Rickets and Tetania
CONF. 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 wellbeing 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 (1,25dihydroxycholecalciferol).
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 1hydroxylation 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.
Pathogeny
The 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
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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 Causes
Lack 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 rickets
Vitamin 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 findings
Category
Serum
Calcium
Serum
Ph3
Serum
Alkaline
Ph3ase
PTH
25-HC
1, 25DHC
Tubular
Reabsrp.
Of Ph3
Urinary
calcium
Vit-D deficiency
Low to
normal
Low
High
High
Low
Low
Low
low
Ph3 deficiency
normal
Low
High
normal
normal
normal
High
High
Gastrointestinal
Low
Low
High
High
Low to
Normal
Low to
Normal
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
Rickets
Biochemical finding
category
Renal tubular acidosis
Serum
calcium
Serum
Ph3
Serum
Alkaline
Ph3ase
PTH
25-HC
1, 25
DHC
Tubular
Reabsrp.
Of Ph3
Urinary
calcium
Low
Low
High
High
N –High
N- High
Low
high
Radiological findings of rickets
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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 diagnosis
Hypophosphatemic Rickets
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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 diagnosis
Hypophosphatemic 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 diagnosis
Hypophosphatemic 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 diagnosis
Vitamin 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 months
Type 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 diagnosis
2)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
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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
Treatment
From 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
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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 targetorgan 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 tetany
b) 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 classification
IV. 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 manifestations
Maneuvers 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
Treatment
2. 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.