Transcript document

HYPOCALCEMIA
Hasan AYDIN, MD
Yeditepe University Medical Faculty
Department of Endocrinology and Metabolism
Overview of Calcium Balance
Etiology
Decreased GI Absorption
Poor dietary intake of calcium
Impaired absorption of calcium
Vitamin D deficiency
Poor dietary intake of vitamin D
Malabsorption syndromes
Decreased conversion of vit. D to calcitriol
Liver failure
Renal failure
Low PTH
Hyperphosphatemia
Increased Urinary Excretion
Low PTH
Thyroidectomy
I131 treatment
Autoimmune
hypoparathyroidism
PTH resistance
Vitamin D deficiency / low calcitriol
Decreased Bone Resorption/Increased Mineralization
Low PTH ( hypoparathyroidism)
PTH resistance ( pseudohypoparathyroidism)
Vitamin D deficiency / low calcitriol
Hungry bones syndrome
Osteoblastic metastases
Parathyroid Related
Disorders
– Absence of the parathyroid glands or of PTH
• Congenital
–
–
–
–
DiGeorge’s syndrome
X-linked or autosomally inherited hypoparathyroidism
Autoimmune polyglandular syndrome type I
PTH gene mutations
• Postsurgical hypoparathyroidism
• Infiltrative disorders
– Hemachromatosis
– Wilson’s disease
– Metastases
• Hypoparathyroidism following radioactive iodine thyroid ablation
– Impaired secretion of PTH
• Hypomagnesemia
• Respiratory alkalosis
• Activating mutations of the calcium sensor
– Target organ resistance
• Hypomagnesemia
• Pseudohypoparathyroidism (Type I and II)
Vitamin D Related Disorders
• Vitamin D deficiency
– Dietary absence
– Malabsorbtion
• Accelerated loss
– Impaired enterohepatic recirculation
– Anticonvulsant medications
• Impaired 25-hydroxylation
– Liver disease
– Isoniazid
• Impaired 1α-hydroxylation
– Renal failure
• Vitamin D dependent rickets type I
• Oncogenic osteomalcia
• Target organ resistance
– Vitamin D dependent rickets type II
– Phenytoin
Other Causes
•
Excessive deposition in to the skeleton
–
–
•
Chelation
–
–
–
–
–
•
Prematurity
Asphyxia
Diabetic mother
Hyperparathyroid mother
HIV infection
–
–
–
•
Foscarnet
Phosphate infusion
Infusion of citrated blood products
Infusion of EDTA containing contrast agents
Fluoride
Neonatal hypocalcemia
–
–
–
–
•
Osteoblastic malignancies
Hungry bone syndrome
Drug therapy
Vitamin D deficiency
Impaired PTH responsiveness
Critical illness
–
–
–
Pancreatitis
Toxic shock syndrome
Intensive care unit patients
Clinical Features
Signs and symptoms depend on
Level of serum calcium
Age at onset and duration
Level of serum magnesium and potassium
Accompanying disturbances in acid-base homeostasis
Sometimes only symptoms of underlying
disorder
Symptoms and Signs
• Systemic
– Confusion
– Weakness
– Mental retardation
– Behavioral changes
Symptoms and Signs
• Neuromuscular
–
–
–
–
–
–
–
–
–
–
Parestesias
Psychosis
Seizure
Carpopedal spasm
Chvostek’s and Trousseau’s signs
Depression
Muscle cramps
Parkinsonism
Irritability
Basal ganglia calcifications
Syptoms and Signs
• Cardiac
– Prolonged QT interval
– T wave changes
– Congestive heart failure

Ocular
Cataracts
Syptoms and Signs
• Dental
– Enamel hypoplasia of teeth
– Defective root formation
– Failure of adult tooth to erupt

Respiratory
Laryngospasm
Bronchspasm
Stridor
Chvostek’s Sign
• Elicited by tapping
over facial nerve
causing twitching of
ipsilateral facial
muscles
Trousseau’s Sign
• Carpal spasm in
response to inflation of
BP cuff to 20 mm Hg
above SBP for 3 min
Differential Diagnosis
Ca
PO4
PTH
25-Vit D
Calcitriol
Hypoparathyroidism
↓
↑
↓
N
↓
Pseudohypoparathyroidism
↓
↑
↑
N
↓N
Liver disease
↓
↑
↓
↓N
Renal disease
↓
↑
N
↓N
↑
Evaluation of Hypocalcemia
•
History:
–
Paresthesias/ cramping
–
Tetany
–
Carpopedal spasm
–
Laryngospasm
–
Seizures
Physical Examination
•
•
•
•
•
Signs of hypocalcemia:
•
Chvostek sign
•
Trousseau sign
•
Hyper-reflexia
Dysmorphism (Di George Syndrome, PHP)
Dental abnormalities
Chronic mucocutaneous candidiasis
Rickets
Investigations
Serum calcium (ionic), phosphate, magnesium
Ionized Ca is physiologically active
0.1 increase in pH increases iCa by 3-8%
10 g/L decrease in albumin increases iCa by 0.2
iPTH
Serum urea and creatinine levels
Vitamin D levels (if available)
Genetic studies (if necessary)
Approach to low serum calcium
PTH Level
Low
High
Mg level
Low
Hypo
magnesemia
Phosphate
High
High
Hypo
parathyroid
Low
Creatinine
High
Renal
Failure
25 OH Vit D
Normal
Low
Normal
PHP
1,25 OH Vit D
Nutrition
Malabsorption
Liver disease
Vit D
Dep Rickets
Vit D
Res Rickets
Treatment
• Symptomatic:
– Parenteral Ca
10% CaCl2: 10 cc ampoules contains 360 mg of elemental Ca
10% Ca gluconate: 10 cc ampoules contains 93 mg of elemental
Ca
– Recommended dose: 100-300 mg of elemental Ca
over 10-20 min followed by an infusion of 0.5-2
mg/kg/h
Treatment
• Side effects:
– Nausea
– Vomiting
– Flushing
– Hypertension
– Bradycardia, heart block (patients should be monitored)
Treatment
• Asymptomatic
– Oral Ca supplementation
• 1-4 g/day in divided doses
• If patient has concurrent hypomagnesemia, Ca replacement alone
will not correct hypocalcemia unless Mg is also replaced (2-4 g IV
for symptomatic patients)
Acute Management Of Hypocalcemia
• Frank Tetany
– 10-20 ml calcium gluconate (93 mgf elemental Ca/10 ml) for 10 min.
• Ongoing severe hypercalcemia
– 10 ampul of 10 ml calcium gluconate infused over 8-10 hours (in saline or
dextrose)
• When due to hypomagnesemia
– 1-2 gram of magnesium sulfate (8-16 mEq) q6h, for several days
SPECIFIC CAUSES OF HYPOCALCEMIA
Developmental Abnormalities
• DiGeorge Syndrome
– Parathyroid dysplasia, thymic hypoplasia, immune deficiency,
cardiac defects, craniofacial malformations, mental retardation
– Deletion on long arm of chromosome 22
• Kenny Caffey Syndrome
– Parathyroid aplasia, medullary stenosis of long bones, growth
retardation
• Barakat syndrome
– Hypoparathyroidism, nerve deafness, renal dysplasia
Disorders of 25-OH D Metabolism
• Hepatic and hepatobiliary disease
– Impairement of synthesis
– Particularly in biliary cirrhosis
• Gastrointestinal disorders
– Malabsorption and disruption of enterohepatic circulation of vitamin D
• Protein wasting syndrome
• Drugs
– Increased conversion of 25 OH D to inactive metabolites
Disorders of 1,25-OH D Metabolism
• Vitamin D dependent rickets type I
• Vitamin D dependent rickets type II
• Vitamin D resistant rickets and osteomalacia
• Hypercalciuric hypophosphatemic rickets
• Tumor induced osteomalacia
Vitamin D Dependent Rickets Type I
Autosomal recessive
Inactivating mutations on chromosome 12
Circulating levels of 1,25 (OH) D are low
Treatment with calcitriol 0,5-3 mcg/day
Vitamin D Dependent Rickets Type II
Target organ resistance to calcitriol
Markedly elevated plasma levels of 1,25 (OH) D
Sporadic and autosomal recessive
Alopecia, epidermal cysts, oligodentia
Low 24,25 (OH)2D3 and 24 (OH)-25-hydroxylase
Treatment with massive doses of vitamin D (10-20
mg/day) or 1,25 (OH)D (6 mcg/kg/day)
Vitamin D Resistant Rickets and Osteomalacia
Sporadic or familial
X-linked hypophosphatemic VDRR
Hypophosphatemia, normocalcemia, normal PTH,
hyperphophaturia
25 (OH)D normal, 1,25 (OH)D low/normal
Treatment with administration of phosphorus
supplements and vitamin D
Tumor Induced Osteomalacia
Release of humoral factors affecting renal phosphate
reabsorption, and formation of 1,25 (OH)2D
Bone pain, muscle weakness, recurrent pathological
fractures, pseudofractures
Hypophosphatemia, hypocalcemia, elevated ALP, PTH
vary
Surgery of tumor
Treatment with phosphorus + vitamin D
Hypoparathyroidism
• Clinically
– Symptoms of neuromuscular hyperactivity
• Biochemically
– hypocalcemia,
– hyperphosphatemia,
– diminished to absent circulating iPTH.
Etiology
• Surgical hypoparathyroidism (most common)
• Familial hypoparathyroidism
• Idiopathic hypoparathyroidism
• Functional hypoparathyroidism
Functional
Hypoparathyroidism
• long periods of hypomagnesemia
– selective gastrointestinal magnesium absorption defects
– generalized gastrointestinal malabsorption
– alcoholism.
• Serum PTH low
• Hypocalcemia
• Mg is required for PTH release
• Mg is probably also required for the peripheral action of
PTH
Classification
• 5 categories based primarily on the concentration of
serum calcium.
–
–
–
–
–
Grades 1  with no hypocalcemia,
Grades 2  inconstant hypocalcemia
Grades 3  serum calcium is below 8.5 mg/dl
Grades 4  serum calcium is below 7.5 mg/dl
Grades 5 serum calcium is below 6.5 mg/dl
• Clinical manifestations of hypoparathyroidism depend
upon the severity and chronicity of the hypocalcemia.
Treatment
• Physiologic replacement of PTH.
• Pharmacologic doses of vitamin D
– (ergocalciferol or its more potent analog dihydrotachysterol, in
combination with oral calcium administration)
• Diets low in phosphate (restriction of dairy products and
meat) and oral aluminum hydroxide gels
PTH Resistance Syndromes
Etiology of
Pseudohypoparathyroidism
• abnormal target tissue responses
– receptor binding of the hormone
– final expression of the cellular actions of PTH
• resistance to several other hormones (vasopressin, glucagon).
• secretion of a biologically inert form of PTH,
• circulating inhibitors of PTH action,
• an intrinsic abnormality of PTH receptors,
• autoantibodies to the PTH receptor,
Pseudohypoparathyroidism
• Rare familial disorder
• Target tissue resistance to PTH,
• Hypocalcemia, hyperphosphatemia
• Increased parathyroid gland function,
• Short stature and short metacarpal and metatarsal bones.
PsHP Type Ia (Albright Syndrome)
•
Hypoparatrhyroidism, short stature, round facies, obesity, brachydactily,
neck webbing, sc calcifications
•
Defect in the function of Gs protein
•
TSH, Glucagon, Gonadotropin resintance
•
Autosomal dominant
•
Intermittant hypocalcemia, elevated PTH, low urine Ca
Pseudopseudohypoparathyroidism
• developmental defects
• without the biochemical abnormalities of
pseudohypoparathyroidism.
• lack evidence of PTH resistance
• 50% reduction in Gs alpha function
• Autosomal dominant
Pseudoidiopathic hypoparathyroidism
• Structurally abnormal form of PTH present
• Fail to respond to own PTH
• Normal response to exogenous PTH