Parathyroid Disorders PDF - College of Medicine, Jeddah, Oct 2024

# Parathyroid Disorders ## College of Medicine, Jeddah, KSAU-HS Dr Salwa Alaidarous Oct 2024 comj.ksau-hs.edu.sa ## Objectives By the end of the lecture, the student should be able to: - Describe the symptoms and signs of Hypo/hypercalcemia - List the causes of hypo/hypercalcemia - List and inte...

# Parathyroid Disorders ## College of Medicine, Jeddah, KSAU-HS Dr Salwa Alaidarous Oct 2024 comj.ksau-hs.edu.sa ## Objectives By the end of the lecture, the student should be able to: - Describe the symptoms and signs of Hypo/hypercalcemia - List the causes of hypo/hypercalcemia - List and interpret the laboratory findings in hypo/hyperparathyroidism and vitamin D deficiency - Discuss the management plan in a patient diagnosed with hypo/hyperparathyroidism or vitamin D deficiency ## Parathyroid Gland - Four tiny glands located in the posterior surface of the thyroid gland. - Small in size (grain of rice) 30-50 mg in weight, 3-4 millimeters - 12-15% of normal persons have a 5th gland - It produces parathyroid hormone PTH ## Parathyroid Hormone (PTH) - PTH 1-84 has a plasma half-life of 2-4 minutes - PTH modulates calcium homeostasis - The major target end organs for PTH action are the kidneys, skeletal system, and intestine. ## PTH Homeostasis A diagram shows a system with the following: - Plasma Ca++ - PTH - Bone - Kidney - Intestinal CaHPO₄ absorption. Effect of PTH on calcium and phosphate metabolism. The net effect is an increase in the plasma calcium concentration with no change or a decrease in the plasma phosphate concentration. PTH: parathyroid hormone; Ca²⁺: calcium ion; CaHPO₄: dicalcium phosphate. ## Normal Calcium Levels | Type | Range | |---|---| | Serum Total Calcium | 8.5 and 10.5 mg/dL (2.12 to 2.62 mmol/L) | | Ionized Calcium | 4.65 to 5.25 mg/dL (1.16 to 1.31 mmol/L) | ## Hypocalcemia ### Definition Serum Ca < 2.12 mmol/l (8.5 mg/dl) ### Mild 1.9 -2.12 mmol/l Asymptomatic ### Severe < 1.9 mmol/l Symptomatic Patients in whom the onset of hypocalcemia is gradual tend to have fewer symptoms ## Etiology of Hypocalcemia ### Low PTH (hypoparathyroidism) - Genetic disorders - Abnormal parathyroid gland development - Abnormal PTH synthesis - Activating mutations of calcium-sensing receptor (Autosomal dominant hypocalcemia or sporadic isolated hypoparathyroidism) - Postsurgical (thyroidectomy, parathyroidectomy radical neck dissection) 75% - Autoimmune - Autoimmune polyglandular syndrome (associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency) - Isolated hypoparathyroidism due to activating antibodies to calcium-sensing receptor - Infiltration of the parathyroid gland (granulomatous, iron overload, metastases) - Radiation-induced destruction parathyroid glands - Hungry bone syndrome (post-parathyroidectomy) - HIV infection ## Etiology of Hypoparathyroidism - Post surgical (75%) - Medical (25%) - Autoimmune disease (the second most common etiology) isolated or as part of APS-1 - Genetic (isolated or as part of complex disease) - Infiltrative disease (iron, copper) - External beam radiation - Hypomagnesaemia - Idiopathic ## Etiology of Hypocalemia ### High PTH (secondary hyperparathyroidism in response to hypocalcemia) - Vitamin D deficiency or resistance - Multiple causes - PTH resistance - Missense mutation in PTH - Pseudohypoparathyroidism - Hypomagnesemia - Renal disease - Loss of calcium from the circulation - Hyperphosphatemia - Tumor lysis - Acute pancreatitis - Osteoblastic metastases - Acute respiratory alkalosis - Sepsis or acute severe illness ## Etiology of Hypocalcemia ### Drugs - Inhibitors of bone resorption (bisphosphonates, calcitonin, denosumab), especially in vitamin D deficiency - Cinacalcet - Calcium chelators (EDTA, citrate, phosphate) - Foscarnet (due to intravascular complexing with calcium) - Phenytoin (due to conversion of vitamin D to inactive metabolites) - Fluoride poisoning ### Disorders of magnesium metabolism Hypomagnesemia can reduce PTH secretion or cause PTH resistance and is therefore associated with normal, low, or high PTH levels ## Clinical Manifestation Of Hypocalcemia ### Acute - Neuromuscular irritability (Tetany) - Paresthesias (peri-oral, extremities) - Muscle twitching - Carpopedal spasm - Trousseau's sign - Chvostek's sign - Seizures - Laryngospasm - Bronchospasm ### Cardiac - Prolonged QT interval - Hypotension - Heart failure - Arrhythmia - Papilledema ### Chronic - Ectopic calcification (basal ganglia) - Extrapyramidal signs - Parkinsonism - Dementia - Subcapsular cataracts - Abnormal dentition - Dry skin ## Signs of Hypocalcemia The classic physical findings: - **Trousseau's sign:** Induction of carpal spasm by inflation of a sphygmomanometer above systolic blood pressure by 20 mmHg for 3-5 minutes. It may also be induced by voluntary hyperventilation for one to two minutes after release of the cuff. - **Chvostek's sign:** Contraction of the ipsilateral facial muscles by tapping the facial nerve just anterior to the ear. ## Chvostek's Sign Image of a person with Chvostek's sign. ## Trousseau's Sign Image of a person with Trousseau's sign. ## Hypocalcaemia ### Cardiovascular - Hypotension - CHF - Prolongation of the QT interval A diagram of a typical EKG showing the QT interval. ## Approach to Hypocalcemia ### Confirm the diagnosis of Hypocalcemia By: - Measuring the ionized Ca. - Measuring the Albumin Each 1 g/dL reduction in the serum albumin concentration will lower the total calcium concentration by approximately 0.02 mmol/L (0.8 mg/dL). ### Find the cause of hypocalcemia - Serum Magnesium - Serum Phosphorus - PTH - Vitamin D ## Management of Hypocalcemia/Hypoparathyroidism - **Correct Magnesium if low** - IV Magnesium Sulfate 1 to 2 gm in 100 to 250 ml on Normal Saline over 1 to 2 hours. - Oral Magnesium oxide 400 to 800 mg three times a day. - **Calcium** - IV: 10% calcium gluconate (90 mg or 2.25 mmol) per 10 mL ampoule over 10 minutes - Infusion calcium gluconate 10 amp in 1L D5W over 24 hours - Oral calcium gluconate, carbonate, citrate, lactate - **In addition to calcium, patients with vitamin D deficiency or hypoparathyroidism require vitamin D supplementation** - **The goals of therapy in patients with hypoparathyroidism are to relieve symptoms and to raise and maintain the serum calcium concentration in the low-normal range.** - **Recombinant PTH is an option in some patients who can't maintain stable calcium levels with the standard therapy. However, long-term safety has not been established.** ## Hypercalcemia ### Parathyroid mediated - Primary hyperparathyroidism (sporadic) - Inherited variants - Multiple endocrine neoplasia (MEN) syndromes - Familial isolated hyperparathyroidism - Hyperparathyroidism-jaw tumor syndrome - Familial hypocalciuric hypercalcemia - Tertiary hyperparathyroidism (renal failure) ### Non-parathyroid mediated - Hypercalcemia of malignancy - PTHrP - Increased calcitriol (activation of extrarenal 1-alpha-hydroxylase) - Osteolytic bone metastases and local cytokines - Vitamin D intoxication - Chronic granulomatous disorders - Increased calcitriol (activation of extrarenal 1-alpha-hydroxylase) ## Hypercalcemia ### Medications - Thiazide diuretics - Lithium - Teriparatide - Abaloparatide - Excessive vitamin A - Theophylline toxicity ### Miscellaneous - Hyperthyroidism - Acromegaly - Pheochromocytoma - Adrenal insufficiency - Immobilization - Parenteral nutrition - Milk-alkali syndrome ## Table 2: Causes of Hypercalcemia | Type | Cause | |---|---| | Parathormone (PTH) mediated | Primary hyperparathyroidism, Lithium induced, Familial hypocalciuric hypercalcemia, Tertiary hyperparathyroidism, Multiple myeloma, PTHrp mediated- Breast, lung, renal cancer, Bone metastases | | Cancer | | | Calcitriol mediated | Granulomatous disease (Sarcoid, infection), Lymphoma (ectopic 1,25 Vit D), Milk alkali syndrome, Exogenous Vitamin D, Dialysis patients(exogenous Vit D) | | Other causes | Vitamin A toxicity, Thyrotoxicosis, Paget's disease, Adrenal insufficiency, Thiazide use | PTHrp - Parathormone related peptide ## Clinical Manifestation of Hypercalcemia | Type | Cause | |---|---| | Renal | Polyuria, Polydipsia, Nephrolithiasis, Nephrocalcinosis, Distal renal tubular acidosis, Nephrogenic diabetes insipidus, Acute and chronic renal insufficiency | | Musculoskeletal | Muscle weakness, Bone pain, Osteopenia/osteoporosis | | Neurologic | Decreased concentration, Confusion, Fatigue, Stupor.coma | | Gastrointestinal | Anorexia, The symptoms depend upon the degree of hypercalcemia, the rate of onset of the elevation | ## Mild Hypercalcemia (calcium <12 mg/dL [3 mmol/L]) - may be asymptomatic - may report nonspecific symptoms, such as constipation, fatigue, and depression ## Moderate Hypercalcemia calcium of 12 to 14 mg/dL (3 to 3.5 mmol/L) ### Acute - Saline Hydration - Bisphosphonate ### Chronic - Same precautions as mild hypercalcemia ## Severe hypercalcemia (calcium >14 mg/dL [3.5 mmol/L]) - Volume expansion with isotonic saline at rate of: 200-300 ml /h 4-6 L required 1st 24 hrs + loop diuretices - Calcitonin 4 iu/kg every 12 hours - Biphosphenate - Zolidronic acid 4 mg IV over 30 min - Pamidronate 60 – 90 mg IV over 2-4 hr - Etidronate 7.5 mg/kg/day for 3-7 days - In patient with 1,25 (OH)D mediated hypercalcemia glucocorticosteroid therapy: - Hydrocortison IV 100-300 mg daily - Prednison 40-60 mg daily for 3 – 7 days ## Table 3: Signs and symptoms of hypercalcemia | Type | Cause | |---|---| | Constitution symptoms | Weakness, fatigue, anorexia | | CNS | Drowsiness, lethargy, altered mental status, stupor, coma | | Cardiac | Short QT interval | | Eye | Band keratopathy* | | GI | Constipation, abdominal pain, peptic ulcer | | Pancreas | Pancreatitis | | Renal | Polyuria, nephrogenic DI, ARF, CKD, nephrocalcinosis, Nephrolithiasis | ARF- acute renal failure, CKD- chronic kidney disease, DI- diabetes insipidus; * calcium deposits in cornea ## Cardiovascular - Bradycardia - Hypertension - AV block - Short QT interval An EKG with typical markings to show the various readings. ## Hypercalcemia An image of a person's eye showing band keratopathy. Calcium phosphate deposit in the cornea ## Investigation - Confirm Hypercalcemia Albumin- Calcium correction - Laboratory evaluation to determine the etiology - Serum Calcium, Phosphate, and albumin - PTH - Renal function - Vitamin D level - 24-hour urinary calcium and creatinine ## Diagnostic approach to hypercalcemia A flow chart diagram showing the following: 1. Elevated serum calcium? 2. Check repeat (total calcium corrected for albumin or ionized calcium). 3. Hypercalcemia confirmed by repeat measurement? 4. Measure intact PTH. 5. The results could be elevated, mid-to-upper normal, minimally elevated, or low-normal/low. 6. Depending on the PTH levels, the results are likely primary hyperparathyroidism, primary hyperparathyroidism with likely familial hypocalciuric hypercalcemia, or non-PTH mediated hypercalcemia. ## Non parathyroid Mediated Hypercalcemia A flow chart diagram showing the following: 1. Measure: PTHrp, 1,25 dihydroxyvitamin D, 25 hydroxyvitamin D 2. Is PTHrp elevated? - Yes: Humoral hypercalcemia of malignancy is more likely - No: Is 1,25 dihydroxyvitamin D elevated? - Yes: Lymphoma, granulomatous diseases (sarcoidosis, tuberculosis) are more likely - No: Is 25 hydroxyvitamin D elevated? - Yes: Vitamin D intoxication is more likely - No: Measure SPEP, UPEP, Serum free light chain assay. - Abnormal: Multiple myeloma - Normal: Assess for other diagnoses (vitamin A intoxication, Hyperthyroidism) ## Management ### Mild Hypercalcemia calcium <12 mg/dL (<3 mmol/L) - Adequate hydration (6-8 glasses of water/day) - Avoid factors that aggravate hypercalcemia - Medication (thiazide) - High calcium diet (> 1 g/d) - Prolong immobilization ### Moderate Hypercalcemia calcium of 12 to 14 mg/dL (3 to 3.5 mmol/L) ### Acute - Saline Hydration - Bisphosphonate ### Chronic - Same precautions as mild hypercalcemia ### Severe hypercalcemia calcium >14 mg/dL (3.5 mmol/L) - Volume expansion with isotonic saline at rate of: 200-300 ml/h 4-6 L required 1st 24 hrs + loop diuretices - Calcitonin 4 iu/kg every 12 hours - Biphosphenate: - Zolidronic acid 4 mg IV over 30 min - Pamidronate 60 – 90 mg IV over 2-4 hr - Etidronate 7.5 mg/kg/day for 3-7 days - In patient with 1,25 (OH)D mediated hypercalcemia glucocorticosteroid therapy: - Hydrocortison IV 100-300 mg daily - Prednison 40-60 mg daily for 3 – 7 days ## Hyperparathyroidism - **Primary Hyperparathyroidism** - **Secondary Hyperparathyroidism** - **Tertiary Hyperparathyroidism** ## Parathyroid Diseases A diagram showing the different parathyroid diseases: - 1° Hyperparathyroidism - 2° Hyperparathyroidism - 1° Hypoparathyroidism - PTH- Independent Hypercalcemia ## Laboratory Findings of Vitamin D Deficiency | Type | PTH | Ca | P | Alk p | 25-OHD | 24 urine Ca | |---|---|---|---|---|---|---| | 1ry/3ry HPTH | ↑ | ↑ | ↓ | ↑ | N | ↑/N| | FHH | ↑ | ↑ | ↓ | ↑ | ↓ | ↓ | | Vit D deficiency | ↑ | ↓ | ↓ | ↑ | ↓ | ↓ | ## Cases ### Case 1 - A 55-year-old lady with backache. X-ray show collapse of D8: - Hb 11.5 g/dl (12.0-16.0 g/dl) - Urea 1.4 mmol/l (1.2-3.0 mmol/l) - Calcium 2.8 mmol/l (2.1-2.6 mmol/l) - Phosphate 0.8 mmol/l (0.8-1.5 mmol/l) - Alk phosphatase 210 IU/L (50-100 IU/L) - Albumin 28 g/l (35-45 g/l) - List your laboratory findings - Low Hb - High Calcium - Low normla Phosphate - High Alk Phosphatase - Low Albumin - What is your next diagnostic test? - iPTH level ### Case 2 - A 16 year old girl presented with growth retardation and worsening facial numbness. There was no history of diarrhea. She was on a nutritious diet and took no regular medications. - Physical exam unremarkable apart from generalized bone tenderness - **Investigations** - CBC, U/E & LFT were normal - Calcium 1.7 mmol/l [2.1-2.6 mmol/l] - Phosphate 0.7 mmol/l [0.8-1.5 mmol/l] - Alk phosphatase 530 IU/L [50-100 IU/L] - PTH 450 pmol/l [10-90 pmol/l] - 25-OHD 8 ng/ml [30-50 ng/l] - Wrist X-ray: cupping of metaphysis, widened and irregular metaphyseal lines. - How would you interpret this laboratory data? - Vitamin D deficiency with secondary hyperparathyroidism ## Thank You! This is the end of the presentation.