class: center, middle, inverse, title-slide .title[ # Hyperparathyroidism (Hypercalcemia) ] .subtitle[ ## 副甲狀腺高能症（高血鈣） ] .author[ ### 盧子文醫師 <br>.lk[(<a href="tel:073121101#7376">簡碼:7376; </a><a href="tel:46-05211">GSM: 46-05211</a>)] ] .institute[ ### 高醫附設中和紀念醫院<br>.lk[<a href="mailto:highker@gap.kmu.edu.tw" class="email">highker@gap.kmu.edu.tw</a>] ] .date[ ### 2024/06/04 (updated: 2024-06-17) ] --- ### 學習目標 .e3[ 1. 瞭解鈣離子在體內的正常代謝並能進一步解釋高血鈣的致病機轉。 2. 高血鈣疾病的鑑別診斷以及鑑別診斷的方法 3. 高血鈣的緊急處理以及治療方法 ] ###學習資源 .e3[ 1. Harrison’s Principle of Internal Medicine, 21th ed 2. 台灣內分泌學會-副甲狀腺新知專刊 3. Williams Textbook of Endocrinology - 14th Edition 4. UpToDate- Primary hyperparathyroidism 5. UpToDate- hypercalcemia 6. Guyton and Hall textbook of medical physiology 11e ] --- class: center, middle #Calcium Metabolism --- ## Calcium Distribution .e3[ - Total 1 to 2 Kg of Ca in adult human body: 1. ~ 99% in the skeleton → hydroxyapatite 2. 0.1~0.15% in ECF (extracellular fluid) 3. 0.6% in ICF (intracellular fluid) - In blood, total Ca is 8.5 to 10.5 mg/dl: 1. 50% is ionized (iCa). 2. 41% bind to proteins (predominantly albumin) 3. ~9% bind to Phosphate, citrate, sulfate, etc. ] --- background-image: url(data:image/png;base64,#./ca01.png) background-position: 50% 50% background-size: 95% .footnote[ https://slideplayer.com/slide/5882552/ ] --- ## Calcium Homeostasis .e3[ - Serum protein concentrations affect measured TCa concentrations: → Adjust TCa (mg/dL) upward by 0.8 times the deficit in serum albumin (g/dL): Corrected Ca=﹝Ca﹞+﹛0.8x﹙4.0-﹝albumin﹞﹚﹜ - The concentration of ionized calcium in the ECF must be maintained within a narrow range because of the critical role calcium plays in a wide array of cellular functions. ] --- background-image: url(data:image/png;base64,#./ca02.png) background-position: 50% 50% background-size: 65% --- ### Calcium Homeostasis-Intestine .e3[ - Intestinal absorption of ingested Ca: 1. Passive (paracellular) mechanism: → 5% of daily Ca intake 2. Active (transcellular) mechanism: → 20% ~ 70%, controlled by `\(1,25(OH)_2D\)` - Locations of active Ca transport: → Mainly in duodenum and proximal jejunum - Gastric acid required for good Ca absorption ] --- ### Calcium Homeostasis-Kidney .e3[ - Renal excretion of absorbed Ca: 1. 8-10 g/d filtered by glomeruli, 2-3% in urine 2. 65% reabsorbed in proximal convoluted tubules.red[ (PCT), coupled to NaCl reabsorption] 3. 20% in thick ascending limb of Henle’s loop 1) Need paracellin-1 (a tight junctional protein) 2) Inhibited by ↑[Ca] or [Mg], via CaSR 4. ~10% in DCT: with calbindin-D28k, `\(Ca^{2+}\)` - ATPases and `\(Na^+/Ca^{2+}\)` exchangers by PTH ] --- background-image: url(data:image/png;base64,#./ca17.png) background-position: 50% 50% background-size: 85% --- ###Calcium Homeostasis-Bone .e3[ - Total skeletal Ca contents change slowly, contrast with relatively high daily rate of Ca fluxes into and out of bone (250~500mg), a process mediated by osteoblast & osteoclast - Sustained Ca intake <200 mg/d → ↑PTH and `\(1,25(OH)_2D\)` → activate osteoclastic bone resorption → bone loss↑ → negative Ca balance - Very high Ca intake >4g/d → downregulate intestine active transport, renal reabsorption ] --- class: center, middle #Calcium related hormone ### Parathyroid Hormone (PTH) ### Parathyroid Hormone-Related Protein (PTHrp) ### Calcitonin ### Vitamin D --- ## Parathyroid Hormone (PTH) .e3[ - Secreted by parathyroid Chief cell - PreproPTH (115 Amino acids) → ProPTH (90 A.a.) → PTH (84-amino-acid single-chain peptide) - Biologically active: amino-terminal portion PTH (1–34) - Extensively metabolized by liver (70%) and kidney (20%) - Half-life in blood: 2 minutes - The primary function of PTH is to maintain the extracellular fluid (ECF) calcium concentration within a narrow normal range. ] --- ## Parathyroid Hormone (PTH) .e3[ Site of action: 1. .red[directly] on kidney and bone - Kidney: (1) inhibit P transport .red[in PCT]. (2) ↑Ca reabsorption in DCT. (3) stimulate 25(OH)D-1α-hydroxylase to enhance the synthesis of 1,25-dihydroxyvitamin `\(D(1,25[OH]_2D)\)` .red[in PCT]. - Bone: (1)continued exposure→ .red[bone resorption] (2)intermittent(1~2h/d) → .red[bone formation] 2. .red[indirectly] on intestine (via 1,25(OH)2D) ] --- background-image: url(data:image/png;base64,#./ca03.png) background-position: 50% 60% background-size: 95% ## Bone Remodeling --- background-image: url(data:image/png;base64,#./ca0402.png) background-position: 80% 80% background-size: 40% ## Parathyroid Hormone (PTH) .e3[ - Bone remodeling: - .y[Osteoblast]: PTH receptors (+), crucial to bone-forming effect of PTH - .y[Osteoclast]: PTH receptors (-), PTH-mediated stimulation of osteoclast act via cytokines from osteoblast ] <div id="htmlwidget-0d4ad7261306e1189455" style="width:45%;height:100%;" class="pixfigure html-widget"></div> <script type="application/json" data-for="htmlwidget-0d4ad7261306e1189455">{"x":{"path":["assets/415bccc43dcbd12eb185b0ea8c80158e.png"],"caption":[],"h":"auto","w":"100%","fit":"cover","position":"center"},"evals":[],"jsHooks":[]}</script> --- ## Parathyroid Hormone-Related Protein (PTHrp) .e3[ - Many different cell types produce PTHrp: ①brain ②pancreas ③heart ④lung ⑤mammary tissue ⑥placenta ⑦endothelial cell ⑧smooth m. - PTH and PTHrp, distinctive products of different genes, exhibit considerable homology - PTH/PTHrp receptor (500 A.a., also known as PTH-1 receptor, PTH1R) respond equally to PTH and PTHrp, while PTH2R respond only to PTH. ] --- background-image: url(data:image/png;base64,#./ca05.png) background-position: 50% 50% background-size: 95% ### Similarities and Differences in Structures of PTH and PTHrp --- ## Calcitonin .e3[ - Hypocalcemic hormone, antagonist to PTH - Medical significance: as tumor marker in MTC and as an adjunctive Tx in severe hyperCa - .red[Inhibit osteoclast-mediated bone resorption] (mainly) and .red[stimulate renal Ca clearance ] - Induce analgesic effects on hypothalamic cell by receptors for calcitonin gene-related peptide (CGRP) or amylin - Major source of calcitonin: the thyroid (parafollicular cells or C cells) ] --- background-image: url(data:image/png;base64,#./ca072.png) background-position: 95% 60% background-size: 50% ## Vitamin D .pull-left[ - Vitamin D must first be converted through a succession of reactions in the liver and the kidneys to the final active product, 1,25-dihydroxycholecalciferol, also called `\(1,25(OH)_2D_3\)` . - Cholecalciferol (Vitamin D3) Is Formed in the Skin. - Cholecalciferol Is Converted to 25-Hydroxycholecalciferol in the Liver. - Formation of 1,25-Dihydroxycholecalciferol in the Kidneys and Its Control by Parathyroid Hormone. - Calcium Ion Concentration Controls the Formation of 1,25-Dihydroxycholecalciferol. ] --- background-image: url(data:image/png;base64,#./ca07.png) background-position: 50% 60% background-size: 80% --- background-image: url(data:image/png;base64,#./ca06.png) background-position: 90% 70% background-size: 45% ### Summary of Effects of Parathyroid Hormone and Vitamin D .pull-left[ - (1) PTH stimulates bone resorption, causing release of calcium into the extracellular fluid; - (2) PTH increases calcium reabsorption and decreases phosphate reabsorption by the renal tubules, leading to decreased excretion of calcium and increased excretion of phosphate; - (3) PTH is necessary for conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol, which, in turn, increases calcium absorption by the intestines. ] --- class: center, middle # Hypercalcemia --- ## Hypercalcemia .e3[ - .red[Primary hyperparathyroidism and malignancy-associated hypercalcemia] are the most common causes (>90%). - Asymptomatic, mild hypercalcemia (11 mg/dL) is usually due to primary hyperparathyroidism - Hypercalcemia of malignancy is usually acute, symptomatic and severe (14 mg/dL) - Hypophosphatemia suggests elevated PTH or PTHrp ] --- ## Hypercalcemia .e3[ - Symptoms and signs (S/S): 1. Usually occur if TCa >12mg/dL and more severe in acute hypercalcemia 2. fatigue, depression, mental confusion, anorexia, nausea, vomiting, constipation, reversible renal tubular defects, polyuria, short QT interval, arrhythmia 3. Stupor, coma, azotemia, and cardiac arrest may develop in severe hypercalcemia (TCa=15~18mg/dL) - “painful bones, renal stones, abdominal groans, and psychic moans” ] --- background-image: url(data:image/png;base64,#./ca08.png) background-position: 50% 50% background-size: 55% --- ### Parathyroid-Dependent Hypercalcemia .e3[ - primary hyperparathyroidism - Tertiary hyperparathyroidism - familial hypocalciuric hypercalcemia(FHH) - lithium-induced hypercalcemia. ] ### Parathyroid-Independent Hypercalcemia .e3[ - In parathyroid-independent hypercalcemia, PTH secretion is appropriately suppressed. - PTH levels are invariably lower than 25 pg/mL(usually lower than normal or undetectable.) - Most affected patients have malignant hypercalcemia ] --- ### Diagnostic studies .e2[ - Hyperparathyroidism (HPT) and malignancy account for 90% of cases of ↑ Ca; - HPT more likely if asymptomatic or chronic; malignancy (usually overt) more likely if acute or symptomatic. - Check iCa, PTH, PO4: - ↑ or high normal PTH: Ca/Cr clearance ratio <0.01 → FHH - ↓ PTH: check PTHrP, ALP, & search for malignancy and vit D: ↑ 25-(OH)D ] --- ## Primary Hyperparathyroidism .e3[ - PTH ↑ → Ca↑, P↓. Great variation in S/S. - Asymptomatic hyperparathyroidism (80%) is the milder form. Hypercalcemic parathyroid crisis (with dehydration and coma) is rare. - Involve mainly the kidney & skeletal system: 1. Nephrolithiasis → urinary tract obstruction and infection → loss of renal function 2. Osteitis fibrosa cystica (subperiosteal resorption): very rare due to early detection ] --- background-image: url(data:image/png;base64,#./ca18.jpg) background-position: 50% 50% background-size: 55% --- ## Primary Hyperparathyroidism .e3[ - Neuromuscular S/S: proximal muscle weakness, easy fatigability, muscle atrophy - Gastrointestinal S/S: vague abdominal complaints, duodenal ulcer (In MEN1, may due to pancreatic tumors secreting excessive gastrin → Zollinger-Ellison syndrome) - Etiology: 85% solitary adenoma (mostly inferior glands), 15% hyperplasia, 1% carcinoma - MEN 1 & MEN 2A ] --- background-image: url(data:image/png;base64,#./ca11.png) background-position: 55% 90% background-size: 65% ### Diagnosis: PTH ↑, sereum Ca↑, serum P↓ ### Localization: Ultrasound, `\(^{99m}Tc\)` MIBI scan, MRI --- background-image: url(data:image/png;base64,#./ca09.png) background-position: 60% 90% background-size: 60% ### Treatment of asymptomatic Primary Hyperparathyroidism .e3[ - Surgery（下表任一條件） - If surgery declined/deferred, can treat with .red[cinacalcet(擬鈣劑)] (↓ Ca & PTH but may not ↑ BMD) ] --- background-image: url(data:image/png;base64,#./ca10.png) background-position: 50% 60% background-size: 80% ### Guidelines for Monitoring Asymptomatic Primary Hyperparathyroidism --- ## Other Parathyroid-Related Cause of Hypercalcemia .e3[ - Lithium therapy: 1. 10% patients treated for bipolar 2. Remitting when lithium is stopped 3. Higher [Ca] required to lower PTH - Familial hypocalciuric hypercalcemia (FHH): .red[CaSR] mutation => Secretion of PTH ↑, renal Ca reabsorption ↑ - Jansen’s disease: Excessive biologic activity of the PTH receptor in target tissues due to PTH1R mutation ] --- ### Malignancy-Related Hypercalcemia .e3[ - Mechanisms of hypercalcemia in malignancy: (as many as 20% of cancer patients) (The etiologic mechanisms may be multiple) 1. .red[PTHrp] responsible for .red[humoral hypercalcemia of malignancy (HHM)]: squamous cell carcinoma of lung and renal tumors 2. .red[Osteoclast activation factor] (__interleukin 1 and lymphotoxin or tumor necrosis factor__): local bone destruction in .ud[leukemia, lymphoma, multiple myeloma] 3. Increased `\(1,25(OH)_2D\)` in blood produced by lymphocytes in B cell lymphomas ] --- ### Vitamin D-Related Hypercalcemia .e3[ - Vitamin D Intoxication: 1. `\(1,25(OH)_2D\)` ↑ 2. Responsive to glucocorticoids Sarcoidosis and Other Granulomatous Diseases (ex: tuberculosis, fungal infection): - Macrophage from granulomatous tissue convert `\(25(OH)D\)` to `\(1,25(OH)_2D\)` - Idiopathic Hypercalcemia of Infancy: 1. Usually referred to as William’s syndrome 2. Aortic stenosis, mental retard, elfin facies ] --- ### Hypercalcemia Associated with High Bone Turnover .e3[ - Hyperthyroidism (20%): → Bone resorption > bone formation - Immobilization: → Rare cause of hypercalcemia - Thiazides: → enhanced .red[proximal] tubular reabsorption of Ca in response to Na depletion of .red[distal] tubule - Vitamin A Intoxication: → ingestion of 50,000~100,000 Unit/D of VitA ] --- ### Hypercalcemia Associated with Renal Failure .e3[ - Severe Secondary Hyperparathyroidism: - Bone pain, ectopic calcification, pruritus - Renal osteodystrophy (osteitis fibrosa cystica) due to excessive PTH action on bone, and .red[osteomalacia related to the circulating levels of FGF23] (inhibiting renal 1-alpha hydroxylase, causing reduction in `\(1,25(OH)_2\)` vitamin D ) - Aluminum Intoxication - “Aplastic” or “adynamic” bone disease - Milk-Alkali Syndrome: - excessive ingestion of Ca ] --- background-image: url(data:image/png;base64,#./ca13.png) background-position: 50% 70% background-size: 80% ### Algorithm for the evaluation of patients with hypercalcemia --- background-image: url(data:image/png;base64,#./ca12.png) background-position: 50% 70% background-size: 80% --- background-image: url(data:image/png;base64,#./ca14.png) background-position: 50% 50% background-size: 95% --- background-image: url(data:image/png;base64,#./ca15.png) background-position: 50% 75% background-size: 85% ### Therapies for Hypercalcemia: Acute management --- ### Therapies for Hypercalcemia: Chronic management .e3[ - For primary hyperparathyroidism: - Avoid thiazide diuretics and extremes of Ca intake (neither too high nor too restrictive) - Estrogen replacement therapy or raloxifene: postmenopausal women - Oral bisphosphonates - For malignant hypercalcemia: - IV bisphosphonates, prednisone, oral phosphate use until anti-cancer Tx takes effect - .red[Denosumab: monoclonal Ab that binds to receptor activator of nuclear factor-κB (RANKL) and prevents it from binding to the receptor RANK on osteoclast precursors and mature osteoclasts] ] --- background-image: url(data:image/png;base64,#./ca16.png) background-position: 50% 50% background-size: 95% --- ## Summary .e3[ - Calcium homeostasis: the role of kidney, bone, intestine, and parathyroid - The most common cause of hypercalcemia and other related differential diagnosis - Treatment guideline of asymptomatic hyperparathyroidism - Mechanisms of malignancy-related hypercalcemia - Therapy for hypercalcemia ] --- class: center, middle # 國考題 --- background-color: #ECF5FF ### 52.下列有關原發性副甲狀腺高能症(primary hyperparathyroidism)的敘述，何者錯誤? .b3[ - A.副甲狀腺瘤造成之副甲狀腺高能症，此時副甲狀腺之腫瘤多半是單一腺瘤(isolated adenoma) - B.副甲狀腺瘤可能是多發性內分泌腫瘤(multiple endocrine neoplasia)的一種臨床表現 - C.常表現高血鈣、高血磷及低血氯 - D.血鈣濃度高於14 mg/dL(3.5 mmol/L)時，病理學報告經常是副甲狀腺癌 ] .e3[ ANS：C ] .footnote[112年第二次專門職業及技術人員高等考試 醫學(三) ] --- .b2[ - C: patients with hyperparathyroidism frequently had .red[phosphate levels in the low normal range (less than 3 mg/100 ml) and chloride levels in the high normal range (greater than 102 mEq/L) 高血鈣、低血磷、高血氯] - D: A potential clue to the diagnosis is offered by the degree of calcium elevation. Calcium values of 3.5–3.7 mmol/L (14–15 mg/dL) are frequent with carcinoma and may alert the surgeon to remove the abnormal gland with care to avoid capsular rupture. ] --- background-color: #ECF5FF ### 10.高血鈣急症的治療原則下列那一項最不適當? .b2[ - A.立即補充生理食鹽水 - B.使用thiazide類利尿劑 - C.惡性腫瘤引發高血鈣可以考慮給予雙磷酸鹽(bisphosphonates) - D.維生素D造成的高血鈣症可以考慮使用類固醇治療 ] .footnote[107年第二次專門職業及技術人員高等考試 醫學(三) ] .e3[ ANS：B ] --- background-image: url(data:image/png;base64,#./hyperca2.png) background-position: 50% 50% background-size: 95% --- background-color: #ECF5FF ### 53.實體腫瘤(solid tumor)引起之高血鈣症，最常因腫瘤分泌下列何者而引起? .b2[ - A.副甲狀腺素(parathyroid hormone) - B.噬骨細胞活化因子(osteoclast activating factor, OAF) - C.副甲狀腺素相關胜肽(parathyroid hormone-related peptide, PTHrP) - D.1,25(OH)2 D ] .footnote[110年第二次專門職業及技術人員高等考試 醫學(三) ] .e3[ ANS：C ] --- class: center, middle # Thanks for your attention! Slides created via the R package [**xaringan**](https://github.com/yihui/xaringan).