Diseases

Anaemia

Anaemia is a condition where the blood does not carry enough oxygen around the body. There are many different causes and many different treatments. Science is continuing its research into newer, more patient-friendly alternative therapies.

What is anaemia? Top

Anaemia is a condition in which the blood does not carry enough oxygen, either because there is a low number of red blood cells (erythrocytes) or because each red blood cell carries less oxygen than normal. Red blood cells are produced in the bone marrow and live for around 120 days. Then they are destroyed and replaced, as part of a normal renewal process. Low numbers of erythrocytes or a low level of haemoglobin (the oxygen-binding protein contained in red blood cells) can be caused by blood loss, deficient synthesis, excessive destruction, or a combination of these changes. Severe anaemia with a haemoglobin level in the blood of less than 7 g/100cc is associated with weakness, vertigo, headache, tinnitus, fatigability, drowsiness and irritability. Finally, heart failure or shock can result. Not investigating mild anaemia is a serious error; its presence indicates an underlying disorder, and its severity reveals little about its origin or true clinical significance.

Who does anaemia affect? Top

Anaemia can be due to a deficiency of iron, which is a main component of haemoglobin. Lack of dietary iron is the world’s leading nutritional deficiency and the most common cause of anaemia. A common cause in women is heavy periods (menorrhagia). Pregnancy can lead to iron-deficiency anaemia, because the growing baby needs iron and takes its supply from the mother. The prevalence of iron-responsive anaemia varies from 9 to 70 per cent in different population groups examined. The incidence is higher in the less developed world and in less-educated segments of populations in industrialised countries. In the tropics, hookworm infection causes irondeficiency anaemia, and is the most common cause worldwide. Other supplements needed to produce erythrocytes include folic acid and vitamin B12. A lack of these in the diet can also cause anaemia.

Worldwide, anaemia of chronic disease states such as infections, inflammatory disease like rheumatoid arthritis and cancer is the second most common form. Here, the major issue is that the body’s bone marrow production capacity fails to expand appropriately in response to the anaemia. In many of these patients, erythropoietin (Epo) production by the kidney and marrow responsiveness is decreased, resulting in deficient erythropoiesis. Macrophage-derived cytokines (e.g., interleukin-1 beta, tumour necrosis factor-alpha, and interferon-beta) have been shown to cause this decreased Epo synthesis.

Also, the presence of anaemia after kidney transplantation is well known, although specific data on the prevalence and risk factors are scarce. Between 25 and 30 per cent of kidney recipients develop moderate or severe anaemia. There is a strong association between haemoglobin concentration and kidney graft function. Evidence suggests that impaired Epo production by the transplanted kidney is the pathogenic factor. Whether this high incidence of anaemia may be an additional cardiovascular risk factor in kidney transplant patients remains to be proven.

Because marrow reserve of the human body is limited, anaemia may result from massive bleeding or haemorrhage associated with spontaneous or traumatic rupture, erosion of an artery by lesions or failure of normal blood clotting. Sudden loss of 30 percent of blood volume may be fatal, but as much as 60 per cent may be lost slowly over a longer time period without such risk. Stomach ulcers, ulcerative colitis (inflammation of the colon), haemorrhoids and bowel cancer may cause prolonged moderate blood loss and result in anaemia. Often, the bleeding is not obvious because the blood is passed unnoticed in the stools. Urological or gynaecological sites can also be causes of unnoticed internal bleeding.

Aplastic anaemia results from a loss of red blood cell precursors, either from a defect in the stem cell pool or an injury to the microenvironment that supports the marrow. The disorder is most common in adolescents and young adults. In 50 per cent of cases, the cause is unknown. Recognized causes are chemicals, radiation, and medicines, e.g., cancer medicines, antibiotics, NSAIDs, and anticonvulsants. The underlying mechanisms are unknown, but selective and perhaps genetic hypersensitivity appears to be the basis.

Anaemia can also be caused by genetic abnormalities of the haemoglobin molecule. Normal haemoglobin consists of two pairs of polypeptide chains. As types of chains and chemical structure of polypeptides in the chains are controlled genetically, defects may result, with abnormal physical or chemical properties. The overall incidence of haemoglobin disorders such as sickle cell disease and thalassaemia is about 4.5% of the world population, thus affecting 250 million people worldwide. Every year there are about 300,000 new births with these abnormalities. Severely affected patients need frequent blood transfusions and treatment with iron chelating agents is required to avoid secondary iron overload.

The solid elements and their proportions in normal blood

Present treatments Top

A critical principle in managing anaemia is to apply targeted therapy, which implies that a specific diagnosis has been established. The response to therapy usually confirms the diagnosis. For many people, the treatment is to prescribe iron supplement. The length of treatment depends on the severity of the disorder. The blood may be tested after a few weeks to check that haemoglobin levels have returned to normal. The best way to prevent iron-deficiency anaemia is to eat a diet containing plenty of iron. The recommended amount is 7mg a day for men and 11mg a day for women. The treatment of anaemia caused by lack of vitamin B12 or folic acid consists of substituting the missing agent.

Immediate therapy of massive haemorrhage consists of stopping the bleeding, restoration of blood volume, and treatment of shock. Transfusion of red blood cells is indicated for severe bleeding with threatening vascular collapse. This form of instant repair must be reserved for patients with cardiopulmonary symptoms, signs of uncontrollable blood loss, or some form of end-organ failure caused by lack of oxygen. Plasma is the most satisfactory temporary substitute for blood. Trials with infused perfluorochemicals capable of transporting oxygen have had only limited success.

Pure red blood cell aplastic anaemia has been shown to be successfully managed with immunosuppressants, especially when an immunological basis is implicated.

Recent American and European guidelines recommend that Epo therapy should be considered whenever the haemoglobin level in the blood is less than10–11 g/100 cc in dialysis and pre-dialysis patients. In September 2004, a less frequently dosed formulation of Epo received EU approval for the dosing regimens in chemotherapy-related anaemia and chronic kidney disease. The new dose in cancer patients is once every three weeks for the treatment of anaemia in adult patients with non-myeloid malignancies who are receiving chemotherapy. In chronic kidney disease, the product can be dosed up to once a month to treat anaemia in those not on dialysis.

What’s in the development pipeline? Top

There are emerging data to show that correcting anaemia in chronic kidney failure patients before they go on dialysis can improve quality of life and survival by reducing the risk of left ventricular hypertrophy. In addition to its use in pre-dialysis patients, new formulations of Epo may have more potential in a variety of cancer related anaemia indications. Several studies are underway looking at quality of life and survival in women with breast cancer and in patients with cervical cancer. Another investigation is evaluating the effect of Epo on tumour response to radio- and chemotherapy in small-cell lung cancer. The underlying theory expects Epo to enhance the sensitivity of cells to radio- and chemotherapy by increasing the oxygen supply to tumours. Therefore, the effect might be more noted in solid tumours than in single cell cancers. Treating patients’ anaemia may also help them cope with the disease on a physical and emotional basis and enhance survival.

Follow-ups of second-generation Epo products are in development. One is a hyperglycosylated analogue, which in preclinical studies has been shown to produce greater in vivo potency than the predecessor molecules. Phase 1 and 2 studies in patients with chemotherapy-induced anaemia started in 2004.

The longer-term future Top

A new potential anaemia treatment targeting the continuous erythropoiesis receptor activator (CERA) is considered to have an innovative mechanism of action that induces prolonged stimulation of erythrocyte production. This could mean administration of the new medicine would be only needed every three to four weeks.

In the past years, research on anaemia has been concentrating on new molecules of recombinant Epo, which addresses anaemia associated with chronic disease and cancer chemotherapy. After Epo and chronic disease, there is now growing interest in the treatment of the haemoglobin disorders such as sickle cell disease and the thalassaemias, and new immunosuppressive treatments for aplastic anaemia.