In the name of God

A 23-years old β-thalassaemia major woman with resistant hypocalcemia

Presentation of Case ID: A 23 years old woman known case of β- thalassaemia major, single, native and resident of Kahnooj city, Kerman province Chief complaint: Bone pain

Presentation of Case Present illness: The patient has regular Red Blood Cell Transfusion Program 2 times monthly. She uses Desferal (deferoxamine) almost regularly. She complain of bone pain since 5-6 days before admission. She also complain of paresthesia in perioral region, hands and feet. The symptoms had increased day by day.

Presentation of Case Present illness (con.) With these complains she was admited in emergency department in kahnooj. On admissin, the lab evaluation showed a hypocalcemia. She was treated with IV Ca- Gluconate. Despite this treatment the serum Ca level didn’t increase and the patient experience a tonic colonic seizure. Because of resistant hypocalcemia she refered to afzalipoor hospital in Kerman.

Presentation of Case Present illness (con.) When she was admited in afzalipoor center she didn’t complain of bone pain and paresthesia. The patient 3 years earlier with similar symptoms of bone pain, parestheisa, nausea, vomiting and a tonic colonic seizure was admitted. She had a hypocalcemia and hyperphosohatemia.

Presentation of case Present illness (con.) At that time the patient was discharged with diagnosis of hypoparathyroidism and advised to follow up regularly prescribed drug: Ca-forte, Caco3 and calcitriol.

Presentation of case Present illness (con.) She had no follow-up in the last three years but had been taking medicine almost regularly. She had not any symptoms during this years until 1 month before recent admission that she had a emotional stress after which, she discontinue her drugs.

Presentation of Case PMH: Thalacemia Major Primary amenorrhoea Short stature and growth failure (less than the 3rd percentile on growth charts) Perforated appendicitis 8 years ago

Presentation of Case DH: Desferal 2 gr sc infuion daily, Caco mg po TDS until 1 mounth before, Calcitriol 0.25 mg po BID until 1 mounth before, FH: father and mother are not relatives AH: non significant PH: non significant

Presentation of Case Physical Examination: General appearance: A young woman with chipmunk facial appearance that was not ill and toxic, the apparent age is not consistent with her chronological age with short stature Vital signs: BP: 90 / 60 PR: 100 RR: 16 T: 36.5 ̊ c (oral) Weight: 45 Kg Height: 147 cm BMI : 20.82

Presentation of Case Head and Neck: pale conjunctiva prominent frontal bossing marked overgrowth of the maxillae Chvostek’s sign: negative No neck scar There is no evidence of candidiasis in mouth and pharynx mucusa

Presentation of Case Chest: Heart: S1 S2 without any murmer Lungs: bilateral clear Breasts development: Tanner stage 3 No growth of axillary hairs

Presentation of Case Abdomen: Midline surgery scar Hepatomegaly liver span measured 20 cm in the midclavicular line Spleenomegaly: 13 cm below the left costal margin

Presentation of Case Extremities: No edema or cyanosis Bone pain : tenderness in extremities There is no muscle weakness The forces are normal Trousseau’s sign: Negative

Presentation of Case Lab data: First day: WBC: neutrophils: 64.8% lymph: 29.1 % RBC: Hb: 10.1 MCV: 79.1 MCH: 27.2 PLT: BS: 136 Urea: 98 Cr: 0.9 Na: 143 K: 3.9 Ca Ionized : 1.3 P: 9.7 AST: 77 ALT: 57 ALK ph: 472 VBG: PH: 7.38 PCO2: 38 HCO3: 22

Presentation of case ECG: Prolonged QT interval Echocardiography Ejection fraction: % Pulmonary artery pressure: 40 – 45 mm Hg LV diastolic dysfunction grade 1 Mild LV systolic dysfunction

Presentation of case Abdominopelvic sonography: Liver shows enlarged size (270 mm) with normal echo pattern. Biliary tree and portal system are normal in diameter. Gallblader shows normal size and wall thikness and contains some stone with maximum diameter of 7 mm. Spleenomegaly is evident (190 mm). Both kidneys shows normal size and echo pattern without evidence of stone or hydronephrosis. Bladder shows normal wall thickness without any filling defect and stone. Uterus shows small size. No adenexal pathology is evident.

The problem: hypocalcemia

CALCIUM HOMEOSTASIS Calcium in the blood is transported:  bound to plasma proteins (about 45 percent), notably albumin  bound to small anions such as phosphate and citrate (about 15 percent)  in the free or ionized state (about 40 percent) Only the ionized calcium is metabolically active

CALCIUM HOMEOSTASIS Normal serum range Total serum calcium: between 8.5 and 10.5 mg/dL Ionized calcium: 4.65 to 5.25 mg/dL

Causes of hypocalcemia Major causes Low PTH (hypoparathyroidism) High PTH (secondary hyperparathyroidism in response to hypocalcemia) Drugs Disorders of magnesium metabolism

Causes 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)

Causes of hypocalcemia Low PTH (hypoparathyroidism) (con.)  Post-surgical (thyroidectomy, parathyroidectomy, radical neck dissection)  Autoimmune Autoimmune polyglandular syndrome type 1 (associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency) Isolated hypoparathyroidism due to activating antibodies to calcium-sensing receptor

Causes of hypocalcemia Low PTH (hypoparathyroidism) (con.)  Infiltration of the parathyroid gland (hemochromatosis, iron overload, Wilson's disease, granulomatous, metastases)  Radiation-induced destruction parathyroid glands  Hungry bone syndrome (post parathyroidectomy)  HIV infection

Causes of hypocalcemia High PTH (secondary hyperparathyroidism in response to hypocalcemia)  Vitamin D deficiency or resistance Multiple causes  Parathyroid hormone resistance Pseudohypoparathyroidism Hypomagnesemia  Renal disease

Causes of hypocalcemia High PTH (secondary hyperparathyroidism in response to hypocalcemia) (con.)  Loss of calcium from the circulation Hyperphosphatemia Tumor lysis Acute pancreatitis Osteoblastic metastases Acute respiratory alkalosis Sepsis or acute severe illness Surgery

Causes of hypocalcemia Drugs  Inhibitors of bone resorption (bisphosphonates, calcitonin), 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  Chemotherapy (Cisplatin is probably most common)

Causes of hypocalcemia Disorders of magnesium metabolism Hypomagnesemia can reduce PTH secretion or cause PTH resistance and is therefore associated with normal, low, or high PTH levels Severe hypermagnesemia, a very rare disorder, can also cause hypocalcemia, by suppressing the secretion of PTH

Diagnostic approach to hypocalcemia The first step is measurement of the serum albumin concentration. Calcium in serum is bound to proteins, principally albumin. As a result, the total serum calcium concentration in patients with low or high serum albumin levels may not accurately reflect the physiologically important ionized (or free) calcium concentration.

Diagnostic approach to hypocalcemia Each 1 g/dL reduction in the serum albumin concentration will lower the total calcium concentration by approximately 0.8 mg/dL without affecting the ionized calcium concentration and therefore without producing any symptoms or signs of hypocalcemia.

Diagnostic approach to hypocalcemia It is important to verify with repeat measurement (ionized calcium or total serum calcium corrected for albumin) Determine the blood PH, It is important to note that the affinity of calcium for albumin is increased in the presence of alkalosis  Acidosis reducing calcium-albumin binding and alkalosis, enhancing it

Diagnostic approach to hypocalcemia CLINICAL EVALUATION The etiology of hypocalcemia may be obvious from the clinical history A history of head and neck surgery (thyroid, parathyroid, or radical neck surgery for head and neck cancer) or the presence of a neck scar suggests postsurgical hypoparathyroidism.

Diagnostic approach to hypocalcemia CLINICAL EVALUATION A family history of hypocalcemia suggests:  genetic cause  polyglandular autoimmune syndrome type I History of Chronic hypocalcemia  An activating mutation of the calcium sensing receptor  pseudohypoparathyroidism

Diagnostic approach to hypocalcemia CLINICAL EVALUATION The presence of chronic mucocutaneous candidiasis and adrenal insufficiency suggests a polyglandular syndrome

Diagnostic approach to hypocalcemia CLINICAL EVALUATION Other causes of hypocalcemia that may be apparent from the history, physical examination, and routine laboratory data:  Acute or chronic kidney disease  Acute pancreatitis  Rhabdomyolysis  Marked increases in tissue breakdown with the release of phosphate from cells, as occurs in the tumor lysis syndrome

Diagnostic approach to hypocalcemia LABORATORY EVALUATION Serum PTH concentrations Creatinin Phosphate Magnesium Vitamin D metabolites Other tests that may be helpful: serum alkaline phosphatase, serum amylase, and 24- hour urinary excretion of calcium and magnesium

Diagnostic approach to hypocalcemia LABORATORY EVALUATION (con.) Among the tests that may be helpful in defining the etiology of hypocalcemia, measurement of serum intact parathyroid hormone is the most valuable and should be performed in all patients with hypocalcemia Other tests should be performed selectively, based upon the patient's history and physical examination

Diagnostic approach to hypocalcemia LABORATORY EVALUATION (con.) Serum PTH concentrations Can be interpreted correctly only when serum calcium is measured simultaneously The serum PTH concentration varies with the cause of the hypocalcemia

Diagnostic approach to hypocalcemia LABORATORY EVALUATION (con.) Serum PTH concentrations Hypoparathyroidism: Serum PTH is reduced or inappropriately normal Acute or chronic kidney disease, vitamin D deficiency, and pseudohypoparathyroidism: Serum PTH is elevated

Diagnostic approach to hypocalcemia LABORATORY EVALUATION (con.) Serum PTH concentrations Hypomagnesemia or autosomal dominant hypocalcemia, a rare disorder characterized by an activating mutation in the calcium-sensing receptor gene : Serum PTH is typically normal or low

Diagnostic approach to hypocalcemia LABORATORY EVALUATION (con.) Magnesium Hypomagnesemia is serum magnesium concentration below 0.8 meq/L (1 mg/dL) Hypomagnesemia causes hypocalcemia by inducing PTH resistance or deficiency. Serum magnesium should be measured in any patient with hypocalcemia in whom the cause is not obvious

Diagnostic approach to hypocalcemia LABORATORY EVALUATION (con.) Phosphate Persistent hypocalcemia and hyperphosphatemia is, in the absence of kidney disease or increased tissue breakdown, virtually diagnostic of either hypoparathyroidism (PTH deficiency) or pseudohypoparathyroidism (PTH resistance) It is due to loss of the stimulatory effect of PTH on urinary phosphate excretion

Diagnostic approach to hypocalcemia LABORATORY EVALUATION (con.) Phosphate A low serum phosphate concentration with excess PTH secretion and hypocalcemia means:  secondary hyperparathyroidism (and some abnormality in vitamin D intake or metabolism)  low dietary phosphate intake

Diagnostic approach to hypocalcemia LABORATORY EVALUATION (con.) Vitamin D metabolites Vitamin D deficiency increases PTH secretion by causing hypocalcemia (due to the reduction in intestinal calcium absorption) and, to a lesser degree, by removing the normal inhibitory effect of calcitriol on PTH production. Vitamin D deficiency also diminishes intestinal phosphate absorption. Excess PTH enhances phosphate excretion and lowers the serum phosphate.

Diagnostic approach to hypocalcemia LABORATORY EVALUATION (con.) Vitamin D metabolites Measurement of serum 25-hydroxyvitamin D (25OHD, calcidiol) provides more information about vitamin D deficiency than does measurement of serum 1,25-dihydroxyvitamin D (calcitriol) because the hypocalcemia-induced increase in PTH secretion stimulates renal 1,25- dihydroxyvitamin D production (in patients without underlying renal insufficiency).

Diagnostic approach to hypocalcemia LABORATORY EVALUATION (con.) Vitamin D metabolites In vitamin D deficiency, serum 25OHD is low whereas 1,25-dihydroxyvitamin D is typically normal or high. In hypoparathyroidism may have normal serum 25OHD and low 1,25-dihydroxyvitamin D concentrations

Presentation of Case Lab data: Second day: Ca Ionized: 2.1 mg/dl Ca Total: 6.6 mg/dl P: 9.5 mg/dl Mg: 2.5 mg/dl Albumin: 4.7 g/dl Total protein: 8.8 g/dl Ferritin: ng/mL PTH: 4 µU/ml (normal range: 8-76) TSH: 2.92 µU/ml (normal range: )

Presentation of Case Ca Total: 6.6 mg/dl Ca Ionized: 2.1 mg/dl P: 9.5 mg/dl PTH: 4 µU/ml hypoparathyroidism

β-thalassaemia major and hypocalcemia Beta-thalassemia major, a hereditary hemoglobin disorder and is characterized by a decreased synthesis of the β-globin chain. Regular blood transfusions and chelation therapy have considerably prolonged survival in thalassemic patients.

β-thalassaemia major and hypocalcemia Despite a significant increase in the lifespan of these patients, many endocrine abnormalities such as growth failure, hypogonadism, diabetes mellitus, hypothyroidism develop due to an iron overload. Hypoparathyroidism is thought to be a rarer complication, usually, but not always, accompanied by hypocalcemia.

β-thalassaemia major and hypocalcemia Osteoporosis represents an important cause of morbidity in the thalassemic population. Although the main role is played by hypogonadism and bone marrow expansion, the etiology of this bone disease is multifactorial (hormonal deficiency, increased iron stores, desferrioxamine toxicity)

β-thalassaemia major and hypocalcemia In addition, calcium and vitamin D deficiency associated with hypoparathyroidism are also implicated in osteoporosis.

β-thalassaemia major and hypocalcemia Hypoparathyroidism usually develops after first decade. All patients over the age of 12 years should have calcium and phosphate levels checked at least every 6 months. If these are abnormal, parathyroid hormone level should be measured. Hypoparathyroidism should be managed as per endocrine standards.

Treatment Calcium The treatment of hypocalcemia varies with its severity and the underlying cause. Patients with hypocalcemia who are severely symptomatic (carpopedal spasm, tetany, seizures, decreased cardiac function, or prolonged QT interval) require rapid correction of calcium levels with IV calcium therapy. IV calcium therapy in asymptomatic patients with an acute decrease in serum corrected calcium to ≤7.5 mg/dL (1.9 mmol/L) should be done.

Treatment Calcium (con.) Intravenous calcium is NOT warranted as initial therapy for asymptomatic hypocalcemia in patients with impaired renal function in whom correction of hyperphosphatemia and of low circulating 1,25- dihyroxyvitamin D are usually the primary goals.

Treatment Calcium (con.) For those with milder symptoms of neuromuscular irritability (paresthesias) and corrected serum calcium concentrations greater than 7.5 mg/dL (1.9 mmol/L), initial treatment with oral calcium supplementation is sufficient. If symptoms do not improve with oral supplementation, intravenous calcium infusion is required. To effectively treat hypocalcemia in patients with concurrent magnesium deficiency, hypomagnesemia should be corrected first.

Treatment Vitamin D When hypoparathyroidism (transient or permanent) or vitamin D deficiency are the cause of hypocalcemia, administration of intravenous calcium is only transiently effective (as long as the infusion continues), and oral calcium may not be well absorbed. In these cases, successful management requires the addition of vitamin D, which often permits a lower dose of calcium supplementation.

Treatment Vitamin D (con.) For the initial management of patients with hypoparathyroidism, vitamin D supplementation in addition to calcium is recommend. Calcitriol is the vitamin D metabolite of choice because it does not require renal activation, it has a rapid onset of action (hours), and a shorter half-life. Other acceptable options include alfacalcidol, vitamin D (ergocalciferol or cholecalciferol), or dihydrotachysterol

Treatment Vitamin D (con.) In individuals with hypocalcemia due to vitamin D deficiency, vitamin D repletion is recommend. Nutritional deficiency (25OHD <20 ng/mL [50 nmol/L]) requires initial treatment with 50,000 units of vitamin D2 or D3 orally once per week for six to eight weeks, and then 800 to 1000 international units of vitamin D3 daily thereafter.

Treatment Permanent hypoparathyroidism In patients with permanent hypoparathyroidism, the goals of therapy are  to relieve symptoms,  to raise and maintain the serum calcium concentration in the low-normal range (eg, 8.0 to 8.5 mg/dL [2.0 to 2.1 mmol/L]),  to avoid hypercalciuria (maintain 24-hour urinary calcium below 300 mg).

Treatment Permanent hypoparathyroidism (con.) All patients with permanent hypoparathyroidism require adequate calcium intake (1.0 to 1.5 g elemental calcium daily).

Treatment Permanent hypoparathyroidism (con.) Along with calcium supplementation, calcitriol rather than recombinant human parathyroid hormone (PTH) is suggested. The long-term safety of recombinant PTH has not been established. In addition, recombinant PTH is much more expensive than standard therapy with calcitriol. However, in patients with refractory hypercalciuria, PTH is a reasonable option.

Treatment Permanent hypoparathyroidism (con.) The initial treatment of hypercalciuria in patients with hypoparathyroidism is reducing the dose of calcium and vitamin D. Some patients will require the addition of thiazide diuretics.

Treatment of the case Amp Calcium gluconate 6 gr IV infusion q 6 hours decrease to 10 gr daily after 1 week Tab Caco3 1 gr po QID Pearl Calcitriol 0.25 mg po TDS Cap Sevelamer 800 mg po daily

Lab data on discharge Ca ionized: 4 mg/dl Ca total : 8.1 mg/dl P : 4.4 mg/dl

Prescription on discharge Tad Caco3 1 gr po TDS Pearl calcitriol 0.25 mg TDS Eff Tad Calcium forte 500 BID

Thanks for your attention