Anemias in children

Anemias in children

Anemia is defined as a reduction of the red blood cell (RBC) volume or hemoglobin concentration below the range of values occurring in healthy persons. Table 453-1 lists the means and ranges for hemoglobin and hematocrit values by age groups of well-nourished children. There may be racial differences in hemoglobin levels. Black children have levels about 0.5 g/dL lower than those of white and Asian children of comparable age and socioeconomic status, possibly in part because of the high incidence of alpha thalassemia in blacks. Alternatively, higher levels of RBC 2,3-diphosphoglycerate (2,3-DPG) have been found in black children, which would permit better oxygen delivery and a lower hemoglobin.

Although a reduction in the amount of circulating hemoglobin deceases the oxygen-carrying capacity of the blood, few clinical disturbances occur until the hemoglobin level falls below 7-8 g/dL. Below this level, pallor becomes evident in the skin and mucous membranes. Physiologic adjustments to anemia include increased cardiac output, increased oxygen extraction (increased arteriovenous oxygen difference), and a shunting of blood flow toward vital organs and tissues. In addition, the concentration of 2,3-DPG increases within the RBC. The resultant "shift to the right" of the oxygen dissociation curve, reducing the affinity of hemoglobin for oxygen, results in more complete transfer of oxygen to the tissues. The same shift may also occur at high altitude. When moderately severe anemia develops slowly, surprisingly few symptoms or objective findings may be evident, but weakness, tachypnea, shortness of breath on exertion, tachycardia, cardiac dilatation, and congestive heart failure ultimately result from increasingly severe anemia, regardless of its cause.

 Table 453-1. Hematologic values during infancy and childhood.

Age	Hemoglobin (g/dL)		Hematocrit (% )		Reticulocytes (% )	MCV (fL)	Leukocytes (WBC/mm3 )		Neutrophils (% )		Lymphocytes (% )	Eosinophils (% )	Monocytes (% )
	Mean	Range	Mean	Range	Mean	Lowest	Mean	Range	Mean	Range	Mean*	Mean	Mean
Cord blood	16.8	13.7-20.1	55	45-65	5.0	110	18,000	(9,000-30,000)	61	(40-80)	31	2	6
2 wk	16.5	13.0-20.0	50	42-66	1.0		12,000	(5,000-21,000)	40		63	3	9
3mo	16.5	9.5-14.5	36	31-41	1.0		12,000	(6,000-18,000)	30		48	2	5
6 mo-6 yr	12.0	10.5-14.0	37	33-42	1.0	70-74	10,000	(6,000-15,000)	45		48	2	5
7-12 yr	13.0	11.0-16.0	38	34-40	1.0	76-80	8,000	(4,500-13,500)	55		38	2	5
Adult
Female	14	12.0-16.0	42	37-47	1.6	80	7,500	(5,000-10,000)	55	(35-70)	35	3	7
Male	16	14.0-18.0	47	42-52		80

 

 

fL = femtoliters; MCV = mean corpuscular volume; WBC = white blood cells.

Anemia is not a specific entity but results from many underlying pathologic processes. A useful classification of the anemias of childhood divides them into three groups by the RBC mean corpuscular volume (MCV): microcytic, macrocytic, or normocytic. RBC size changes with age, and before an anemia can be specifically characterized with respect to RBC size, normal developmental changes in the MCV should be understood (see Table 453-1) . Table 453-2 classifies the important anemias of childhood by the MCV. Anemias in childhood may also be classified by variations in cell size, as reflected by alterations in the RBC distribution width (RDW). The RDW, as determined by the use of electronic cell counting, is the coefficient of variation of RBC size (standard deviation of the MCV ÷ mean MCV × 100). Knowledge of both the MCV and the RDW can be helpful in the initial classification of anemias of childhood (Table 453-3) . In every case of significant anemia, it is essential to review the appearance of RBCs on a peripheral blood smear (Fig. 453-1) . Specific morphologic features may point to the underlying diagnosis. In addition, the presence of polychromatophilia, which correlates roughly with the degree of reticulocytosis, indicates that the marrow is able to respond to RBC loss or destruction.

When oxygen delivery by red blood cells (RBCs) to tissues is decreased, various mechanisms, including expanded cardiac output, increased production of 2,3-diphosphoglycerate (2,3-DPG) in RBCs, and higher levels of erythropoietin (EPO) help the body to modify the deficiency. RBC production by the bone marrow in response to EPO may expand severalfold and may compensate for mild to moderate reductions in RBC life span. In various anemias, the bone marrow loses its usual capacity for sustained production and expansion of the RBC mass. In these instances, absolute reticulocyte numbers in the peripheral blood are decreased. If the normal reticulocyte percentage of total RBCs during most of childhood is about 1.0% and the expected RBC count is approximately 4.0×106 /mm3 , then the normal absolute reticulocyte number should be about 40,000/mm3 . In the presence of anemia, EPO production and the absolute number of reticulocytes should rise. A normal or low absolute number or percentage of reticulocytes in response to anemia indicates relative bone marrow failure or ineffective erythropoiesis (e.g., megaloblastic anemia, thalassemia). Measurement of the serum transferrin receptor (TfR) level or examination of the bone marrow distinguishes between these possibilities, because TfR is elevated in ineffective erythropoiesis (or in iron deficiency) and is decreased in marrow RBC hypoproliferation.

Table 453-2. Classification of Anemiax.

Microcytic

Iron deficiency   Thalassemias   Lead poisoning   Chronic disease     Infection     Cancer     Inflammation     Renal disease   Vitamin B6 responsive   Copper deficiency   Sideroblastic (some)

Normocytic

Decreased production     Aplastic anemia       Congenital       Acquired     Pure RBC aplasia       Congenital (Diamond-Blackfan)       Acquired (transient erythroblastopenia)     Bone marrow replacement       Leukemia       Tumors       Storage diseases       Osteopetrosis       Myelofibrosis   Blood loss     Internal or external   Sequestration

Hemolysis: Intrinsic RBC abnormalities     Hemoglobinopathies     Enzymopathies     Membrane disorders       Hereditary spherocytosis       Acquired: paroxysmal nocturnal hemoglobinuria

Hemolysis: Extrinsic RBC abnormalities     Immunologic       Passive (hemolytic disease of the newborn)       Active: Autoimmune     Toxins     Infections     Microangiopathic       Disseminated intravascular coagulation (DIC)

Hemolytic uremic syndrome       Hypertension       Cardiac disease

Macrocytic

Normal newborn (spurious)   Reticulocytosis (spurious)   Vitamin B12 deficiency   Folate deficiency   Oroticaciduria   Myelodysplasia   Liver disease   Hypothyroidism (some)   Vitamin B6 deficiency (some)   Thiamine deficiency

RBC = red blood cell.

 

TABLE 453-3 -- Proposed Classification of Anemic Disorders Based on Red Blood Cell Mean (MCV) and Heterogeneity (RDW)

Microcytic Homogeneous (MCV low, RDW normal)	Microcytic Heterogeneous (MCV low, RDW high)	Normocytic Homogeneous (MCV normal, RDW normal)	Normocytic Heterogeneous (MCV normal, RDW high)	Macrocytic Homogeneous (MCV high, RDW normal)	Macrocytic Heterogeneous (MCV high, RDW high)
Heterozygous thalassemia	Iron deficiency	Normal	Mixed deficiency	Aplastic anemia	Folate deficiency
Chronic disease	Hb S-beta-thalassemia; hemoglobin H; red cell fragmentation	Chronic disease, chronic liver disease; nonanemic hemoglobinopathy (e.g., AS, AC); transfusion; chemotherapy; chronic myelocytic leukemia; hemorrhage; hereditary spherocytosis	Early iron deficiency anemia; anemic hemoglobinopathy (e.g., SS, SC); myelofibrosis; sideroblastic	Preleukemia	Vitamin B12 deficiency; immune hemolytic anemia; cold agglutinin; high count

MCV = mean corpuscular volume; RDW = red blood cell distribution width; AS = sickle cell trait, AC = hemoglobin C trait; SS = sickle cell anemia; SC = hemoglobin SC disease.

Iron-deficiency anemia

Anemia resulting from lack of sufficient iron for synthesis of hemoglobin is the most common hematologic disease of infancy and childhood. Its frequency is related to certain basic aspects of iron metabolism and nutrition. The body of a newborn infant contains about 0.5g of iron, whereas the adult content is estimated at 5g. To make up for this discrepancy, an average of 0.8mg of iron must be absorbed each day during the first 15yr of life. In addition to this growth requirement, a small amount is necessary to balance normal losses of iron by shedding of cells. Accordingly, to maintain positive iron balance in childhood, about 1mg of iron must be absorbed each day.

Iron is absorbed in the proximal small intestine, mediated in part by duodenal proteins (HFE, hephaestin, Nramp2 , and mobilferrin). Because absorption of dietary iron is assumed to be about 10%, a diet containing 8-10mg of iron daily is necessary for optimal nutrition. Iron is absorbed two to three times more efficiently from human milk than from cow's milk, perhaps partly because of differences in calcium content. Breast-fed infants may, therefore, require less iron from other foods. During the first years of life, because relatively small quantities of iron-rich foods are eaten, it is often difficult to attain sufficient iron. For this reason, the diet should include such foods as infant cereals or formulas that have been fortified with iron; both of these are very effective in preventing iron deficiency. Formulas with 7-12mg Fe/L for full-term infants and premature infant formulas with 15mg/L for infants less than 1,800g at birth are effective. Infants breast-fed exclusively should receive iron supplementation from 4mo of age. At best, an infant is in a precarious situation with respect to iron. Should the diet become inadequate or external blood loss occur, anemia ensues rapidly.

Adolescents are also susceptible to iron deficiency because of high requirements due to the growth spurt, dietary deficiencies, and menstrual blood loss. In the United States, about 9% of 1-2yr-olds are iron deficient; 3% have anemia. Of adolescent girls, 9% are iron deficient and 2% have anemia. In boys, a 50% decrease in stored iron occurs as puberty progresses.

ETIOLOGY.

Low birthweight and unusual perinatal hemorrhage are associated with decreases in neonatal hemoglobin mass and stores of iron. As the high hemoglobin concentration of the newborn falls during the first 2-3mo of life, considerable iron is reclaimed and stored. These reclaimed stores are usually sufficient for blood formation in the first 6-9mo of life in term infants. In low birthweight infants or those with perinatal blood loss, stored iron may be depleted  earlier, and dietary sources become of paramount importance. Anemia caused solely by inadequate dietary iron is unusual before 4-6mo but becomes common at 9-24mo of age. Thereafter, it is relatively infrequent. The usual dietary pattern observed in infants with iron deficiency anemia is consumption of large amounts of cow's milk and of foods not supplemented with iron.

Blood loss must be considered a possible cause in every case of iron deficiency anemia, particularly in older children. Chronic iron deficiency anemia from occult bleeding may be caused by a lesion of the gastrointestinal (GI) tract, such as a peptic ulcer, Meckel's diverticulum, a polyp, or hemangioma, or by inflammatory bowel disease. In some geographic areas, hookworm infestation is an important cause of iron deficiency. Pulmonary hemosiderosis may be associated with unrecognized bleeding in the lungs and recurrent iron deficiency after treatment with iron. Chronic diarrhea in early childhood may be associated with considerable unrecognized blood loss. Some infants with severe iron deficiency in the United States have chronic intestinal blood loss induced by exposure to a heat-labile protein in whole cow's milk. Loss of blood in the stools each day can be prevented either by reducing the quantity of whole cow's milk to 1pint/24hr or less, by using heated or evaporated milk, or by feeding a milk substitute. This GI reaction is not related to enzymatic abnormalities in the mucosa, such as lactase deficiency, or to typical "milk allergy." Involved infants characteristically develop anemia that is more severe and occurs earlier than would be expected simply from an inadequate intake of iron.

Histologic abnormalities of the mucosa of the GI tract, such as blunting of the villi, are present in advanced iron deficiency anemia and may cause leakage of blood and decreased absorption of iron, further compounding the problem.

Intense exercise conditioning, as occurs in competitive athletics in high school, may result in iron depletion in girls; this occurs less commonly in boys.

CLINICAL MANIFESTATIONS.

Pallor is the most important clue to iron deficiency. Blue scleras are also common, although also found in normal infants. In mild to moderate iron deficiency (hemoglobin levels of 6-10g/dL), compensatory mechanisms, including increased levels of 2,3-diphosphoglycerate (2,3-DPG) and a shift of the oxygen dissociation curve, may be so effective that few symptoms of anemia are noted, although affected children may be irritable. Pagophagia, the desire to ingest unusual substances such as ice or dirt, may be present. In some children, ingestion of lead-containing substances may lead to concomitant plumbism. When the hemoglobin level falls below 5g/dL, irritability and anorexia are prominent. Tachycardia and cardiac dilation occur, and systolic murmurs are often present.

The spleen is enlarged to palpation in 10-15% of patients. In long-standing cases, widening of the diploe of the skull similar to that in congenital hemolytic anemias may occur. These changes resolve slowly with adequate replacement therapy. Children with iron deficiency anemia may be obese or may be underweight, with other evidence of poor nutrition. The irritability and anorexia characteristic of advanced cases may reflect deficiency in tissue iron, because with iron therapy striking improvement in behavior frequently occurs before significant hematologic improvement.

Iron deficiency may have effects on neurologic and intellectual function. A number of reports suggest that iron deficiency anemia, and even iron deficiency without significant anemia, affects attention span, alertness, and learning of both infants and adolescents. In a controlled trial, adolescent girls with serum ferritin levels of 12 ng/L or less but without anemia improved verbal learning and memory after taking iron for 8wk.

Monoamine oxidase (MAO), an iron-dependent enzyme, has a crucial role in neurochemical reactions in the central nervous system. Iron deficiency produces decreases in the activities of enzymes such as catalase and cytochromes. Catalase and peroxidase contain iron, but their biologic essentiality is not well established. Iron deficiency causes rigidity of red blood cells (RBCs) and may be associated with stroke in young children. Administration of iron may decrease the frequency of breath-holding spells, suggesting a role for iron deficiency or anemia.

LABORATORY  FINDINGS.

 

In progressive iron deficiency, a sequence of biochemical and hematologic events occurs. First, the tissue iron stores represented by bone marrow hemosiderin disappear. The level of serum ferritin, an iron-storage protein, provides a relatively accurate estimate of body iron stores in the absence of inflammatory disease. Normal ranges are age dependent, and decreased levels accompany iron deficiency. Next, serum iron level decreases (also age dependent), the iron-binding capacity of the serum increases, and the percent saturation falls below normal (also varies with age). When the availability of iron becomes rate limiting for hemoglobin synthesis, a moderate accumulation of heme precursors, free erythrocyte protoporphyrins (FEP), results.

As the deficiency progresses, the RBCs become smaller than normal and their hemoglobin content decreases. The morphologic characteristics of RBCs are best quantified by the determination of mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV). Developmental changes in MCV require the use of age-related standards for diagnosis of microcytosis (see Table 453-1) . With increasing deficiency, the RBCs become deformed and misshapen and present characteristic microcytosis, hypochromia, poikilocytosis, and increased RBC distribution width (RDW). The reticulocyte percentage may be normal or moderately elevated, but absolute reticulocyte counts indicate an insufficient response to anemia. Nucleated RBCs may occasionally be seen in the peripheral blood. White blood cell counts are normal. Thrombocytosis, sometimes of a striking degree (600,000-1,000,000/mm3 ), may occur or, in a few cases, thrombocytopenia. The mechanisms of these platelet abnormalities are not clear. They appear to be a direct consequence of iron deficiency, perhaps with associated GI blood loss or associated folate deficiency, and they return to normal with iron therapy and dietary change. The bone marrow is hypercellular, with erythroid hyperplasia. The normoblasts may have scanty, fragmented cytoplasm with poor hemoglobinization. Leukocytes and megakaryocytes are normal. Hemosiderin cannot be demonstrated in marrow specimens by Prussian blue staining. In about a third of cases, occult blood can be detected in the stools.

Iron deficiency must be differentiated from other hypochromic microcytic anemias. In lead poisoning associated with iron deficiency, the RBCs are morphologically similar, but coarse basophilic stippling of the RBCs, an artifact of drying the slide, is frequently prominent. Elevations of blood lead, FEP, and urinary coproporphyrin levels are seen. The blood changes of beta-thalassemia trait resemble those of iron deficiency, but RDW is usually normal or only slightly elevated. alpha-Thalassemia trait occurs in about 3% of blacks in the United States and in many Southeast Asian peoples. The diagnosis requires direct identification of DNA defects or difficult globin synthesis studies after the newborn period. The diagnosis can be assumed when a patient having familial hypochromic microcytic anemia with normal iron studies, including ferritin, has normal levels of Hb A2 and Hb F and normal hemoglobin electrophoresis. In the newborn period, infants with alpha-thalassemia trait have 3-10% Bart hemoglobin and the MCV is decreased. Thalassemia major, with its pronounced erythroblastosis and hemolytic component, should present no diagnostic confusion. Hb H disease, a form of alpha-thalassemia with hypochromia and microcytosis, also has a hemolytic component due to instability of the beta-chain tetramers resulting from a deficiency of alpha globin. The RBC morphology of chronic inflammation and infection, though usually normocytic, may be microcytic, but in these conditions both the serum iron level and iron-binding ability are reduced and serum ferritin levels are normal or elevated. The serum transferrin receptor (TfR) level is useful in the distinction between iron deficiency anemia and anemia of chronic disease, because it is not affected by inflammation. The concentration is elevated in iron deficiency and within the normal range in anemia of chronic disease. An elevation of the TfR/log ferritin ratio is especially sensitive in detecting iron deficiency anemia. Elevations of FEP are not specific to iron deficiency and are observed in patients with lead poisoning, chronic hemolytic anemia, anemia associated with chronic disorders, and some of the porphyrias.

TREATMENT.

The regular response of iron deficiency anemia to adequate amounts of iron is an important diagnostic and therapeutic feature. Oral administration of simple ferrous salts (sulfate, gluconate, fumarate) provides inexpensive and satisfactory therapy. No evidence shows that addition of any trace metal, vitamin, or other hematinic substance significantly increases the response to simple ferrous salts. For routine clinical use, physicians should be familiar with an inexpensive preparation of one of the simple ferrous compounds. The therapeutic dose should be calculated in terms of elemental iron; ferrous sulfate is 20% elemental iron by weight. A daily total of 6mg/kg of elemental iron in three divided doses provides an optimal amount of iron for the stimulated bone marrow to use. Intolerance to oral iron is uncommon in children. A parenteral iron preparation (iron dextran) is an effective form of iron and is usually safe when given in a properly calculated dose, but the response to parenteral iron is no more rapid or complete than that obtained with proper oral administration of iron, unless malabsorption is a factor.

 

While adequate iron medication is given, the family must be educated about the patient's diet, and the consumption of milk should be limited to a reasonable quantity, preferably 500mL (1 pint)/24hr or less. This reduction has a dual effect: The amount of iron-rich foods is increased, and blood loss from intolerance to cow's milk proteins is reduced. When the re-education of child and parent is not successful, parenteral iron medication may be indicated. Iron deficiency can be prevented in high-risk populations by providing iron-fortified formula or cereals during infancy.

The expected clinical and hematologic responses to iron therapy are described in Table 461-1 . Within 72-96hr after administration of iron to an anemic child, peripheral reticulocytosis is noted. The height of this response is inversely proportional to the severity of the anemia. Reticulocytosis is followed by a rise in the hemoglobin level, which may increase as much as 0.5g/dL/24hr. Iron medication should be continued for 8wk after blood values are normal. Failures of iron therapy occur when a child does not receive the prescribed medication, when iron is given in a form that is poorly absorbed, or when there is continuing unrecognized blood loss, such as intestinal or pulmonary loss, or with menstrual periods. An incorrect original diagnosis of nutritional iron deficiency may be revealed by therapeutic failure of iron medication.

 

TABLE 461-1 -- Responses to Iron Therapy in Iron Deficiency Anemia

Time After Iron Administration	Response
12-24 hr	Replacement of intracellular iron enzymes; subjective improvement; decreased irritability; increased appetite
36-48 hr	Initial bone marrow response; erythroid hyperplasia
48-72 hr	Reticulocytosis, peaking at 5-7 days
4-30 days	Increase in hemoglobin level
1-3 mo	Repletion of stores

 

 

Because a rapid hematologic response can be confidently predicted in typical iron deficiency, blood transfusion is indicated only when the anemia is very severe or when superimposed infection may interfere with the response. It is not necessary to attempt rapid correction of severe anemia by transfusion; the procedure may be dangerous because of associated hypervolemia and cardiac dilatation. Packed or sedimented RBCs should be administered slowly in an amount sufficient to raise the hemoglobin to a safe level at which the response to iron therapy can be awaited. In general, severely anemic children with hemoglobin values less than 4g/dL should be given only 2-3mL/kg of packed cells at any one time (furosemide may also be administered as a diuretic). If there is evidence of frank congestive heart failure, a modified exchange transfusion using fresh-packed RBCs should be considered, although diuretics followed by slow infusion of packed RBCs may suffice.

Anemias of newborns.

Anemia in newborns can be caused by hemorrhage, hemolysis or failure to produce red blood cells. In the premature infant, the hemoglobin races its nadir at approximately 8 – 12 weeks and is 2 – 3 g/dL lower than that in the term infant. The lower nadir in the premature appears to be the result of a decreased erythropoietin response to the low red cell mass. That’s why it is very important not only perform the diagnosis in time, but also prevent the development of anemia in premature newborns. 

NORMAL BLOOD VALUES In the newborn the range of normal values is wider than at any other age:

Hb    14.5 - 21.5 g/dl

PCV  45-65%

MCV  110-128 fl

WBC  6-30 x 10⁹/l

Differential count:
      polymorphs predominate at birth
      lymphocyte predominance develops after seven days
I/T ratio less than 12%
Platelets 100-300 x 10⁹/l

Iron requirements

Newborn term infants have approximately 75 mg/kg of body iron, 75% of which is in the form of hemoglobin. On average, infants almost triple their blood volume during the first year of life and will require the absorption of 0.4 to 0.6 mg daily of iron during that time to maintain adequate stores.

Premature infants have a lower level of body iron at birth, approximately 64 mg in infants weighing 1 kg. The loss of blood drawn for laboratory tests and the rapid rate of postnatal growth lead to a higher requirement for dietary iron than in term infants — 2.0 to 2.5 mg/kg daily to prevent late anemia.

Assuming that 10% of the iron in a mixed diet is absorbed, the recommended iron intake is approximately 7 mg/d for term infants aged 5 to 12 months, 6 mg/d for toddlers aged 1 to 3 years and 8 mg/d for children aged 4 to 12 years.

ANAEMIA
Background: Anemia frequently is observed in the infant who is hospitalized and premature. Although many causes are possible, anemia of prematurity (AOP) is the most common diagnosis. AOP is a normocytic, normochromic, hyporegenerative anemia that is characterized by the existence of a low serum erythropoietin (EPO) level in an infant who has what may be a remarkably reduced hemoglobin concentration.

Although common, AOP remains a controversial issue for clinicians. Few universally accepted signs or symptoms are attributable to AOP. Even less agreement exists regarding the timing, method, and effectiveness of current therapeutic interventions in individuals with AOP. With an increasing number of transfusion-related complications reported in the last 2 decades, caregivers and families of infants understandably are concerned about the use of blood products. This article reviews the pathophysiology of AOP, the means of reducing blood transfusions, and the current status of recombinant EPO.

Mortality/Morbidity: Although a premature infant is unlikely to be allowed to become so anemic as to die, complications from necessary blood transfusions ultimately can be responsible for the death of a patient. Anemia is blamed for a variety of signs and symptoms, including apnea, poor feeding, and inadequate weight gain.

Age:

·                   The more immature the infant, the more likely the development of AOP. AOP typically is not a significant issue for infants born beyond 32 weeks' gestation.

·                   The nadir of the hemoglobin level typically is observed when the tiniest infants are aged 4-8 weeks.

·                   AOP spontaneously resolves by the time most patients are aged 3-6 months.

Pathophysiology: The 3 basic mechanisms for the development of anemia in any patient are inadequate red blood cell (RBC) production, shortened RBC life span or hemolysis, and blood loss. AOP has its roots in each of these processes.

Inadequate red blood cell production The first mechanism of anemia is inadequate RBC production. The location of EPO and RBC production changes during gestation of the fetus. EPO synthesis initially occurs in cells of monocyte or macrophage origin that reside in the fetal liver, with production gradually shifting to the peritubular cells of the kidney. By the end of gestation, the liver remains a major source of EPO.

In the first few weeks of embryogenesis, fetal erythrocytes are produced in the yolk sac. This site is succeeded by the fetal liver, which, by the end of the first trimester, has become the primary site of erythropoiesis. Bone marrow then begins to take on a more active role in producing erythrocytes. By approximately 32 weeks’ gestation, the burden of erythrocyte production in the fetus is shared evenly by the liver and bone marrow. By 40 weeks’ gestation, the marrow is the sole erythroid organ. Premature delivery does not accelerate the ontogeny of these processes.

Although EPO is not the only erythropoietic growth factor in the fetus, it is the most important. EPO is synthesized in response to both anemia and hypoxia. The degree of anemia and hypoxia required to stimulate EPO production is far higher for the fetal liver than for the fetal kidney. As a result, new RBC production in the extremely premature infant (whose liver remains the major site of EPO production) is blunted despite what may be marked anemia.

In addition, EPO, whether endogenously produced or exogenously administered, has a larger volume of distribution and is eliminated more rapidly by neonates, resulting in a curtailed time for bone marrow stimulation. Erythroid progenitors of premature infants are quite responsive to EPO when that growth factor finally is produced or administered.

Shortened red blood cell life span or hemolysis Secondly, the average life span of a neonatal RBC is only one half to two thirds that of the RBC life span in an adult. Cells of the most immature infants may survive only 35-50 days. The shortened RBC life span of the neonate is a result of multiple factors, including diminished levels of intracellular ATP, carnitine, and enzyme activity; increased susceptibility to lipid peroxidation; and increased susceptibility of the cell membrane to fragmentation.

Blood loss Finally, blood loss may contribute to the development of AOP. If the neonate is held above the placenta for a time after delivery, a fetal-placental transfusion may occur. More commonly, because of the need to closely monitor the tiny infant, frequent samples of blood are removed for various tests. Because the smallest patients may be born with as little as 40 mL of blood in their circulation, withdrawing a significant percentage of an infant’s blood volume in a short period is relatively easy. In one study, mean blood loss in the first week of life was nearly 40 mL.

Taken together, the premature infant is at risk for the development of AOP because of limited synthesis, diminished RBC life span, and increased loss of RBCs.

Classification

І. Posthemorrhagic anemia (after hemorrhage):

А. Antenatal:

1. rupture of placenta

2. anomaly of the umbilical cord, and it’s vessels

3. feto-fetal transfusion

4. feto-maternal transfusion

B. Intranatal:

1.                            obstetric complications (Cesarean section, preterm placental separation, cord rupture, placental presentation)

2.                            cord compression during delivery

3.                            birth injury

4.                            placental transfusion

C. Postnatal:

1. internal hemorrhages (intraventricular, large cephalhematoma, rupture of the inner organs)

2. gastro-intestinal tract bleeding

3. cord vessels bleeding

4. iatrogenic blood loses

ІІ. Hemolytic (as a result of increased hemolysis)

А. Hereditary predisposed:

1. membranopathies (hereditary microspherocytosis)

2. enzymopathies (G-6-PD deficiency)

3. hemoglobinopathia

B. acquired:

1. immune (hemolytic disease by АВО and Rh-factors)

2. vitamin E deficiency

3. infectious (CMV-infection, toxoplasmosis, congenital syphilis, hepatitis C, В, sepsis)

ІІІ. Anemia due to hemopoesis depression

А. Hereditary: Fanconi anemia, Diamond-Blackfan anemia

B. Acquired: deficiency anemia (vit B 12, folic acid, Fe, protein, aminoacids, microelements).

CLINICAL Obstetric history:

1. maternal hemorrhages during pregnancy, delivery

2. maternal diseases during pregnancy (acute, chronic)

3. peculiarities of feeding during pregnancy

4. preterm birth

5. multiple pregnancy – feto-fetal transfusion (difference of hemoglobin concentration more than 50 g/l

6. perinatal or postnatal infections

7. family anamnesis (hematological diseases, jaundices)

Few symptoms are universally accepted as attributable to AOP; however, the following are among the symptoms that clinicians attribute to AOP:

·        Poor weight gain

·        Apnea

·        Tachypnea

·        Decreased activity

·        Pallor

·        Tachycardia

·        Flow murmurs

Physical: Debate regarding the presence or absence of physical findings in the infant with AOP is ongoing. Clinical trials designed to determine the efficacy of blood transfusions in relieving these findings have produced conflicting results.

1.                   Poor growth Inadequate weight gain despite adequate caloric intake often is attributed to AOP.

2.                   Apnea If severe enough, anemia may result in respiratory depression manifested by increased periodic breathing and apnea.

3.                   Decreased activity: Lethargy frequently is attributed to anemia, with subjective improvement subsequent to transfusion.

4.                   Metabolic acidosis Significant anemia can result in decreased oxygen-carrying capacity less than the needs of the tissue, resulting in increased anaerobic metabolism with production of lactic acid.

5.                   Tachycardia Infants with AOP may respond by increasing cardiac output through increased heart rates, presumably in response to inadequate oxygen delivery to the tissues caused by anemia. Blood transfusions have been associated with a lowering of the heart rate in infants who are anemic.

6.                   Tachypnea

7.                   Flow murmurs

DIFFERENTIALS

Criterions	Posthemorrhagic anemia	Hemolytic anemia	Early anemia of premature child	Late anemia of premature child	Hypo- and aplastic anemia
History             Incidence         Clinical                     Laborato-ry findings	Feto-fetal, feto-maternal transfusion; Postnatal blood loses; Iatrogenic loses;   On the 2-3 day of life       Skin pallor, cardiorespira-tory syndrome, hypovolemia, unconsciousness         normochromic, later hypochromic anemia,  decreasing of the serum Fe	АВО-system or Rh-factor incompatibility; complicated genetical history     After birth, on the 1st day       jaundice, splenomegaly, in hard cases – kernicterus               Nonconjugated hyperbilirubin-emia, positive Coombs test, reticulocytosis	Prematurity             before 2 months         skin and mucus membranes pallor, loss of appetite, height and weight retardation  moderate hepatosplenomegaly, CNS depression         hypochromic and normochromic hyporegenerative anemia, anisocytosis,	Prematurity             In 4-5 months         syderopenic, astenoneurotic cardiovascular syndromes, hepatosplenomegaly, depression of immune system   hypochromic anemia, decreasing of the serum Fe, increasing of the Fe conjugating ability of  the serum	complicated genetical history, toxin or medicine influence     gradual, with maximal clinical feature on the 2-3 months   progressive pallor, hemorrhages,  hepatosplenomegaly, stigmas of dysembriogene-sis,         normochromic anemia, leucopenia, thrombocyto-penia, reticulocito-penia, erythroid shoot hypoplasia

 

Lab Studies:

1. Complete blood count

·                   The CBC demonstrates normal white blood cell (WBC) and platelet lines.

·                   The hemoglobin is less than 10 g/dL but may descend to a nadir of 6-7 g/dL; the lowest levels generally are observed in the smallest infants.

·                   RBC indices are normal (eg, normochromic, normocytic) for age.

2. Reticulocyte count

·                   The reticulocyte count is low when the degree of anemia is considered as a result of the low levels of EPO.

·                   The finding of an elevated reticulocyte count is not consistent with the diagnosis of AOP.

3.                Peripheral blood smear: No abnormal forms are observed.

4.                Maternal and infant blood typing: In the evaluation of anemia, consider the possibility of hemolytic processes, such as the ABO blood group system and Rh incompatibility.

5.                Direct antibody test (Coombs): This test may be coincidentally positive; however, with such a finding, ensure that an immune-mediated hemolytic process is not ongoing.

6.                Serum bilirubin: With an elevated serum bilirubin level, consider other possible explanations for the anemia.

TREATMENT

Dietary sources of Iron Other factors affecting iron sufficiency are the amount and the bioavailability of dietary iron. The form of the iron influences its absorption: absorption is good from ferrous sulfate (the iron source generally used in infant formulas) and elemental iron of small particle size (e.g., the electrolytic iron used in infant cereals). In general, iron absorption from foods of animal origin surpasses that from foods of plant origin. Vitamin C, meat, fish and poultry facilitate iron absorption.

One litre of human milk contains only 0.3 to 0.5 mg of iron. About 50% of the iron is absorbed, in contrast to a much smaller proportion from other foods. Term infants who are breast-fed exclusively for the first 6 months may not be at risk for iron depletion or for the development of iron deficiency. However, if solid foods are given they may compromise the bioavailability of iron from human milk. Although some term infants who are exclusively breast-fed may remain iron-sufficient until 9 months of age, a source of dietary iron is recommended starting at 6 months (or earlier if solid foods are introduced into the diet) to reduce the risk of iron deficiency.

Infant formulas based on cow's milk contain 1.0 to 1.5 mg of iron per litre; soy-based formula and iron-fortified formula based on cow's milk contain 12 to 13 mg of iron per litre. The iron source of fortified formulas is ferrous sulfate, which is significantly more available than the iron used in infant cereals. The availability of iron from soy-based formulas appears to be lower than that from milk-based products. The optimal amount of iron in formula based on cow's milk remains to be determined. Formulas in North America contain higher amounts of iron than those suggested in the United Kingdom (1.0 mg/100 kcal) and France (1.5 mg/100 kcal).

The decreased incidence of iron deficiency anemia in the United States since 1969 has been attributed to the increased and longer use of iron-fortified formulas, an increase in breast-feeding and the use of iron-fortified infant cereals. Contrary to popular belief, significant behavioural or gastrointestinal problems do not develop in most infants fed iron-fortified formulas. Theoretically, the iron from neonatal reserves in term babies is sufficient to cover their needs during the first 3 months of life. However, in order to avoid possible confusion with formula changes during the first few months, iron-fortified formulas should be used from birth.

Cow's milk is not recommended for infants younger than 9 to 12 months of age. Although it contains approximately the same amount of iron as human milk (0.5 mg/L) the iron is poorly absorbed. Even when given iron-fortified cereals and other foods, some infants fed cow's milk from 6 months of age have significantly lower mean serum ferritin levels and corpuscular volume and a greater incidence of hemoglobin concentration below 6.8 mmol/L at 12 months of age than infants fed iron-supplemented formula. In addition, cow's milk compromises the absorption of dietary and medicinal iron.

Occult blood loss from the gastrointestinal tract has been demonstrated in infants younger than 4 months of age fed exclusively with unmodified cow's milk. A more recent study of the effects of cow's milk on infants from 168 to 252 days old showed significant gastrointestinal blood loss in the experimental group, as measured by a sensitive quantitative method; however, this group's iron nutritional status was not significantly different from that of the control (formula-fed) group.

Iron-fortified cereals are an important source of iron: they contain approximately 30 to 50 mg per 100 g of cereal, of which 4% in average will normally be absorbed. Although the bioavailability of iron in infant cereals has been challenged, several studies have demonstrated that it is 50% to 70% of the bioavailability of ferrous sulfate, a generally accepted standard. Furthermore, clinical studies have shown that iron-fortified infant cereals and formulas can maintain adequate iron status in healthy term infants.

Recommendations

Term infants who are exclusively breast-fed do not need supplemental iron until they are 6 months of age. If solid foods are introduced earlier, they should contain an adequate amount of iron. After 6 months of age, breast-fed infants should receive extra iron in the form of iron-fortified infant cereals and other iron-rich foods. These infants should be offered an iron-fortified infant formula after they have been weaned from breast milk.

Term infants who are not breast-fed should be given an iron-fortified infant formula from birth. Studies are still under way to determine the optimal iron content of these formulas: and further studies are encouraged. Until the results are known, the use of currently available iron-fortified formulas seems appropriate. After 4 to 6 months of age, iron-fortified infant cereals provide a good additional source of iron.

For premature infants, an iron supplement should be started by at least 8 weeks of age and continued until the first birthday. Iron-fortified formula for bottle-fed infants or commercial iron drops for breast-fed infants are the recommended source of supplemental iron.

Cow's milk should not be introduced until an adequate amount of solid food containing iron and vitamin C is included in the diet, preferably at 9 to 12 months of age.

For children over 1 year of age, the recommended daily nutrient intake of iron should be given. Iron-containing foods such as meats, some vegetables, legumes, fruits and iron-fortified infant or toddler cereals provide iron in sufficient amounts. Supplemental iron is not required unless the diet is lacking in these foods.

Medical Care: The medical care options available to the clinician treating an infant with AOP are prevention, blood transfusion, and recombinant EPO treatment.

Prevention

·                     Reducing the amount of blood taken from the premature infant diminishes the need to replace blood. When caring for the premature infant, carefully consider the need for each laboratory study obtained. Hospitals with care for premature infants should have the ability to determine laboratory values using very small volumes of serum.

·                     Manufacturers are developing an array of technologies that require extremely small amounts of blood for a steadily increasing number of tests. Likewise, devices that allow blood gases and serum chemistries to be determined at bedside via an analyzer attached to the umbilical artery catheter without loss of blood recently have been developed. The impact of such devices on the development of anemia and/or the need for transfusions has yet to be determined.

·                     The use of noninvasive monitoring devices, such as transcutaneous hemoglobin oxygen saturation, partial pressure of oxygen, and partial pressure of carbon dioxide, may allow clinicians to decrease blood drawing; however, no data currently support such an impact of these devices.

Blood transfusion

·                     Packed red blood cell (PRBC) transfusions: Despite disagreement regarding timing and efficacy, PRBC transfusions continue to be the mainstay of therapy for the individual with AOP. The frequency of blood transfusions varies with gestational age, degree of illness, and, interestingly, the hospital evaluated.

·                     Reducing the number of transfusions: Studies derived from individual centers document a marked decrease in the administration of PRBC transfusions over the past 2 decades, even before the use of EPO. This decrease in transfusions is almost certainly multifactorial in origin. One frequently mentioned component is the adoption of transfusion protocols that take a variety of factors into account, including hemoglobin levels, degree of cardiorespiratory disease, and traditional signs and symptoms of pathologic anemia. Using various audit criteria and indications for transfusions suggested by Canadian, American, and British authorities, the Medical University of South Carolina has instituted the following transfusion guidelines:

o                     Do not transfuse for phlebotomy losses alone.

o                     Do not transfuse for hematocrit alone, unless the hematocrit level is less than 21% with a reticulocyte count less than 100,000.

o                     Transfuse for shock associated with acute blood loss.

o                     For an infant with cyanotic heart disease, maintain a hemoglobin level that provides an equivalent fully saturated level of 11-12 g.

o                     Transfuse for hematocrit levels less than 35-40% in the following situations:

§                                              Infant with severe pulmonary disease (defined as requiring >35% supplemental hood oxygen or continuous positive airway pressure [CPAP] or mechanical ventilation with a mean airway pressure of >6 cm water)

§                                              Infant in whom anemia may be contributing to congestive heart failure

o                     In the following situations, transfuse for a hematocrit level that is 25-30% or less:

§                                              The patient requires nasal CPAP of 6 cm water or less (supplemental hood oxygen of <35% by hood or nasal cannulae).

§                                              The patient has significant apnea and bradycardia (defined as >9 episodes in 12 h or 2 episodes in 24 h, requiring bag-mask ventilation while receiving therapeutic doses of methylxanthines).

§                                              The patient has persistent tachycardia or tachypnea without other explanation for 24 hours.

§                                              Weight gain of patient is deemed unacceptable in light of adequate caloric intake without other explanation, such as known increases in metabolic demands or known losses in metabolic demands (malabsorption).

§                                              The patient is scheduled for surgery; transfuse in consultation with the surgery team.

·                     Reducing the number of donor exposures: In addition to reducing the number of transfusions, reducing the number of donor exposures is important. This can be accomplished as follows:

o                     Use PRBCs stored in preservatives (eg, citrate-phosphate-dextrose-adenine [CPDA-1]) and additive systems (eg, Adsol). Preservatives and additive systems allow blood to be stored safely for up to 35-42 days. Infants may be assigned a specific unit of blood, which may suffice for treatment during their entire hospitalization.

o                     Use volunteer-donated blood and all available screening techniques. The risk of cytomegalovirus (CMV) transmission can be reduced dramatically (but not entirely) through the use of CMV-safe blood. This can be accomplished by using either CMV serology-negative cells or blood processed through leukocyte-reduction filters. This latter method also reduces other WBC-associated infectious agents (eg, Epstein-Barr virus, retroviruses, Yersinia enterocolitica). The American Red Cross now is providing exclusively leukocyte-reduced blood to hospitals in the United States.

Recombinant erythropoietin treatment

1.                Multiple investigations have established that premature infants respond to exogenously administered recombinant human EPO with a brisk reticulocytosis. Modest decreases in the frequency of PRBC transfusions have been documented primarily in premature infants who are relatively large.

2.                Recent trials have evaluated the impact of EPO treatment in populations of the most immature neonates. These studies likewise have demonstrated that infants with VLBW are capable of responding to EPO with a reticulocytosis and that the drug appears to be safe. Conversely, the hemoglobin level of infants treated with EPO falls to at or below the hemoglobin level of the control group within 1 week of treatment cessation, and the impact on transfusion requirements ranges from nonexistent to small.

3.                No agreement regarding timing, dosing, route, or duration of therapy exists. In short, the cost-benefit ratio for EPO has yet to be clearly established, and this medication is not accepted universally as a standard therapy for the individual with AOP. When the family has religious objections to transfusions, the use of EPO is advisable.

Diet: Provision of adequate amounts of vitamin E, vitamin B-12, folate, and iron are important to avoid exacerbating the expected decline in hemoglobin levels in the premature infant.

MEDICATION

Epoetin alfa (Epogen, Procrit) Adult Dose Mother: 400 U/kg/dose IV/SC 3 times/wk until postconceptional age 35 wk. Pediatric Dose 72 hours: 200 U/kg/d IV for 14 d; 10 days: 200 U/kg/dose SC 3 times/wk for 6 wk; 10-35 days: 100 U/kg/d IV 2 times/wk for 6 wk.

Ferrous sulfate (Feosol) 5 mg/kg/wk (based on elemental iron content) IV; alternatively, 6 mg/kg/d PO.

Vitamin E (Aquasol E, Vitec) 25 IU/d PO initially; measure plasma tocopherol within 1 wk and adjust dose accordingly.

Folic acid (Folvite) 50 mcg/d PO

Further Outpatient Care: After discharge from the hospital, ensure regular determination of hematocrit levels in infants with APO. Once a steady increase in the hematocrit level has been established, only routine checks are required.

Deterrence/Prevention:

·                     Limit diagnostic blood draws to a minimum.

Complications:

1.     Transfusion-acquired infections (eg, hepatitis, CMV, HIV, syphilis)

2.     Transfusion-associated fluid overload and electrolyte imbalances

3.     Transfusion-associated exposure to plasticizers

4.     Transfusion-associated hemolysis

5.     Posttransfusion graft versus host disease

Prognosis: Spontaneous recovery in the individual with AOP occurs by age 3-6 months.

LITERATURE:

Nelson Textbook of Pediatrics, 16e edition.

Hoffman R, Benz EJ, Shattil SJ, et al: Hematology: Basic Principles and Practices, 3rd ed. New York, Churchill Livingstone, 1999.

Miller DR

, Baehner RL: Blood Diseases of Infancy and Childhood, 7th ed. St. Louis, CV Mosby, 1995.

Nathan DG, Orkin SH: Nathan and Oski's Hematology of Infancy and Childhood, 5th ed. Philadelphia, WB Saunders, 1998.

Williams WJ, Beutler E, Erslev AJ, Lichtman MA: Hematology, 4th ed. New York, McGraw-Hill, 1990.

WEB-adresses

http://www.emedicine.com

http://www.meadline

htttp;//www.babynet.at

http://www.neonatology.org/neo.clinical.html

 

 

 

 

 

Rickets. Etiology, pathogenesis, clinical features, treatment and prophylactic.

 

 Rickets is a disorder involving softening and weakening of the bones (of children) primarily caused by lack of Vitamin D, or lack of calcium or phosphate. It is a general disease of the children's organism characterised by deep damage of all types of metabolism, especially mineral metabolism, damaging of different organs and systems, inadequate or delayed mineralisation of bones and an excess of osteoid.

Etiology:

A lack of vitamin D may arise because of

1) Insufficient endogenous synthesis;

2) A primary deficiency state due to a dietary lack of the nutrient;

3) Secondary deficiency caused by malapsorption of the lipid-soluble vitamin D (diseases of pancreas, billiard tract, intestinal diseases).

 

 

 Pathogenesis:  A deficiency of vitamin D induces not only abnormal serum levels of calcium and phosphate, but also secondary hyperparathyroidism and skeletal morphologic changers. It is now clear that vitamin D itself is not active in calcium metabolism. It must first conversion to its active metabolite, 1-Alfa-, 25 - dihydroxyvitamin D3 which is essence constitutes a hormone since it is formed in the kidney and acts on distant target organs.

If there is a deficiency of Vitamin D, the body is unable to properly regulate calcium and phosphate levels.

When the blood levels of these minerals become too low, it results in destruction of the support matrix of the bones.

 Pathogenesis:

 •         In the vitamin D deficiency state, hypocalciemia develops, which stimulates excess parathyroid hormone, which stimulates renal phosphorus loss, further reducing deposition of calcium in the bone.

 •          The parathyroid gland may increase its functioning rate to compensate for decreased levels of calcium in the bloodstream.

 To increase the level of calcium in the blood the hormone destroys the calcium present in the bones of the body and this results in further loss of calcium and phosphorous from the bones.

•         Early in the course of rickets, the calcium concentration in the serum decreases.

 •         After the parathyroid response, the calcium concentration usually returns to the reference range, though phosphorus levels remain low.

 •          Alkaline phosphatase, which is produced by overactive osteoblast cells, leaks to the extracellular fluids so that its concentration rises to anywhere from moderate elevation to very high levels.

 

Clinical Symptoms

·        Bone pain or tenderness (arms, legs, spine, pelvis)

·        Increased tendency toward bone fractures

·        Fever, especially at night

  

Restlessness, especially at night weakness

·        Decreased muscle tone (loss of muscle strength)

·        Decreased muscle development

·        Muscle cramps

·        Impaired growth (short stature and slow growth)

 

Skeletal deformities:

·        Bow legs

·        Forward projection of the breastbone (pigeon chest)

·        "Bumps" in the rib cage (rachitic rosary)

·        Asymmetrical or odd-shaped skull

·        Spine deformities (spine curves abnormally, including scoliosis or kyphosis)

·        Pelvic deformities

Dental deformities:

·        Delayed formation of teeth

·        Defects in the structure of teeth, holes in the enamel

·        Painful teeth, aching aggravated by sweets, or by cold/hot food or drinks

·        Increased incidence of cavities in the teeth (dental caries)

 

Diagnostic signs and tests

·        Serum calcium and serum phosphorus may be low.

·        Serum alkaline phosphatase may be high.

·        Arterial blood gases may reveal metabolic acidosis.

·        Bone X-rays may show decalcification or changes in the shape or structure of the bones.

 

Classification of the rickets

( by Lukyanova O.M., 1991)

Classical Rickets or acquired, congenital, caused by vit D deficiency	Vitamin -D-dependent rickets or pseudodeficiency	Vitaminresistent rickets	Secondary rickets
Levels of severity :I- mild; II –moderate, III- severe Disease Course character: acute, subacute, reccurent Disease variant: 1- with serum calcium decreasing. 2- with serum phospro decreasing. 3 – without any calcium and phosphor changes	Type I – genetic defect of kidney synthesis of 1,25(OH)2 D Type II – genetic resistance of organ receptors for  1,25(OH)2 D	Family congenital hypophosphatemic rickets or phosphat-diabet De-Toni-Debre-Phankoni disease Kidney tubular acidosis Hypophosphatasia	In case of kidney and liver diseases and biliary ducts obstruction In case of malabsorbtion syndrome In case methabolic disoders diseases Long-term treatment with anticonvulsant medications, such as phenytoin, can stimulate liver enzymes that break down and inactivate calcitriol.

 

TREATMENT

1 STAGE - VITAMINE D – “VIDEIN – 3” - 2000 IU 1 TIME\DAY 30 DAYS

2  STAGE - VITAMINE D – “VIDEIN – 3” - 3500 IU 1 TIME\DAY 40 DAYS

3 STAGE - VITAMINE D – “VIDEIN – 3” - 5000 IU 1 TIME\DAY 45 DAYS

THEN PROFILACTIC DOSE – 500 IU TILL THE END OF THE SECOND YEAR OF LIFE

 

SPECIFIC POSTNATAL PROFILACTIC

 HEALHU BABY - 500 IU TILL THE END OF THE SECOND YEAR OF LIFE

 

PREMATURE BABY – FROM THE 10-14 DAYS OF LIFE

 1 STAGE OF PREMATURING

 VITAMINE D – “VIDEIN – 3” - 500 IU 1 TIME\DAY 6 MONTHS

 2  STAGE OF PREMATURING

VITAMINE D – “VIDEIN – 3” - 1000 IU 1 TIME\DAY 6 MONTHS

 3 STAGE OF PREMATURING - VITAMINE D – “VIDEIN – 3” - 2000 IU 1 TIME\DAY 6 MONTHS

 THEN PROFILACTIC DOSE – 2000 IU DURING 30 DAYS 2-3 TIME \YEAR WITH INTERVALES 3-4 MONTHS TILL 3-D YEAR OF LIFEAYTILL THE END OF THE SECOND YEAR OF LIFE

 Prevention of Rickets and Vitamin D Deficiency: New Guidelines for Vitamin D Intake

Rickets in infants attributable to inadequate vitamin D intake and decreased exposure to sunlight continues to be reported in the United States. It is recommended that all infants, including those who are exclusively breastfed, have a minimum intake of 200 IU of vitamin D per day beginning during the first 2 months of life. In addition, it is recommended that an intake of 200 IU of vitamin D per day be continued throughout childhood and adolescence, because adequate sunlight exposure is not easily determined for a given individual. These new vitamin D intake guidelines for healthy infants and children are based on the recommendations of the National Academy of Sciences.

Cases of rickets in infants attributable to inadequate vitamin D intake and decreased exposure to sunlight continue to be reported in the United States.^1–3 Rickets is an example of extreme vitamin D deficiency. A state of deficiency occurs months before rickets is obvious on physical examination. The new recommended adequate intake of vitamin D by the National Academy of Sciences (NAS) to prevent vitamin D deficiency in normal infants, children, and adolescents is 200 IU per day.⁴ This differs from the 400 IU per day that has been recommended in previous editions of the Pediatric Nutrition Handbook of the American Academy of Pediatrics (AAP). The new NAS guidelines for infants are based on data primarily from the United States, Norway, and China, which show that an intake of at least 200 IU per day of vitamin D will prevent physical signs of vitamin D deficiency and maintain serum 25-hydroxy-vitamin D at or above 27.5 nmol/L (11 ng/mL). Although there are generally less data available for older children and adolescents, the NAS has come to the same conclusions for this population.⁴ Also, it is acknowledged that most vitamin D in older children and adolescents is supplied by sunlight exposure.⁴ However, dermatologists and cancer experts advise caution in exposure to sun, especially in childhood, and recommend regular use of sunscreens.^5–11 Sunscreens markedly decrease vitamin D production in the skin.

SUNLIGHT EXPOSURE

A potential source of vitamin D is synthesis in the skin from the ultraviolet B light fraction of sunlight. Decreased sunlight exposure occurs during the winter and other seasons and when sunlight is attenuated by clouds, air pollution, or the environment (eg, shade). Lifestyles or cultural practices that decrease time spent outdoors or increase the amount of body surface area covered by clothing when outdoors further limit sunlight exposure. The effects of sunlight exposure on vitamin D synthesis are also decreased for individuals with darker skin pigmentation and by the use of sunscreens.⁵ All of these factors make it very difficult to determine what is adequate sunshine exposure for any given infant or child. Furthermore, the Centers for Disease Control and Prevention, with the support of many organizations including the AAP and the American Cancer Society, has recently launched a major public health campaign to decrease the incidence of skin cancer by urging people to limit exposure to ultraviolet light.⁶ Indirect epidemiologic evidence now suggests the age at which direct sunlight exposure is initiated is even more important than the total sunlight exposure over a lifetime in determining the risk of skin cancer.^7–11 Thus, guidelines for decreasing exposure include directives from the AAP that infants younger than 6 months should be kept out of direct sunlight, children’s activities that minimize sunlight exposure should be selected, and protective clothing as well as sunscreens should be used.¹¹

BREASTFEEDING AND VITAMIN D

Infants who are breastfed but do not receive supplemental vitamin D or adequate sunlight exposure are at increased risk of developing vitamin D deficiency or rickets.^1–3,12,13 Human milk typically contains a vitamin D concentration of 25 IU/L or less.^14–16 Thus, the recommended adequate intake of vitamin D cannot be met with human milk as the sole source of vitamin D for the breastfeeding infant. Although there is evidence that limited sunlight exposure prevents rickets in many breastfed infants,^17,18 in light of growing concerns about sunlight and skin cancer and the various factors that negatively affect sunlight exposure, it seems prudent to recommend that all breastfed infants be given supplemental vitamin D. Supplementation should begin within the first 2 months of life. As noted above, it is very difficult to determine what is adequate sunlight exposure for an individual breastfed infant. Additional research is suggested to more fully understand the factors underlying the development of vitamin D deficiency and rickets in some breastfed infants.

FORMULAS AND VITAMIN D

All infant formulas sold in the United States must have a minimum vitamin D concentration of 40 IU/100 kcal (258 IU/L of a 20-kcal/oz formula) and a maximum vitamin D concentration of 100 IU/100 kcal (666 IU/L of a 20-kcal/oz formula).¹⁹ All formulas sold in the United States actually have at least 400 IU/L.²⁰ Thus, if an infant is ingesting at least 500 mL per day of formula (vitamin D concentration of 400 IU/L), he or she will receive the recommended vitamin D intake of 200 IU per day.

VITAMIN D SUPPLEMENTS

If the intake of vitamin D-fortified milk or formula is less than 500 mL per day, a vitamin D supplement can be provided by currently available multivitamin preparations containing 400 IU of vitamin D per mL or tablet. Currently available solitary vitamin D preparations (containing up to 8000 IU/mL) are too concentrated to be safe for routine home use. It is important that special efforts be directed toward supplementing populations at increased risk of developing rickets and vitamin D deficiency, including those with increased skin pigmentation and decreased sunlight exposure.

SUMMARY

To prevent rickets and vitamin D deficiency in healthy infants and children and acknowledging that adequate sunlight exposure is difficult to determine, we reaffirm the adequate intake of 200 IU per day of vitamin D by the National Academy of Sciences⁴ and recommend a supplement of 200 IU per day for the following:

1. All breastfed infants unless they are weaned to at least 500 mL per day of vitamin D-fortified formula or milk.

2. All nonbreastfed infants who are ingesting less than 500 mL per day of vitamin D-fortified formula or milk.

3. Children and adolescents who do not get regular sunlight exposure, do not ingest at least 500 mL per day of vitamin D-fortified milk, or do not take a daily multivitamin supplement containing at least 200 IU of vitamin D.

Vitamin D in Health and Disease

Vitamin D functions in the body through both an endocrine mechanism (regulation of calcium absorption) and an autocrine mechanism (facilitation of gene expression). The former acts through circulating calcitriol, whereas the latter, which accounts for more than 80% of the metabolic utilization of the vitamin each day, produces, uses, and degrades calcitriol exclusively intracellularly. In patients with end-stage kidney disease, the endocrine mechanism is effectively disabled; however, the autocrine mechanism is able to function normally so long as the patient has adequate serum levels of 25(OH)D, on which its function is absolutely dependent. For this reason, calcitriol and its analogs do not constitute adequate replacement in managing vitamin D needs of such patients. Optimal serum 25(OH)D levels are greater than 32 ng/mL (80 nmol/L). The consequences of low 25(OH)D status include increased risk of various chronic diseases, ranging from hypertension to diabetes to cancer. The safest and most economical way to ensure adequate vitamin D status is to use oral dosing of native vitamin D. (Both daily and intermittent regimens work well.) Serum 25(OH)D can be expected to rise by about 1 ng/mL (2.5 nmol/L) for every 100 IU of additional vitamin D each day. Recent data indicate that cholecalciferol (vitamin D₃) is substantially more potent than ergocalciferol (vitamin D₂) and that the safe upper intake level for vitamin D₃ is 10,000 IU/d.

Investigation of the effects of vitamin D and its metabolites and analogs has literally exploded in the past 10 yr, leading to substantial revisions in understanding of both the mode of action of vitamin D and the extent of its role in the functioning of a still growing number of body tissues, systems, and organs. Figure 1A illustrates the canonical scheme of vitamin D action that prevailed at the time when the most recent dietary intake recommendations for the vitamin were promulgated (1). In this scheme, vitamin D input to the body (whether cutaneous or oral) resulted in conversion to 25-hydroxyvitamin D [25(OH)D] in the liver, with subsequent conversion of 25(OH)D to calcitriol [1,25(OH)₂D] in the kidney. Calcitriol functioned as a hormone, circulating in the blood to stimulate the induction of various components of the calcium transport system in the intestinal mucosa. The net result was that active calcium absorption was increased and the efficiency of calcium absorption, normally low, was augmented so as to enable controlled adaptation to varying calcium intakes.

View larger version:

Figure 1.

Metabolic pathways by which vitamin D exerts its many effects in the body. (A) The prevailing scheme before recognition of the role of peripheral 1-α-hydroxylation. In this scheme, essentially all conversion of 25-hydroxyvitamin D [25(OH)D] to calcitriol occurs in the kidney, and the synthesized calcitriol appears in the serum, where it can be measured. Calcium-binding protein (CaBP) is a stand-in for the complex calcium absorptive apparatus induced in the enterocyte by calcitriol. (B) The current scheme, explicitly incorporating extrarenal 1-α-hydroxylation, with the resulting calcitriol appearing mainly intracellularly, where it is clinically unmeasureable. (Copyright Robert P. Heaney, 2008. Used with permission.)

This scheme remains correct, so far as it goes, but it is now understood that many tissues, particularly components of the immune apparatus and various epithelia, are able to express 1-α-hydroxylase and to synthesize calcitriol locally, as depicted in Figure 1B. The upper right-hand branch represents the endocrine pathway, and the lower branch represents the autocrine pathway. There are three key features of the revised scheme: (1) The bulk of the daily metabolic utilization of vitamin D is by way of the peripheral, autocrine pathway; (2) among other effects, the autocrine action always results in expression of the 24-hydroxylase; as a result, locally synthesized calcitriol is degraded immediately after it acts, and, thus, no calcitriol enters the circulation; and (3) local concentrations of calcitriol required to support various tissue responses are higher than typical serum concentrations of calcitriol.

In the cells and tissues that are the locus of the autocrine pathway, the synthesized calcitriol serves as a key link in the signaling apparatus that connects extracellular stimuli to genomic response. It has become clear in recent years that many tissues possess the proteins, enzymes, and signaling molecules that they need only in virtual form (i.e., encoded in the DNA blueprints in the nucleus). When the cells of such tissues are exposed to an extracellular stimulus or signal that calls for them to mount a response that requires some of these proteins or catalysts, they do so by opening up their library of DNA blueprints, finding the ones that are appropriate for the situation, and then synthesizing those proteins by transcribing the information that is encoded in the DNA. Figure 2 illustrates this process, showing specifically the key role played by intracellularly synthesized calcitriol.

View larger version:

Figure 2.

Diagram of the key role that calcitriol, synthesized within the cell concerned, plays in cellular responses requiring gene expression. (Copyright Robert P. Heaney, 2008. Used with permission.)

When bound to the vitamin D receptor and a variety of other helper proteins, calcitriol seems to be just the right key to open up the locked stores of DNA information, allowing the cell to transcribe the plans and produce the proteins needed for tissue-specific responses. The helper proteins that are a part of this complex determine the region of the DNA that will be transcribed. Without vitamin D, the ability of the cell to respond adequately to pathologic and physiologic signals is impaired. For example, the ductal epithelium of the breast requires vitamin D to mount an adequate response to cyclic variation in estrogen and progesterone (2). Also, macrophages use vitamin D to enable the synthesis of the bactericidal peptides needed to deal with bacterial invaders (3). In addition, most of the epithelial structures in the body, which turn over relatively rapidly, use vitamin D to signal the transcription of proteins that regulate cell differentiation, cell proliferation, and apoptosis (4).

There are several consequences of this revised understanding. Perhaps most important is that this scheme permits tissue-specific action of vitamin D (as contrasted with what would otherwise be near-universal activation if all tissues were directly responsive to circulating calcitriol concentrations). A second key insight is that the 1-α-hydroxylase in the tissues concerned functions well below its k_M (5); hence, the amount of calcitriol that it can produce locally depends on the availability of the precursor compound [i.e., 25(OH)D]. Thus, serum concentration of 25(OH)D becomes a critical factor in ensuring optimal functioning of the various systems that require vitamin D as a part of their signaling apparatus.

Until recently, it had been customary, in the management of ESRD, to supplement patients with calcitriol or one of its analogs—a logical move, given that renal synthesis of calcitriol in such patients is effectively knocked out. The resulting serum concentrations of calcitriol, however, are generally too low to enable the autocrine functions of the vitamin. Also, because of the short biologic half-life of calcitriol, serum calcitriol concentrations in such patients tend to be low most of the time. Finally, replacing calcitriol increases metabolic clearance of 25(OH)D (6) and certainly does nothing to support normal serum levels of this key metabolite. Thus, calcitriol is not a replacement for vitamin D and, at best, functions solely as a poor replacement for its endocrine function.

The inadequacy of calcitriol as a substitute for vitamin D itself is further emphasized by three lines of evidence indicating that even the canonical function of vitamin D (facilitation of calcium absorption) cannot be achieved by calcitriol alone. (1) Without doubt, calcitriol is the principal regulator of calcium absorption in typical adults, but it has been recognized for many years that those with frank vitamin D deficiency (e.g., adults with osteomalacia) exhibit calcium malabsorption, despite frequently normal to high-normal levels of circulating calcitriol. This defect is corrected not by giving more calcitriol but by raising serum levels of 25(OH)D. (2) Furthermore, 25(OH)D, administered as such, has been shown to elevate calcium absorption efficiency in typical adults, and it does so without elevating serum calcitriol levels (7). (3) Despite high parenteral dosages of calcitriol (e.g., 2 μg intravenously three times per week), calcium absorption efficiency remains severely depressed in patients who have ESRD and are on renal dialysis (R. Lund, personal communication). A working conclusion is that the optimal regulation of calcium absorption requires both molecules [25(OH)D and calcitriol]. How 25(OH)D is functioning in this setting is unclear, but it may be through binding to membrane vitamin D receptors (8) that, in turn, open calcium channels in the enterocyte and thereby facilitate the transfer of calcium across the cell.

Patients with ESRD, particularly those on renal dialysis, tend to be sick and spend little time outdoors and often have sufficiently dark skin to impede efficient vitamin D synthesis on sporadic sun exposure. For these reasons at least, serum 25(OH)D concentrations in such patients tend to be suboptimal and, in many cases, frankly deficient. Moreover, as is widely recognized, such patients have a very high excess mortality rate and increased risk for many chronic diseases. Whether the vitamin D deficiency that is common in such patients contributes to these risks and to their poor quality of life remains to be determined.

Canonical Function

The canonical function of vitamin D, described briefly in the previous section, is the facilitation of calcium absorption through the endocrine pathway of Figure 1. Figure 3 illustrates the relationship of absorption fraction in healthy adults to serum 25(OH)D, showing a plateau effect at serum 25(OH)D levels of approximately 80 nmol/L (9). Below that level, calcium absorption is impaired, as Figure 3 shows. It might be inferred from Figure 3 both that 25(OH)D is itself responsible for directly increasing absorption efficiency and that maximal absorption amounts to approximately 30%. Both are probably incorrect. Even at full vitamin D repletion [i.e., 25(OH)D levels ≥80 nmol/L), absorption fraction may be higher or lower than the plateau level shown in Figure 3, depending solely on calcitriol production, which reflects calcium need. (Calcitriol, in turn, is regulated by parathyroid hormone, itself reacting to perceived calcium need.) Below 80 nmol, absorption depends on both 25(OH)D and calcitriol. Although 25(OH)D has been shown to alter absorption directly (7), the size of that effect is too small to account for the ascending limb of the curve in Figure 3. What Figure 3 shows is not so much what vitamin D does as what it permits. Vitamin D enables the physiologic regulation of absorption so that vitamin D supply is not rate limiting. In one key study (10), participants with 25(OH)D concentrations averaging 86 nmol/L (34 ng/ml) absorbed at nearly 70% higher efficiency than did the same women studied at 50 nmol/L (20 ng/ml).

View larger version:

Figure 3.

Relationship of calcium absorption fraction to vitamin D nutritional status [as measured by serum 25(OH)D] (9). Note that efficiency rises up to 25(OH)D levels of approximately 80 nmol/L (32 ng/ml), above which regulation of absorption is no longer limited by vitamin D status. (Copyright Robert P. Heaney, 2005. Used with permission.)

Prevailing Vitamin D Status

Several population-based studies have reported vitamin D status in age groups from children to centenarians, as well as in isolated groups of individuals with discrete diseases (11–15). Individuals who would otherwise be considered healthy typically have serum 25(OH)D levels averaging in the range of 50 to 65 nmol/L, and from 65 to 100% of such populations have levels <80 nmol/L. As just noted, values of ≥80 nmol/L are necessary to optimize the canonical role of vitamin D. Outdoor workers in the tropics typically have serum 25(OH)D levels ranging from 120 to 200 nmol/L. These observations suggest that vitamin D deficiency is perhaps the most widespread deficiency condition in developed nations. It is important also to understand that the term “deficiency” in this sense does not necessarily connote clinically explicit disease (as would the term “deficiency” for nutrients such as vitamin C [scurvy] or thiamin [beriberi]). Rather it connotes an increase in risk for certain untoward outcomes, such as those reviewed briefly below in Vitamin D and Chronic Disease. This explains the seeming paradox that individuals who are ostensibly healthy today may nevertheless be “deficient.”

Vitamin D Requirement

The last published recommendations for vitamin D intake (1) are 200 IU/d for children and for adults up to age 50, 400 IU/d from age 50 to 70, and 600 IU/d thereafter. (The rise in the recommendations with age is an explicit reflection of the fact that, although cutaneous synthesis is understood to be occurring in most individuals, the efficiency of that synthesis declines with age [16,17].) These recommendations are explicitly pegged to the prevention of rickets in children and are presumably adequate for the prevention of osteomalacia in adults but are otherwise unconnected with any of the other disorders or functions reviewed in this article. At the time the recommendations were published, there was no clear evidence of how much vitamin D was typically synthesized in the skin, and, indeed, vitamin D presents a unique challenge among all of the nutrients because it is not typically present in most foods and because people with ample sun exposure have, effectively, no need at all for oral vitamin D.

Quantitative studies performed since the publication of the these recommendations have made it clear that at a presumably optimal level of ≥80 nmol/L, daily metabolic utilization of vitamin D is on the order of 4000 IU (18). Because dietary sources account for typically for no more than 5 to 10% of that total, the rest must be coming from skin or, lacking that, must result in a suboptimal 25(OH)D concentration.

Much work is being done (16,19,20) with respect to cutaneous synthesis of vitamin D and its relative role in the total vitamin D economy, but, for the moment, emphasis has to be on the oral supplementation that may be needed to achieve desired serum 25(OH)D concentrations. The quantitative work alluded to previously (18) has resulted in a “rule of thumb” to the effect that each 100 IU of additional daily oral vitamin D intake produces an elevation of serum 25(OH)D of approximately 1 ng/ml (2.5 nmol/L). Thus, a patient with a starting value of 15 ng/ml (37.5 nmol/L) would require approximately 1500 IU/d to bring his or her serum 25(OH)D level up to 30 ng/ml (75 nmol/L). At the same time, it must be stressed that individual response to standard dosages varies widely, and the rule of thumb is only an approximation.

Vitamin D and Chronic Disease

Following is a very brief review of some of the chronic disorders in which vitamin D deficiency has been found to play a role, either from epidemiologic studies or from randomized, controlled trials of vitamin D intervention. (A more extensive treatment may be found in Holick's review of that topic [21].) Table 1 lists several of these disorders with a rough indication for each of the extent and quality of the evidence connecting vitamin D deficiency with risk for or severity of the disorder concerned. Four pluses designate strong evidence including one or more randomized trials; three pluses strong and consistent epidemiologic evidence, without, however, evidence from randomized trials; and one and two pluses designate less strong evidence that is nevertheless suggestive. For some entries (e.g., multiple sclerosis with two pluses), it is not so much that there is contrary evidence as that the studies concerned are few in number. Also, by the same token, the absence of clinical trial data does not mean that there were null trials, so much as that the trials that are needed to confirm a causal connection have not been done. Furthermore, it is worth noting that, in certain instances, such trials might be extremely difficult to conduct (e.g., with a rare disorder such as multiple sclerosis).

Osteoporosis

The role of vitamin D in the pathogenesis and course of osteoporosis involves both its canonical function and the autocrine activity of the vitamin. For the canonical function, facilitation of calcium absorption, it is difficult to dissect apart the respective roles of calcium and vitamin D and probably not relevant, in any case. This is simply because one cannot absorb sufficient calcium from plausible diets unless one has reasonably normal vitamin D status, and, at the same time, one cannot absorb sufficient calcium, no matter what the vitamin D status, if calcium intake itself is absolutely low (22). Hence, given the prevalence of low intakes of both nutrients, it is not surprising that most of the clinical trials showing fracture prevention with calcium supplementation have involved treatment with vitamin D as well. All such trials show protection against age-related bone loss and, in many instances, reduction in fracture risk as well. Where fractures have been reduced, the induced serum 25(OH)D level was in excess of 75 to 80 nmol/L, and dosages that failed to achieve such serum levels generally failed to show fracture reduction (23). In addition, apparently through an autocrine pathway, vitamin D has been shown to reduce fall risk within only a few weeks of starting treatment, in some trials by as much as 50% (24,25). It is likely that this effect is partly responsible for the reduced fracture risk observed in treatment studies.

Cancer

There is a large body of epidemiologic data showing an inverse association between incident cancer risk and antecedently measured serum 25(OH)D (26–29). This evidence has been accumulated for such cancers as prostate, colon, breast, lung, and marrow/lymphoma, among others. Risk reduction for breast cancer, for example, is reported to be as much as 70% for the top quartile of serum 25(OH)D (>75 nmol/L) relative to the bottom quartile (<45 nmol/L) (29). Furthermore, there is an even larger body of animal data showing that vitamin D deficiency in experimental systems predisposes to development of cancer on exposure to typical carcinogens (30,31). This has been shown both for animals with knockout of the vitamin D receptor and for animals with induced, nutritional vitamin D deficiency. Capping these lines of evidence is a recent randomized, controlled trial of postmenopausal women showing substantial reduction in all-cancer risk, amounting to from 60 to 75%, over the course of a 4-yr study (32). Figure 4 presents the Kaplan-Meier survival curves free of cancer for individuals from that study.

Kaplan-Meier survival (free of cancer) for postmenopausal women in the randomized trial of Lappe et al. (32). In the three treatment arms of the study (placebo, 1500 mg calcium [Ca], and 1500 mg of Ca + 1100 IU of vitamin D₃ [Ca + D]), 6.9% of participants had developed cancer by the end of the trial on placebo, 3.8% on Ca only, and 2.9% on Ca + D (P < 0.02). The risk for the group that received vitamin D relative to placebo was 0.402 (95% confidence interval 0.20 to 0.82). (Copyright Robert P. Heaney, 2006. Used with permission.)

Immunity/Response to Infection

In the days when rickets was rampant, children with this disorder frequently died of respiratory infections. Calcitriol in its autocrine role has been recognized for roughly 20 yr as playing a role in various aspects of the immune response (33), best illustrated in the study of Liu et al. (3) for innate immunity. Clinically, it has been noted in randomized, controlled trials that vitamin D co-therapy substantially improved response to standard antitubercular therapy in patients with advanced pulmonary tuberculosis (34) and, as a secondary outcome, reduced risk for influenza in postmenopausal black women who received vitamin D (35). Also, phagocytic function of human macrophages is enhanced in individuals who received vitamin D supplementation (36). In brief, response to infection is hampered when vitamin D status is suboptimal.

Diabetes

Both type 1 and type 2 diabetes have been associated with low vitamin D status, both current and antecedent (37–39). For example, in a study based in the National Health and Nutrition Examination Survey (NHANES) data, participants without a known history and/or diagnosis of diabetes were much more likely to have high blood sugar values, both fasting and after a glucose challenge, when they had low vitamin D status (37). In an interesting report from Finland, adults who had received 2000 IU/d vitamin D during the first year of life had an >80% reduction in risk of incident type 1 diabetes, relative to individuals who had not received such supplement (39).

Hypertension and Cardiovascular Disease

The association of vitamin D status and hypertension is particularly strong. Both controlled trials and meta-analyses have shown a protective effect of high calcium intake for both pregnancy-related and essential hypertension (40–44), whereas risk for incident hypertension is inversely related to antecedently measured serum 25(OH)D concentration. Specifically, in a 4-yr prospective study involving both the Health Professionals Follow-up Study and the Nurses’ Health Study, Forman et al. (40) reported a relative risk for incident hypertension of 3.18 for individuals with 25(OH)D levels <15 ng/ml, relative to those with levels >30 ng/ml. From the Framingham Offspring Study, with 5.4 yr of follow-up, individuals with 25(OH)D values <15 ng/ml were 53% more likely to experience a cardiovascular event than those above that level, and those with values <10 ng/ml were 80% more likely (41).

Finally, Giovannucci et al. (45), analyzing data from the Health Professionals Follow-up Study, reported a nearly 2.5-fold increase in risk of myocardial infarction for individuals with 25(OH)D levels below 15 ng/mL, compared to those above 30 ng/mL.

Vitamin D₂versus Vitamin D₃

The natural form of vitamin D in all animals and the form synthesized in human skin on exposure to sunlight is cholecalciferol, vitamin D₃. Ergocalciferol (vitamin D₂) is a synthetic product derived by irradiation of plant sterols/ergosterol. Until very recently, the two forms of the vitamin were considered to be interchangeable and equivalent (hence their quantification with the same unitage); however, since the availability of the measurement of serum 25(OH)D as an indicator of vitamin D functional status, it has become clear that vitamin D₂ is substantially less potent, unit for unit, than vitamin D₃ (46,47). The two seem to be absorbed from the intestine and to be 25-hydroxylated in the liver with equal efficiency (47); however, vitamin D₂ seems to upregulate several 24-hydroxylases, leading to increased metabolic degradation of both the administered D₂ and endogenous D₃. Thus, although it is certainly possible to treat patients satisfactorily with vitamin D₂ (48), ergocalciferol seems to have no advantage over vitamin D₃ (cholecalciferol), which, as noted, is the natural form of the vitamin and which is, today, less expensive. It should be noted that, in this brief review, all of the evidence brought forth with respect to the relationship of vitamin D status to health and disease has been developed mainly for cholecalciferol (vitamin D₃).

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Toxicity

Vitamin D, particularly its active hormonal form, calcitriol, is a highly potent molecule, capable of producing serious toxic effects, including death, at milligram intake levels. There is thus a healthy fear of the compound relating in part to cases of sporadic poisoning (49) as well as to medical misadventure 70 yr ago, involving administration of millions of units per day of the vitamin. Nevertheless, despite these appropriate concerns, there is, in fact, a comfortable margin of safety between the intakes required for optimization of vitamin D status and those associated with toxicity. It is worth noting, for example, that a single minimum erythema dosage of ultraviolet radiation (e.g., 15 min in the sun in a bathing suit in July) produces, in a light-skinned individual, 10,000 to 20,000 IU of vitamin D. Repeated day after day, this can add up to substantial vitamin D inputs. Nevertheless, there has never been a reported case of vitamin D intoxication from sun exposure. Controlled metabolic studies, necessarily limited in scope (although extending into the 100s of individuals), showed that dosages up to 50,000 IU/d for from 1 to 5 mo produce neither hypercalcemia nor hypercalciuria. A recent publication, reviewing the totality of the toxicity data, concluded that there were no cases of intoxication reported for daily intakes of <30,000 IU/d for extended periods (50) and no cases of vitamin D intoxication for serum 25(OH)D levels <200 ng/ml (500 nmol/L). Thus, it was concluded that a daily intake of 10,000 IU should be considered the tolerable upper intake level. There is no known medical reason for dosages approaching that level; hence, there is a comfortable margin of safety between therapeutic and toxic intakes.

Discussion

In the foregoing brief summary, which touched on only a small fraction of a vast body of work that has been developed in this area, several features stand out. Perhaps most important is the pluriform nature of the benefit, involving systems ranging from epithelial carcinogenesis to neuromuscular functioning. This diversity of effect seems to be an expression of the fact that there are roughly 800 human genes for which there is a vitamin D response element (4). Most of these genes have nothing to do with the canonical function of vitamin D (calcium absorption) but instead relate to the expression of proteins necessary for control of cell proliferation, differentiation, and apoptosis. Because these functions are critical for most body tissues, notably epithelial integrity and the immune response, it is perhaps not surprising that inadequate vitamin D availability may limit both the performance of the tissues concerned and their control of various aspects of the cell cycle.

A second feature of the list of diseases involved is that they all are multifactorial in origin, and it is likely that vitamin D deficiency, rather than being directly causal (as with rickets and osteomalacia), operates by hampering the ability of the tissues concerned to deal adequately with both physiologic stimuli and pathologic signals. Accordingly, it is likely that medical science does not really know the true, underlying burden of many of these chronic diseases and cannot know it until the widespread problem of vitamin D deficiency has been corrected. Undoubtedly, various cancers, infections, and hip fractures will continue to occur under conditions of optimal vitamin D status. It is just that risk will be lower. This is strongly suggested by the fact that incidence of virtually all of the disorders concerned is directly correlated with latitude, with populations living farther from the equator (with lower cutaneous synthesis of vitamin D) being at greater risk.

Also, in the case of patients with ESRD, it is not certain what fraction of their symptom complex is due to the vitamin D deficiency that is widespread in that population. Several randomized, controlled trials are now under way to evaluate the effects, if any, of vitamin D supplementation, and answers to this question should be forthcoming in the relatively near future.

 

  REFERENCES:

1.     Textbook of Pediatrik Nursing.  Dorothy R. Marlow; R. N., Ed. D. –London, 1989.-661p.

2.      Pediatrics ( 2^nd edition, editor – Paul H.Dworkin, M.D.) – 1992. – 550 pp.

3.     Brody, T. Nutritional Biochemistry, 2nd Edition. San Diego, CA: Academic Press, 1999: pages 565-593.

4.     Holick, M.F. Vitamin D. In Shils, M. et al. Eds. Nutrition in Health and Disease, 9th Edition. Baltimore: Williams & Wilkins, 1999: pages 329-345.

5.     DeLuca, H.F. & Zierold, C.F. Mechanisms and functions of vitamin D. Nutrition Reviews. 1998; volume 56(2): pages S4-S10.

6.     Janeway, C.A. & Travers, P. Immunobiology: the immune system in health and disease. 3rd Edition. New York, NY: Garland Publishing Inc., 1997: pages 1:23-1:30.

7.     Cantorna, M.T. Vitamin D and autoimmunity: Is vitamin D status an environmental factor affecting autoimmune disease prevalence? Proceedings of the Society for Experimental Biology and Medicine. 2000; volume 223: pages 230-233.

8.     Buist, N. Vitamin D deficiency in Oregon: nutritional rickets resurgent. The Doernbecher Journal. 2000: volume 6(2): pages 13-17.

9.     Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press, 1997: pages 250-287. 

10. Shearer, M.J. The roles of vitamin D and vitamin K in bone health and osteoporosis prevention. Proceedings of the Nutrition Society. 1997; volume 56: pages 915-937.

11. Dawson-Hughes, B. et al. Effect of vitamin D supplementation on wintertime and overall bone loss in health postmenopausal women. Annals of Internal Medicine. 1991; volume 115: pages 505-512.

12. Dawson-Hughes, B. et al. Rates of bone loss in postmenopausal women randomly assigned to one of two dosages of vitamin D. American Journal of Clinical Nutrition. 1995; volume 61: pages 1140-1145.

13. Dawson-Hughes, B. et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age and older. The New England Journal of Medicine. 1997; volume 337: pages 670-676.

14. Dawson-Hughes, B. et al. Effect of withdrawl of calcium and vitamin D supplements on bone mass in elderly men and women. American Journal of Clinical Nutrition. 2000; volume 72: pages 745-750.

15. Feldman D, Glorieux FH, Pike JW: Vitamin D. San Diego: Academic Press 1997.

16. Harrison HE, Harrison HC: Disorders of calcium and phosphate metabolism in childhood and adolescence. Philadelphia: WB Saunders Co. 1979.

17. Shah BR, Finberg L: Single-day therapy for nutritional vitamin D-deficiency rickets: a preferred method. J Pediatr 1994 Sep; 125(3): 48``7-90.

18. Zmora E, Gorodischer R, Bar-Ziu J: Multiple nutritional deficiencies in infants from a strict vegetarian community. Am J Dis Child 1979; 133: 141.

 

 

 

 

Protein-vitamin insufficiency in children. Malnutrition.

Clinical features, diagnostics, treatment and prophylaxis.

 

Malnutrition is absence of adequate caloric and volume feeding of the child There are numerous causes of malnutrition including recurrent bacterial diarrhea, often upper respiratory tract infections, congenital gastrointestinal diseases, diseases of the mother during pregnansy. This state is associated with anergy, infectious complications, high mortality.

Etiology: inadequate feeding, low level of ferments of gastrointestinal tract. Organic factors include congenital heart defects, neurologic lesions, microcephaly, chronic urinary tract infection, gastroesophageal reflux, renal insufficiency, endocrine dysfunction, cystic fibrosis. Malnutrition can also be caused by psychosocial factors, the problem being between the child and primary caregiver, usually the mother. In this situation the lack of physical growth and development is secondary to the lack of emotional and sensory stimulation.

Pathogenesis: Digestive defects mainly include those conditions in which the enzymes, necessary for digestion are diminished or absent, such as cystic fibrosis, in which pancreatic enzymes are absent; biliary or liver disease, in which bile production is affected, or lactase deficiency, in which there is congenital or secondary lactose intolerance. Absorptive defects include those conditions in which the intestinal mucosal transport system is impaired. It may be because of primary defect such as celiac disease or gluten enteropathy or secondary to inflammatory disease of the bowel, that results in impaired absorption because bowel motility is accelerated. Anatomic defects  such as short bowel syndrome, affect digestion by decreasing the transit time of substances with the digestive juices and affect absorption by compromising the absorptive surface. All this causes leads to maldigestion and malabsorption syndrome, damage of function of all organs and systems of the organism.

 

 

 

 Main clinical symptoms are: abdomen pain, regurgitation, periodic vomiting, bad appetite, frequent liquid stool, decreasing or absense of subcutaneous fat. Becides the obvious signs of malnutrition and delayed development, the child seems to have a characteristic posture of “body language”. The child may be unpliable, stiff and rigid. He is uncomforted by unyielding to cuddling and is very slow in smiling or social responding to others. The other extreme is the floppy infant, who is like the rag doll.

 

 

Frequently there is a history of difficult feeding, vomiting, sleep disturbances, excessive irritability. Difficulties of infant feeding may include poor appetite, poor suck, crying during feeding, vomiting, hoarding food in the mouth, ruminating after feeding, refuse of liquids and solids, aversion behavior such as turning from food or spitting food. In addition, chronic reduction in caloric intake can lead to appetite depression, which compounds the problem. Another outstanding feature of children with malnutrition is their irregularity in activities of daily living. Some of these children called as “difficult child pattern”. However, another type is the passive, sleepy, lethargic child who does not awake up for feeding.

Other clinical symptoms range from moderate growth failure ( a common occurance in underdeveloped countries ) to more severe conditions such as marasmus and kwashiorcor. The former results from an anadequate intake of a suitable diet; the latter resulrs from a diet with a low protein, energy ratio, frequently with protein of poor biologic quality. The three stages of protein-energy malnutrition are marasmus, marasmic-kwashiorcor and kwashiorcor.They are compounded by a whole spectrum of nutritional disorders that include deficiences of one or more vitamins, minerals and trace minerals. The three stages of protein-energy malnutrition can be differenciated most clearly on the basis of clinical findings.  Intermediate forms known as marasmic-kwashiorcor also are seen. Growth retardation, weight loss, psychic changers, muscular atrophy, pellagroid dermatitis, hair changes, edema, gastrointestinal changers and other abnormalities are present in various combinations. Marasmus which predominate in infancy, is characterised by severe weight reduction , gross wasting of muscle and subcutaneous tissue, no detectable edema and marked stunting. Marasmus results from inadequate energy intake, impaired absorption of protein, energy, vitamins and minerals. The hair and skin changes and hepatomegaly resulting from fatty infiltration of the liver. The marasmic child, characteristically irritable and apathetic, is the skin and bones portrait of the skeleton.

Kwashiorcor results from either inadequate protein  intake , or, more commonly, from acute or chronic infection. It appears predominantly in older infants and younger children. Clinically it is characterised by edema, skin lesions, hair changers, apathy, anorexia, a large fatty liver, and decreased a serum albumine. Weight loos is also usual, without a decrease of energy intake. The edema of kwashiorcor can only partially be explained by the low serum albumine, other contributing factors include increased capillary permeability, increase cortisol, and antidiuretic hormones lewel.

 

 

 

 

Marasmic – Kwashiorcor presents with the clinical findings of both marasmus and kwashiorcor. The child has edema, gross wasting and usually stunted. There may also be mild hair and skin changers and a palpable fatty-infiltrated liver. The child with marasmus-kwashiorcor is one who demonstrated the combined defects of an inadequate intake of nutrients to meet requirements plus superimposed infection.

3. General examination of the patient: patients have asthenic constitution, reduced degree of nourishment, weight loss, the abdomen is great, distended, meteorism, the skin and mucus membranes are dry, turgor of skin is decreased, muscular hypotonia, abdomen is asymmetrical, CNS dysfunktion (retardation of the development).

 

CLASSIFICATION OF MALNUTRITION

 

Origin	Stage	Period	Prenatal malnutrition forms
Alimentary factors Infection factors Regime breaking, care  and upbringing defects Prenatal factors Hereditary pathology and congenital development defects	I ( mild) II (moderate) III ( severe)	Initial Progressive Stabilization Reconvalecsention (recovery)	Neuropathic Neurodystrophic Encephalopathic Neuroendocrinilogical

 

MALNUTRITIONAL STAGES

 

STAGES	WEIGHT DEFICITE	LENTH DEFICITE	CHULITSKA NUTRITIONAL INDEX
І	10-20%	-	10 – 15
ІІ	20-30%	2-4 sm	0 – 10
ІІІ	More than 30%	7-10 sm	negative

 

Interpretation

 

	Weight for Height (wasting)	Height for Age (stunting)
Normal	> 90	> 95
Mild	80 - 90	90 – 95
Moderate	70 - 80	85 – 90
Severe	< 70	< 85

 

CHULITSKA NUTRITIONAL INDEX (characterizes a degree  of the child fattenies:

      3 contours of a shoulder (sm.) + contour of thigh (sm.) + contour of shin (sm.) - growth (sm.);

Norm: by one year - 20-25 sm.; smaller 20 sm. - gipotrophija; greater 25 sm. -  paratrophija.

Weight of a body: 1. I month - plus 600gr.

                                  II month – plus  800 gr.

                                   III month - plus 800 gr., for each next month on 50 gr.less, than for previous.

Growth: for І sq. - + 3 sm. monthly (for one quarter 9 sm.);

          For ІІ sq. + 2,5 sm. monthly (for one quarter 7,5 sm.);

          For ІІІ sq.+1,5 sm.monthly (for one quarter 4,5 sm.);

          For IU sq. +1,0 sm monthly (for one quarter 3 sm).

 

 

 

A Scoring System for Classifying Severe Protein-Calorie Malnutrition in Young Children

 

Parameter	Finding	Points
Edema and dermatitis	edema plus dermatitis	6
	edema without dermatitis	3
	dermatitis without edema	2
	both absent	0
Hair changes	present	1
	absent	0
Hepatosplenomegaly	present	1
	absent	0
Serum albumin or total serum protein	< 1 g/dL albumin < 3.25 g/dL total protein	7
	1.00 - 1.49g/dL albumin 3.25 - 3.99 g/dL total protein	6
	1.50 - 1.99 g/dL albumin 4 - 4.74 g/dL total protein	5
	2.00 - 2.49 g/dL albumin 4.75 - 5.49 g/dL total protein	4
	2.50 - 2.99 g/dL albumin 5.5 - 6.24 g/dL total protein	3
	3.00 - 3.49 g/dL albumin 6.25 - 6.99 g/dL total protein	2
	3.50 - 3.00g/dL albumin 7 - 7.74 g/dL total protein	1
	> 4.0 g/dL albumin > 7.75 g/dL total protein	0

nutrition score =

= SUM(points for the 4 parameters)

Interpretation

∙ minimum score: 0

∙ maximum score: 15

Score	Type of Malnutrition
0 - 3	Marasmic
4 - 8	Marasmic kwashiorkor
9 - 15	Kwashiorkor
Parameter		Finding		Points
Weight for height		< 3rd percentile		2
		3rd to 10th percentile		1
		> 10th percentile		0
Triceps skinfold thickness		< 5.6 mm		2
		5.6 √ 7.0 mm		1
		> 7.0 mm		0
Serum albumin or prealbumin		serum albumin < 3.0 g/dL or prealbumin < 8 mg/dL		2