Paratyroid Disease

PARATHYROİD DISEASE Prof.Dr.Yusuf Bükey

Anatomy

Anatomy

Anatomy / Embryology

Parathyroid Anatomy and Histopathology: The Normal Parathyroid Gland  

Supernumerary fifth parathyroid found between 0.7%-5.8% patients 5th glands found in the mediastinum (thymus or related to the aortic arch), thyrothymic tract

PATHOLOGY  HYPERPARATHYROIDISM 

1 : 1,000 prevalence

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F:M 2:1

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Usually mild / asymptomatic

Histopathology of the Parathyroid Glands   

Parathyroid gland composed of chief cells, oxyphilic cells and intermediate cells Solitary parathyroid adenoma ~80%-85% of patients with primary hyperparathyroidism Variations in parathyroid adenoma includes other subtypes (oncocytic adenoma, lipoadenoma, large clear cell adenoma, water-clear cell adenoma, and atypical adenoma).

Ob P1- parathyroid glands and the physiology of calcium hemostasis.

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Synthesize and secret parathyroid hormone, which along with vitamin D maintains calcium hemostasis.

Calcium

Bone resorption, urine phosphorus

PTH

Renal resorption

Parathyroids

Ca++ PTH

-

1,25D Kidney

↑

or b s b a Ca r e

1,25D

GI tract

Ca++

Bone

Calcium Metabolism     

Intestine Bone kidney (2.1-2.6 mmol/l) 97% of reservoir in bone, chronic regulation. Kidney involved in minute to minute flux.Filters 8000mg daily. Net intestinal absorption is 200mg daily.. If long term calcium losses exceed net calcium absorption the deficit is resorbed from bone leading to demineralisation.

Calcium Metabolism - PTH  Parathyroid Hormone (PTH), 84 AA

structure. Secreted from parathyroid gland in response to hypocalcemia.  Amino terminal (1-34 AA) contains the biological activity.  PTH acts on receptors in target tissues leading to stimulation of adenylaye cyclase activity.

Calcium Metabolism- Vitamin D 

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Vitamin D formed in skin(D3 or cholecalciferol) by uv light. Major source of vitamin D (90%). Also present in diet. This is the inert form Hydroxylated in the liver to 25-OH-VitD. Renal hydroxylation to 1,25 dihydroxy vitamin D (very active metabolite). Renal also produces 24,25 dihydroxy vit D. (inactive) Calcium deficiency leads to 1,25 Dit D production 1,25 vit D acts on small intestine to increase calcium absorption. Also acts on bone to cause resorption.

Effects of PTH  Increases calcium reabsorption by the

kidney.  Decreases phosphate reabsorption by the kidney.  Increases osteoclastic bone resorption.

Three forms of calcium in serum  Ionised (physiological form).  Protein-bound (50%), mainly to albumin  Complexed to citrate and phosphate(1-

2%).

Causes of Hypercalcaemia   

COMMON (97%) of all cases Primary Hyperparathyroidism Malignancy

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LESS COMMON Familial benign hypercalcaemia (FBH) Sarcoidosis Thyrotoxicosis Vitamin D poisoning Acute renal failure

Causes of Hypercalcemia-RARE        

Immobilisation VIPomas Tuberculosis Milk-alkali syndrome Addison’s Disease Lithium Thiazide diuretics Parenteral feeding

List the causes, symptoms, and signs of hypercalcemia.

 Stones 

Nephrolithiasis

 Bones 

Painful resorption of bone

 Moans and Psychatric overtones 

Fatigue, depression, confusion

 Abdominal groans 

Peptic ulcer and pancreatitis

Symptoms  Tiredness and lethargy  Proximal muscle weakness  Polyuria,

nocturia and thirst  Nausea Vomiting and constipation  Depression, psychosis and impaired consciousness.

SIGNS AND SYMPTOMS OF HYPERCALCEMIA CNS Lethargy, drowsiness Depression Psychosis Stupor, coma

Neuromuscular Weakness Proximal muscle weakness Hypotonia

SIGNS AND SYMPTOMS OF HYPERCALCEMIA 

Cardiovascular 

HTN

Arrhythmia  Short QT Renal 

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

 

Polyuria and polydipsia volume depletion Renal stones Nephrocalcinosis

SIGNS AND SYMPTOMS OF HYPERCALCEMIA 

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Musculoskeletal  Myalgias and arthralgias  Metastatic calcifications − Ca-PO4 product > 70 Bone  Osteitis fibrosis cystica  Osteoporosis  Fracture

SIGNS AND SYMPTOMS OF HYPERCALCEMIA GI tract Constipation Anorexia, N/V Dyspepsia, PUD Pancreatitis

Know the difference between 1°, 2°, 4° hyperparathyroidism.

 Primary Hyperparathyroidism

PTH calcium (normal renal function) 83% parathyroid adenoma, 15% parathyroid hyperplasia, carcinoma is rare 1-2%  Secondary Hyperparathyroidism poor renal function

calcium,

PO4

PTH normal Ca

 Tertiary Hyperparathyroidism

Hyperplastic parathyroids from chronic stimulation continue post renal transplant

Primary HPT  500 cases/million  More common in females  Incidence increases with

age  Autonomous production of PTH  Benign Adenoma  Asymptomatic pick-up.

Hyperparathyroidism in other syndromes (RARE)  

MEN Type 1 (Parathyroid adenoma, Pituitary adenoma, and pancreatic islet cell tumours). MEN Type 2 (Parathyroid adenoma, medullary thyroid carcinoma and phaeochromocytoma)

Discuss ddx of a paitent with hypercalcemia.

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Hyperparathyroidism Malignancy  

    

Hematologic PTHrP producer

Hyperthyroidsm Multiple myeloma Sarcoidosis Milk-alkili syndrome Vit D or A intoxication

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Paget’s disease Immobilization Thiazide diuretics Addisonian Crisis Familial hypocalcuric hypocalcemia Neonatal severe hyperparathyroidism.

HYPERCALCEMIA DIFFERENTIAL DIAGNOSIS       

Primary hyperparathyroidism Hypercalcemia of malignancy Familial hypocalcuric hypercalcemia Granulomatous disease Endocrinopathies Drugs Immobilization

DISEASES ASSOCIATED WITH HYPERCALCEMIA Primary Hyperparathyroidism

111 (54%)

Malignant Disease

72 (35%)

Unknown

12 ( 6%)

Other Causes

12 ( 6%)

TOTAL

207 (100%)

ETIOLOGY OF HYPERCALCEMIA 

Primary hyperparathyroidism     

Most common etiology in outpatients 1 in 500 to 1 in 1000 Most common in 6th decade Women > men, 3:2 ratio Many patients found on routine screening with minimal symptoms

ETIOLOGY OF HYPERCALCEMIA 

Primary hyperparathyroidism 

80% due to solitary adenoma

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4 gland hyperplasia − Association with MEN I and MEN II A

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5% are carcinoma

ETIOLOGY OF HYPERCALCEMIA 

Primary hyperparathyroidism  Labs - ↑ Ca ++, ↓ PO 4 ↑ PTH ↑ urinary calcium excretion

ETIOLOGY OF HYPERCALCEMIA 

Hypercalcemia of malignancy  Humoral hypercalcemia of malignancy – Mediated by PTH-RP – Most often seen in solid tumors  Lung CA - squamous cell, adenocarcinoma, large cell  Breast CA  Squamous cell CA of head and neck or female repro tract  Renal cell CA – Not associated with bone mets – Labs - ↑ Ca ++, ↓ PTH, ↑ PTHrP

ETIOLOGY OF HYPERCALCEMIA 

Hypercalcemia of malignancy  Local osteolytic bone metastasis • Hematologic malignancies multiple myeloma • May be seen with breast CA • Local release of osteoclast activating cytokines • Labs - ↑ Ca ++, ↓ PTH and PTH-rP

ETIOLOGY OF HYPERCALCEMIA 

Familial hypocalcuric hypercalcemia  Autosomal dominant syndrome of asymptomatic hypercalcemia  Must be ruled out before sending patient to surgery for primary HPTH  Due to defect in calcium receptor  Diagnose by measuring calcium/creatinine clearance (CaU/CrU X CrS/CaS) – HPTH > 0.03 – FHH < 0.01

ETIOLOGY OF HYPERCALCEMIA 

Granulomatous disease  Increased formation of 1,25D within granulomas – Sarcoidosis – TB – Eosinophilic granuloma – Histo, cocci, candida – Lymphoma  Hypercalcuria preceeds hypercalcemia  Labs - ↑ Ca ++, ↑ 1,25D, normal 25D ↓ PTH, ↑ ↑ urinary calcium excretion

ETIOLOGY OF HYPERCALCEMIA 

Endocrinopathies  Hyperthyroidism – Direct effect to increase bone resorption  Adrenal insufficiency – Volume contraction vs no glucocorticoids to oppose 1,25D action in gut  Pheochromocytoma – Volume contraction – Changes in PTH set point – Associated with MEN 2A

ETIOLOGY OF HYPERCALCEMIA 

Drugs  Vitamin D or A intoxication  Thiazides - decrease urinary Ca excretion by potentiation of PTH action in kidney  Lithium - increased set point for inhibition of PTH secretion  Milk-alkali syndrome – Associated with use of large doses of calcium carbonate

ETIOLOGY OF HYPERCALCEMIA  Immobilization – Weight bearing is required for normal bone remodelling – Prolonged bedrest results in increased osteoclastic resorption and decreased bone formation – Usually not seen with normal renal function. Renal insufficiency or volume depletion precedes development of hypercalcemia – Labs - ↑ Ca ++, ↓ PTH, normal 25hydroxy and 1,25 dihydroxyvitamin D

Hypercalcemia intact PTH Suppressed

Elevated

Known malignancy

2 25(OH)vitamin D and 1,25(OH) vitamin D

Fractional excretion calcium

Low < 0.01

High > 0.03

Normal to low 25-vit D High 1,25-vit D

Granulomatous disease Familial hypocalcuric Primary or lymphoma hypercalcemia hyperparathyroidism

Normal 25-vit D High 25-vit D and 1,25-vit D and 1,25-vit D

Vitamin D intoxication

Malignancy Endocrine causes Drugs Immobilization

Localization Studies 

Noninvasive preoperative methods 1. 2. 3. 4. 5. 6.

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Invasive preoperative methods 1. 2. 3. 4.

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Ultrasonography Radioiodine or technetium thyroid scan Thallium-technetium scintigraphy Technetium-99m sestamibi scintigraphy Computed tomography scan Magnetic resonance imaging Fine-needle aspiration Selective arteriography or digital subtraction angiography Selective venous sampling for parathyroid hormone assay Arterial injection of selenium-ethionine

Intraoperative Methods 1. 2. 3. 4.

Intraoperative ultrasonography Toluidine blue or methylene blue Urinary adenosine monophosphate Quick parathyroid hormone intraoperative

Sestamibi-Technetium 99m Scintography     

Sestamibi taken up mitochondria of parathyroid cells greater than surrounding parenchyma. Inject 20 to 25 millicuries of technetium-99m sestamibi. Images obtained at 10-15 minutes then 2-3 hours after the injection. Late phase preferable for detecting parathyroid adenomas, as thyroid nodules clear uptake faster than do parathyroid neoplasms. Sensitivity (solitary adenoma) ~100%, Specificity ~90%. False-positive: 1. 2. 3. 4.

Solid thyroid nodules (adenomas) Hurthle cell carcinoma Malignant thyroid lymph node metastases No false-positive with cystic lesions of the thyroid gland

Continued….  Tc-99m

Sestamibi suggested parathyroid adenoma in R inferior pole of thyroid gland.

Primary HPT - Diagnosis  Persistent Hypercalcaemia.  Low serum phosphate.  High normal or elevated PTH

concentration.  24h urinary Calcium excretion  Sestemebi scan

Indications for surgery 

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

Nephrolithiasis, bone disease, and neuromuscular symptoms respond well to surgery. Primary hyperparathyroidism due to adenoma is cured surgically by excision of the adenoma. All four glands must be identified though! Primary hyperparathyriodism due to parathyroid hyperplasia is treated with subtotal parathyroidectomy (3 1/2) or total parathyroidectomy with autotranspantation into the arm.

Surgical indications for asymptomatic hyperparathyroidism 

On initial evaluation  

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Markedly elevated CA Hx of life threatening hypercalcemia (??) Reduced Cr CL. Nephrolithiasis Markedly elevated 24hr U Ca Substantially reduced bone mass

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Following asymptomatic pt  

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Pt becomes symptomatic Ca 1-1.6 mg/100 ml above normal Nephrolithiasis Decline in bone mass Neuro or psych problems Pt desire to fix.

HYPERCALCEMIA TREATMENT 

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Acute treatment for any etiology  Volume repletion with NS to increase Ca++ filtration  Can add lasix (promotes calcium excretion) when volume replete More long term therapy is dependent on the etiology

TREATMENT OF HYPERCALCEMIA GENERAL PRINCIPLES 

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Virtually all patients with severe and symptomatic hypercalcemia will be volume depleted. Volume replacement should be started first. Acute therapy of hypercalcemia is usually effective. Long term therapy is more problematic.

TREATMENTS FOR HYPERCALCEMIA GENERAL SPECIFIC Vol. Expansion (saline) I.V. Pamidronate Diuresis (Lasix) I.V. Zoledronate Mobilization Calcitonin Restrict PO Calcium Gallium nitrate Dialysis Plicamycin Glucocorticoids Phosphate Indomethacin Antitumor Therapy

Surgical Management  2. 3. 4. 5. 6.

7.

Clinical indicators for surgery* Serum calcium is >1.0 mg/dL above the upper limit of normal. Creatinine clearance is reduced >30% for age in the absence of another cause. Twenty-four hour urinary calcium is >400 mg/dL. Patients are younger than 50 years of age. Bone mineral density measurement at the lumbar spine, hip, or distal radius is reduced >2.5 standard deviations (by T score). Patients request surgery, or patients are unsuitable for long-term surveillance. *Consensus conference held by the National Institutes of Health in 2002

Continued…. Adenoma 2. Directed unilateral cervical exploration. 3. Curative in >95% of patients 4. Preoperative localization with technetium-99m sestamibi + IOPTH 

Continued…. MEN 1

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Subtotal vs. total with autotransplantation.

1.



Men 2a1.

2.

100% cure rate with no recurrences whether total parathyroidectomy, subtotal parathyroidectomy, or excision of enlarged glands performed. R/O pheochromocytoma prior to OR trip (hypertensive crisis).

Continued…. 

Non-MEN familial hyperparathyroidism (NMFH). 1.



Subtotal or total (autotransplant) with bilateral cervical thymectomy.

Familial neonatal hyperparathyroidism. 1.

Total (autotransplant) + bilateral transcervical thymectomy

Continued…. Renal failure-induced hyperparathyroidism.

 1.



Subtotal vs. total parathyroidectomy (autotransplant) with or without cryopreservation.

Parathyroid Carcinoma 1.

2.

3.

en bloc resection of the tumor and areas of potential local invasion and/or regional metastasis (ipsilateral central neck contents including the thyroid lobe and tracheoesophageal soft tissues, lymphatics, and resection of soft tissues within the superior anterior mediastinum) RLN, esophageal wall, or strap muscles may require sacrifice if the tumor adheres to them. Not enough data to recommend for or against chemotherapy or RT.

Continued…. MIRP Preoperative administration of technetium 99m sestamibi before operation + intraoperative hand-held gamma probe. Advantages:

 2. 3.    

Improved patient comfort postoperatively. Performance of ambulatory procedures. Reduced cost. Avoidance of general anesthetic.

Disadvantages:

4. 1.

2.

Potential for conversion to bilateral dissection in event of failed exploration. Patient anxiety when conversion needed (general anesthesia).

Familial Benign Hypercalcaemia (FBH).  Familial, AD. Family history important.  Often come to light after failed

parathyroidectomy  Benign. Asymptomatic.  Low urinary calcium excretion.

Primary HPT- treatment  Parathyroidectomy.  Serum calcium should be normal within

24h.  Postoperative hypocalcaemia.  Recurrent laryngeal nerve injury.

TREATMENT 

Hypercalcemia of malignancy  IV Pamidronate – Inhibits osteoclastic bone resorption – Takes 2-4 days to see full effect – Must be given every 30-60 days to prevent recurrence of hypercalcemia  Calcitonin – Inhibits osteoclast action – See an effect within 24 hrs – Effect wears off within 2-3 days due to tachyphalaxis

TREATMENT 

Increased 1-hydroxylation of vitamin D due to granulomatous disease  High dose steroids are effective in sarcoidosis  Questionable whether steroids are effective in other granulomatous diseases

Hypercalcaemia of malignancy  Carcinomas of breast, lung, head and

neck,renal.  Usually squamous carcinomas.  PTHrP increased  PTH normal  Low serum albumin, high ESR, anemia.  Myeloma, local bone resorption.

Sarcoidosis  Small numbers of patients with sarcoidosis

develop hypercalcaemia.  May develop after prolonged sun exposure.  1,25 diOH Vit D high, prodiced by alveolar macrophages. PTH is normal.  Corrected by Steroids

Thyrotoxicosis  Severe thyrotoxicosis  Increased calcium release from bone

(Thyroxine acts on bone)  PTH is normal  Takes 4-6 weeks to resolve with antithyroid treatment  Persistent hypercalcaemia usually means concomitant HPT.

 Band Keratopathy

HYPOCALCEMIA: ETIOLOGIES 

HYPOPARATHYROID STATES:  AUTOIMMUNE  CONGENITAL • DIGEORGE SYNDROME  POSTSURGICAL  SEVERE MAGNESIUM DEFICIENCY  NECK IRRADIATION  INFILTRATIVE • HEMOCHROMATOSIS • SARCOIDOSIS • WILSON’S DISEASE  HUNGRY BONE SYNDROME

HYPOCALCEMIA: ETIOLOGIES 

NONHYPOPARATHYROID STATES  VITAMIN D DEFICIENCY • LACK OF SUNLIGHT EXPOSURE • DIETARY LACK • MALABSORPTION • UPPER GI SURGERY • LIVER DISEASE • RENAL DISEASE • ANTICONVULSANTS • VITAMIN D DEPENDENT RICKETS (1α-HYDROXYLASE DEFICIENCY)

HYPOCALCEMIA: ETIOLOGIES 

NONHYPOPARATHYROID STATES  PARATHYROID HORMONE STATES • PSEUDOHYPOPARATHYROIDISM • SEVERE MAGNESIUM DEFICIENCY  VITAMIN D RESISTANCE  DRUGS • BISPHOSPHONATES • CISPLATINUM • KETACONAZOLE • PENTAMIDINE • FOSCARNET

HYPOCALCEMIA: ETIOLOGIES 

MISCELLANEOUS  ACUTE PANCREATITIS  MASSIVE TUMOR LYSIS  OSTEOBLASTIC METASTASES  PHOSPHATE INFUSION  MULTIPLE CITRATED BLOOD TRANSFUSIONS  ACUTE RHABDOMYOLYSIS  ACUTE SEVERE ILLNESS

MANEFESTATIONS OF HYPOCALCEMIA NEUROLOGIC  PERIPHERAL IRRITABILITY (TETANY) +CHVOSTEK’S AND TROUSSEAU’S SIGNS  CENTRAL IRRITABILITY (SEIZURES)  INTRACRANIAL CALCIFICATIONS (BASAL GANGLIA)  PAPILLEDEMA  MENTAL CHANGES  CATARACTS  ABNORMAL DENTITION  CARDIOVASCULAR  PROLONGED Q-T INTERVAL  CHF, DIGITALIS RESISTANCE 

HYPOCALCEMIA: SIGNS

TREATMENT OF HYPOCALCEMIA 

ACUTE HYPOCALCEMIA  ASX PATIENT WITH MILD HYPOCALCEMIA (7.5-8.5 MG/DL): WATCH; MAY USE ORAL CALCIUM (500 TO 1000 MG PER DAY ELEMENTAL CALCIUM)  PATIENT WITH TETANY MUST TREAT WITH PARENTERAL CALCIUM  PATIENT WITH SERUM CALCIUM < 7.5 OR WITH SX’S, TREAT WITH PARENTERAL CALCIUM  USE CALCIUM GLUCONATE (90 MG/ 100 ML) • 1 TO 2 AMPULES IN 50 TO 100 ML OF 5% DEXTROSE (180 MG ELEMENTAL CALCIUM) OVER 5 TO 10 MIN • FOLLOW WITH 15 TO 20 MG/KG ELEMENTAL CALCIUM OVER 4 TO 6 HR • WILL RAISE SERUM CALCIUM BY 2-3 MG/DL • IF HYPOCALCEMIA IS LIKELY TO PERSIST, INITIATE ORAL CALCIUM (1-2 GM PER DAY) WITH CALCITRIOL (O.5-1.0 µg/day)  MONITOR SERUM MAGNESIUM AND REPLACE IF NECESSARY

TREATMENT OF HYPOCALCEMIA 

CHRONIC HYPOCALCEMIA  START SUPPLEMENTAL ORAL CALCIUM (1-2 GM PER DAY) AND A VITAMIN D PREPARATION (ERGOCALCIFEROL 50,000 UNITS ONCE PER WEEK TO DAILY; OR ROCALTROL 0.5-1.0 ΜICROGRAMS PER DAY)  MAINTAIN SERUM CALCIUM IN THE LOW NORMAL RANGE BECAUSE OF THE RISK OF HYPERCALCIURIA AND NEPHROLITHIASIS

Complications of parathyroid surgery.  Hypocalcemia  Persistent hypercalcemia  Recurrent laryngeal nerve injury