Rickets and TetaniaCONF. DR. INGRITH MIRON

DR. ADRIANA MOCANU

DEFINITION

• Disease of growing bones in which defective mineralisation occurs in both bone and cartilage of epiphyseal growth plate, associated with:–Growth retardation– Skeletal deformities

Epidemiology

• Vitamin D deficiency in pediatric patients has serious implications for both childhood well-being as well as lifelong health.

• Vitamin D is well known for its role as a mediator of calcium homeostasis, and in the development and maintenance of the skeleton

• Alarming prevalence of medical problems related to this nutritional problem, ranging from severe nutritional rickets to subclinical vitamin D deficiency, even with inindustrialized societies

Sources of Vitamin D

• Sun light– Synthesis in the body from precursor sterol

• All Milk products (fortified)• Fish liver oil• Egg yolk

Physiology of vitamin D

Cholecalciferol (ie, vitamin D-3) - formed in the skin from 5-dihydrotachysterol.

hydroxylation in 2 steps:- first hydroxylation : position 25 (liver)

→calcidiol (25-hydroxycholecalciferol):good indicator of overall vitamin D status;

- second hydroxylation: 1 position (kidney) →active metabolite calcitriol (1,25-dihydroxycholecalciferol).

Physiology of vitamin D

• Calcitriol promotes:- absorption of calcium and phosphorus from

the intestine,- increases reabsorption of phosphate in the

kidney, - acts on bone to release calcium and

phosphate,- directly facilitate calcification

Physiology of vitamin D

These actions increase the concentrations of calcium and phosphorus in extracellular fluid :

- leads to the calcification of osteoid, primarily at the metaphyseal growing ends of bones but also throughout all osteoid in the skeleton;

- Parathyroid hormone facilitates the 1-hydroxylation step in vitamin D metabolism.

Pathogeny • The primary pathology : defective

mineralisation of bone matrix• The primary bone matrix mineral =

hydroxyapatite = Ca10(Po4)6(OH)2

• Any disease that limit the availability of calcium or phosphate will lead to rickets

• 2 main categories– Hypocalcaemia rickets• Disfunctions of vitamin D metabolism or vitamin D

action– Hypophosphatemic rickets• Abnormalities of phosphate metabolism

Pathogeny In the vitamin D deficiency : hypocalcemia:- stimulates excess parathyroid hormone→ stimulates renal

phosphorus loss→ reducing deposition of calcium in the bone;

- Excess parathyroid hormone : produces changes in the bone similar to those occurring in hyperparathyroidism.

- Early in the course of rickets, the calcium concentration in the serum decreases;

- parathyroid response, the calcium concentration usually returns to the reference range, though phosphorus levels remain low;

- Alkaline phosphatase (produced by overactive osteoblast cells) leaks to the extracellular fluids so that its concentration rises to anywhere from moderate elevation to very high levels.

PathogenyThe main anomalies of phosphocalcic balance resulting in : • intestinal malabsorption of calcium and phosphorus due to

deficiency of vitamin D and secondary hyperparathyroidism. • the sequence of main steps in vitamin D deficiency causes a

tendency to hypocalcemia with changing ratio Ca / P and the occurrence of compensatory secondary hyperparathyroidism (PTH ↑) produces calcium mobilization from bone and renal phosphorus removal - what makes the SEC ions to be inadequate mineralization, leading to:

- ossified matrix; - calcifying osteoid tissue; - deformed bone static and mechanical; - deformities typical of rickets.

ETIOLOGY• Nutritional: commonest cause in the developing countries • Malabsorption• Drugs that increases metabolism of vitamin D in the liver• Chronic liver disease• Renal rickets – Chronic renal failure

• Hereditary rickets – Vitamin D dependent rickets ( Type 1& 2)– Vitamin D resistant rickets

Nutritional CausesLack of vitamin D• Commonest cause in Saudi Arabia and in developing

countries• Lack of exposure to U/ V sun light

– Dark skin– Covered body– Kept in-door

• Exclusive breast feeding– Limited intake of vitamin –D fortified milk and diary products

• During rapid growth– Infancy– puberty

• Except in pediatric patients with chronic malabsorption syndromes or end-stage renal disease, nearly all cases of rickets occur in breastfed infants who have dark skin and receive no vitamin D supplementation.

• Incidence in Europe is similar to that in the United States. In sunny areas, such as in the Middle East, rickets may occur when infants are bundled in clothing and are not exposed to sunlight.

Clinical features• The earliest sign of rickets in infant is craniotabes (abnormal

softness of skull)• Delayed closure of anterior fontanel• Widening of the forearm at the wrist (widened metaphysis= area

between epiphysis and diaphysis)• Rachitic rosary

– Swelling of the costo-chondral junction • Harrison’s groove

– Lateral indentation of the chest wall at the site of attachment of diaphragm

• Bowing of tibia and fibula may be observed at any age• Growth retardation due to impaired calcification of bone

epiphysis (epiphysis= area of growth plates)• Hypocalcaemic manifestations

– hypotonia– Seizure, tetany,muscle weakness, paraesthesia, numbness

Biochemical findings of ricketsVitamin D deficiency rickets– Low- normal serum calcium level– Increased secretion of PTH (secondary

hyperparathyroidism) to compensate for low calcium

– Hyperparathyroidism will increase renal excretion of phosphate, leads to low serum phosphate level

– Elevated alkaline phosphatase enzyme– Reduced urinary calcium level– Low level of both 25 and 1,25- di hydroxy vitamin D– Elevated parathyroid hormone level

Rickets

Biochemical findingsCategory Serum

CalciumSerumPh3

Serum AlkalinePh3ase

PTH 25-HC 1, 25-DHC

Tubular Reabsrp. Of Ph3

Urinarycalcium

Vit-D deficiency Low tonormal

Low High High Low Low Low low

Ph3 deficiency normal Low High normal normal normal High High

Gastrointestinal Low Low High High Low toNormal

Low toNormal

Low low

Vit- D resistsnt phosphaturia

Normal Low High Normal Normal Normal Low Normal

Type-I dependent Low Low High High Normal Low Low low

Type –II vit-D dependent

low low High High N- High

N- High

Low low

category Serumcalcium

SerumPh3

Serum AlkalinePh3ase

PTH 25-HC 1, 25DHC

Tubular Reabsrp. Of Ph3

Urinary calcium

Renal tubular acidosis Low Low High High N –High N- High Low high

Rickets

Biochemical finding

Radiological findings of rickets• Generalized osteopenia• Widening of the unmineralised epiphyseal growth plates• Fraying of metaphysis of long bones • Bowing of legs• Pseudo-fractures (also called loozer zone)

– Transverse radio lucent band, usually perpendicular to bone surface

• Complete fractures• Features of long standing secondary hyperparathyroidism

(Osteitis fibrosa cystica)– Sub-periosteal resorption of phalanges– Presence of bony cyst (brown Tumor)

Rikcets - diagnosis

• History & physical examination finding• Radiographic abnormality• Special etiology confirmed with biochemical

tests

Rickets:Differential diagnosis

1.Hereditary Rickets:• Hypophosphatemic rickets (Vit D resistant)

• Vitamin D dependent rickets

Rickets:Differential diagnosisHypophosphatemic Rickets

• X-linked dominant / Autosomal dominant • Males affected more than females• Commonest inherited form of rickets• Prevalence 1: 25000• Phosphate wasting by renal tubules leads to:– Low serum phosphate– Normal calcium

• In-appropriate low or normal 1,25-di hydroxy vitamin D– phosphate is the major stimulus for 1 hydroxylase

• Severe rickets and short stature by 1-2 years

Rickets:Differential diagnosisHypophosphatemic Rickets

• Nutritional phosphate deficiency• Prematurity • Decreased intestinal absorption of phosphate– Ingestion of phosphate binders (aluminum

hydroxide)• Renal phosphate wasting– RTA– Vitamin D resistant rickets

• Tumor induced osteomalacia (oncogenic osteomalacia)

Rickets:Differential diagnosisHypophosphatemic Rickets

Biochemical findings :• Low serum phosphate level• Normal calcium level• Normal parathyroid hormone level• High alkaline phosphatase level• In-appropriate low or normal 1,25-di hydroxy

vitamin D– phosphate is the major stimulus for 1

hydroxylase

Rickets:Differential diagnosisVitamin D dependent rickets

Type 1 • Rare, autosomal recessive• Lack of 1 hydroxylase enzyme• Clinically and Biochemically similar to nutritional rickets

except it appears early at 3-4 monthsType 2• Rare autosomal recessive disorder• 1 hydroxylase enzyme is present • Lack of Calcitriol receptors• Common in Arabs• Baldness• Severely affected individuals• Unresponsive to treatment

Rickets:Differential diagnosis2)Celiac disease 3)Pancreatic insufficiency– Cystic fibrosis

4)Hepato-biliary disease– Biliary Atresia– Cirrhosis– Neonatal hepatitis

5)Drugs– Anti-convulsants

• Phenobartbital• Phenytoin

6)Diet – Excess of phytate in diet with impaired calcium

absorption (cereals, flour)

Rickets:Differential diagnosis Chronic liver disease

• Cirrhosis reduces 25-hydroxylation of vitamin D

• Biliary obstruction:• prevents absorption of fat soluble vit D• Interrupts its enterohepatic circulation

Rickets:Differential diagnosis Chronic renal failure

• Reduces 1 hydroxylation of 25 hydroxy vitamin D leads to low concentration of 1,25-di hydroxy vitamin D

• Consequently impair calcium absorption from the gut• Renal osteodystrophy– Osteitis fibrosa cystica due to long standing secondary

hyperparathyroidism

When GFR falls below 30 ml/min/1.73m2

• Impaired growth• Osteitis fibrosa results

• Sub-periosteal resorption at middle and distal phalanges

• Bone pain

• Muscle weakness

Rickets:Differential diagnosis Renal Tubular Acidosis (RTA)

• Metabolic acidosis from proximal or distal tubular disease

• Renal wasting of calcium (hypercalciuria)• Accompanied with other urinary loss:– Phosphate– Glucose– Protein

• Isolated or generalized forms• Fanconi (generalized form of RTA)– Associated with cystinosis, tyrosinemia,

Wilson's disease

Treatment• Treatment may be gradually administered over

several months or in a single-day dose of 15,000 mcg (600,000 U) of vitamin D

• gradual method 125-250 mcg (5000-10,000 U) daily for 2-3 months until healing is well established and the alkaline phosphatase normal Intramuscular injection is also available 200 000 ui X 3 doses every other day

• In nutritional rickets, the phosphorous level rises in 96 hours and radiographic healing is visible in 6-7 days

TreatmentFrom birth to 18 months

• The recommended dose to the newborn to 18-month 500 IU / day. • Increasing the dose of 1000 - 1500 IU / day for a limited period of time

is required in some cases to: - small infants whose mothers did not receive vitamin D prophylaxis

during pregnancy; - dismaturii premature and at least the first month of life. - young infants (up to 3-4 months) born in cold weather. - infants with frequent acute illnesses and those with frequent and

prolonged hospitalizations. - children in polluted environments. - Children with skin hyperpigmentation.

Treatment- children with poor environmental conditions. - children in some residential institutions (swing,

orphanages) that move less air and less out in the sun.

- Children with chronic anticonvulsant therapy (phenytoin, phenobarbital), cortisone In such situations will be given vitamin D daily dose of 1500 IU / day, but not more than one month, and then restarted at 400-500 IU or 500 IU alternate dose 1-2 weeks at a dose of 1000 IU; generally higher doses of 1500 IU are therapeutic

Treatment

After 18 months • Vitamin D is administered only during the months

of the year neînsorite with R, from September to the end of April until the age of 12-15 years.

• dose: daily 400-500 IU or every 7-10 days by 4000-5000 IU Vitamin D is given in oil solution (Vit. A + D2) administered po

• only fractional administration of vitamin D is physiological, as it ensures a good, especially if vitamin D is given a meal of milk;

Treatment If severe deformities have occurred,

orthopedic correction may be required after healing. Most of the deformities correct with growth.

Human milk contains little vitamin D and contains too little phosphorus for babies who weigh less than 1500 g.

Infants less than 1500 g need supplementation (ie, vitamin D, calcium, phosphorus) if breast milk is their primary dietary source.

Treatment

Curative treatment of rickets Objectives: • prevention or correction of skeletal deformities of

rickets and secondary hyperparathyroidism reagent; • prevention and correction hiopocalcemiei and related

symptoms (tetany, sudden death); • ensure normal growth and development; • application of vitamin D dose to provide a therapeutic

effect while avoiding adverse effects that: hypercalcemia, hypercalcuria.

Treatment

Lifestyle and nutrition • It is important in the treatment and prevention of

rickets triggered the disease. Preventive measures add the following recommendations:

• - Child with rickets evolving not be encouraged early to sit nor stand up and walk to the stabilization of the disease.

• - Recommend wearing supportive shoes with soles or you can, bare foot up to age 3.

Treatment

Curative therapy (schemes): Mild and medium forms:- oral daily administration - 2000-4000 IU Vitamin D

for 6-8 weeks and then returned to prophylactic - typically for 6 months each 1000 IU / day).

Severe forms: manifest hypocalcemia (convulsions) and children with malabsorption.

- administration of 3 doses of 100 000 UI Stoß vitamin D2 or D3 intramuscularly every 3 days, then a dose of 200 000 IU after 30 days oral or i.m.

Rickets:Evolution and prognosis

Evolution is generally favorable when rickets is controlled. Evolution untreated rickets-consequences:

1. Immediate consequences: - recurrent respiratory infections (favored by excessive flexibility and muscular hypotonia chest -lung rickety); - poor psychomotor development - hypocalcemia in infants caused certain complications: tetanie, laryngospasm, convulsions; - development of a microcytic,hypochromic anemia 2. Late consequences : - bone changes in the knees (genu varum, genu valgum) ; -signs of bone may persist for some time after correcting biological syndrome florid rickets, and in this case they do not require the setting treatment.

Rickets:Evolution and prognosis Evolution of treated rickets :

- Clinical signs within 2-4 weeks; - Biochemical normalization in 2-4 weeks, - in 1-5 days hypocalcemia,- hypophosphatemia and hyperparathyroidism in 2-3 weeks.- alkaline phosphatase activity levels remain elevated for

several weeks (6-8 weeks), to complete the correction of the deficiency bone mineralization, is a biological marker of cure of rickets.

- 25 OHD plasma levels to normal within 1-2 days. - Improving radiological observed 2-4 weeks after beginning

treatment with vitamin D in the form of dense linear deposits in the metaphyseal lines. Epiphyses and metaphyses is found normalization after 3 months.

TETANIA (Hypocalcemia)

Definition

Spasmophilia or tetanys -pathological states of the central nervous system and peripheralnervous system due to extracellular ionic changes involved in the function of neurons and peripheral nerves.

• A 70-kg person has approximately 1.2 kg of calcium in the body, stored as hydroxyapatite in bones (>99%).

• 1% (5-6 g) of this calcium is located in the intracellular and extracellular compartments, with only 1.3 g located extracellularly.

• calcium concentration in the plasma is 4.5-5.1 mEq/L (9-10.2 mg/dL)

• fifty percent of plasma calcium is ionized, 40% is bound to proteins (90% of which binds to albumin

Pathophysiology• Ionized calcium is the necessary plasma fraction

for normal physiologic processes. In the neuromuscular system, ionized calcium levels facilitate nerve conduction, muscle contraction, and muscle relaxation

• Normocalcemia requires PTH and normal target-organ response to PTH

• PTH stimulates osteoclastic bone reabsorption and distal tubular calcium reabsorption and mediates 1,25-dihydroxyvitamin D (1,25[OH]2 D) intestinal calcium absorption.

Pathophysiology

• Vitamin D stimulates intestinal absorption of calcium, regulates PTH release by the chief cells, and mediates PTH-stimulated bone reabsorption

• A reduction in total serum calcium can result from a decrease in albumin secondary to liver disease, nephrotic syndrome, or malnutrition.

• Hypocalcemia causes neuromuscular irritability and tetany.

• Alkalemia induces tetany due to a decrease in ionized calcium, whereas acidemia is protective.

Tetania

Clinical classification distinguishes two forms: 1. tetany manifested - manifested by seizures

(CNS excitability), carpopedal spasm (peripheral motor nerves) and paresthesias (sensory nerves).

2. latent tetany or spasmophilia - characterized by motor expressions obtained by a trigger such as ischemia, hyperpnea, electrical or mechanical stimulation.

Tetania- etiological classification

I. Hypocalcemic tetany The need for calcium: 50mg/kg/zi.

Contributing factors are artificial alimentation, season without sun, prematurity, neonatal infection, meso-diencephalic impairments, nephropathy.

a) parathyroid hypocalcemic tetany : 1. Transient hypoparathyroidism of newborn (high birth weight, diabetic mothers, hypoxia); 2. Primary congenital hypoparathyroidism - rare; 3. Secondary hypoparathyroidism; 4. Pseudo-and pseudo-pseudohipoparatiroidismul characterized by resistance to parathyroid hormone target organs.

Tetania- etiological classification

I. Hypocalcemic tetanyb) hypocalcemic tetany deficiency of vitamin D

or vitamin D metabolic abnormalities:- deficiency rickets ; - steatorrhea secondary rickets; - vitamin D resistant rickets. Hypocalcemia may occur at certain stages of rickets (I and III).

Tetania- etiological classification

II. Hypomagnesiemic tetany- low magnesium and calcium;

- Hypocalcemia is due to reduced release of endogenous PTH, alteration organ response to PTH and possible alteration of gastrointestinal absorption of calcium. III. Tetany with normal calcium - normal serum calcium, decreases calcium ion fraction or psychogenic tetany of adolescent with normal calcium

Tetania- etiological classificationIV. Other causes:

- Alkalosis; - Hypernatremia plus potassium deficiency (Conn's

syndrome) due to primary aldosteronism; - Postacidotic (in severe diarrhea); - Chronic renal failure; - Blood transfusions citrate in large quantities.• Critical illness and severe sepsis• After correction of thyrotoxicosis• Acute pancreatitis• Drugs: Bisphosphonates, Anticonvulsant therapy ,

Foscarnet, Ethylenediaminetetraacetic acid (EDTA) , Fluoride poisoning

Tetania – clinical manifestations

• numbness and tingling sensations in the perioral area or in the fingers and toes • muscle cramps, particularly in the back and lower

extremities; may progress to carpopedal spasm (ie, tetany) • wheezing; may develop from bronchospasm • abdominal pain,• dysphagia • voice changes (due to laryngospasm)

Tetania – clinical manifestations• irritability, impaired intellectual capacity, depression,

and personality changes • fatigue • seizures (eg, grand mal, petit mal, focal) • other uncontrolled movements• chest tightness, • ticks, twitch, headache, dizziness, confusional

episodes, • insomnia or restless sleep, sweating,• cardiovascular signs : tachycardia, hypertension or

breathing - shallow tachypnea.

Tetania – clinical manifestationsManeuvers to to induce neuromuscular hyperexcitability:a) ischemia - Trousseau sign. The cuff pressure is applied for 3 minutes at a medium pressure and motor follows the occurrence of events.b) mechanical stimulation (percussion) of the peripheral nerves

- Facial nerve - Chvostek sign;- Peroneal nerve - Lust sign (dorsiflexion and

abduction of the foot);- Orbital apophysis - mark Weiss (upper eyelid

orbicularis).c) electrical stimulation – Erb sign: response to electrical stimulation of the motor nerves galvanic current, of lower intensity than physiological.

Tetania: biochemical tests

Hypocalcemic tetany or hypomagnesaemic tetany- Low total serum calcium (N = 10 mg% or 5mEq / l); - Low calcium ion (2,5-3mEq N / m); - Low magnesium (n = 1.6-2.6 mg%); - Phosphorus can be decreased or increased:• the phosphor is low in rickets.• Phosphorus elevated (parathyroid reaction):

hyperphosphatemia spasmophilia;

Tetania: paraclinic investigations

1.Biochemical tests- Increased alkaline phosphatase (in rickets) (N =

130-140 IU / ml); - pH (Astrup) increased - alkalosis (N = 7.35); - Ionograma : hyponatremia or hyperkalemia; - Parathyroid hormone (PTH) low - rarely dosed; - Low serum levels of 25-OH cholecalciferol and

1,25 (OH) 2 cholecalciferol - often dispensed.

Tetania

2.ECG - useful for rapid diagnosis and surveillance of hypocalcemic tetany.

• Signs of hypocalcaemia (PAUP criteria and Dalloz) - QT prolongation; - T wave high, sharp,

symmetrical; - Display / R-R equal to 0.5 or above 0.5.

3.Calciuria, phosphaturia :present.4. Radiography of the skeleton - showing lesions of rickets and / or osteoporosis.

prolongation of the QTc interval because of lengthening of the ST segment, which is directly

proportional to the degree of hypocalcemia

Treatment

Treatment is a pediatric emergency and consists of:- nonspecific measures for seizures - oxygenotherapy .

Seizures are brief and rarely need treatment anticonvulsant ( diazepam ) .

- Diazepam iv a dose of 0.3-0.5 mg / kg administered slowly (1 R = 2 ml = 10 mg , 0.1 ml = 0.5 mg ) .A. hypocalcemic tetany :

1. Emergency treatment :2. Background therapy

Treatment

1. Emergency treatment • IV calcium - 2ml/kg/dose Calcium gluconate 10%

-slowly over 10-15 minutes. It is administered under the control of heart rate (AV ) , following the AV does not fall below 80 beats / minute. Discontinue administration if bradycardia when AV drops below 80 beats / min .

• Calcium is continued until the disappearance of the clinical signs and ECG . Dose: 15-30 mg elemental calcium / kg / day or 500-1000 mg/m2/day

Treatment2. Background therapy - continued administration of the

same dose of oral calcium 500-1000 mg calcium elemental/m2/24 hours.

• Duration 3-6 weeks with oral calcium to normalize biochemical/radiological normalization.

• Calcium : careful clinical and laboratory control to avoid the risk of hypercalcemia. The doses of calcium is adjusted by repeat determination of serum calcium and calcium excretion, serum calcium as to be in the normal range of 8-10 mg/100 ml and does not exceed 6-8 urinary calcium excretion mg / kg / day. Add vitamin D therapy in rickets with hypocalcemia .

Treatment

B. Hypomagnesiemic tetany• Administered iv magnesium preparations that

the same hazard as the administration of calcium in the treatment and maintenance treatment procedures.

• Magnesium sulfate is used in 20% (SO4Mg 20%), 1 f = 10 ml 2000 mg Mg = 2 g = 1 ml = 200 mg.