Megaloblastic anemia in children

Introduction to pediatric megaloblastic anemia Megaloblastic anemia (megaloblasticanaemia), also known as large cell anemia, is mainly caused by direct or indirect deficiency of folic acid and/or vitamin B12, mostly caused by insufficient intake. Its blood cell morphology is characterized by a large red blood cell volume, excessive neutrophil nuclear lobes, and giant erythrocyte proliferation in the bone marrow. basic knowledge The proportion of illness: 0.0035% Susceptible people: children Mode of infection: non-infectious Complications: jaundice, purpura, epistaxis

Causes of megaloblastic anemia in children

Improper feeding (25%):

Folic acid is mainly found in green leafy vegetables. Others such as yeast, liver, kidney and other foods are also more, while vitamin Bl2 is mainly located in animal liver, muscle and kidney. When breast milk is fed alone, vitamin B12 and folic acid are not added in time. Into, the folic acid contained in goat's milk is very small. Therefore, the feeding of sheep milk alone is prone to the lack of folic acid.

Cause of disease (20%):

The main absorption site of folic acid is the upper part of the small intestine, and the main absorption site of vitamin B12 is located at the end of the ileum. Therefore, any cause of small intestinal lesions can cause malabsorption of folic acid and vitamin B12, resulting in a lack of both, such as chronic diarrhea. Severely affect the absorption of folic acid and vitamin B l2. Surgical removal of jejunum can cause folic acid deficiency, while ileal resection can cause deficiency of vitamin B12. In addition, liver lesions can affect the normal metabolism of folic acid, causing obstacles in the biotransformation of folic acid. .

Congenital defects (35%):

(1) Congenital folate absorption defects in the small intestine: it is an autosomal recessive hereditary disease that can cause malabsorption of folic acid.

(2) juvenile type of pernicious anemia: the disease is rare and belongs to autosomal recessive inheritance. The disease is caused by the absorption of vitamin B12 by the cells in the stomach wall that cannot secrete internal factors (IF).

(3) Congenital transcobalamin deficiency: transcobalamine protein II (TCII) is the main transporter of vitamin B12, and congenital transcobalamin deficiency can lead to vitamin B 12 transport disorder, resulting in an indirect defect of vitamin B l2 The disease belongs to autosomal recessive inheritance.

(two) pathogenesis

1. Folic acid and metabolism of vitamin B12

(1) Metabolism and utilization of folic acid: After folic acid (decanoylglutamic acid) in food, it is absorbed by folate binding protein located on epithelial cells of small intestinal mucosa, and decanoyl monoglutamate is more than decanoyl Glutamate is easily absorbed, while the phthaloyl glutamate hydroxylase located at the brush edge promotes the conversion of decanoyl polyglutamic acid to decanoylglutamate, which is beneficial to the absorption of folic acid. The folic acid has intestinal and intestinal circulation, plasma. Most of the folic acid binds to serum albumin. Folic acid itself has no biological activity. They must be reduced to tetrahydrofolate by the action of dihydrofolate reductase and then transported into tissue cells. The folate requirement of normal adults is 100g per day, the mother of pregnancy can be increased to 350g per day, in terms of kilograms of body weight, infants and young children need more folic acid than adults.

(2) Metabolism and utilization of vitamin Bl2: Vitamin Bl2 is derived from cobalamin in animal foods. Humans cannot synthesize vitamin B12, but intestinal bacteria can be synthesized and used by humans. Cobalamin in food. The hormone is released under the action of gastric acid, and immediately passes through the duodenum after binding to the R protein and the internal factor, wherein the R protein is hydrolyzed by the pancreatic protease and absorbed by the special receptor of the residual vitamin B122-inner factor complex. In addition, when a large dose of vitamin B12 is administered, it can also be absorbed in the oral and intestinal mucosa by a gradient diffusion mechanism. Vitamin B12 in plasma is combined with transcobalamin (TC) I, II, III, of which TCII is especially Importantly, 'TCII-cobalamin enters the cell through a specific receptor-mediated endocytosis, and then cobalamin is converted to methylcobalamin and adenosylcobalamin, the latter two being active forms, involved in the transfer Methyl action and synthetic DNA.

2. Pathogenesis

Folic acid and vitamin B2 are important coenzymes in the process of DNA synthesis. They are mainly used for transmethylation. In the absence of uridine deoxynucleotides, methylation cannot be methylated, which hinders the deoxygenation of thymidine, an important raw material for synthetic DNA. The synthesis of nuclear and glycosidic acids, which in turn affects the synthesis of DNA. Under normal circumstances, cell division occurs when intracellular DNA is increased by a factor of 2 (4n). When folic acid and vitamin B12 are deficient, DNA synthesis is impaired, and young red blood cells divide. Delayed, while hemoglobin is still continuing to synthesize, so that the synthesis of hemoglobin in young red blood cells is increasing and the volume is getting larger and larger, while the DNA content has not been able to meet the requirements necessary for cell division, causing the young red blood cells to undergo giant changes.

This megaloblastic red blood cell is easily destroyed in the bone marrow, causing ineffective hematopoiesis, which causes megaloblastic anemia. The effects of folic acid and vitamin B1 deficiency on cell division are not only found in the erythroid lineage, but also in the granulocyte and megakaryocyte cell lines. Granules and rod-shaped nucleated cells are large in volume, swollen in the nucleus, loose in structure, and excessive in nuclear lobes, up to more than 5 leaves. Because of the short survival time of granulocytes, this change precedes the erythroid system and can be used as folic acid or vitamins. Bl2 lacks the basis for early diagnosis, the volume of megakaryocytes is also increased, the number of nuclear lobes is too high, platelet production is disordered, and giant platelets are visible. When vitamin B12 is deficient, in addition to the changes in the blood system, the mental nervous system can be affected. It is due to the deficiency of vitamin sulfur, which can cause the nervous system to have lipid metabolism disorder of sheath nerve fibers. The sheath of sheath nerve fibers is rich in sphingomyelin. The intermediate metabolite in lipid metabolism is methylmalonic acid. With the participation of vitamin B12, it is converted into succinic acid and enters the tricarboxylic acid cycle. When vitamin B12 is deficient, methylmalonic acid cannot be converted into succinic acid. Methylmalonic acid accumulates in the nerve sheath, destroying the formation of the nerve sheath and causing neuropsychiatric symptoms.

Pediatric megaloblastic anemia prevention

Pregnant women should eat more fresh vegetables and animal protein. Folic acid should be supplemented during pregnancy to correct children's bad eating habits and incorrect cooking methods. For chronic hemolytic anemia or long-term anti-epileptic drugs, folic acid should be given prophylactic treatment. Gastrectomy should be done once a month with preventive intramuscular injection of vitamin B12.

Pediatric megaloblastic anemia complications Complications, jaundice, purpura, nosebleed

Can be complicated by jaundice, purpura, nosebleeds, heart enlargement, cardiac insufficiency, malabsorption, sublingual ulcers, symmetry numbness of the hands and feet, sensory disturbances, mental retardation, developmental backwardness or mental retrogression, convulsions and so on.

Symptoms of megaloblastic anemia in children Common symptoms Appetite is poor, tired lips, pale hair, thin yellow, sparse, irritability, restless splenomegaly, anorexia, white blood cells, reduced hoarseness

The onset of the disease is often not noticed by the parents. The severity of the systemic symptoms and the degree of anemia are not necessarily proportional. The skin color can be pale, the lips, the conjunctiva, the nail bed is pale, the hair is yellow, fine, dry, sparse, edema, often with tongue. Smooth, anorexia, nausea, vomiting, diarrhea, occasional difficulty in swallowing, hoarseness, irritability, fatigue, weakness, dull expression, unresponsiveness, direct vision, poor appetite, lethargy, pre-cardiac area It can be audible and systolic murmur. Due to the relationship between extramedullary hematopoiesis, liver and spleen can be enlarged to varying degrees, which is related to the age of onset. The younger the age, the more obvious the liver and splenomegaly are. Skin may appear sputum, ecchymosis, leukopenia susceptible to bacterial infection, vitamin Bl2 deficiency, in addition to the above performance, there may be obvious neurological symptoms, slow movements, unconscious movements of the hands and feet, head and Limb tremor, tremor first seen in the hands, lips, tongue, due to repeated tremors and tongue ligaments can appear ulcers; then the upper limbs, head, and even the whole body, after stimulation can make the tremor plus Drama, severe cases can be seen in the limbs flexion, convulsions, long-term lack of unreplenished, can appear mental retardation.

Examination of megaloblastic anemia in children

1. Peripheral blood: The number of red blood cells is more obvious than that of hemoglobin. When the early hemoglobin is still in the normal range, the number of red blood cells has decreased, the volume of red blood cells has increased, and the size of the red blood cells may vary from small to large, mainly in large cells. The hemoglobin filling degree is good, the central light-stained area is reduced, the average red blood cell volume (MCV) and the average red blood cell hemoglobin content (MCH) are greater than normal, MCV>100fl, but the average red blood cell hemoglobin concentration (MCHC) is in the normal range, indicating the anemia. For simple large cell anemia, the granulocyte volume increases, the number decreases, the nuclear chromatin is loose, and the nuclear lobes are more, more than 5 leaves, more than 5% of the cells above the 5th leaf of the nuclear lobule or 6 The leaf has diagnostic value, the number of platelets can be reduced, the volume is increased, and the bleeding time is prolonged.

2. Bone marrow: Most of the bone marrow cells are compensatory hyperplasia, but also have normal hyperplasia or hyperplasia, but all have red blood cells, large cell bodies, large nuclear chromatin, strong cytoplasmic eosinophilia, nuclear and plasma development imbalance. The development of the nucleus lags behind the cytoplasm, the granulocyte is large, the nuclear lobes are many, the nucleus is shifted to the right, the megakaryocyte nucleus is excessively lobulated, the granules are reduced, and the platelets in the bone marrow are also larger.

3. Determination of plasma folic acid and vitamin Bl2: folate or vitamin Bl2 decreased or both decreased, when the plasma folic acid content <3g / L (6.7nmol / L), red blood cell folic acid <227nmol / L (100ng / ml) can determine folic acid Lack of plasma vitamin B12 content <100 ~ 140ng / L can help to confirm the diagnosis.

4. Determination of gastric acid: Children's stomach acid is often reduced, and can be recovered after treatment.

5. B-ultrasound: visible hepatosplenomegaly.

6. X-ray examination: chest X-ray examination of the lungs inflamed shadows.

7. EEG examination: There is an abnormal waveform.

Diagnosis and diagnosis of megaloblastic anemia in children

diagnosis

The diagnosis should be based on clinical manifestations, feeding history and laboratory tests, and the laboratory results are the main basis for the diagnosis of the disease. According to the history and clinical manifestations, there are typical hematological changes:

Blood picture

Large cell anemia (MCV>100fl), excessive neutrophil lobulation (5 leaves accounted for more than 5% or 6 leaves).

2. Bone marrow

A proliferative anemia and a typical megaloblastic change in the erythroid line can be diagnosed as megaloblastic anemia.

3. Folic acid and/or vitamin B12 deficiency

To further clarify the lack of folic acid or vitamin B12 deficiency, the following tests can be further performed:

(1) Folic acid and vitamin B12 levels: serum folic acid <6.81nmol / L (3ng / L), erythrocyte folic acid <227nmol / L (100ng / ml) can determine folic acid deficiency, serum vitamin B12 <75pmol / L (100pg / L) Indication of the lack of further determination of serum homocysteine or methylmalonic acid diagnosis, in order to determine the cause of vitamin B12 deficiency, when the condition can be measured internal antibody and vitamin B12 absorption test.

(2) Experimental treatment: In the unconditional test, the experimental treatment can be used for the purpose of diagnosis. The physiological dose of folic acid (or vitamin B12) is only effective for patients with folic acid (or vitamin B12) deficiency. B12 (or folic acid) deficiency is ineffective. If the patient's clinical symptoms, blood and bone marrow are improved and restored after treatment, they can be identified. Folic acid and vitamin B12 are also common, and the dietary quality is poor. At the same time vegetarian, partial eclipse, and some patients with digestive tract diseases, in addition, should also pay attention to nutritional megaloblastic anemia, iron staining, serum iron and transferrin saturation is increased, otherwise it should be considered whether there is iron .

Differential diagnosis

In order to identify the deficiency of vitamin Bl2 or the lack of internal factors, 57Co-labeled vitamin B l2 can be used for Schilling test. The megaloblastic anemia should be differentiated from erythroleukemia, congenital brain hypoplasia, and the megaloblastic red blood cells in erythroleukemia. Primary staining (PAS) showed huge PAS-positive granules, but megaloblastic anemia did not show this; mental retardation of congenital brain hypoplasia occurred at birth, and the mental decline of megaloblastic anemia was secondary. The intelligence at birth is normal and it is not difficult to identify.

Differential diagnosis

(1) Whole blood cell reduction: megaloblastic anemia can reduce whole blood cells, and it is clinically differentiated from other diseases with reduced whole blood cells, such as aplastic anemia, myelodysplastic syndrome (MDS), paroxysmal hemoglobinuria ( PNH), hypersplenism, etc., from clinical manifestations, blood features, bone marrow morphology and necessary physical examination and identification is not difficult.

(2) pathological hematopoiesis: megaloblastic anemia caused by folic acid and/or vitamin B12 deficiency has obvious abnormalities in blood cell morphology, such as increased proportion of erythroid and multi-stage changes in megaloblastic nucleus And over-leaf, meganuclear multi-leaf and large platelets, MDS, erythroleukemia (M6), etc. may also have erythroid increased with erythroid giant changes and other pathological hematopoiesis, but its blood and bone marrow, clinical outcomes and other characteristics can be identified.

(3) hemolytic anemia: megaloblastic anemia with proliferative anemia with mild jaundice should be differentiated from hemolytic anemia.

(4) Nervous system: The disease has neurological involvement and needs to be differentiated from nervous system diseases. Infancy patients should be differentiated from brain hypoplasia and other genetic metabolic diseases with neurological manifestations. Larger children should be demyelinated with nerves. Identification of diseases, identification of etiology: Although nutrient deficiency of folic acid, vitamin B12 is the most common cause of children, but should be differentiated from anemia caused by other causes, vitamin B12 absorption test can be carried out, abnormally given internal factors after vitamin B12 If the absorption is normal, it can be diagnosed as a lack of internal factors. If it is still abnormal, other causes such as stomach, intestinal lesions or surgery, chemotherapy drugs, alcohol or liver disease caused by metabolic disorders may be considered.

2. Special types of megaloblastic anemia

(1) Glucose enteropathy and celiac disease (non-tropical stomatitis diarrhea or idiopathic fat sputum): Glucose enteropathy is called celiac disease in children, usually in temperate regions, characterized by villi of small intestinal mucosa Atrophy, epithelial cells change from columnar to scorpion-like, lymphatic infiltration in the mucosa, and the disease is related to the consumption of some wheat cereals, such as fat, protein, carbohydrates, vitamins and minerals. There are obstacles in the absorption of substances. The clinical manifestations are fatigue, intermittent diarrhea, weight loss, indigestion, abdominal distension, glossitis and anemia. The stool is watery or mushy, with a large amount, a lot of foam, stinky, a lot of fat, blood and Bone marrow is a typical megaloblastic anemia, serum and erythrocyte folate levels are reduced, and treatment with folic acid is not important for foods containing gluten.

(2) tropical inflammatory diarrhea (tropical vegetative megaloblastic anemia): the cause of this disease is unclear, more common in India, Southeast Asia, Central America and the Middle East and other tropical areas of residents and tourists, clinical symptoms and gluten sausage disease Similarly, serum folate and erythrocyte folate levels are reduced. Treatment with broad-spectrum antibiotics with folic acid can alleviate symptomatic relief and anemia, and after treatment, low-dose folic acid maintenance therapy is used to prevent recurrence.

(3) hereditary whey aciduria: a disease characterized by abnormal metabolism of autosomal recessive hereditary pyrimidine, mostly in infancy, in addition to megaloblastic anemia, often stagnant growth, mental retardation, but also There are congenital malformations and immunodeficiency, a large amount of orotonic acid crystals in the urine, the patient's serum folic acid or vitamin B12 concentration is not low, treatment with folic acid or vitamin B12 is ineffective, treatment with uridine or yeast can correct anemia.

(4) Juvenile pernicious anemia: juvenile pernicious anemia refers to the congenital lack of intrinsic factor of the infancy in infants, the inability to absorb vitamin B12 and the occurrence of pernicious anemia. The parents and brothers and sisters can find defects in the secretion of internal factors, and their serum is also There are no antibodies against parietal cells and anti-inner factors. The disease needs to be differentiated from childhood pernicious anemia. The latter is over 10 years old, has gastric mucosal atrophy, gastric acid deficiency, and antibodies in serum.

(5) Pernicious anemia: Most of the causes are caused by lymphocyte-mediated immune response, which is caused by the destruction of gastric parietal cells. The lack of internal factors caused by surgical removal of gastric tissue is not a pernicious anemia. Most patients develop from 50 to 70 years old. The incidence rate is high, but it is rare in Asians. The clinical manifestations are anemia, gastrointestinal symptoms, nervous system symptoms and signs, such as fatigue, shortness of breath, severe heart failure, loss of appetite, glossitis, etc., in children and infants. It is not obvious that young children have slow growth and mental retardation. They are diagnosed with vitamin B12 deficiency megaloblastic anemia. At the same time, there may be gastric mucosal atrophy, gastric acid reduction, blood and gastric wall cell antibody and internal factor antibody positive. Schilling test abnormality indicates There is vitamin B12 malabsorption, can be corrected after giving internal factors, this test can determine the lack of internal factors, treatment patients need lifelong vitamin B12 supplemental therapy, should not be administered orally, monthly intramuscular injection of vitamin B12 100g, neurological symptoms are obvious medication The amount should be increased to 1 mg.

(6) Genetic defects:

1 Familial selective vitamin B12 malabsorption: autosomal recessive, ileal mucosal cells lack the receptor of the internal factor-B12 complex, or the receptor is normal, but the function is abnormal, starting from 1 to 15 years old, Most of them start in infancy, showing vitamin B12 deficiency megaloblastic anemia, persistent proteinuria, normal stomach and intestinal mucosa, normal secretion of gastric acid and internal factors, no endogenous factor antibodies, and Schilling test for vitamin B12 malabsorption. And can not be corrected by internal factors, patients must be treated with vitamin B12 for life.

2 hereditary transcobalamin II deficiency: autosomal recessive inheritance, 3 to 4 weeks after birth, vomiting, diarrhea, slow growth, weakness and paleness, severe, typical megaloblastic anemia, nerve Systemic symptoms appeared in a few months, serum vitamin B12 and gastric acid secretion were normal, and there was no evidence of endogenous factors and parietal cell antibodies. The occurrence of this disease is related to malabsorption and utilization of vitamin B12. Weekly injection of 2000 g of vitamin B12 Hematological changes can be alleviated.

3 methylmalonic aciduria: autosomal recessive inheritance, the child is normal at birth, but with the protein intake, drowsiness, slow growth, low muscle tone, respiratory distress, repeated vomiting and dehydration, the patient has blood , a significant increase in urinary methylmalonic acid, in addition to blood, urinary ketone body and glycine elevation, elevated blood ammonia, metabolic acidosis, the pathogenesis is due to the enzyme protein of methylmalonyl-CoA transposase Changes in structure, decreased affinity for vitamin B12, vitamin B12 has a short-term effect, patients with complete devoid enzymes do not respond to vitamin B12 treatment, therefore must limit the intake of amino acids metabolized by the propionic acid pathway, such as ammonia Acid, isoleucine, methionine and threonine, etc., the disease has a poor prognosis.

4 adenosine cobalamin deficiency (cblA disease and cblB disease): autosomal recessive inheritance, cell mitochondria can not synthesize adenosine cobalamin, so that methylmalonyl-CoA mutase can not have normal function, infancy onset The clinical manifestations are the same as those of mutase, but the condition is mild, and the severity of the disease is related to the response to vitamin B12 treatment. It can be treated with cyanocobalam and hydroxocobalamin.

5 adenosine cobalamin-methylcobalamin combined defect (cblC disease, cblD disease and cblF disease): there may be defects in the enzyme before the synthesis stage of methylcobalamin and adenosine cobalamin, so that the two kinds of cells cannot be synthesized. Cobalamin, onset in early infants, cdlD disease started slightly later, in addition to the characteristics of adenosine cobalamin deficiency, patients also have homocysteine blood (urine) and hypomethionemia, serum B12 And folic acid did not decrease, and there was an increase in treatment with hydroxycobalamin.

6 methylcobalamin deficiency (cblE disease and cblG disease): autosomal recessive inheritance, intracellular can not synthesize methylcobalamin, so that methionine synthetase loses function, onset within 2 years old, also mainly manifests Young cell anemia and neurological symptoms, homocysteine blood (urine) and hypomethioninemia, no blood, elevated urinary methylmalonic acid, cobalamin treatment can improve hematological abnormalities, but not Change the nervous system symptoms that have already occurred.

7 methylenetetrahydrofolate reductase deficiency: infants are underdeveloped, with neurological symptoms such as convulsions, microcephaly, mental disorders, etc., serum and erythrocyte folate levels are abnormally increased, giant red blood cells can be seen in the bone marrow, and the liver is found in the liver. The activity of N5-methyltetrahydrofolate transferase is lower than normal, causing N5-methyltetrahydrofolate to accumulate in the body, while other active folate is deficient, resulting in the proliferation of giant red blood cells in the bone marrow, which is difficult to treat.

8 glutamate imidomethyltransferase deficiency: the patient's mental and physical insufficiency, accompanied by anemia, bone marrow cells slightly giant young, although the serum folic acid concentration increased, but the excretion of the imine in the urine The acyl glutamic acid is abnormally large, which is caused by a decrease in the activity of the imine methyltransferase, which causes an imbalance in the metabolism of histidine, resulting in an increase in the excretion of the intermediate metabolite imidoformylglutamic acid.

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