Approach to Diagnosis of Anemia in Children

Anemia is a widespread public health problem associated with an increased risk of morbidity and mortality, especially in pregnant women and young children. Globally 1.62 billion people are anemic, while among the preschool children the prevalence of anemia is 47.4%. Nutritional anemia in South Asia accounts for nearly half of global cases of anemia. In India, anemia continues to be the major health problem in young children, adolescent girls, and pregnant women. Approximately 50% of the population suffers from nutritional anemia as known in countries where meat consumption is low. In India, about 89 million children are anemic. The prevalence of anemia was 70% in children aged 6–59 months.


Introduction
Anemia can be defined as a reduction in hemoglobin concentration, haematocrit or number of RBC per cubic mm.The lower limit of normal range is set at two standard deviation below the mean for age and sex of the normal population. 1 Anemia is a widespread public health problem associated with an increased risk of morbidity and mortality, especially in pregnant women and young children. 2 Globally 1.62 billion people are anemic, while among the preschool children the prevalence of anemia is 47.4%.Nutritional anemia in South Asia accounts for nearly half of global cases of anemia.In India, anemia continues to be the major health problem in young children, adolescent girls, and pregnant women.Approximately 50% of the population suffers from nutritional anemia as known in countries where meat consumption is low. 3In India, about 89 million children are anemic.The prevalence of anemia was 70% in children aged 6-59 months. 4 clinical practice, anemia is one of the most frequently encountered clinical sign.It could be the manifestation of so many diseases. 5To go for the diagnosis of anemia the approach should begin right from the commencement of history taking and physical examination and later with the help of laboratory support.
To start clinically the causes are to be considered first.It could be Nutritional, malabsorption, bone marrow dysfunction, bone marrow infiltrative disorders and hemolysis.Therefore, one should be very systematic and judicious in the approach to detect the cause and reach the diagnosis.

The genesis of anemia
Different disorders lead to different kind of events and disruption of normal activities and homeostasis of the body.As Hb and RBCs are in the central stage of anemia the stuffs required for the synthesis of Hb and RBCs, if remain deficient, cause deficiency anemias.Therefore, whenever there are deficiency of iron, folic acid, vitamins like cyanocolbalamin, pyridoxine, vitamin C, copper and others, it lead to inadequate synthesis of Hb causing reduction of Hb and anemia.The above mentioned factors are found deficient in case of nutritional deficiencies, poor intake, chronic or recurrent diarrhea, malabsorptions, congenital structural Gastro-intestinal disorders, or some post surgical conditions or reparative surgeries.Therefore, these finally lead to poor absorption of the stuffs required for Hb synthesis or cell membrane integrity of RBCs leading to anemia. 7ere can be hemorrhage, acute or chronic ones, those also lead to disorders of anemia.Acute bleeding resulting in anemia is usually profuse.The chronic ones usually are minute and sometimes unrecognisable in naked eyes.In these conditions, if blood is not replaced or transfused, lead to anemia. 8emia almost invariably accompanies the diagnosis of Acute Leukemias in children and is considered to be one of the most common clinical complications of the disease.In addition a low hemoglobin level is often responsible for fatigue when other associated symptoms usually point out to the cause.As a result decline in quality of life of these children becomes notable.The contributing factors likely are overcrowding of the marrow by malignant cells or blasts, coexisting infections and nutritional deficits. 9Similarly, in Lysosomal Storage disorders crowding of the bone marrow spaces affect RBC production and results in anemia. 10emia also is produced when bone marrow spaces become hypoplastic or aplastic.It can affect all the precursors like erythroid, myeloid and megakaryocytic or it can only affect the erythroid ones.Consequently anemia occurs on account of low RBC productions.These conditions can occur due to direct insult to the stem cells or the supportive structures or the damage to the environment of marrow spaces required for hemopoiesis.As discussed before these can be either due to the effects of drugs, chemicals, virus infections, or due to immunologic responses to any molecule or any adverse event.Besides these acquired conditions Aplastic or hypoplastic anemiacan also be primary or idiopathic. 11Occasionally they are associated with some congenital syndromes related to chromosomal or genetic abnormalities. 12e anemia resulting from abnormal or excessive or undesired breakdown of RBCs cause reduction of RBC number and thereby causes hemolytic anemia This can be hereditary, or it can be acquired.Hereditary causes related to cell membrane abnormalities or Hb abnormalities or enzyme make RBCs more susceptible to hemolysis in the spleen or extravascular spaces.These breaking down of RBCs release the haem from Hb into circulation and causes increase in haem metabolites like bilirubin and as a result hyperbilirubinemia occurs. 13To compensate for this deficiency increased demand of Hb is created and there are medullary and extra-medullary hyperplasia causing some evident structural deformities in the face and enlargement of liver and spleen.The iron gathered from relentless hemolysis are accumulated in the body in its different organs and also leads to increased morbidities and cause mortalities. 13 case of hereditary Enzyme deficiency disorders, red cells are broken in the circulation and evoke a different kind of sequence of events.These conditions do occur in challenges by some foods, infections (viral or bacterial) and drugs.Intravascular hemolysis are usually acute and consequences are anemia, hyperbilirubinemia, bilirubinuria, hemoglobinuria and black water urine. 14On the other hand because of attaching Hb to albumin, hemopexin and haptoglobin it results in hypoalbuminemia and low haptoglobin levels.There are other acquired conditions when RBCs undergo some mechanical stress having wear and tears inflicted to their cell walls during circulation causing RBC lysis and anemia.Additionally, some immune conditions also cause red cell break down either by antibodies or complement mediated actions when intravascular hemolysis occurs leading to similar events as mentioned in other intravascular causes of hemolysis.In case of hemolysis, intravascular or extravascular, immune or nonimmune, acquired or genetic, some compensatory physiological responses lead to increased activities of bone marrow and the other parts of reticuloendothelial system. 15e history to be covered The history should be taken as when the disease was started or for how long the anemia has been for to identify if it is an acute or a chronic disease or if it is a congenital or acquired disorder.This history can enable us to detect the hereditary anemias like Thalassemia and other RBC cell membrane disorders.Some hypoplastic anemias of congenital causes (Diamond Blackfan anemia), with or without dysmorphism (like Fanconi's anemia), with or without congenital anomalies (Fanconi's anemia, TAR syndrome) can be detected.The above mentioned causes are all chronic causes.There can be some acquired hypoplastic bone marrow related causes which can present as acute or chronic disorders.There can be some acute causes of anemias e.g Autoimmune Hemolytic Anemia and alloimmune hemolytic anemia, acute leukemias.History of fever and association with bleeding disorders could be important clues in the history to diagnose the cause of anemia. 16,17  findings associated with anemia Having finished history, the most important thing for a clinician is collecting the clinical findings through physical examination.
The anemia and its severity should be noted first for the idea about the status.
A rapidly developing severe anemia is likely to give rise to heart failure.On the other hand, severe anemia that developed over a period of months or years is much less likely to give rise to dyspnea or heart failure.There can be facial dysmorphism for the medullary hyperplasia giving the characteristic impression of Hereditary Hemolytic Anemia with failure to thrive usually associated with it.In those cases jaundice and hepatosplenomegaly are likely findings.Jaundice and splenomegaly or hepatosplenomegaly can be associated with anemia in acute hemolysis like Enzyme deficiency or Autoimmune Hemolytic Anemia.All of these patients are usually afebrile.
Hepatosplenomegaly with fever can be due to Acute Leukemia, Non Hodgkin's Lymphoma (NHL), Malaria and Kala-azar and rarely Hodgkin's disease.Hepatosplenomegaly and lymphadenopathy can give rise to the suspicion for Histiocytosis and Tuberculosis but anemia of severe degree is not expected in these diagnoses.
Another important aspect is Anemia without organomegaly, if with fever and cutaneous or mucosal hemorrhage Hypoplastic Anemia and without fever and Hemorrhage Nutritional anemia are to be considered.Although blood loss anemia should not cause hepatosplenomegaly yet GastroIntestinal bleeding from Portal Hypertension can give rise to blood loss anemia with splenomegaly and sometimes hepatomegaly pretty much like Hereditary Hemolytic Anemia. 16,17  lab investigations in anemia To know the etiology we may have to do some more investigations like Iron profile, vitamin B12, folate assay, schilling test, Radio assay of RBC life span, imaging, endoscopy, colonoscopy, Hb electrophoresis, OBT etc. 16,17 The diagnostic approach From the above discussion it has been clear that diagnosis of anemia requires a wide array of disease spectrum.Therefore, a definite diagnostic approach is necessary but difficult.Here, a diagnostic approach on the basis of clinical impression, is being proposed, that is as follows.

conclusion
Anemia is the manifestation of many diseases.Therefore, diagnosis of the disease is important.A rational diagnostic approach based on history and physical examination as well as stepwise lab support is very important.Besides differentials, crucial investigations are MCV, Reticulocyte count, bilirubin, DAT and Hb electrophoresis.A good drill through the clinical and laboratory procedures enables cliniciansidentify the cause of anemia and reach the diagnosis.