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Vitamin D,E and K

Anna Lee S. Fernandez,M.D.

Bone consists of a protein matrix called osteoid and a mineral phase, principally composed of calcium and phosphate, mostly in the form of hydroxyapatite. Osteomalacia is present when there is inadequate mineralization of bone osteoid; it occurs in children or adults Rickets, a disease of growing bone, occurs in children only before fusion of the epiphyses, and is due to unmineralized matrix at the growth plates. .

Physical and Metabolic Properties and Food Sources of the Vitamins (D, E, and K)
NAMES AND SYNONYMS CHARACTERIS TICS BIOCHEMICAL ACTION EFFECTS OF DEFICIENCY EFFECTS OF EXCESS SOURCES Vitamin D3 (3-cholecalciferol), skin Vitamin D2 (from plants or yeast) are biologically equivalent; 1 g = 40 IU vitamin D biologic activity Fat-soluble, stable to heat, acid alkali, and oxidation; Bile necessary for absorption; Hydroxylation in the liver and kidney necessary for Necessary for gastrointestinal absorption of calcium; Increases absorption of phosphate; direct actions on bone, including mediating resorption Rickets in growing children; Hypercalcemia, which may cause emesis, anorexia, pancreatitis, hypertension, arrhythmias, central nervous system effects, polyuria, nephrolithiasis, and renal failure Exposure to sunlight (ultraviolet light); fish oils, fatty fish, egg yolks, and vitamin D fortified formula, milk, cereals, and bread

Causes of Vitamin D Deficiency

Nutritional vitamin D deficiency Congenital vitamin D deficiency Secondary vitamin D deficiency Malabsorption Increased degradation Decreased liver 25-hydroxylase Vitamin Ddependent rickets type 1 Vitamin Ddependent rickets type 2 Chronic renal failure

Calcium Deficiency
Low intake Diet Premature infants (rickets of prematurity) Malabsorption Primary disease Dietary inhibitors of calcium absorption

Inadequate intake Premature infants (rickets of prematurity) Aluminum-containing antacids

Chief Complaints
skeletal deformities or have difficulty walking failure to thrive and symptomatic hypocalcemia

Clinical Evaluation
Dietary history, emphasizing intake of vitamin D and calcium. Exact composition of the formula or milk Cutaneous synthesis mediated by sunlight exposure is an important source of vitamin D. Maternal risk factors for nutritional vitamin D deficiency Determining a child's intake of dairy products. High dietary fiber may interfere with calcium absorption. Medications History of liver or intestinal disease-Fat Malabsorption

Clinical Evaluation
A history of renal disease (proteinuria, hematuria, urinary tract infections) Polyuria may occur in children with chronic renal failure or Fanconi syndrome. history of dental caries, poor growth, delayed walking, waddling gait, pneumonia, and hypocalcemic symptoms genetic causes of rickets, although most are rare

Clinical Features of Rickets

GENERAL Failure to thrive Listlessness Protuding abdomen Muscle weakness (especially proximal) Fractures HEAD Craniotabes Frontal bossing Delayed fontanelle closure Delayed dentition; caries Craniosynostosis HYPOCALCEMIC SYMPTOMS Tetany Seizures Stridor due to laryngeal spasm

Clinical Features of Rickets

CHEST Rachitic rosary Harrison groove Respiratory infections and atelectasis BACK Scoliosis Kyphosis Lordosis EXTREMITIES Enlargement of wrists and ankles Valgus or varus deformities Windswept deformity (combination of valgus deformity of 1 leg with varus deformity of the other leg) Anterior bowing of the tibia and femur Coxa vara Leg pain

Laboratory Findings
Hypocalcemia is a variable finding due to the actions of the elevated PTH to increase the serum calcium concentration. Hypophosphatemia is due to PTH-induced renal losses of phosphate, combined with a decrease in intestinal absorption. Wide variation in 1,25-D levels (low, normal, or high) is secondary to the upregulation of renal 1-hydroxylase due to concomitant hypophosphatemia and hyperparathyroidism. The level of 1,25-D is only low when there is severe vitamin D deficiency. Some patients have a metabolic acidosis secondary to PTH-induced renal bicarbonate-wasting. There may also be generalized aminoaciduria.

Combination of a history of poor vitamin D intake and risk factors for decreased cutaneous synthesis, radiographic changes consistent with rickets, and typical laboratory findings . A normal PTH level almost never occurs with vitamin D deficiency and suggests a primary phosphate disorder. Calcium deficiency may occur with or without vitamin D deficiency. A normal level of 25-D and a dietary history of poor calcium intake support a diagnosis of isolated calcium deficiency.

Vitamin D Synthesis
The final step in activation occurs in the kidney 1,25-dihydroxyvitamin D (1,25-D)

Stoss therapy 300,000600,000 IU of vitamin D are administered orally or intramuscularly as 24 doses over 1 day The alternative is daily, high-dose vitamin D, with doses ranging from 2,0005,000 IU/day over 46 wk. Either strategy should be followed by daily vitamin D intake of 400 IU/day, typically given as a multivitamin. It is important to ensure that children receive adequate dietary calcium and phosphorus; this is usually provided by milk, formula, and other dairy products.

Most children have an excellent response to treatment, with radiologic healing occurring within a few months. Laboratory test results should also normalize rapidly. Many of the bone malformations improve dramatically, but children with severe disease may have permanent deformities.

Most cases of nutritional rickets can be prevented by universal administration of a daily multivitamin containing 200400 IU of vitamin D to children who are breast-fed.

Congenital rickets
Occurs when there is severe maternal vitamin D deficiency during pregnancy. Maternal risk factors include poor dietary intake of vitamin D, lack of adequate sun exposure, and closely spaced pregnancies. Hypocalcemia, intrauterine growth retardation, and decreased bone ossification, with classic rachitic changes

Fanconi Syndrome
Generalized dysfunction of the renal proximal tubule .There are renal losses of phosphate, amino acids, bicarbonate, glucose, urate, and other molecules that are normally reabsorbed in the proximal tubule. The most clinically relevant consequences are hypophosphatemia due to phosphate losses and proximal renal tubular acidosis due to bicarbonate losses. The findings of aminoaciduria, glucosuria, and a low serum uric acid level are helpful diagnostically. Fanconi syndrome in children is often secondary to an underlying genetic disorder. Cystinosis is the most common genetic etiology; other causes include Wilson disease, Lowe syndrome, and tyrosinemia. Heavy metal exposure or drug toxicity (ifosfamide, valproate, aminoglycosides).

Vitamin E
Antioxidant, but its precise biochemical functions are not known. Vitamin E deficiency, which may cause hemolysis or neurologic manifestations, occurs in premature infants, in patients with malabsorption, and in an autosomal recessive disorder affecting vitamin E transport.

-tocopherol is the most potent and the most common form

Who are at Risk?

ANSWER: Premature infants Manifestations: thrombocytosis, edema, and hemolysis potentially causing anemia. The risk is increased by the use of formulas for premature infants that had a high content of polyunsaturated fatty acids. This led to a high content of polyunsaturated fatty acids in red blood cell membranes, making them more susceptible to oxidative stress, which could be ameliorated by vitamin E.

Physical and Metabolic Properties and Food Sources of the Vitamins (D, E, and K)

Vitamin E
Group of related compounds with similar biologic activities; tocopherol is the most potent and the most common form

Fatsoluble;readily oxidized by oxygen, iron, rancid fats; bile acids necessary for absorption

Antioxidant;protection of cell membranes from lipid peroxidation and formation of free radicals

Red cell hemolysis in premature infants; posterior column and cerebellar dysfunction; pigmentary retinopathy


Vegetable oils, seeds, nuts, green leafy vegetables, and margarine

Clinical Manifestations
Patients may have cerebellar disease, posterior column dysfunction, and retinal disease. Loss of deep tendon reflexes is usually the initial finding. Subsequent manifestations include limb ataxia (intention tremor, dysdiadochokinesia), truncal ataxia (wide-based, unsteady gait), dysarthria, ophthalmoplegia (limited upward gaze), nystagmus, decreased proprioception (positive Romberg test), decreased vibratory sensation, and dysarthria. Some patients have pigmentary retinopathy. Cognition and behavior may also be affected. Myopathy and cardiac arrhythmias are less common findings.

Measuring the ratio of vitamin E to serum lipids; a ratio <0.8 mg/g is abnormal. Premature infants with hemolysis due to vitamin E deficiency also often have elevated platelet counts. Neurologic involvement may cause abnormal somatosensory evoked potentials and nerve conduction studies. Abnormalities on electroretinography may precede physical examination findings in patients with retinal involvement.

Premature infants with unexplained hemolytic anemia after the 1st month of life, especially if thrombocytosis is present, either should be empirically treated with vitamin E or should have serum vitamin E and lipid levels measured. Children with neurologic findings and a disease that causes fat malabsorption should have their vitamin E status evaluated.

Neonates, the dose of vitamin E is 2550 units/day for 1 wk, followed by adequate dietary intake. -Tocopheryl polyethylene glycol succinate (TPGS) is a water-soluble preparation of vitamin E that is absorbed in the absence of bile salts. It is effective in children with vitamin E deficiency secondary to severe malabsorption. Doses are 2025 units/kg/day, with adjustment based on the ratio of vitamin E to serum lipids. Itenhances absorption of the other fat-soluble vitamins (A, D, and K) and a variety of medications

The hemolytic anemia in infants resolves with correction of the vitamin E deficiency. Some neurologic manifestations of vitamin E deficiency may be reversible with early treatment, but many patients have little or no improvement. Treatment prevents progression.

Premature infants should receive sufficient vitamin E and formula without a high content of polyunsaturated fatty acids. Children at risk for vitamin E deficiency due to malabsorption should be screened for deficiency and given adequate vitamin E supplementation. Vitamin preparations with high content of all of the fat-soluble vitamins are available.

Vitamin K
Necessary for the synthesis of clotting factors II, VII, IX, and X, may result in clinically significant bleeding. This typically affects infants, who experience a transient deficiency related to inadequate intake, or patients of any age who have decreased vitamin K absorption. Mild vitamin K deficiency may affect long-term bone and vascular health

Physical and Metabolic Properties and Food Sources of the Vitamins (D, E, and K)
NAMES AND SYNONYMS CHARACTERIS TICS BIOCHEMICAL ACTION EFFECTS OF DEFICIENCY EFFECTS OF EXCESS SOURCES Vitamin K Group of naphthoquinones with similar biologic activities; K1 (phylloquinone) from diet; K2 (menaquinones) from intestinal bacteria Natural compounds are fat-soluble; stable to heat and reducing agents; labile to oxidizing agent, strong acids, alkali, light; bile salts necessary for intestinal absorption Vitamin Kdependent proteins include coagulation factors II, VII, IX, and X;proteins C, S, Z; matrix Gla protein, osteocalcin Hemorrhagic manifestations; long-term bone and vascular health Not established; analogues (no longer used) caused hemolytic anemia, jaundice, kernicterus, and death Green leafy vegetables, liver, and certain legumes and plant oils; widely distributed

Forms of Vitamin K
Phylloquinone, called vitamin K1, is present in a variety of dietary sources, with green leafy vegetables, liver, and certain legumes and plant oils having the highest content. Vitamin K2 is a group of compounds called menaquinones, which are produced by intestinal bacteria

Forms of Vitamin Kdeficiency bleeding (VKDB) of the newborn

1. Early VKDB, formerly called classic

hemorrhagic disease of the newborn, occurs at

114 days of age. It occurs mostly in breast-fed infants due to the low vitamin K content of breast milk (formula is fortified). Delayed feeding is an additional risk factor.

Forms of Vitamin Kdeficiency bleeding (VKDB) of the newborn

2.Late VKDB most commonly occurs at 212 wk & can occur up to 6 mo after birth. Breast-fed infants due to the low vitamin K content of breast milk. An additional risk factor is occult malabsorption of vitamin K, such as occurs in children with undiagnosed cystic fibrosis or cholestatic liver disease (e.g., biliary atresia, 1 antitrypsin deficiency). Without vitamin K prophylaxis, the incidence is 4 10/100,000 newborns.

Forms of Vitamin Kdeficiency bleeding (VKDB) of the newborn

3. 3rd form of VKDB of the newborn occurs at birth or shortly thereafter. It is secondary to maternal intake of medications (warfarin, phenobarbital, phenytoin) that cross the placenta and interfere with vitamin K function.

Clinical Manifestations
In early VKDB, the most common sites of bleeding are the gastrointestinal tract, mucosal and cutaneous tissue, the umbilical stump, and the post-circumcision site; intracranial bleeding is less common. In contrast, the most frequent site of bleeding in late VKDB is intracranial, although cutaneous and gastrointestinal bleeding may be the initial manifestation. Older children with vitamin K deficiency may present with bruising, mucocutaneous bleeding, or more serious bleeding.

Laboratory Findings
Prothrombin time (PT) is prolonged. Partial thromboplastin time (PTT) is usually prolonged, but may be normal in early deficiency because factor VII has the shortest half-life of the coagulation factors (isolated factor VII deficiency does not affect the PTT). The platelet count and fibrinogen level are normal. Measurement of undercarboxylated factor II (PIVKA-II) can be used to detect mild vitamin K deficiency.


The diagnosis is established by the presence of a prolonged PT that corrects rapidly after administration of vitamin K.

Diagnosis and Differential Diagnosis

Coumarin derivatives inhibit the action of vitamin K by preventing its recycling to an active form after it functions as a cofactor for glutamyl carboxylase. B leeding can occur with overdosage of the commonly used anticoagulant warfarin or with ingestion of rodent poison, which contains a coumarin derivative. High doses of salicylates also inhibit vitamin K regeneration, potentially leading to a prolonged PT and clinical bleeding.

Infants with VKDB should receive 1 mg of parenteral vitamin K. The PT should decrease within 6 hr and normalize within 24 hr. Adolescents, the parenteral dose is 2.510 mg. Fresh frozen plasma, which corrects the coagulopathy rapidly. Children with vitamin K deficiency due to malabsorption require chronic administration of high doses of oral vitamin K (2.5 mg twice/wk5 mg/day). Parenteral vitamin K may be necessary if oral vitamin K is ineffective.

Administration of either oral or parenteral vitamin K soon after birth prevents early VKDB of the newborn. A single intramuscular injection of vitamin K (1 mg), the current practice in the USA, is almost universally effective, except in children with severe malabsorption.

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