Anaemia

Iron deficiency anaemia is the most common cause of anaemia. Symptoms are related to the overall decrease in number of red blood cells and/or level of haemoglobin. The most common signs and symptoms include:

• feeling of tiredness, fatigue
• lack of energy

 Symptoms that are typical of iron deficiency and which may appear as iron stores in the body decrease may include brittle or spoon-shaped nails, swollen or sore tongue, cracks or ulcers at the corners of the mouth (“angular cheilosis”) or a craving to eat unusual non-food substances such as ice or dirt (also known as “pica”).

Iron is an essential trace element and is necessary for the production of healthy red blood cells (RBCs). It is one component of haem, a part of haemoglobin, the protein in RBCs that binds to oxygen and enables RBCs to transport oxygen throughout the body. If not enough iron is absorbed by the body, then iron that is stored in the body will be used up. If iron stores are low then fewer red blood cells are made and they have decreased amounts of haemoglobin in them which results in anaemia.

Some of the causes of iron deficiency include:

• Bleeding—if bleeding is excessive or occurs over a period of the time (chronic), the body may not take in enough iron or have enough stored to produce sufficient haemoglobin and/or red blood cells to replace what is lost. In women, iron deficiency may be due to heavy menstrual periods, but in older women and in men, the bleeding is often from disease of the stomach or intestines such as ulcers and cancer.
• Dietary deficiency—iron deficiency may be due simply to not eating enough iron in the diet. In children and pregnant women especially, the body needs more iron, Pregnant and nursing women frequently develop this deficiency since the baby requires large amounts of iron for growth. Lack of iron can lead to low birth weight babies and premature delivery. Pre-pregnant and pregnant women are routinely given iron supplements to prevent these complications. Babies who are taking milk from anaemic mothers tend to have iron deficiency anaemia as well.
• Absorption problem—certain conditions affect the absorption of iron from food in the gastrointestinal (GI) tract and over time can result in anaemia. These include, for example, coeliac disease, Crohn’s disease, lack of acid in the stomach (“achlorhydria”) or previous surgery to remove part of the bowel

Laboratory Tests
Initial blood tests typically include a full blood count (FBC). Results may show:

• Haemoglobin (Hb)—may be normal early in the disease but will fall as the anaemia worsens
• Red blood cell indices—early on, the RBCs may have a normal size and color (normocytic, normochromic) but as the anaemia progresses, the RBCs become smaller (microcytic) and paler (hypochromic) than normal.
  • Average size of RBCs (MCV)—may be decreased
  • Average amount of Hb in RBCs (MCHC)—may be decreased
  • Increased variation in the size of RBCs (red cell distribution width or “RDW”)

 A blood film may reveal RBCs that are smaller and paler than normal as well as RBCs that vary in size (anisocytosis) and occasionally in shape (poikilocytosis). Abnormally shaped red cells may include target cells and pencil cells. The blood film may also give clues to causes of inflammation. For example it might show signs of an underactive spleen, which can be due with coeliac disease, in which iron is sometimes not absorbed well.

If your doctor suspects that your anaemia is due to iron deficiency, they may request several additional tests to confirm the iron deficiency. These may include:

• Serum iron—the level of iron in your blood; the result is usually decreased. It is important that patients fast before a serum iron blood test or the result may be misleadingly high.
• Total iron-binding capacity (TIBC) or Unbound iron-binding capacity (UIBC)—measurement of the protein (transferrin) that carries iron through the blood will be increased.
• Transferrin saturation index (ratio of serum iron to iron binding capacity). A result less than 15% may indicate iron deficiency.
• Ferritin—reflects the amount of stored iron in your body and is usually low in anaemia. Ferritin is considered to be the most specific for identifying iron deficiency anaemia, unless infection or inflammation are present

 All blood tests for iron may be influenced by other illnesses or factors and they should be interpreted with caution. Sometimes they clearly indicate iron deficiency, sometimes they are unclear and sometimes they can be misleading and unhelpful.

Rarely, if your doctor is unsure whether or not you have iron deficiency anaemia and wants to be sure, they may even request a bone marrow aspirate to look directly at your iron stores. Absence of iron in a good quality bone marrow sample proves iron deficiency. Bone marrow aspirates are quickly performed and very safe, but uncomfortable and thankfully your doctor will only very rarely request this test.

If the iron deficiency is thought to be due to abnormal blood loss, such as chronic bleeding from the intestine, then other tests and procedures may be performed including a referral for colonoscopy to look and see if blood is being lost into the intestine.

A test for Helicobacter pylori may detect a bacterium that can cause ulcers in the GI tract which may be a cause of chronic bleeding. Blood tests showing antibodies to Helicobacter may be misleading however and examination of the faeces for the bacterium (faecal Helicobacter antigen testing) may be used instead.

If any of these tests are positive or if it is strongly suspected a GI bleed exists, then procedures such as endoscopy or colonoscopy may be done to find the location of the bleeding so that it can be treated.

Treatment of iron deficiency typically involves iron supplements. These are usually given by mouth. In patients intolerant of iron supplements or who can not absorb iron, it can be replaced by using intravenous infusion. If iron-deficiency is suspected to be due to abnormal blood loss, further testing is often required to determine the reason for the bleeding. When the underlying cause is found and treated then the anaemia usually resolves.

Some forms of haemolytic anaemia can lead to iron deficiency.

Vitamin B12 is found only in animal foods including meat, dairy and egg products. Very strict Vegan vegetarians require vitamin B12 supplements to remain healthy.

Pernicious anaemia is a condition in which the body does not make enough of a substance called intrinsic factor. Intrinsic factor is a protein produced by parietal cells in the stomach. It binds to vitamin B12 and allows it to be absorbed from the small intestine. Vitamin B12 is important in the production of red blood cells (RBCs). Without enough intrinsic factor, the body cannot absorb vitamin B12 from the diet and cannot produce enough normal RBCs, leading to anaemia.

Other causes of vitamin B12 deficiency and anaemia include conditions that affect absorption of the vitamin from the small intestine such as surgery, certain drugs, digestive disorders (coeliac disease, Crohn’s disease) and infections.

Vitamin B12 deficiency can result in general symptoms of anaemia as well as nerve problems. These may include:

• weakness or tiredness
• lack of energy
• numbness and tingling that start first in the hands and feet
• lemon discolouration of the skin (a combination of anaemia and mild jaundice)

 Additional symptoms may include muscle weakness, slow reflexes, loss of balance and unsteady walking. Severe cases can lead to confusion, memory loss, depression and/or dementia.

Folic acid is another B vitamin and deficiency in this vitamin may also lead to anaemia. Folic acid, also known as folate, is found in many foods, especially in green, leafy vegetables. Some breakfast cereals are fortified with folic acid. Folic acid is needed during pregnancy for normal development of the baby’s brain and spinal cord. It is important for women considering pregnancy to take folate supplements before they get pregnant and during pregnancy to make sure they are not folate deficient. Folate deficiency early in pregnancy can cause problems in the development of the brain and spinal cord of the baby (e.g. “spina bifida”).

Anaemias resulting from vitamin B12 or folate deficiency are sometimes referred to as macrocytic anaemia because red blood cells are larger than normal, or “megaloblastic” due to abnormally large immature red cells in the bone marrow. A lack of these vitamins does not allow RBCs to grow and then divide as they normally would during development which leads to their large size. This leads to a reduced number of abnormally large RBCs and anaemia.

Laboratory Tests
Symptoms of anaemia will usually be investigated initially with a full blood count (FBC) and differential. In pernicious anaemia or vitamin B12 deficiency, these usually show:

• A low haemoglobin level
• For red cell indices, the mean corpuscular volume (MCV), which is the average size of RBCs, is often high

A blood film will reveal red blood cells that are abnormally large, abnormally shaped, and sometimes occasional giant white blood cells.

Folic acid deficiency leads to the same pattern of changes in haemoglobin and red cell size as vitamin B12 deficiency.

If the cause of your anaemia is thought to be due to pernicious anaemia or dietary deficiency of B12 or folate, additional tests are usually requested to make the diagnosis. Some of these include:

• Vitamin B12 level - blood level may be low when deficient in B12
• Folic acid level- blood level may be low if deficient in this B vitamin
• Methylmalonic acid (MMA) - may be high with vitamin B deficiency
• Homocysteine - may be high with either folate or vitamin B deficiency
• Reticulocyte count- is usually low
• Antibodies to intrinsic factor or parietal cell antibodies - may be present in pernicious anaemia

Sometimes a bone marrow aspiration may be performed. This may reveal larger than normal sizes in the cells that eventually mature and become RBCs (“megaloblastic” precursors) or giant immature white blood cells.

Treatment in these conditions involves supplementation with the vitamin that is deficient. Vitamin B12 is usually given by injection, typically every 3 months , although tablets can sometimes be given. Treatment of underlying causes such as a digestive disorder or infection may help to resolve the anaemia.

For more on this, see the article on Vitamin B12 and Folate Deficiency

Aplastic anaemia (also known as idiopathic aplastic anaemia) is a rare disease, caused by a decrease in the number of all types of blood cells produced by the bone marrow. Normally, the bone marrow produces a sufficient number of new red blood cells (RBCs), white blood cells (WBCs) and platelets for normal body function. If the bone marrow is not able to produce enough blood cells to replace those that die, a number of symptoms, including those due to anaemia, may result.

Symptoms of aplastic anaemia can appear abruptly or can develop more slowly. Some general symptoms that are common to different types of anaemia may appear first and are due to the decrease in number of RBCs. These include:

• Feeling of tiredness
• Lack of energy

Some additional signs and symptoms that occur with aplastic anaemia include those due to decreased platelets:

• Prolonged bleeding
• Frequent nosebleeds
• Bleeding gums
• Easy bruising

and due to a low WBC count:

• Increased number and severity of infections.

Causes of aplastic anaemia usually have to do with damage to the stem cells in the bone marrow that are responsible for blood cell production. Most often, no obvious underlying cause is found and this is labelled idiopathic aplastic anaemia. Sometimes, specific factors that may be involved with bone marrow damage and that can lead to aplastic anaemia are identified and include:

• Exposure to toxic substances such as arsenic, benzene or pesticides
• Cancer therapy (radiation or chemotherapy)
• Autoimmune disorders such as lupus or rheumatoid arthritis
• Viral infections such as hepatitis, EBV, HIV, CMV.

Rarely, aplastic anaemia is due to an inherited (genetic) disorder such as Fanconi anaemia. (For more on this condition, see the Fanconi Anemia Research web site. 

Laboratory Tests
The initial test for anaemia, the full blood count (FBC), may reveal many abnormal results.

• Haemoglobin and/or haematocrit may be low
• RBC and WBC counts are low
• Platelet count is low
• The MCV (average red cell size) may be normal or slightly raised
• The differential white blood count shows a decrease in most types of cells but not lymphocytes.

Some additional tests that may be performed to help discover the type and cause of anaemia include:

• Reticulocyte count -result is usually low
• Erythropoietin - usually increased in aplastic anaemia
• A bone marrow aspiration and trephine biopsy will show a decrease in the number of all types of mature cells.
• Tests for infections such as hepatitis, EBV, CMV help to discover the cause
• Test for arsenic (a heavy metal) and other toxins
• Iron tests or tests for vitamin B12 may be done to rule out other causes
• Antibody tests such as ANA to find out if the cause is autoimmune disease

A physical examination or complete medical history may reveal possible causes for aplastic anaemia such as exposure to toxins or certain drugs (for example, chloramphenicol) or prior treatment for cancer.

Some cases of aplastic anaemia are temporary while others have lasting damage to the bone marrow. Treatment depends on the cause. Reducing or eliminating exposure to certain toxins or drugs may help resolve the condition. Medications may be given to stimulate bone marrow production, to treat infections or to suppress the immune system in cases of autoimmune disorders. Blood transfusions and a bone marrow transplant may be needed in severe cases.

Pure red cell aplasia is a disease with some similarities to aplastic anaemia, except only the red blood cell precursors are absent. This can also occur with cancers (especially of the thymus gland) and autoimmune conditions. Infection with parvovirus B19 can cause temporary pure red cell aplasia.

Rarely, anaemia is due to problems that cause the red blood cells (RBCs) to die or be destroyed early in their life. Normally, red cells live in the blood for about 4 months. In haemolytic anaemia, this time is shortened, sometimes to only a few days. The bone marrow is not able to produce new RBCs quickly enough to replace those that have been destroyed leading to a decreased number of RBCs in the blood which in turn leads to a reduced ability to carry oxygen to all parts of the body. This results in the typical symptoms of anaemia including:

• weakness and/or tiredness
• lack of energy

Depending on its cause, haemolytic anaemia can be chronic, developing and lasting over a long period or lifetime, or may be acute, occurring very rapidly with the development of serious signs and symptoms. The various forms of haemolytic anaemia can have a wide range of signs and symptoms.

The different causes of haemolytic anaemia fall into two main categories:

• Inherited forms in which a gene or genes are passed from one generation to the next and result in abnormal RBCs or haemoglobin
• Acquired forms in which something other than inherited disease results in the early destruction of RBCs

Inherited Haemolytic Anaemia
Two of the most common causes of inherited haemolytic anaemia are sickle cell anaemia and thalassaemia:

Sickle cell anaemia, due to production of an abnormal form of haemoglobin called HbS, usually causes no difficulties in people with the “trait” (when you carry only one mutated gene from one of your parents), but severe clinical problems as the “disease” (when you carry two mutated genes, one from each of your parents). The red blood cells are misshapen, unstable (leading to haemolysis) and can block blood vessels, causing pain and anaemia. Screening is usually done on newborns – particularly those of African descent. Sometimes screening is done prenatally on a sample of amniotic fluid. Follow up tests for haemoglobin variants may be performed to confirm a diagnosis. Treatment is usually based on the type, frequency and severity of symptoms.

Thalassaemia is a hereditary abnormality of haemoglobin production and results in small red blood cells that resemble those seen in iron deficiency. In its most severe form, the red cells have a shortened life span. In milder forms (such as thalassaemia trait), anaemia is usually mild or absent, and the disease may be detected by finding small blood cells on a routine FBC.

This genetic disease is found frequently in people of Mediterranean, African, and Asian heritage. The defect in production may involve one of two components of haemoglobin called the alpha and beta protein chains. The disease is called alpha thalassaemia or beta thalassaemia accordingly. The "beta minor" form (sometimes called beta thal trait, as with sickle cell) occurs when a person inherits half normal genes and half beta thalassaemia genes. It causes a mild anaemia and no other symptoms. The "beta major" form (due to inheriting two beta thalassaemia genes and also called Cooley’s anaemia) is more severe and may result in growth problems, jaundice (yellowing of the skin and whites of the eyes), and severe anaemia.

Other less common types of inherited forms of haemolytic anaemia include:

• Hereditary spherocytosis—a weakness in the red cell wall which results in abnormally shaped small dark rounded RBCs which may be seen on a blood film
• Hereditary elliptocytosis—another red cell wall defect causing abnormally cigar-shaped RBCs seen on a blood film
• Glucose-6-phospate dehydrogenase (G6PD) deficiency—G6PD is an enzyme that is necessary for RBC survival. Its deficiency may be diagnosed with a test for its activity
• Pyruvate kinase deficiency—Pyruvate kinase is another enzyme important for RBC survival and its deficiency may also be diagnosed with a test for its activity
• Abnormal haemoglobins (“haemoglobinopathies”) other than sickle disease – there are many of these, often extremely rare.

Laboratory Tests
Since some of these inherited forms may have mild symptoms, they may first be detected on a routine FBC and blood film which can reveal various abnormal results that give clues as to the cause. Follow up tests are then usually performed to make a diagnosis. Some of these include:

• Tests for haemoglobin variants such as haemoglobin electrophoresis
• DNA analysis—not routinely done but can be used to help diagnose haemoglobin variants, thalassaemia, and to determine carrier status.
• G6PD test—to detect deficiency in this enzyme
• Osmotic fragility test—detects RBCs that are more fragile than normal which may be found in hereditary spherocytosis

These genetic disorders cannot be cured but often the symptoms resulting from the anaemia can be reduced by treatment. Sometimes these disorders may have implications for planned pregnancies, especially if both partners have abnormal types of haemoglobin, and specialist advice and sometimes further investigations may be helpful in assessing risks for future babies.

Acquired Haemolytic Anaemia
Some of the conditions or factors involved in acquired forms of haemolytic anaemia include:

• Autoimmune haemolytic anaemia (AIHA) or cold agglutinin disease (CHAD)—conditions in which the body produces antibodies against its own red blood cells.
• Transfusion reaction—result of blood donor-recipient incompatibility. This occurs very rarely but when it does can have some serious complications.
• Mother-baby blood group incompatibility (especially rhesus antigen incompatibility where mothers are Rhesus-negative)—may result in haemolytic disease of the newborn.
• Drugs—certain drugs such as penicillin can trigger the body into producing antibodies directed against RBCs or cause the direct destruction of RBCs. Other drugs, such as some antimalarial drugs and some anaesthetics can cause destruction of red cells in susceptible individuals with G6PD deficiency or some forms of abnormal haemoglobin.
• Physical destruction of RBCs by, for example, an artificial heart valve or cardiac bypass machine used during open-heart surgery
• Paroxysmal Nocturnal Haemoglobinurina (PNH)—a rare condition in which the different types of blood cells including RBCs, WBCs and platelets may be abnormal. Because the RBCs are defective they are susceptible to destruction by the body’s immune system. As the name suggests, people with this disorder can have acute, recurring episodes in which many RBCs are destroyed. This disease occurs due to a change or mutation in a gene called PIGA in the stem cells that make blood. Though it is a genetic disorder, it is not passed from one generation to the next (it is not an inherited condition). Patients will often pass dark urine due to the haemoglobin released by destroyed RBCs being cleared from the body by the kidneys. This is most noticeable first thing in the morning when urine is most concentrated. Episodes are thought to be brought on when the body is under stress during illnesses or after physical exertion. (For more on this, see the Genetic Home Reference webpage.)

These types of haemolytic anaemias are often first identified from signs and symptoms see during physical examination and after taking a medical history. A medical history can reveal, for example, a recent transfusion, treatment with penicillin or cardiac surgery. A FBC and/or blood film may show various abnormal results. Depending on those findings, additional follow up tests may be performed. Some of these may include:

• Tests for autoantibodies for suspected autoimmune disorders
• Direct antiglobulin test (DAT) (formerly known as a “Coombs’ test”) in the case of transfusion reaction, mother-baby blood type incompatibility, or autoimmune haemolytic anaemia
• Haptoglobin – this protein mops up free haemoglobin in the blood for recycling after blood cells are haemolysed and may be reduced in the blood during periods of haemolysis.
• Reticulocyte count – reticulocytes are young red blood cells and an increase reflects increased production of red cells in the bone marrow to keep up with haemolysis.

Treatment for haemolytic anaemia depends on the cause. In general, the goals are the same: to treat the underlying cause of the anaemia, to decrease or stop the destruction of RBCs and to increase the RBC count and/or haemoglobin level to alleviate symptoms. This may involve, for example:

• Drugs that suppress the immune system and decrease production of autoantibodies that destroy RBCs
• Blood transfusions to increase number of healthy RBCs
• Bone marrow transplant—to increase production of normal RBCs
• Avoiding triggers that cause the anaemia such as the cold in some forms of autoimmune haemolytic anaemia or fava beans and certain drugs for those with G6PD deficiency

Chronic (long term) illnesses can cause anaemia. Often, anaemia caused by chronic diseases goes undetected until a routine test such as a full blood count reveals abnormal results. Several follow-up tests may be used to discover the underlying cause. The anaemia in these cases is generally caused inflammation causing too much or too little production of various substances and resultant suppression of the normal function of the bone marrow. There are many chronic conditions and diseases that can result in anaemia. Some examples of these include:

• Kidney disease—Red blood cells are produced by the bone marrow in response to a hormone called erythropoietin, made primarily by the kidneys. Chronic kidney disease can cause anaemia resulting from too little production of this hormone; the anaemia can be treated by giving erythropoietin injections.
• Inflammatory conditions—Whenever there are chronic diseases that stimulate the body’s inflammatory system, the ability of the bone marrow to respond to erythropoietin is reduced. For example, rheumatoid arthritis (a severe form of joint disease caused by the body attacking its own joints, termed an autoimmune disease) can cause anaemia by reducing the effectiveness of erythropoietin on bone marrow.
• Other diseases that can produce anaemia in the same way as inflammatory conditions include chronic infections (such as with HIV or tuberculosis), cancer, and cirrhosis.

A number of additional tests may be requested after initial tests (FBC and blood film) have been found to be abnormal. These will help discover the underlying cause of chronic anaemia. Some of these may include:

• Reticulocyte count
• Tests for inflammation such as ESR or CRP
• Kidney function tests such as serum creatinine
• Erythropoietin (often known as “Epo”)

Treatment of anaemia due to chronic conditions usually involves determining and/or resolving the underlying disease. Blood transfusions may be used to treat the condition in the short term. Erythropoietic stimulating agents such as synthetic versions of Erythropoietin are widely used in patients with chronic kidney diseases.