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  • Primary sources and configurations of vitamin D. Adapted from Lucas et al. (2)‏
  • Rickets lecture

    1. 1. The Department of Pediatrics V.N. Karazin Kharkiv National University
    2. 2. RICKETS Assistant of the Department of Pediatrics Lyudmyla Olexandrivna Rakovska
    3. 3. The plan of the lecture: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Definition and types of Rickets Metabolism of Vitamin D, Ca, and P Etiology of Rickets Pathogenesis of Rickets Classification of Rickets Clinical manifestations of Rickets Laboratory and radiological findings Differential diagnosis Treatment and Prevention of Rickets Hypervitaminosis D: pathogenesis, clinical features, diagnosis, differential diagnosis, treatment
    4. 4. Rickets (Rachitis)  is a metabolic disease of growing bone that is unique to children (especially of first 2 years) and adolescents. It is caused by a failure of osteoid to calcify in a growing person.
    5. 5. Rickets  characterized by a failure of bone tissue to be properly mineralized, especially by imperfect calcification, typically resulting in soft bones and skeletal deformities.
    6. 6. “English disease” is another name of Rickets old English word wrick, (wrickken) means "to twist”.  The Greek word "rachitis" (ῥαχίτης, meaning “to bend” 
    7. 7. Types of Rickets Nutritional Rickets or vitamin D-deficiency Rickets Vitamin D-dependent Rickets   • •   Type I Type II Vitamin D-resistant Rickets (“looks like Rickets”) Secondary Rickets
    8. 8. ETIOLOGY  Main cause of Rickets is vitamin D deficiency
    9. 9. VITAMIN  Vitamin D is a fat-soluble vitamin. It is often called the "sunshine" vitamin
    10. 10. Role of vitamin D calcium homeostasis absorption of Ca and P in the small intestine reabsorption Ca and P in the renal tubule normal mineralization of bone
    11. 11. Vitamin D D3 cholecalciferol D2 ergocalciferol
    12. 12. Vitamin D Metabolism ( Adapted from Lucas et al.) 2009;10:e590-e599 ©2009 by American Academy of Pediatrics Taylor S N et al. Neoreviews
    13. 13. Pathophysiology
    14. 14. Vitamin D and Health Results of vitamin D deficiency:  rickets in children  osteomalacia in adults  fractures in adults and older adults  cancers (breast, prostate, colon)  autoimmune diseases  infectious diseases  type I diabetes mellitus and other
    15. 15. PATHOGENESIS Causes of vitamin D deficiency 1. Disorders associated with Vitamin D synthesis • • Deficiency in cutaneously synthesized vitamin D Lack of dietary intake 2. Disorders associated with Vitamin D absorbtion 3. Chronic diseases of the liver or kidney 4. Hereditary (congenital) anomalies of metabolism of Vitamin D, Ca, P.
    16. 16. Sun Exposure  20 to 30 minutes of sun (especially between the hours of 10:00 am and 3:00 pm) three or four times a week ensure enough vitamin D in people.
    17. 17. Causes of vitamin D deficiency cutaneously synthesized Cance r???
    18. 18. Lack of dietary Intake
    19. 19. Vitamin D malabsorption problems celiac sprue,  short bowel syndrome,  cystic fibrosis 
    20. 20. Medications are associated with vitamin D deficiency Steroids  Antiepileptic (anticonvulsants) drugs: Phenobarbital and Phenytoin (brand name Dilantin®)  Orlistat (brand names Xenical® and alliTM) and the cholesterol-lowering drug Cholestyramine (brand names Questran®, LoCholest®, and Prevalite®) 
    21. 21. Secondary Rickets Chronic liver diseases  End-stage renal diseases (renal osteodystrophy) 
    22. 22. Hereditary (congenital) anomalies of metabolism of Vitamin D, Ca and P  Vit D-dependent rickets of I type (pseudovitamin D-deficiency rickets) - defect in the gene coding of renal 1-alpha-hydroxylase. Autosomal recessive desease.   Vit D-dependent rickets of II type (hereditary 1-alfa, 25-dihydroxyvitamin Dresistent rickets) - mutation exists in the vitamin D receptors (VDR). Autosomal recessive desease. Vit D-resistent rickets (familial hypophosphatemic rickets) - mutations of the phosphate-regulating gene on the X chromosome
    23. 23. Classification of Rickets Degree Period of disease Initial Height (manifest) Mild (“Florid rickets”) (I) Moderate Reconvalescenction (reparation) (II) Residual symptoms Severe (permanent (III) changes) Course Acute Subacute Recurring
    24. 24. CLINICAL MANIFESTATIONS I. Findings specific to the bone tissue in rickets  Symptoms of osteomalacia:  Symptoms of hyperplasia of osteoid tissue  Symptoms of hypoplasia of osseous tissue II. Findings not specific to the bone tissue in rickets
    25. 25. Findings specific to the bone tissue Symptoms of osteomalacia: сraniotabes  softening of the big fontanel's edges  softening of ribs  kyphosis  bowing in the legs 
    26. 26. Findings specific to the bone tissue Symptoms of hyperplasia of osteoid tissue: increase of frontal and occipital tubers (frontal bossing, “caput quadratum”)  costohondral prominence ("rachitic rosary")  chest deformities (Harrison’s groove and pigeon breast) 
    27. 27. Findings specific to the bone tissue Symptoms of hypoplasia of osseous tissue: delayed fontanel closure  delayed teething  enamel hypoplasia  costal or lower extremity fractures (particularly greenstick fractures)  lag of growth of tubular bones in length in severe cases. 
    28. 28. Findings not specific to the bone tissue in rickets: occipital alopecia  muscular hypotonia  constipation,  hypocalcemic convulsions,  anemia,  increased risk for respiratory infections.  growth retardation and low height−for−age (rachitic dwarfism). 
    29. 29.    In acute course of rickets symptoms of osteomalacia prevail, in subacute – symptoms of hyperplasia of osteoid tissue. Skeletal deformities become obvious in stage II and worsen in stage III. Initial period is starting from 2-3 month of life, lasts from 2-3 weeks to 2-3 months. In breast-fed infants whose mothers have osteomalacia, rickets may develop before 2 mo. Florid rickets appears toward the end of the 1st and during the 2nd year of life. Later in childhood, manifest vitamin D deficient rickets is rare.
    30. 30. PHYSICAL EXAMINATION: Head Craniotabes (areas of thinning and softening of bones of the skull) manifests early in infants older than 2−3 months. It detected by pressing firmly over the occiput or posterior parietal bones. A ping-pong-ball sensation will be felt. 
    31. 31. PHYSICAL EXAMINATION: Head  frontal bossing which give the head a boxlike or "square headed" appearance (caput quadratum)
    32. 32. PHYSICAL EXAMINATION: Chest  knobby deformities «rachitic rosary» (“rosary beads”) along the costochondral junctions
    33. 33. PHYSICAL EXAMINATION: Chest The weakened ribs pulled by muscles also produce flaring over the diaphragm, which is known as Harrison groove.
    34. 34. PHYSICAL EXAMINATION: Chest  pigeon-breast deformity
    35. 35. PHYSICAL EXAMINATION: Extremities  enlargement thickening of the wrists
    36. 36. PHYSICAL EXAMINATION: Extremities  enlargement thickening of the ankles
    37. 37. Вowing in the legs
    38. 38. Genu varum  bowlegs or “O“−type leg deformity occurs when the femoral intercondylar distance exceeds 5 cm
    39. 39. Genu varum
    40. 40. Genu valgum  knock-knees or “X“−type leg deformity
    41. 41. PHYSICAL EXAMINATION: Spine   kyphos
    42. 42. PHYSICAL EXAMINATION: non specific symptoms Muscular hypotonia Generalized muscular hypotonia  "floppy baby syndrome" or "slinky baby" (such that the baby is floppy or slinky-like) 
    43. 43. PHYSICAL EXAMINATION: non specific symptoms Neurologic abnormalities  observed in all cases and revealed at initial period of disease as irritability, interrupted sleep, sweating.
    44. 44. PHYSICAL EXAMINATION: non specific symptoms Occipital alopecia  Increased sweating, particularly around the head, may also be present as non specific symptom. It leads to occipital alopecia and occurs in 30%.
    45. 45.  rachitic rosary (62.1%), craniotabes (49%), occipital alopecia (31.4%) and enlargement of the wrists (27.1%) were the four most common physical examination findings for the age group 0−6 months
    46. 46. TETANY (SPASMOPHILIA)  disease of infants, resulting from disturbances of Ca metabolism and characterized by the development of tonetic and tonoclonic convulsions.
    47. 47. Most frequent symptoms and signs of latent Tetany Chvostek’s sign;  Trousseau’s symptom;  Maslov’s symptom;  Erb’s symptom;  Lust’s sign 
    48. 48. Most frequent symptoms and signs of Manifest Tetany Laryngospasm  Carpopedal spasm  General tonic convulsions  Convulsive spasm of a heart muscle leading to child’s death is possible!!!
    49. 49.  In a patient suspected to have rickets based on clinical findings, the diagnosis is confirmed by biochemical and radiological findings.
    50. 50. LABORATORY FINDINGS Obligatory serum measurements :  Calcium  Phosphorus (N)  Alkaline phosphatase (N) Additional:  25-hydroxy vitamin D  Parathyroid hormone  Sulkovich’s test of urine
    51. 51. Calcidiol (25-hydroxy vitamin D) PTH
    52. 52. Serum 25(OH)D (calcidiol) vitamin D deficiency-insufficiecy Normal ≥50 nmol/L (≥20 ng/mL) 0 25 50 ** 1 nmol/L = 0.4 ng/mL 75 potential adverse effects >125 nmol/L (>50 ng/mL) 125 nmol/L
    53. 53. Sulkovich’s test This test gives approximate presentation about Ca content in blood from is presents in urine.  Assessment of result: “+” – normal level “++, ++++” – hypercalcaemia and hypercalciuria 
    56. 56.   Rickets leads to cupping and to a brush−like appearance of the epiphyseal ends on radiograms. Radiographs of the knee of a 3.6-yearold girl with hypophosphatemia depict severe fraying of the metaphysis. N Active Rickets recovery
    57. 57. RADIOLOGICAL FINDINGS  Anteroposterior and lateral radiographs of the wrist demonstrates cupping and fraying of the metaphyseal region.
    58. 58. RADIOLOGICAL FINDINGS   Rosary beads of rickets curved back
    59. 59. DIFFERENTIAL DIAGNOSIS    Vitamin Vitamin Vitamin D ̶ deficient rickets D ̶ dependent rickets (types I and II) D-resistent Rickets (“looks like Rickets”): • Hereditary X-linked hypophosphatemic rickets with hypocalciuria • Familial hypophosphatrmic • Phosphat-diabetes • Achondrodroplasia • Fanconi syndrome (De Toni-Debre-Fanconi desease) (types I and II)      Pseudohypoparathyroidism Renal tubular acidosis Cystinosis Tyrosinemia Secondary Rickets (renal, gastrointestinal, tumorassociated, medications, malabsortion syndromes et all)
    60. 60. Familial hypophosphatemic Low stature in the family, dental deformities, orthopaedic abnormalities, and consanguineous marriage indicated for hereditary hypophosphatemic rickets
    61. 61. Renal osteodystrofy  Chronic renal failure IV st, prolonged of haemodyalis
    62. 62.  Achondrodroplasia
    63. 63. Differential diagnosis tetany  includes hyperthermic convulsions, complicated pneumonia, meningitis, viral diseases. In hypoparathyroidism which is very rare in babies, hypocalcemia and hyperphosphatemia are usual. Eclamptic form is necessary to differentiate from epilepsy.
    64. 64. TREATMENT Common measures in rickets treatment irrespective of its form are the following:  adequate feeding, regimen and walks;  massage and physical training
    65. 65. Ergocalciferol is a form of vitamin D, also called vitamin D2.  It is marketed under various names including Deltalin (Eli Lilly and Company), Drisdol (Sanofi-Synthelabo) and Calcidol (Patrin Pharma).
    66. 66. Cholecalciferol is a form of vitamin D, also called vitamin D3 or calciol
    67. 67. 1. Low dosage and long−term vitamin D therapy (gradual method)        1000− 10 000 IU/day (125-250 mcg) for 2−3 months Vitamin D can be given according to the infant’s age as follows: 1000 IU/day for infants < 1 month of age, 1000-5000 IU/ day for children 1-12 mon. 5000-10 000 IU/day for children > 12 mon. If hypocalcemia is seen the initial dose of vit D must be doubled. Afterwards, it is recommended to give maintenance therapy of 400 IU/ day.
    68. 68.    Because this method requires daily treatment, success depends on compliance. Levels of Ca and P are normalized in 6−10 days by this therapy, while it takes 1−2 months for PTH to reach normal levels. Depending on the severity of the disease, it may take 3 months for the normal serum ALP levels to be restored and the radiological findings of rickets to disappear. In this treatment model, lack of compliance is an important cause of lack of response
    69. 69. 2. Stoss therapy (single-day therapy) For patients who are suspected to have poor compliance, a high dose of vitamin D can be given orally or intramuscularly as a single dose of 100 000−600 000 IU after the first month of life.  This dose is usually divided into 4 or 6 oral doses. An intramuscular injection is also available. 
    70. 70. Stoss therapy (single-day therapy) Administration of 150 000−300 000 units of vitamin D and 600 000 units (15,000 mcg) in severe rickets is an effective and safe method of treatment.  Vitamin D (cholecalciferol) is well stored in the body and is gradually released over many weeks. This treatment evokes a rapid clinical response, resulting in biochemical recovery in a few days and radiological recovery in 10−15 days. 
    71. 71.  The single-day therapy avoids problems with compliance and may be helpful in differentiating nutritional rickets from familial hypophosphatemia rickets (FHR). In nutritional rickets, the phosphorus level rises in 96 hours and radiographic healing is visible in 6-7 days. Neither happens with FHR.
    72. 72. Ca therapy  Ca administration becomes necessary when clinical signs of tetany or convulsions are present.
    73. 73. Emergency care of tetany    10% Ca gluconate (1−2 ml/kg, or 0,3-0,5 mgkg 3 times a day) IV and slowly while monitoring ECG (bradicardia, arrhythmia). In convulsions it is necessary to inject i.v. seduxen (0.1 ml/kg or 0,5 mgkg of 0,5% solution), MgSO4 (0,2-0.5 ml/kg of 25% solution), sodium oxybutirate (0.5 ml/kg or 50-120 mgkg of 20% solution), oxygen inhalations. In laryngospasm it is necessary to create a dominant focus of excitement in the brain (irritation of nasal mucosa, skin with a prick, tap).
    74. 74. Ca levels should then be maintained with oral Ca supplements.  Infants with latent tetany may respond orally calcium gluconate (5%) or calcium chloride (1-2%) – 1 teaspoonful x 3 times a day.  Restriction of cow milk because of great quantity of phosphates.  After 3-4 days – vit D 2-4 000 twice a day is prescribed. 
    75. 75. Orthopedic correction  If severe deformities have occurred, orthopedic correction may be required after healing. Most of the deformities correct with growth.
    76. 76. Pharmacologic Therapy of D ̶ resistant rickets familial hypophosphatemic rickets  The usual vitamin D preparations are not useful for treatment in this disorder, because they lack significant 1-alphahydroxylase activity. Original treatment protocols advocated vitamin D at levels of 25,000-50,000 U/d (at the lower limit of toxic dosage). Amiloride and hydrochlorothiazide are administered to enhance calcium reabsorption and to reduce the risk of nephrocalcinosis.
    77. 77. Result of treatment of familial hypophosphatemic rickets
    78. 78. PREVENTION Postnatal Antenatal nonspecific nonspecific specific specific specific specific nonspecific nonspecific nonspecific nonspecific specific specific specific specific
    79. 79. Physiological method to prevent vitamin D insufficiency/deficiency  To educate society, sufficiently exposed to sunlight mothers and infants and rational feeding (balanced diet rich in Ca and vitamin D), individual care, gymnastics, massage.
    80. 80.   Natural nutritional sources of vitamin D are limited primarily to fatty, ocean-going fish. The fortification of milk with vitamin D beginning in the 1930s has made rickets a rare disease in the United States. Thus, the disorder is rarely seen today in countries where "fortified" milk is available. Dietary Intake
    81. 81. Specific methods of prevent of vitamin D-deficiency Rickets (VDR)   Supplementation vitamin D for mother and child. Today, vitamin D prophylaxis means not only prevention of clinical rickets (VDD) but also maintenance of optimal serum 25 (OH)D level in order to prevent vitamin D insufficiency.
    82. 82.  The daily maintenance dose of vitamin D varies by age. It has been reported that the dose of prophylactic vitamin D should be between 400 and 1000 IU/day to maintain the serum 25(OH)D at optimum levels (50-75 nmol/L).
    83. 83.   The 2003 American Academy of Pediatrics (AAP) vitamin D guidelines recommended a minimal vitamin D dose of 200 IU/day due to evidence demonstrating that this dose would maintain serum 25(OH)D concentrations greater than 27.5 nmol/L. The 2008 AAP guidelines recommend an increased minimum supplementation of 400 IU/day to ensure serum 25(OH)D values greater than 50 nmol/L to avoid vitamin D-deficient rickets. AAP report recommends 400 IU/day for all infants, children, and adolescents, with initiation of the supplementation in the “first few days” after birth.
    84. 84. The Endocrine Society recommends (2011) :     The Endocrine Society, along with the Canadian Society of Endocrinology and Metabolism and the National Osteoporosis Foundation, published a clinical practice guideline in 2011 titled "Evaluation, Treatment and Prevention of Vitamin D Deficiency." 400 IU (10 mcg) for children aged 0-1 year 600 IU/day (15 mcg) for children aged 118 years 1500-2000 IU for all men and women older than 18 years, including lactating and pregnant women whose infants are not ingesting vitamin D.
    85. 85.  Also with a perspective to prevent early rickets, it is recommended that vitamin D at a dose of 2000 IU/day should be administered during the last trimester of pregnancy to mothers with poor exposure to sunlight due to various reasons and who are at high risk of Vitamin D deficiency.
    86. 86.  Ergocalciferol and Cholecalciferol are used for specific prevent of rickets. Use of total 2-5 daily doses in one intake (correspondingly every 2-5 days).
    87. 87. Prophylactic course of vitamin D may be interrupted by UV irradiation.  Specific prevention isn’t carried out in the children receiving formula feeding. 
    88. 88.  Families with inherited rickets may seek genetic counseling.
    89. 89. HYPERVITAMINOSIS D  Hypervitaminosis D is a condition result from toxic action of vitamin D and is characterized with intoxication of different degree, affection of organs and systems and development of hypercalcemia.
    90. 90. HYPERVITAMINOSIS D 10,000 - 40,000 IU/day
    91. 91. Pathogenesis  direct toxic action upon cellular membranes, metabolism, and consequences of hypercalcemia.
    92. 92. Classification of Hypervitaminosis D Course Form Acute (as Nervous neurotoxicosis Gastroor toxicosis intestinal with Renal dehydration of Cardio1-3 degree) vascular Chronic Period Clinical manifestations Residual signs
    93. 93. Symptoms of vitamin D poisoning include: Dehydration (polyuria, vomiting)  Decreased appetite (anorexia)  Irritability  Constipation  Fatigue  Muscle weakness 
    94. 94.  An excess of vitamin D causes abnormally high blood concentrations of calcium (hypercalcemia), which can cause overcalcification of the bones, soft tissues, heart and kidneys.
    95. 95. Laboratory findings:      A serum 25(OH)D concentration >500 nmol/L (>200 ng/mL) hypercalcemia, hypophosphatemia. hypomagnesemia, hypokalemia, increased levels of cholesterin ; metabolic acidosis. Blood: leucocytosis; Urine: increase of calcium, Sulkowitch's test is positive (++++);
    96. 96. Treatment    To cancel immediately vit D, and limited quntety of cow milk (that is rich in calcium). Intensive detoxicative therapy: i.v. injections of albumin, 5% solution of glucose with Ringer’s solution, cocarboxylase, vit C, prednisolone (1-2mg/kg), vit A (5-10000 IU/day), vit E, furosemid (1 mg/kg 3 times/d), thyreocalcitonin (75-150 U i.m. every day), 3% solution of ammonium chloride (1 teaspoonful 3 times a day), almagel, chlolestiramine (0.5 g/kg 3 times/day),Trilon B 50 mg/kg 2-3 times/d orally, in severe cases –i.v. are used.