that cognitive faculties are less sharp, Whether these non: specific features of PHIPT are truly part of the disease process, reversible upon successful parathyroid surgery, remains ander active investigation Clinical Forms of Primary Hyperparathyroidism Asymptomatic PHPT with serum calcium levels within 1 mg/dL above the upper limite of normal is the most common clinical presentation. Most patients do not have specific complaints and {do not show evidence of any target argan complications. In parts fof the world where severe vitamin D deficiency is common, more symptomatic PHPTis seen, Unueal clinical presentations of PHPT mnclde MEN-Tand MEN IL, familial FHPT not associated with any other endocrine disorder, familial cystic parathyroid adenomatosis, jaw cumor syndrome, and neonatal PHPT. Over the past decade, yet another presentation of PHPT can be seen in individuals with nor ‘mal serum calcium concentrations but elevated PTH levels. Poten= tial secondary causes of elevated PTH levele have to be ruled out such as vitamin D deficiency, renal insufficiency, medications such as thiazide diuretics or lithium. Normocaleemic primary hyper parathyroidism, this newer phenotype of primary hyperparathy- roidism, may represent in some patients the earliest stage of PHPT, wien there is glandular overproduction of hormone, before hypercalcemia becomes evident Diagnosis and Evaluation Hypercalcemia and elevated levels of PTH, of levels inappropri- ately in the upper range of normal with hypercalcemia, establish the diagnosis. The serum phosphorus concentration tends to be inthe lower range of normal, Serum alkaline phosphatase activity may be elevated. More specific markers of bone formation (bone- specific alkaline phosphatase, osteocalcin) and bone resorption (urinary deoxypyridinoline, N- or C-telopeptide of collagen) tend to be inthe upper range of normal. ln some patients, the actions of| PTH in altering renal acid-base handling leads toa small increasein the serum chloride concentration and a concomitant stall decrease in the serum bicarbonate concentration. Urinary caleium excretion, when elevated, is not generally excessively high. The circulating 25-hydroxyvitamin D concentration is low, and the 1,25-dihydroxyvitamin D concentration tends to be in the upper ange of normal, reflecting the disposition of parathyroid hormone to facilitate the conversion of 25-hydroxyvitamin D to 1,25-dihy- droxyvitamin D. Role of Bone Mass Measurement Dual-energy x-ray absorptiometry shows pattern of skeletal involvement that is consistent with the physiologic actions of PTH, namely a proclivity to be eatabolic at cortical bone. Thu, ‘he typical patent with PHPT shows reductions in bone density that are most marked in the distal third ofthe foreazm, a corteal site, swith much less involvement of the lumbar spine, a cancellous site ‘The hip region, a mixture of cortical and cancellous bone, shows changes that are intermediate between changes in he forearm land the lumbar spine. This classic densitometric presentation is not consistent with epidemiologic data that has suggested a more general increase in fracture risk, including vertebral fractures. More recently, application of non-invasive high resolution peripheral imaging by CT has shown reduced trabecular microstructure as we! as cortical involvement in primary hyperparathyroidism, Treatment Localization Tests Prior to Surgery Imaging of abnormal parathyroid tissue is accomplished accu rately with technetium-99m sestamibi. Sestamibs is taken up by both thyroid and parathyroid tissue, butt persists in the parathy roid glands. Various approaches tothe use of rechnetiam-99m se5- tamibi_ include using, the imaging agent alone, and thereby depending upon a difference in uptake kinetics beeween thyroid land. parathyzoid issue, oF i combination with iodine 123 Cp, ‘Combining sestamibi with single-photon emission come puted tomography ean be helpful. Ultrasound, computed tomor- raphy, and magnetic resonance imaging are also used to localize abnormal parathyroid tissue. In the hands of some experes,ulta- sound and computed tomography can be very successful localiza tion approaches. Invasive localization tests with arteriography and selective venous sampling for PTH are rarely used anymore. Non- invasive preoperative imaging bas become routine in all patients who ate to undergo parathyroid surgery. If there are no plans for parathyroid surgery, parathyroid imaging is not necessary of recommended Guidelines for Surgical Management of Primary Hyperparaihyroidism ‘The Fourth International Workshop on the Management of Asymptomatic Pamary Hyperparathycoidism was held in 2013, and the proceedings were published in 2014. The Workshop reviewed new data since the previous workshop in 2008 and sug gested revised guidelines for surgical management (Table 2). The Iajor changes are summarized here, Since deal energy absorpti- fometry alone may not be the best predictor of vertebral facture sk in primary hyperparathyroidism, measures sich as vertebral xerays, vertebral facture analysis (VEA), or newer imaging approaches such as Tigh’ Resolution peripheral Compsted Tomography are recommended, ‘The 24hour urinary «alia excretion is secommended and when clevated, furher measuze ments of urinary risk facors for stones, sich aa urinary biochem ical stone rsk factor analyse are recommended. Real imaging by scray, ultrasound, or CTs recommended because ofthe apprise ble mcidence of silent renal stones or nephrocalenosis Surgery PHPT is cured when abnormal parathyroid tissue is removed. Asymptomatic patients are advieed to have surgery ifthey meet cur rent guidelines (see Table 2). Symptomatic patients are always advised to undergo parathyroid surgery if there are no medical con. traindications. At the present time, a number of different surgical procedures can be performed. While the standard four-gland para- thyroid gland operation under general or local anesthesia i sil 2013 Guidelines for Parathyroid Surgery in oa Asymptomatic PHPT MEASUREMENT ‘SURGERY RECOMMENDED IF Serum calcium (>upper Tint of normal Skeletl >1.0 mgldl. (0.25 mmol) 4 BMD by DXA:Tscore <-2.5 alumbar spine, total hip, femoral neck or distal Us radius? Vertebral facture by x-ray, CT, MRT or VFA Renal 4. Creatinine clearance <60 celmin 1. 24rhour urine for calcium >400 mg/day {>10 mmoliday and increased stone rok by bioebeancl stone sk aalges sence of nephrolithiasis or ‘epheocaleinoss by x-ray ultrasound, orc Age <50 performed, minimally invasive parathyroid surgery has gained in popularity. This procedure depends upon preoperative localization of the parathyroid adenoma by an imaging technology and Confirmation ofthe success of abnormal gland removal with intrao- perative PTH measurements before and minutes after parathyzoid. ectomy. The circulating PTH level should fall to less than 50% of the preoperative value within minutes after removal ofthe parathy- roid adenoma and be within the normal range. Minimally invasive parathyroid surgery, this latter approach, has become a standard {for many parathyroid surgeons now. Medical Management In patients who do not meet surgical guidelines or who, for other reasons, will not undergo parathyroid surgery, the following medical principles apply. Adequate hydration and ambulation arealwaysencoutaged. Thiazide diuretics arco be avoided because they may lead to worsening hypercalcemia. Dietary intake of eal cum should be moderate, avoiding both high- and low-calcium diets. Low-caleium diets theoretically could fuel abnormal parathyroid tissue to secrete more PTH. High-calcium dite could be detrimental by worsening hypercalcemia, especially if the 41,25-dihydroxy vitamin D level is elevated. Monitoring with annual measurements of the serum calesum and annual or every~ fther-year measurements of bone mase by dual-energy x-ray absorptiometry are recommended. In. patients whose 25- hydroxyvitamin D level is low, careful replacement seems reason able. The serum caleium concentration musthe monitored guatd against the potential for worsening hypercalcemia insome patents ‘Pharmacological management of primary hyperparathyroidism, depends on the goal. Ifthe goal is to increase bone mineral density, ‘bisphosphonate such as alendronate ie reasonable and has been shown to be effective in this regard, One would not use bispho- sphonate therapy instead of surgery, if the surgical guideline of Tow bone mineral density is met, unless the patient is nota cand) date for parathyroid surgery. Bisphosphonate therapy in primary hyperparathyrosdisi has not been shown to reduce serum calcium of PTH concentrations If the goal of pharmacological therapy is to reduce the serum. calcium, caleimimetie therapy with einacaleet can be effective. ‘Ginacalce is approved by the FDA for the management of primary byperparathyroidism, The serum caleiumn concentration typically becomes normal and remains within normal limite for as long as ‘he deug is used, Interestingly, the serum PTH level falls only mod- estly and continues to be elevated despite correction of the hyper- calcemia by the drug. Bone mineral density does not change, One would not use cinacalcet instead of surgery, ifthe guideline of hypercalcemia is met (>Img/dl. above normal) unless the patient is nota candidate for parathyroid surgery. : i 76911 Endocrine and Metabolic Disorders m0 TED) causes of Hypoparsthyroidism Parathyroid gland destruction Posteurical Auroimmune Sporadic Polyglandslaesyndromet Activa 1 anibodie against dhe caleiumesensing reeeptor Infiltration ros, copper Malignancy Granulomatout Genetic Activating mutations ofthe calium-sensing ceceptor TInaetivating mutations inthe PTH gene DiGeorge smndrome Ipaived secretion andior action of PTE Hypomagnesemia Pseudobypoparathyroidism Hypoparathyroidism Hypoparathyroidism is much more uncommon than is PHPT and, ip fact, is defined in the United States as an orphan disease Recent estimate. place the prevalence at less than’ 100,000. Hypoparathyroidism results from the destruction, removal, of dysfunction ofall parathyroid tissue Etiology “The most common causes of hypoparathyroidism are neck surgery and an autoimmune process (72 le 3). Surgical bypoparathyroid- ism can follow the operation by many years and can occur after any neck surgery. Autoimmune destruction of the parathyroid glands ean occur in an isolated fashion or in connection with a variety of polyglandular syndromes. Activating mutations of the caleium-sensing receptor or of the parathyroid gene itself can be associated with hypoparathyroidism. Parathyroid gland destruc tion is rarely due to infiltration of the glands by iron, copper, granulomas, or malignancy. In severe magnesium deficiency, para thyroid secretion is impaired along with a peripheral resistance to the actions of PTH. Mild hypoparathyroidism can become symp. tomatic in the presence of a potent bisphosphonate such as alendronate Clinical Features Increased neuromuscular isrtability is the clinical hallmark of hypoparathyroidiem, Features of hypoparathyroidism can range from mild paresthesias around the mouth, fingers, and toes to smuscle cramping, and, at their worst, carpal, pedal, or laryngos- ppasm, Central nervous system seizure activity 18 also seen as a severe manifestation of hypocalcemia. These symptom are duc, {in part, to the actual serum calcium level but also to the rate at which the serum calcium level falls. Rapid declines in the serum caleium concentrations ate mote likely so be associated with symptoms than are situations in which the serum calcium concen: tration has fallen gradually If respiratory ot metabolic alkalosis is present, symptoms can worsen because the partition between bound and free calcium is shifted to the bound state when the blood pH rises. Signs of hypocalcemia include the Chvostek sign (evoked facial nerve iritability), che Trousseau sign (carpal spasms when the blood pressure cull is inflated co pressures above systolic), and a prolonged QT interval on the electrocardiogram. When severe hypocalcemia is present, impaired cardiac contzactlity, unresponsive to inotropic agents until the hypocale: mia is corrected, has been reported. Pecudopapilledema and sub- capsular cataracts can be seen, In some individuals, bhypoparathyroidiem is detected only by an asymptomatic reduc. tion in the serum calcium concentration. Pseudohypoparathyroid- 1m isa group of genetic disorders ofthe PTH recepeorlG protein teansduction system responsible for PTH action. In the type I var= iant, subjects have a classic phenotype (Albright’s hereditary osteodystrophy) with short stature, brachydactyly, subcutaneous and basal ganglia calcifications, zounded facies, shortened neck, seizures, and below-average intelligence. The endocrine glands, such as the thyroid and gonads, can also be dysfunctional, In the type If form of pseudohypoparathyroidism, PHT res is present in the absence ofthe clinical phenotype. Diagnosis Hypocalcemia and an elevated serum phosphorus concentration in association with absent PTH levele confirm the diagnosis of hypoparathyroidism, In pscudohypoparathyroidism, PTH levels are elevated, reflecting the PTHresstant state, but otherwise the biochemical findings of hypocalcemia and hyperphosphatemia are similar to those of hypoparathyroidism, The urinary caleium ‘oneentzation is usually not elevared because the filtered load of calcium is low, but actully renal handling of calcium is impaired n this setting because of the lack of PTH, Such individuals have an :ncrease in urinary calcium forthe given filtered calcium load, even though the actual amount of urinary caleium exeretion might not Treatment ‘The goals of treatment are to establish a serum calcium concentra tion that is not associated with symproms or signs and to prevent long-term complications of hypocalcemia, Acute, symptomatic hypocalcemia is a medical emergency and must be treated ‘urgently. The management of chronic hypocalcemia follows a dif- ferent set of guidelines Acute Management The initial approach is to infuse intravenously 1 to 2 ampules of calcium gluconate (90-180 mg of elemental calcium) diluted in 50 to 100 mL of 5% dextrose over a 10- to 15-minute period. If the seute symptoms are not quickly ameliorated, another 1 t0 2 mpulles can be administered, To raise the serum calcium conce tration further, but more gradually, an infusion of 15 mgkg of eal- cium gluconate in I L of 9% dexteose over 8 to 10 hous will raise the seram calcium concentration by 2 to 3 mg/dL. Because 1 mpulle of calcium gluconate contains 90 mg of elemental calcium, 9 t0 11 ampules of caleium gluconate are required for an average” size adult (60-70 kg). The serum calcium concenteation should be monitored frequently. If the hypocalcemia is duc to magnesium deficiency, these measures are also appropriate while magnesium is being replaced, Acute administration of magnesium without ca: cium will not immediately correct hypocalcemia because periph- «zal resistance to PTH, one component of hypocalcemia induced by magnesium deficiency, is not corrected for several days. Intra- venous replacement of magnesium is 24 mgikg, up to 180 mg, lover a 10-minute period or a continuous infusion of S76 mg of magnesium over 24 houts, Chronic Management ral calcium supplementation is required in virtually all patents. ‘The amount varies buts generally inthe range of to 3 gin divided doses. The carbonate or citrated form of calcium is most commonly tured. Calcium carbonate is generally preferred because ie contains the highest amount of elemental calesum, When caleium prepara~ tions are given with meals, both the carbonate and the citrated form of caleium are equally bioavailable, The presence of food obviates the need for gastric acid when calcium carbonate is used. ‘Mose patients also require vitamin D. The amount of exgocalet- ferol vitamin D,) or cholecaleifero vitamin D,) can be modest or as high as 200,000 TU daily (1.25-10 mg). These large amountsare required because the absence of PTH and hyperphosphaternia ‘both sometimes limit the amount of vitamin D that ultimately is converted to 1,25-dihydroxy-vitamin D, the active metabolite in the kidney. Because activation of vitamin D is impaired, much more vitamin D is required. There is no impairment of the first activation step in the liver, namely, from vitamin D to 25; hydroxyvitamin D, the storage form. Because there is no impait- ‘ment in this step, large amounts of 25 hydroxyvitamin D can accu imulate in fat tissues. At times and unpredictably, these stores can bbe mobilized and lead to hypercalcemia. Sometimes, the hypercal- cemia is severe, requiring emergent treatment. Other times, a sim- ple adjustment in the amount of ealeiaim andlor vitamin D is sufficient. In any event, patients receiving large doses of vitamin D should always be regularly monitored for serum calcium con- centrations approximately every 3 to 6 months. ‘Although many patients with hypoparachyroidism can be ade~ quately managed with oral calcium and vitamin D, many patients also requite therapy with 1,25-dihydroxyvitamin D, the active metabolite of vitamin D. 1,25-Dihydroxyvitamin D is wed in addition to, but not in place of, vitamin D because 1,25- dlihydroxyvitamin D alone does not provide for smooth control. Perhaps shie is because 1,25-dibydroxyvitamin Dis not stored to any appreciable extent an fat tissue, The halflife of 1,25: dibydroxyvitamin D is as short as 6 hours. Therefore, patients managed without parent vitamin D- but with 1,25 dliydroxyvitamin D as the only source of vitamin D are more likely to have unpredictable fluctuations in serum calcium coneen- tration. The amount of 1,25-dihydroxyvitamin D ranges from 0.5 10 1.0 g/day. Some patients require more, Enhanced gastrointes- tinal absorption of calcium with 1,25-dibydeoxyvitamin D can lead to hypercaleiuria because in hypoparathyroidism there is no PTH to facilitate calcium eabsorption inthe renal tubule. Us nary calcium should be checked on a regular basis. If hypercal- ciuzia ovcurs, the doses of 1,25-dibydroxyvitamin D, vitamin D and/or calcium should be adjusted downward. In this situation, a thiazide diuretic such as hydrochlorothiazide' can be used to reduce urinary calcium excretion, ‘Another reason for variability in the control of serum caleium concentration in hypoparathyroidism is 2 change in medications. For example, if « thiazide o loop diuretic is started for hyperten- sion, the serum calcium concentration may increase or decrease, respectively, Glucocorticoids can lead to a reduction in the serum calcium concentration because glucocorticoids interfere with vita- ‘min D action in the gastrointestinal tract, Bile-sequestering resins caninterfee with vitamin D absorption, Mideyele changes in estto- zen levels in premenopausal women can lead to altered control Hypoparathyroidism is one of the few endocrine disorders for which the replacement hormone, namely, PTH, ie not yet avai- able. A recent double blind, placebo-conerolled clinical trial of PTH(1-84) showed significant reductions in the need for oral cal; cium and 1,25-dihydroxyvitamin D while maintaining seram cal- cium levels. The protocol called for titration of PTH(L-84), injected subcutaneously, from 50 to 100 pg per day. "Not FDA approved for this indication References Amol ,Shastck TM, Maly SM, eta. pursthroidem, | Bone Neer Res 2002.17 Spel [nulann J Kaen A, Poi Je J ea ypopartbceda nt ad: epi ‘gy cago, pthophyolgy urge organ acme reaeen chal Tenge for fre sear] Bone Mine Res 2011;26251 7-5 Bien J. Khan AA, Pos J. 2008 Gaines forthe Management of Asyng Komatc Bimary Hyperparahyoldvar Suroary Suterment hems the Pours Ibtenasonal Worksop] hn Eedociol Metab 20149596 Bieztian J Sverre). Pemary hypeparthyrony, hr Rosen editor, Primer “on the Metabolic Bone Dncaes ad Disord of Cia Metbolat, he Sot Rove Min Research, 2008p 302-6 ro NE Siete), Bien J Normocaeem Mim] Cn Denaromery 201316339 nal Brands ML, Costa A, D'Amus, aback DM, Thaker BV. Diagaos of ‘easy hypeparthyeaidam, ) Cn Eedowsol Meabal 2014 i pees Butel Role A, Beupd SL ea 2008 Diagbos of Asynptomae Pinay ypepscathyrondss Proceeding of he The ltersasonal Worshop. | Cod Enlotn! Metal 200994 34650, ‘ey Ar Luss J Hosoe Ae “Frain option ptns with pia bye Punihyodin and coset vem Deut] Ck Eadie Seas Bonssiaos ‘rnbycorthomone at a ypoparatysadin (REPLACE s dab lng Fisch cond, randomed pte 3 say. Lancet Dab Eade Macc Bole, Khan AA, Shock D. Mil managment of priacy Msn of Appa inary Hyperparyes. Cin Endo ents onesa gat. Peacock Mesa J Bolognese MA, erly M6, Scamp, Sing Lea “Secale Hl rede hyena rary bypepeym ne mie sperm of dees sever} Cen Eeactzal Mesabl oT seh ace i. Bien J, Klan Sea. Cia dcr mann long ‘Tom parmesan patents nh may byperparigrsn] Cn Eade (cial Aeab 200590 185-41 Baia MR Sesssan JP MeMshon D, etal The atura itary of primary ype parts with or wthoutparnproid rer fer 18 yea Ch Ed Ebel Metab 200898 2460-7 ShebackD. Clie pace lyppazethyroidion.N Engl J Med 2008 Jul 243559 Svein Sh Biexkian JR Primacy hyperparathyroidim, In: DeGroot LJ, Tsevoa editors Eadoceislogy Sh Econ Pi seobia: Sounders Eee 2010. p Lite Sibebeg 8, Bienia The dingoovis and management of ssmnptomatic Duty" perpaatiyeoidam. “Nat” Cin Peuctce” Eodaciaol Sea Sooeteni208 Siverberg 8), Lewicei EM, Moteid Le a. 2009 Fresiaton of Asymptomatic Jin Badan! Merb 209940351-85 seem B Sa RE, Boy 5h 8 eal Far hypepartnadn ‘tinea pntmenapaueal worn. Bone Miner 913,285) 10290 \dduman B Akram Gy hag fhe Surge Management of Asymptomatic ‘emaryFiperparehroim. J hn Endocrinol Metabo 2018 in pres ‘personal experience. ] Clin Denstem 2013,16. 54-3 Vignal, Vices 6, Disc Dal Norphometnevertbralracersin postmen ‘psaal wren wich pomacyhyperparayrodiem.) Cin Endocr! rsa all MD, MeMabor DI lakoet WB, sta. Ncurpeyhologial faa in HPT ‘peogectne stdy | Cin Encesnal Mab 2008 6 OSI HYPERPROLACTINEMIA Method of Janet A. Schlechte, MD + Ahistory and physical examination; assessment of thyroid, Iver, and kidney function; and a pregnancy test will exclude rary Causes of hyperprolactinemis. + Asingle prolactin measurements usualy adequate for diagnosis. + Inpatients with prolactinomas, prolactin levels generally parallel PzAevres THERAPY + Medication-induced yperprolactinemia is reversible upon discontinuation of the drug. +A dopamine agonist is the treatment of choice for 2 prolactinoma + Discontinuation of therapy usually associated with recurrence of hyperprolactinerna. m11 Endocrine and Metabolic Disorders 3 Epidemiolo pituitary rumors and are more common in women. yperprolse= finemia occurs in about one thitd of patients with chronic kidney disease and resolves after successful transplantation. About 10 ‘of patients with primary hypothyroidism have a small increase in serum prolactin, and hyperprolactinemia is reported in about 30% of women with polyeyste ovarian syndrome. About 5% co 20% of patients with cirthosis have clevated prolactin levels. ‘Occasionally no cause of hyperprolactinemia ean be identified {idiopathic hyperprolactinemia), and these patients might have pituitary adenomas too small to detect on magnetic resonance imaging (MRI) Risk Factors Estrogen can increase serum prolactin, and hyperprolactinemia is often detected after discontinuation of an oral contraceptive, but ‘ae control studies have shown no relation between the use of estrogen and the formation of prolactinomas Pathophysiology “The secretion of prolactin from pituitary lactoteophs is regulated by hypothalamic dopamine, Prolactin secretion is episodic, and scrum levels are usually less than 25 ng/ml in women and less than 20 ng/ml in men. During pregnancy, esteogen induees hyperplasia of pituitary lactotrophs, which leads to a progressive increase in prolactin and a 10-fold elevation aterm, tn lactating women, pro- {actin levels remain elevated until about 6 weeks after delivery. The primary action of prolactin isto stimulate mammary tssue, but {sthe prolactin-induced suppression of gonadotropins and sex ste roids that brings patients to clinical atent Clinical Manifestations In both sexes, hyperprolactinemia is associated with hypogonad. ism, infertility, and bone loss. In women galactorthea is also com- monly observed, Prolactin-secreting tumors in women are usually small and are rarely astociated with pituitary hypofunction, Men with prolactinomas usually have large tumors and present with headaches, neurologic deficits, visual loss, and hypopituitarism sn additional to gonadal dysfunction, Diagnosis A single measurement of serum prolactin obtained at any time of day is usually adequate to make the diagnosis of hyperprolactine mia, Stress can increase prolactin, and minimally elevated levels should be repeated before the diagnosis of hyperprolactinemia is confirmed. A history and physical examination; assessment of thy- 101d, liver, and kidney function; and a pregnancy test will exclude most causce of hyperprolactinemia. Provocative tests “using thyrotropin-releasing hormone, levodopa (t-dopa), domperidone jotillim,nomifensine (Merital), and insulin-induced bypo lyeemia are not useful or necessary. When other causes of hyper- prolactineria have been excluded, gadolinium-enhanced MRI hould be used to visualize the pituitary. In general, serum pral tin levels parallel tumor size, Prolactinomas larger than Lem are typically associated with prolactin levele greater than 250 ng! ab, and levels can exceed 1000 ng/ml, Differential Diagnosis Medications are the most common cause of hyperprolactinemia ‘other shan tumor (ox 1). By blocking dopamine receptors, metor clopramide (Reglan], phenothiazines, and risperidone (Risperdal) lead to prolactin levels greater than 200 ng/mL, but tricyelie anti depressants, verapamil (Calan, and estrogen cause only mild Not avalable inthe United States tnvertgntional drug inthe United Sates, FD asses cFtperotcineri Prolactinomas Pregnancy Medications + Phenothiazines + Metoclopramide (Reglan) Estrogen Veraparril (Calan) Buryrophenones Risperidone (Risperdal) * Trieylic antidepressants Primary hypothyroidism Renal failure Nonfunctioning pituitary tumors Hypothalamic disease Nipple stimulation Idiopathic clevation, In general, medication-indueed hyperprolactinemia is fssociated with prolactin levels htween 25 and 100 ng/mL. Other causes of hyperprolaetinemia include pregnancy, chest trauma, nipple stimulation, and hypothalamic disease. Treatment Medication induced hyperprolactinemia is reversible, and it usw ally takes 3 t0 4 days for prolactin to normalize after drug wi drawal, It ie not always possible to discontinue a drug causing ‘levated prolactin. For example, in a patient with byperprolactine- tia, an antipsychotic agent should not be changed or discontinued without consulting the patient's psychiatrist. I medication can- rot be safety discontinued in a patient with medication-induced hyperprolactinemia, radiographic evaluation of the pituitary may be necessary to exelude a pituitary tumor “The goals in treating a prolactinoma are to normalize prolactin, restore gonadal function and fertility, and reduce tumor size. The preferred treatment i a dopamine agonist, and the drugs approved for use in the United States are bromocriptine (Parlodel) and caber- goline (Dostinex). Both bind to pituitary dopamine receptors, thereby decreasing prolactin and reducing tumor size. Prolactin levels nozmalize within days of drug administration, and tumor shrinkage or disappearance is usually apparent 3 to 6 months after nstitating therapy. Bromocriptine is less expensive, has a half-life of § hours, and must be given twice daly. Cabergoline has a half- ife of about 24 hours and can be administered once ot ewice weekly. Both drugs are available in generic form. ‘Bromocriptine should be initiated at bedtime with a dose of 0.625 mg and a snack. After 1 week, twice-daily dosing should be initiated by adding a morning dose of 1.25 mg. At weekly intervals the dosage should beincreased toa total ofS mg daly, and ater 6 0 Swvecks of therapy prolactin level should be repeated. Mostpatients require 5 mgof bromocriptine daily. The starting dose ofeabergoline i 0.25 mg weekly. After 1 week, twice-weekly dosing should be niiated by adding 0.25 mg. At weekly intervals the dose should be increased to a total of 0.5 mg twice weekly. After 6 to 8 weeks of therapy a prolactin level should be repeated, Most patients will require Img of cabergoline weekly, Treatment with either drug can restore gonadal function without normalizing prolactin If this lccurs, itis not necessary to increase the dosage just to normalize the prolactin. The lowest dosage possible should always be used “The major disadvantage of both dopamine agonist ie that dis continuation usually leads to tumor regrowth and recurrence of hyperprolactinemia. Recent reports suggest that discontinuing therapy may be feasible in selected patients, but the optimal length of therapy has not heen established and there are no precise criteria to predict which patients will benefit from drug wi rawal. I recommend a minimum of 2 years of therapy beforeconsidering withdrawal of therapy. Drug withdrawal is more likely to be successfl if the prolactin has normalized andino tumor is visble on MRI before the drug is discontinved. ‘When ferilty is the goal, bromocriptine is the treatment of choice. After starting bromocriptine a woman should use mechan ial contraception until at least two regular menstrual eycles have ‘occurred, and the drug should be discontinued a soon as pregnancy isconfirmed, When administered in this fashion, bromocriptine hat rnot been associated with an increased incidence of congenital malformations. Although cabergoline has not been associated with fn increased risk of congenital malformations, it ie not currently recommended because less information aboutits safety is available rot necessary to measure prolactin levels during pregnancy because rising levels do not reliably correlate with tumor enlarge- ment. The risk of clinically significant tumor growth during preg- nnaney is less than 2%, s0 it is not necessary to perform serial [MRI scans or visual field examinations during pregnancy in women ‘who have small tumors. In contrast, there isa 15% t0 30% risk of tumor enlargement during pregnaney in women with macroa: ddenomas (>1 cm). With large oF invasive tumors there is no single therapeutic option, and treatment must be individualized Monitoring Small proictinomas rarely progressively increase in sie, so pre- vention of tumor growth Is not an indication for teatment eis {rucal, however, fo teat prolacti-induced gonadal dystunction When ferlity is not desired, one option isto administer a dopa rine agonist. Another option when feraity ir not an issue i #9 use estrogen oF testostecane instead of a dopamine agonist. Sex te- roids ae beer tolerated snd less expensive than either dopamine $gomiat and effectively teat hypogonadism ad protect the skele- ton, Short term use of estrogen in women with prlactinomas bas not been associated with tumor growth, but it should be used with min women wit vey larg tumors. With ether option, peo ‘evel should be monitored yearly: Tumar growth is urually preceded by an elevation of serum prolactin, so itis not necessary to perform yearly MRI examinations. An MBI i indicated if cline jeal symptoms of tumor expansion occur of if the prolactin increases substantially. Complications Both dopamine agonists ean cause nasal stuffiness, nausea, and crthostatic hypotension, but fewer women taking cabergoline dlemonsteate dug intolerance. Pleusal thickening, setcoperitoneal IHbrosis, and cardiac valve regurgitation have’ becn noted in patients who have Parkanson’s disease and are taking high doses (3 mg daly) of abergoline.. Long-term therapy of hyperprolacti- nema with bromocriptine as not been associated with pulmo- nary complications, and clinically relevant valvular repurgitation has not been seen i patients who have prolactino- ‘mas and ate taking (0 2 mg ofcabergoline weekly. Piuicary surgery may be necessary for occasional patients who cannot tolerate ether of the dopamine agonists, When performed bby an experienced neurosurgeon, tanssphenoidal surgery nrmal- ines prolactin in about 70% of patients with microadenomas and about 30% with macroadenomas, but recurrence of hyperprolac- References Gila ME, Melich ME, Lonard G, Colao A. Adve in he teste of po Tacioman Endo Rov 9006.7 95-5 Kethunh A roactinonn. Nl} Med 2010;362121926 2a05 0.050." [Malrch ME. elactioons ané peznaney Pray 2005;831-8, HYPERTHYROIDISM Method of Wiliam J, Hueston, MD + Hyperthyroidism or thyrotoxicosis is most often caused by Graves' disease, toxic nodular geiter (Plirrmer's disease), ot acute thyroiditis, + Common symptoms in hyperthyroidism are tachycardia, ele vated systolic blood pressure, tremor, and anxiety. Patients with Graves! disease also might exhibit exephthalmas. In cortrast, clderly patients can present with apathetic hyperthyroidism, hich can be confused with hypothyroid'sm. + Hyperthyroidism should be suspected in all patients who pre sent with arial ibrilaton, palpitations, panic disorder, or unex plained tremors Thyroid storm is an acute, lfethreatening condition usually ‘occurring in patients with undiagnosed or untreated hyperthy- reidism placed under physiologic stress. + An elevated free Ty, usually with a low thyroid-stimulating hormone is the hallmark of hyperthyroidism, and ant= thyroid-stimulating hormene antibadies can help identify Graves’ disease + Ultimately, 2 thyroid scan and uptake are usualy necessary to differentiate the cause of hyperthyroidism, + Inpatients with Graves" disease or autonomous thyroid nodules (foric nodular goiter), shorsterm treatment includes thyroid Suppression medications (such as methimazole [Tapazole]) and Bblockers (such as propranolol Inderal}. Long-terrn man agement with radioiodine thyroid gland ablation ts offen pur sued once symptoms are controlles + Patients with acute thyroiditis might need transient ¢-blockade but can often be managed expectantly until symptoms abate and thyroid hormone levels normalize. A small number of patients (~10%) have persistent hypothyroidism following an epizode of illness, + Thyroid storm is a medical emergency that requires close mon: itoring slong with an antithyroid drug, g-blockers, corticoste raids, and iodine-patassium solution (Lugol's solution). Tho DR a Epidemiology Hyperthyroidism is relatively uncommon and usually caused by three conditions: Graves’ disease, toxic nodular goiter, or acute thyroiditis, Graves" disease is the most common cause Of bypecthyroidism in the United States and usually affects younger patients from the teens to the 40s. Like other autoime mune diseases, women are at higher risk (seven to eight times) chan men. Toxic nodular goiter accounts for 15% to 30% of hyperthyroid diagnoses. It usually occurs after age 50 years, is more common in women, and follows several decades of ‘multinodular thyroid disease” A less-common cause is adminis- tration of amiodarone. Amiodarone is about one third iodine and can cause hyperthyroidism either through iodine-induced hyroid damage or from inereased thyroxine synthesis owing Hyperthyroidism m11 Endocrine and Metabolic Disorders ™ SET Graves! disease Autonomous thyreid nodule (toxic nodular goiter) Acute thyroiditis Hashimoto's thyroiditis + Subacute granulomatous thyroiditis (de Quervain’s thyroiditis) + Subacute ymphooytic thyroiditis (elent or painless thyroiditis) + Suppuratve thyroiditis (bacterial infection of thyroid) Excessive exogenous thyroid use + Over-replacerment after thyroid ablation or for hypothyroidism + Thyroxine (Synthroid) abuse for weightloss lodine everconsumption Amniodarone administration Risk Factors ‘There ate no known enviconmenal or reversible risk factors for any of the causes of hyperthyroidism. Graves’ disease is asso ciated with a specific human leukocyte antigen (LILA) region on chromosome 6 (CTLA 4). Pathophysiology ‘The most common causes of hyperthyroidism are shown in Box 1 Graves’ disease is an autoimmune disorder caused by antibodies against thyvoid-stimulating hormone (TSH) receptors on the thyroid gland. Graves’ disease is associated with many other auto {immune diseases, including pernicious anemia, vitigo, type 1 dis- betes melitus, autoimmune adrenal disease, Sjogren's syndrome, sheumatoid arthritis, and lupus. As with these other disorders, the etiology is unknown “Toxic nodular goiter, also known as Plummer's disease, results from the development of autonomous thyroid adenoma, Patients who develop a toxic nodular goiter usually have a long history of any other nodules that spontaneously burn out overtime, ut then develop a single large nodile (usually 25 em or greater) that continues to produce thyroid hormone in such large quantities that patients become hyperthyroid. No clear cause is known for the evelopment of the nodules. ‘Acute thyroiditis can also produce hyperthyroidism. Several diferent conditions can cause thyroiditis (ze Box 1), The inflam sation resulting in thyroiditis is thought to be related co subacute viral infections or autoimmune reactions; suppurative thyroiditis isa rare bacterial thyroid infection, usualy caused by Staphylococ cus aureus, During the acute period of thyroid inflammation, dam- age to the gland leads to the release of stored thyroxine from ‘hyroid lakes, producing hyperthyroidism. However, tial release of thyroid hormone fom the stored lakes, da the gland inhibits production of new thyroxine. After the inital surge in thyroid hormone levels, thyroxine levels drop, often to levels that ean resul in transient hypothyroidism. Most patients return to the euthyroid state after the thyroid gland heals, but about 10% of patients with acute thyroiditis remain chronically hypothyroid Other less common causes of hyperthyroidism include excessive exogenous administration of thyroid medications. This is most commonly the result of over-replacement of thyroxine (Levoxyl, Synthroid) in patients with hypotayroidism, but it may be inten tional for weight loss. Because thyroxine and triiodothyronine "T,} are highly protein bound, overzeplacement is most common If patients experience hypoproteinemia, such as in nephrotic syndrome, cisthoss, or malnutrition Excessive iodine consumption can also lead to thyrotoxicosis. Prevention ‘There are no known strategies to prevent hyperthyroidism. For patients with hypothyroidism, annual monitoring of TSH levels fs recommended to ensure that patients receive the appropriate replacement dose and not overreplacement. Clinical Manifestations Patients with hyperthyroidism complain ofa variety of symptoms that can include anxiety, tachycardia, wide-pulse pressure hyper- tension, palpitations, fine tremor, weight loss, heat intolerance, and, particularly in the elderly, confusion or delirium. Patients with Graves” disease also have ophthalmopathy characterized by lid retraction and exophthalmoses that can lead to optic nerve damage. In contrast, older patients can have few of the classic signs of hyperthyroidism and instead might complain of fatigue or weakness {apathetic hyperthyroidism), unexplained delirium, weight loss, heart failure, or isolated azial fibrillation. ‘Some patients have a rapid escalation of symptom severity (thy roid storm) that is life-threatening if not identified and treated promptly. These patients usually have underlying thyrotoxicosis from Graves’ disease complicated by a secondary physiologic stressor such as infection, surgery, or tauma. This is a medical emergency and needs immediate attention, including hospitaliea- tion with close observation, ‘On physical examination, patients with hyperthyroidism due to Graves’ disease or thyroiditis might have a diffusely enlarged and mildly tender thyroid gland. In suppurative thyroiditis, the thyroid sland is red, hot, and very tender and accompanied by a fever and ‘ther systemic signe of severe infection. Patients with toxic nodu- lar goiter can have palpable nodules in their thyroid gland and often have a single palpable nodule Diagnosis Hyperthyroidism is diagnosed by finding an elevation in the free thyroxine (T,) level accompanied by a low TSH level. Patients with Graves” disease often have positive anti-thyroid receptor antibody titers. Only anti-thycoglobulin receptor antibody testing i helpful because it can help differentiate Graves’ disease from other causes. No other anti-thyroid tests are clinically indicated. ‘Once the thyroid level abnormalities are found, a definitive diagnosis ofthe cause for the hyperthyroidism is needed to select, the appropriate treatment strategy ‘Other conditions can produce a depressed TSH but normal free Tz levels. These include T, toxicosis and subelinical hyperthyr0i sm. T toxicosis refers to situations where triiodothyronine (Ts) i= produced in excess rather than thyroxine (Ty); this can occur in any of the conditions that can cause hyperthyroidism as well as in surreptitious triiodothyronine (Cytomel) ingestion. ‘Thyroid scanning and radiolabel uptake are usually necessary to differentiate the causes of hyperthyroidism. Thyroid scanning and ‘uptake rely on the thyroid gland to concentrate radioactive mole- eiles, such as iodine-131 ('1) or technetium. Because ofthe risk fof thyroid storm with iodine administration, patients should be treated with antithyroid drugs for 2 to 8 weeks before a scan and the druge should he stopped at least 4 days before the test. Parients with Graves’ disease show increases in uprake and diffuse distribution of the tracer throughout the thyroid gland. Patients with toxic nodular goiter also have incteased uptake, but the iso- tope is concentrated in a one or a few focal areas, with the remain dder of the thyroid gland suppressed. In contrast, patients with thyroiditis have decreased uptake of the radiolabel and a washed-out or mottied distribution on scanning. Differential Diagnosis Symptoms of hyperthyroidism also occurin patients with pane dis- corder and other anxiety conditions. These patents can have snus tachycardia, tremor, and nervousness that mimic hyperthyroidism. Treatment Treatment depends on the cause of the hyperthyroidism (Table 1) In Graver’ disease immediate goals of treatment include reducing thyroid hormone production and blocking the peripheral effects of the excessive thyroid hormone. About 30% to 60% of patients mostly adolescents, enter remission spontaneously, and the remis" sion may be permanent, Remission rates are highest for those with 4 small goiter, no ophthalmopathy, thyroglobulin levels less than