Haematological disorders
Haemoglobin production in the fetus and newborn
The most important difference between haemopoiesis in the fetus compared with postnatal life is the changing pattern of haemoglobin (Hb) production at each stage of development. The composition and names of these haemoglobins are shown in Table 22.1. Understanding the developmental changes in haemoglobin helps to explain the patterns of abnormal haemoglobin production in some inherited childhood anaemias. Embryonic haemoglobins (Hb Gower 1, Hb Gower 2 and Hb Portland) are produced between 4 and 8 weeks’ gestation, after which haemoglobin production switches to fetal haemoglobin (HbF). HbF is made up of 2 α chains and 2 γ chains (α2γ2) and is the main Hb during fetal life. HbF has a higher affinity for oxygen than adult Hb (HbA), and is therefore better able to hold on to oxygen, an advantage in the relatively hypoxic environment of the fetus (Fig. 22.1). At birth, the types of Hb are: HbF, HbA and HbA2. HbF is gradually replaced by HbA and HbA2 during the first year of life. By 1 year of age, the percentage of HbF is very low in healthy children and increased proportions of HbF are a sensitive indicator of some inherited disorders of haemoglobin production (haemoglobinopathies) .
Table 22.1
Embryonic, fetal and adult haemoglobins
| Haemoglobin type | Globin chains | |
| α-gene cluster | β-gene cluster | |
| Embryonic | ||
| Hb Gower 1 | ξ2 | ε2 |
| Hb Gower 2 | α2 | ε2 |
| Hb Portland | ξ2 | γ2 |
| Fetal | ||
| HbF | α2 | γ2 |
| Adult | ||
| HbA | α2 | β2 |
| HbA2 | α2 | δ2 |
| Haemoglobin types in newborns and adults | ||
| Newborn | HbF 74%, HbA 25%, HbA2 1% | |
| Children >1 year old and adults | HbA 97%, HbA2 2% | |
Haematological values at birth and the first few weeks of life
• At birth, the Hb in term infants is high, 14–21.5 g/dl, to compensate for the low oxygen concentration in the fetus. The Hb falls over the first few weeks, mainly due to reduced red cell production, reaching a nadir of around 10 g/dl at 2 months of age (Fig. 22.2). Normal haematological values at birth and during childhood are shown in the Appendix.
• Preterm babies have a steeper fall in Hb to a mean of 6.5–9 g/dl at 4–8 weeks chronological age.
• Normal blood volume at birth varies with gestational age. In healthy term infants the average blood volume is 80 ml/kg; in preterm infants the average blood volume is 100 ml/kg.
• Stores of iron, folic acid and vitamin B12 in term and preterm babies are adequate at birth. However, in preterm infants, stores of iron and folic acid are lower and are depleted more quickly, leading to deficiency after 2–4 months if the recommended daily intakes are not maintained by supplements.
• White blood cell counts in neonates are higher than in older children (10–25 × 109/L).
• Platelet counts at birth are within the normal adult range (150–400 × 109/L).
Anaemia
Anaemia is defined as an Hb level below the normal range. The normal range varies with age, so anaemia can be defined as:
Anaemia results from one or more of the following mechanisms:
• Reduced red cell production – either due to ineffective erythropoiesis (e.g. iron deficiency, the commonest cause of anaemia) or due to red cell aplasia
• Increased red cell destruction (haemolysis)
There may be a combination of these three mechanisms, e.g. anaemia of prematurity.
Using this approach, the principal causes of anaemia are shown in Figure 22.3 and a diagnostic approach to identifying their causes is shown in Figure 22.4.
The definition of anaemia varies with age: Hb <10 g/dl in infants (post-neonatal), Hb <11 g/dl from 1 to 12 years old.
Causes of anaemia in infants and children
Diagnostic clues to ineffective erythropoiesis are:
• Abnormal mean cell volume (MCV) of the red cells: low in iron deficiency and raised in folic acid deficiency.
Iron deficiency
The main causes of iron deficiency are:
Inadequate intake of iron is common in infants because additional iron is required for the increase in blood volume accompanying growth and to build up the child’s iron stores (Fig. 22.5). A 1-year-old infant requires an intake of iron of about 8 mg/day, which is about the same as his father (9 mg/day) but only half that of his mother (15 mg/day).
• Breast milk (low iron content but 50% of the iron is absorbed)
• Infant formula (supplemented with adequate amounts of iron)
• Cow’s milk (higher iron content than breast milk but only 10% is absorbed)
• Solids introduced at weaning, e.g. cereals (cereals are supplemented with iron but only 1% is absorbed).
Iron deficiency may develop because of a delay in the introduction of mixed feeding beyond 6 months of age or to a diet with insufficient iron-rich foods, especially if it contains a large amount of cow’s milk (Box 22.1). Iron absorption is markedly increased when eaten with food rich in vitamin C (fresh fruit and vegetables) and is inhibited by tannin in tea.
Infants should not be fed unmodified cow’s milk as its iron content is low and poorly absorbed.Clinical features
Most infants and children are asymptomatic until the Hb drops below 6–7 g/dl. As the anaemia worsens, children tire easily and young infants feed more slowly than usual. The history should include asking about blood loss and symptoms or signs suggesting malabsorption. They may appear pale but pallor is an unreliable sign unless confirmed by pallor of the conjunctivae, tongue or palmar creases. Some children have ‘pica’, a term which describes the inappropriate eating of non-food materials such as soil, chalk, gravel or foam rubber (see Case History 22.1). There is evidence that iron deficiency anaemia may be detrimental to behaviour and intellectual function.
Iron requirements during childhood
Management
For most children, management involves dietary advice and supplementation with oral iron. The best tolerated preparations are Sytron (sodium iron edetate) or Niferex (polysaccharide iron complex) – unlike some other preparations these do not stain the teeth. Iron supplementation should be continued until the Hb is normal and then for a minimum of a further 3 months to replenish the iron stores. With good compliance, the Hb will rise by about 1 g/dl per week. Failure to respond to oral iron usually means the child is not getting the treatment. However, investigation for other causes, in particular malabsorption (e.g. due to coeliac disease) or chronic blood loss (e.g. due to Meckel diverticulum) is advisable if the history or examination suggests a non-dietary cause or if there is failure to respond to therapy in compliant patients. Blood transfusion should never be necessary for dietary iron deficiency. Even children with an Hb as low as 2–3 g/dl due to iron deficiency have arrived at this low level over a prolonged period and can tolerate it.
Treatment of iron deficiency with normal Hb
Some children have biochemical evidence of iron deficiency (e.g. low serum ferritin) but have not yet developed anaemia. Whether these children should be treated with oral iron is controversial. In favour of treatment is the knowledge that iron is required for normal brain development and there is evidence that iron deficiency anaemia is associated with behavioural and intellectual deficiencies, which may be reversible with iron therapy. However, it is not yet clear whether treatment of subclinical iron deficiency confers significant benefit. Treatment also carries a risk of accidental poisoning with oral iron, which is very toxic. A simple strategy is to provide dietary advice to increase oral iron and its absorption in all children with subclinical deficiency and to offer parents the option of additional treatment with oral iron supplements.
Treatment of iron deficiency anaemia is with dietary advice and oral iron therapy for several months.
Red cell aplasia
There are three main causes of red cell aplasia in children:
• Congenital red cell aplasia (‘Diamond–Blackfan anaemia’)
• Transient erythroblastopenia of childhood
• Parvovirus B19 infection (this infection only causes red cell aplasia in children with inherited haemolytic anaemias and not in healthy children).
The diagnostic clues to red cell aplasia are:
Diamond–Blackfan anaemia (DBA) is a rare disease (5–7 cases/million live births). There is a family history in 20% of cases; the remaining 80% are sporadic. Specific gene mutations in ribosomal protein (RPS) genes are implicated in some cases. Most cases present at 2–3 months of age, but 25% present at birth. Affected infants have symptoms of anaemia; some have other congenital anomalies, such as short stature or abnormal thumbs. Treatment is by oral steroids; monthly red blood cell transfusions are given to children who are steroid unresponsive and some may also be offered stem cell transplantation.
Transient erythroblastopenia of childhood (TEC) is usually triggered by viral infections and has the same haematological features as Diamond–Blackfan anaemia. The main differences between them is that, unlike Diamond–Blackfan anaemia, transient erythroblastopenia of childhood always recovers, usually within several weeks, there is no family history or RPS gene mutations and there are no congenital anomalies.
Increased red cell destruction (haemolytic anaemia)
Haemolytic anaemia is characterised by reduced red cell lifespan due to increased red cell destruction in the circulation (intravascular haemolysis) or liver or spleen (extravascular haemolysis). The lifespan of a normal red cell is 120 days and the bone marrow produces 173 000 million red cells per day. In haemolysis, red cell survival may be reduced to a few days but bone marrow production can increase about eight-fold, so haemolysis only leads to anaemia when the bone marrow is no longer able to compensate for the premature destruction of red cells.
In children, unlike neonates, immune haemolytic anaemias are uncommon. The main cause of haemolysis in children is intrinsic abnormalities of the red blood cells:
• Red cell membrane disorders (e.g. hereditary spherocytosis)
• Red cell enzyme disorders (e.g. glucose-6-phosphate dehydrogenase deficiency)
• Haemoglobinopathies (abnormal haemoglobins, e.g. β-thalassaemia major, sickle cell disease).
Haemolysis from increased red cell breakdown leads to:
The diagnostic clues to haemolysis are:
• Raised reticulocyte count (on the blood film this is called ‘polychromasia’ as the reticulocytes have a characteristic lilac colour)
• Unconjugated bilirubinaemia and increased urinary urobilinogen
• Abnormal appearance of the red cells on a blood film (e.g. spherocytes, sickle shaped or very hypochromic) (Fig. 22.6)
• Positive direct antiglobulin test (only if an immune cause, as this test identifies antibody-coated red blood cells)
Hereditary spherocytosis
HS occurs in 1 in 5000 births in Caucasians. It usually has an autosomal dominant inheritance, but in 25% there is no family history and it is caused by new mutations. The disease is caused by mutations in genes for proteins of the red cell membrane (mainly spectrin, ankyrin or band 3). This results in the red cell losing part of its membrane when it passes through the spleen. This reduction in its surface-to-volume ratio causes the cells to become spheroidal, making them less deformable than normal red blood cells and leads to their destruction in the microvasculature of the spleen.
Clinical features
The disorder is often suspected because of the family history. The clinical manifestations are highly variable. Although hereditary spherocytosis-affected individuals may be completely asymptomatic, the clinical features include:
• Jaundice – usually develops during childhood but may be intermittent; may cause severe haemolytic jaundice in the first few days of life
• Anaemia – presents in childhood with mild anaemia (haemoglobin 9–11 g/dl), but the haemoglobin level may transiently fall during infections
• Mild to moderate splenomegaly – depends on the rate of haemolysis
• Aplastic crisis – uncommon, transient (2–4 weeks), caused by parvovirus B19 infection
Diagnosis
The blood film is usually diagnostic but more specific tests are available (e.g. osmotic fragility, dye binding tests), although seldom required. Autoimmune haemolytic anaemia is also associated with spherocytes and this should be excluded with a direct antibody test in the absence of a family history of hereditary spherocytosis.
Management
Most children have mild chronic haemolytic anaemia and the only treatment they require is oral folic acid as they have a raised folic acid requirement secondary to their increased red blood cell production. Splenectomy is beneficial but is only indicated for poor growth or troublesome symptoms of anaemia (e.g. severe tiredness, loss of vigour) and is usually deferred until after 7 years of age because of the risks of post-splenectomy sepsis. Prior to splenectomy all patients should be checked that they have been vaccinated against Haemophilus influenzae (Hib), meningitis C and Streptococcus pneumoniae and lifelong daily oral penicillin prophylaxis is advised. Aplastic crisis from parvovirus B19 infection usually requires one or two blood transfusions over 3–4 weeks when no red blood cells are produced. If gallstones are symptomatic, cholecystectomy may be necessary.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
G6PD deficiency is the commonest red cell enzymopathy affecting over 100 million people worldwide. It has a high prevalence (10–20%) in individuals originating from central Africa, the Mediterranean, the Middle East and the Far East. Many different mutations of the gene have been described, leading to different clinical features in different populations.
G6PD is the rate-limiting enzyme in the pentose phosphate pathway and is essential for preventing oxidative damage to red cells. Red cells lacking G6PD are susceptible to oxidant-induced haemolysis. G6PD deficiency is X-linked and therefore predominantly affects males. Females who are heterozygotes are usually clinically normal as they have about half the normal G6PD activity. Females may be affected either if they are homozygous or, more commonly, when by chance more of the normal than the abnormal X chromosomes have been inactivated (extreme Lyonisation – the Lyon hypothesis is that, in every XX cell, one of the X chromosomes is inactivated and that this is random). In Mediterranean, Middle Eastern and Oriental populations, affected males have very low or absent enzyme activity in their red cells. Affected Afro-Caribbeans have 10–15% normal enzyme activity.
Clinical manifestations
Children usually present clinically with:
• Neonatal jaundice – onset is usually in the first 3 days of life. Worldwide it is the most common cause of severe neonatal jaundice requiring exchange transfusion
• Acute haemolysis – precipitated by:
Haemolysis due to G6PD deficiency is predominantly intravascular. This is associated with fever, malaise and the passage of dark urine, as it contains haemoglobin as well as urobilinogen. The haemoglobin level falls rapidly and may drop below 5 g/dl over 24–48 h.
Diagnosis
Between episodes, almost all patients have a completely normal blood picture and no jaundice or anaemia. The diagnosis is made by measuring G6PD activity in red blood cells. During a haemolytic crisis, G6PD levels may be misleadingly elevated due to the higher enzyme concentration in reticulocytes, which are produced in increased numbers in response to the destruction of mature red cells. A repeat assay is then required in the steady state to confirm the diagnosis.
Management
The parents should be given advice about the signs of acute haemolysis (jaundice, pallor and dark urine) and provided with a list of drugs, chemicals and food to avoid (Box 22.2). Transfusions are rarely required, even for acute episodes.
Haemoglobinopathies
These are red blood cell disorders which cause haemolytic anaemia because of reduced or absent production of HbA (α- and β-thalassaemias) or because of the production of an abnormal Hb (e.g. sickle cell disease). α-Thalassaemias are caused by deletions (occasionally mutations) in the α-globin gene. β-Thalassaemia and sickle cell disease are caused by mutations in the β-globin gene. Clinical manifestations of the haemoglobinopathies affecting the β-chain are delayed until after 6 months of age when most of the HbF present at birth has been replaced by adult HbA (Fig. 22.7, Table 22.2).
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