Normal erythropoiesis

It is thought that white cells, red cells and platelets are all derived from a common cell known as the pluripotent stem cell found in the bone marrow. As these cells mature, they become committed to a specific cell line (Fig. 49.1). The red cells mature through the various stages, during which time they synthesise haemoglobin, DNA and RNA. Reticulocytes are found in the peripheral circulation for 24 h before maturing into erythrocytes. Reticulocytes are released into the peripheral circulation prematurely during times of increased erythropoiesis.

Fig. 49.1 Simplified diagram of some of the stages within erythropoiesis.

Erythropoietin is a hormone produced by the cells of the renal cortex. The kidney responds to hypoxia and anaemia by increasing the production of erythropoietin. The red cell progenitors BFU-E and CFU-E have receptors on their surface. When erythropoietin binds to these receptors, it promotes differentiation and division, and consequently increased erythropoiesis. Patients with end-stage renal disease fail to produce appropriate amounts of erthropoietin and so develop anaemia. Erythropoietin production is also impaired in other conditions such as rheumatoid arthritis, cancer and sickle cell disease, though the impairment is not as great as in renal disease. Also of interest is the fact that theophylline decreases erythropoietin production, though the clinical relevance of this is uncertain.

Each day approximately 2 × 10¹¹ erythrocytes enter the circulation. Normal erythrocytes survive in the peripheral circulation for about 120 days. Abnormal erythrocytes have a shortened lifespan. At the end of their life, the red cells are destroyed by the cells of the reticuloendothelial system found in the spleen and bone marrow. Iron is removed from the haem component of haemoglobin and transported back to the bone marrow for reuse. The pyrole ring from globin is excreted as conjugated bilirubin by the liver, and the polypeptide portion enters the body’s protein pool.

Clinical manifestations

In its mildest form anaemia results in tiredness and lethargy; at its most severe it results in death unless treated. There is some suggestion that even mild anaemia may inhibit physical exercise and result in reduced mental performance. The reduced oxygen-carrying capacity of the blood leads to reduced tissue oxygenation and widespread organ dysfunction (Box 49.1).

A rapid blood loss, for example, haemorrhage, produces shock, with collapse, dyspnoea and tachycardia. Anaemia that develops over a period of time allows the body to partially compensate. As the anaemia becomes worse, more and more signs and symptoms may develop.

Even though in anaemia the amount of haemoglobin is reduced, all the blood that passes through the lungs is fully oxygenated. Increasing the respiratory rate or increasing the FiO₂ (fraction of inspired oxygen) will not improve tissue oxygenation. When the haemoglobin falls below 7 or 8 g/dL, there is almost always a compensatory increase in cardiac output.

Investigations

It is essential to find the cause of the anaemia; there is no place for ‘blind’ treatment. In most patients, the anaemia is a consequence of a reduced concentration of haemoglobin in each red cell and/or a reduced number of red cells in the peripheral circulation. Blood volumes may be increased in pregnancy and heart failure and haemoglobin concentration appear falsely low. Splenomegaly and signs of heart failure are sure signs of an increased blood volume. A blood transfusion in such a patient would precipitate left ventricular failure.

The most important parameter to assess anaemia is the haemoglobin concentration of the blood. It is also usual to count the number of red cells. In addition the size, shape and colour all contribute to the investigation (Box 49.2). The mean corpuscular volume (MCV) is a useful parameter that helps determine the type of the anaemia. However, care must be taken since the MCV indicates the average size of the cells. If there are two pathologies, where one causes large cells and other causes small cells, the MCV may appear normal or be misleading. Following on from this baseline other investigations may be required. Bone marrow examination by either aspiration or trephine may be needed to make a diagnosis.

Epidemiology

Iron deficiency anaemia is the commonest form of anaemia worldwide and may be present in up to 20% of the world’s population. A diet deficient in iron, parasitic infestations, for example, hookworm (causing blood loss), and multiple pregnancies contribute to its high prevalence in underdeveloped countries. Even in Western societies, it has been reported that as many as 20% of menstruating females show a rise in haemoglobin levels on iron therapy.

Aetiology

In Western societies, the commonest cause of iron deficiency is due to blood loss. In women of childbearing age, this is most commonly due to menstrual loss. Amongst adult males, the most likely cause is gastro-intestinal bleeding. Other causes of blood loss associated with iron deficiency anaemia include haemorrhoids, nosebleeds or postpartum haemorrhage. A loss of 100 mL of blood represents the amount of iron normally absorbed from a Western diet over 40 days. The major causes of iron deficiency are listed in Box 49.3.

Pathophysiology

The elimination of iron is not controlled physiologically, so the homeostasis is maintained by controlling iron absorption. Iron is absorbed mainly from the duodenum and jejunum. Absorption itself is inefficient; iron bound to haem (found in red meat) is better absorbed than iron found in green vegetables. The presence of phosphates and phytates in some vegetables leads to the formation of unabsorbable iron complexes, whilst ascorbic acid increases the absorption of iron. In a healthy adult, approximately 10% of the dietary iron intake will be absorbed. Iron is transported around the body bound to a serum protein called transferrin. Normally, this protein is only one-third saturated with iron.

Anaemia may result from a mismatch between the body’s iron requirements and iron absorption. The demand for iron varies with age (Table 49.2). Diets deficient in animal protein or ascorbic acid may not provide sufficient available iron to meet the demand. Poor nutrition in children in inner cities in the UK frequently leads to anaemia. Milk fortified with iron given to inner city infants up to the age of 18 months has been shown to increase haemoglobin levels and improve developmental performance compared to unmodified cow’s milk (Williams et al., 1999). A systematic review showed that iron supplementation in children over seven improved intelligence tests scores in those who were initially anaemic (Sachdev et al., 2005). However, universal iron supplementation may not be appropriate because there is a theoretic increased risk of susceptibility to infectious diseases, although this has only been demonstrated for diarrhoea (Gera and Sachdev, 2002) and malaria in endemic areas (Prentice et al., 2007). Targeting supplementation only to children with anaemia and withholding iron supplementation during malaria treatment is sensible as iron may inhibit treatment, and absorption of oral iron is blocked by the inflammatory response.

Table 49.2 Typical daily requirements of iron

Malabsorption of iron has been reported in patients with coeliac disease and in 50% of patients following partial gastrectomy. Tetracyclines, penicillamine and fluoroquinolines bind iron in the gastro-intestinal tract and reduce the absorption of iron from supplements. They probably do not affect the absorption of dietary iron.

During pregnancy, there is an increase in red cell mass but there is also a proportionally bigger increase in plasma volume, which results in a physiological dilutional anaemia. It is thought that the gut increases its ability to absorb iron during pregnancy to meet the additional demands of fetal red cell production. Some of the increased demand is met by the stopping of menstruation. If, however, there is inadequate iron absorption, then anaemia may result.

Clinical manifestations

In addition to the general symptoms of anaemia, various other features may be present (Box 49.4). The colour of the skin is very subjective and often unreliable. Patients at risk of heart failure may present with breathlessness when anaemic. Koilonychia, dysphagia and pica are found only after chronic iron deficiency and are relatively rare.

A full blood count is an essential screening test. The cells of the peripheral blood are microcytic and hypochromic with poikilocytes (often pencil shaped) and occasional target cells (abnormal thin erythrocytes which when stained show a dark centre and peripheral ring).

The main parameter used to help establish the iron status of the patient is the serum ferritin. The serum ferritin level is low in iron deficiency anaemia and markedly raised in iron overload. It is a good measure of the iron stores in the body. Care needs to be used in interpreting raised ferritin levels as these are sometimes found in cancer, inflammatory conditions and liver disease. Serum iron is a less useful parameter and exhibits diurnal variation, being higher in the morning.

Investigations

The aim of treatment is to correct the anaemia and replenish iron stores. Although the treatment of iron deficiency anaemia is relatively simple, it should not be embarked upon lightly. It is important to resolve the underlying cause as far as possible. Since gastro-intestinal blood loss is the most common cause in men and postmenopausal women, examination of the upper and lower tract is an important investigation. If necessary, this may need to include upper gastro-intestinal tract endoscopy, colonoscopy, barium enema and small bowel biopsy.

Over-the-counter sales of iron should be discouraged except in those patients who have been fully investigated. It is not unknown for patients to be given iron unnecessarily, resulting in iron overload. Also, giving iron therapy to a patient who is continuing to bleed from their gastro-intestinal tract will not help resolve the underlying problem.

Treatment

Prophylaxis of iron deficiency anaemia was widely used in pregnancy (together with folic acid); however, it is now only used for women who have additional risk factors for iron deficiency, for example poor diet. Prophylaxis may also be used in menorrhagia, after partial gastrectomy and in some low birth weight infants, for example, premature twins.

If gastro-intestinal investigation has been performed and any underlying cause treated, all patients should receive iron supplementation to correct their anaemia and replenish stores. Oral iron in the ferrous form is cheap, safe and effective in most patients. Depending on the state of the body’s iron stores, it may be necessary to continue treatment for up to 6 months to both correct the anaemia and replenish body stores. The standard treatment is ferrous sulphate 200 mg two to three times a day. It typically takes between 1 and 2 weeks for the haemoglobin level to rise 1 g/dL. An earlier indication of the patient’s response can be seen by looking at the reticulocyte count, which should start to rise 2–3 days after starting effective treatment. Nausea or abdominal pains trouble some patients and this tends to be related to the dose of elemental iron. Giving the iron with food makes it better tolerated but tends to reduce the amount absorbed. Alternative salts of iron are sometimes tried; these tend to have fewer side effects simply because they contain less elemental iron (Table 49.3). Taking fewer ferrous sulphate tablets each day would have the same effect. A change in bowel habit (either constipation or diarrhoea) is sometimes reported, and this is probably not dose related. During the early stages of treatment, the body absorbs oral doses of iron better. Absorption is commonly around 15% of intake for the first 2–3 weeks but falls off to an average of 5% thereafter. It has been shown that for some patients eradication of Helicobacter pylori aids recovery from iron deficiency anaemia (Annibale et al., 1999).

Table 49.3 Elemental iron content of common oral preparations

There are a number of modified-release oral preparations available. They have no clear therapeutic advantage over ferrous sulphate and are not recommended. Indeed, the modified-release characteristic may cause the oral iron to be carried into the lower gut, which is much poorer at absorbing iron than the duodenum. Modified-release preparations may be more likely to exacerbate diarrhoea in patients with inflammatory bowel disease or diverticulae.

There is a limited place for parenteral iron in iron deficiency anaemia; it should be reserved for patients who fail on oral therapy, usually because of poor adherence or intolerable gastro-intestinal side effects. For most patients when equivalent doses of oral and parenteral iron are used, there is no difference in the rate of at which the haemoglobin level rises. Patients who have lost blood acutely may require blood transfusions. The need for a rapid rise in haemoglobin is not an indication for parenteral iron. Intravenous iron has been shown to have some benefit during the perioperative management of anaemia in selected patients undergoing orthopaedic surgery, but not been observed in other types of surgery (Beris et al., 2008).

There is a risk of anaphylactoid reactions with intravenous iron but the incidence appears to be lower with the newer products than with the older preparations which have now been discontinued. Patients given the newer licensed products, iron dextran (CosmoFer®), iron sucrose (Venofer®), iron III isomaltoside (Monofer®) and ferric carboxymaltose (Ferinject®) should have a test dose, and there should be facilities for cardiopulmonary resuscitation available. The dose for all products is calculated from the body weight and iron deficit. The manufacturer’s product information provides details on administration. Some products can be given as a bolus injection (small doses) or by a short intravenous infusion or by a total dose infusion method. There seems to be a higher incidence of adverse reactions with the total dose infusions. Iron dextran may also be given by deep intramuscular injection. Intravenous iron should not be given during acute bacterial infections, since it may stimulate bacterial growth. As intravenous iron significantly reduces the oral absorption of iron, there is no rationale for giving oral iron for several days after administering intravenous iron.

Patient care

It is usual practice to advise patients to take iron products with or after meals as this probably reduces the incidence of nausea. Patients should be told that their faeces may become darker and that this is nothing to worry about. This is important in patients who have had malaena since they may associate their dark stools with the bleed and worry that they are still bleeding from the gastro-intestinal tract. The length of treatment, and adherence should be discussed and an explanation given that iron stores need to be replenished and that this takes time.

Epidemiology

This is the second most common form of anaemia (after iron deficiency). It is associated with a wide variety of inflammatory diseases including arthritis, malignancies, inflammatory bowel disease, HIV and other infections. It is increasingly being referred to as ‘anaemia of inflammation’. Related to anaemia of inflammation are the anaemias associated with chronic kidney disease and chronic heart failure.

Aetiology

In anaemia of inflammation, there appears to be impaired response to erythropoietin and the inflammatory cytokines lead to a reduction in the availability of circulating iron. This cytokine-mediated shift of iron from the circulation into reticuloendothelial system leads to iron restricted erythropoiesis, despite normal iron stores. In malignancies, in addition to the anaemia of inflammation, the cytotoxic treatments themselves decrease erythrocyte production through their anti-proliferative effects on the bone marrow. Certain cytotoxic agents, such as platinum-based therapies, are more likely to cause anaemia.

In chronic kidney disease and chronic heart failure, the reduced renal blood flow leads to a decreased production of erythropoietin.

Pathophysiology

During infections, inflammation and cancer, the inflammatory cytokines, in particular interleukin-6 released from macrophages, lead to an increased production of hepcidin. Hepcidin, a peptide produced by hepatocytes, plays a key role in iron availability. The hepcidin causes

The reduction of circulating iron is thought to limit this essential nutrient’s availability to invading microbes and tumour cells, blocking their proliferation.

In addition, the inflammatory cytokines increase the production of white blood cells which potentially lead to fewer stem cells being available for red cell production.

Clinical manifestations

Patients have the general symptoms of anaemia in addition to their symptoms of the chronic inflammatory condition. The anaemia frequently leads to a reduced quality of life for these patients.

Investigation

Patients have a hypochromic microcytic anaemia similar to iron deficiency anaemia, but the two conditions can be differentiated by reviewing other serum factors (see Table 49.4).

Table 49.4 Differentiation between iron deficiency anaemia and anaemia of chronic disease

Treatment

Treating the underlying chronic condition is important. Blood transfusions are rarely needed in anaemia of inflammation. Oral iron therapy is not usually indicated despite the apparent reduced iron availability since these patients have a functional iron deficiency rather than an actual iron deficiency; also, the raised hepcidin levels reduce the oral absorption of iron.

A number of patients with chronic renal failure appear to have a functional iron deficiency that responds to intravenous iron. These patients, despite receiving oral iron and erythropoietin analogues, do respond with a rise in haemoglobin when given regular intravenous iron together with an erythropoietin analogue (Silverberg et al., 1996). Intravenous iron in combination with erythropoietin analogues is widely used in chronic kidney disease. The patient’s serum ferritin is monitored to check for iron overload. Concerns have been expressed about the possible long-term complications of intravenous iron, for example, atherosclerosis or increased risk of infection (Cavill, 2003). There appears to be a slightly increased risk of infections, but the improvement in anaemia leads to an improved quality of life.

Patients with anaemia-associated inflammatory bowel disease or with rheumatoid arthritis respond to intravenous iron; however, the use of intravenous iron in chronic inflammatory conditions is not generally recommended because of an increased risk of infections and also possible increased risk of acute cardiovascular events. Some small studies have shown intravenous iron to be beneficial in patients with heart failure, but currently this should be reserved for patients with proven iron deficiency and failure on oral iron (Dec, 2009).

Some patients with chronic disorders respond to erythropoietin analogues, none are licensed for use in chronic disease states other than anaemia associated with chronic renal failure or cancer. Elevated endogenous erythropoietin levels in patients with heart failure are associated with adverse outcomes (Felker, 2010). Some clinical trial data show a higher mortality and increased risk of tumour progression in patients with anaemia associated with cancer who have been treated with erythropoietins. It is not recommended that erythropoietin analogues are routinely used in the management of cancer treatment-induced anaemia (NICE, 2008). However, they may be considered, in combination with intravenous iron, for:

Tocilizumab, the interleukin-6 antagonist monoclonal antibody licensed for use in rheumatoid arthritis, has been shown to improve haemoglobin levels (Raj, 2009). It has also been suggested that drugs which downregulate interleukin-6 may have some effect (Altschuler and Kast, 2005). Olanzepine and quetiapine (potent H₁ antagonists) are known to be regulators of interleukin-6 but are not used clinically for this purpose. Furthermore, it is not known what the other effects of modifying interleukin-6 or hepcidin would have on the chronic inflammatory condition.

Patient care

Some patients hearing they have anaemia may be tempted to go and purchase iron or other supplements. Careful explanation will help them make an informed decision.

Epidemiology

Sideroblastic anaemias are a group of conditions that are diagnosed by finding ring sideroblasts in the bone marrow. There are both hereditary and acquired forms. The hereditary forms are rare, whilst some of the acquired forms are relatively common with as many as 30% of alcoholics admitted to hospital having sideroblastic anaemia.

Aetiology

In the majority of hereditary forms, there is an X chromosome-linked pattern of inheritance. Both autosomal dominant and autosomal recessive families have been described. The main defect is a reduced activity of the enzyme 5-aminolevulinate synthase (ALAS) which is involved in haem synthesis.

The acquired forms include idiopathic forms, forms associated with myeloproliferative disorders and forms secondary to the ingestion of drugs (Box 49.5). Regardless of the cause, there is impaired haem synthesis, where the body has adequate iron stores but is unable to incorporate it into haemoglobin.