Iron-Deficiency Anaemia (IDA

)
Please note that there are separate articles entitled 'Anaemia in Childhood' and 'Anaemia in Pregnancy' that cover iron deficiency anaemia in these patient groups. Iron deficiency anaemia (IDA) occurs when the body is iron deficient to the extent that red blood cell production is reduced.1,2 A state of non-anaemic iron deficiency usually precedes actual anaemia. Iron deficiency is the most common cause of anaemia worldwide. The World Health Organisation defines anaemia as:1 • • • Hb <13 g/dL in men over 15 years old Hb <12 g/dL in non-pregnant women over 15 years old Hb <12 g/dL in children aged 12-14 years

Failure to investigate IDA properly by practitioners in primary care can cause significant delay in final diagnosis with associated morbidity.3 This article is based on the Clinical Knowledge Summary Guidance on iron deficiency anaemia.4 Epidemiology • • • In the developed world, 2-5% of adult men and post-menopausal women have iron deficiency anaemia.5 4-13% of referrals to gastroenterologists are because of iron deficiency anaemia.5 Pre-menopausal women have a higher incidence of iron deficiency anaemia because of heavy menstrual blood losses and pregnancy.2

Aetiology Causes of iron deficiency may be classified as those due to:

Excessive blood loss
• • • • Blood loss from the gastrointestinal tract is the commonest cause of iron deficiency anaemia in adult men and postmenopausal women.4 Blood loss due to menorrhagia is the commonest cause of iron deficiency in premenopausal women. In other countries, infestation of the gut may cause IDA, especially with hookworm and schistosomiasis. Common causes of blood loss include:

• • • • • • •

Non steroidal anti-inflammatory drug (NSAID) use Χολονιχ χαρχινοµα Γαστριχ χαρχινοµα Gastric or duodenal ulceration Ανγιοδψσπλασια Heavy menstruation

Other causes include: • • • • • • • • • • Other gastrointestinal tract malignancies Βλεεδινγ οεσοπηαγεαλ ϖαριχεσ Ινφλαµµατορψ βοωελ δισεασε Ηαεµορρηοιδσ Οεσοπηαγιτισ and gastro-oesophageal reflux disease Ποστ−παρτυµ ηαεµορρηαγε Recurrent epistaxis Malignancy of the renal tract After major surgery of major trauma if replacement has been inadequate After blood donation

Dietary inadequacy
• • Dietary iron deficiency is fairly uncommon. Meat tends to be more rich in iron than vegetables and so vegetarians are at greater risk. However, green vegetables are a good source of iron and a proper vegetarian diet should not lead to deficiency. Growing children and elderly people with iron-poor diets may become deficient.

Failure of iron absorption
• • Not only does the diet have to contain adequate amounts of iron but the iron has to be in a form that can be absorbed. Iron can be absorbed in the ferrous state much more readily than in the ferric

state. • Factors affecting iron absorption: • Some drugs can bind to iron and prevent absorption. Tetracyclines and quinolones chelate with iron so that neither the antibiotic nor the iron is absorbed. Antacids and proton pump inhibitors may also impair absorption by raising gastric pH.4 Phytate (found in wholegrain cereals, nuts, seeds and legumes), polyphenols (found in tea and coffee) and calcium (in dairy products) impair iron absorption. Iron absorption can be increased in a diet rich in fish, red and white meat.6,7 Vitamin C may enhance iron absorption. Patients can be encouraged to drink a glass of orange juice with their iron tablets. Μαλαβσορπτιον conditions such as coeliac disease (usually accompanied by folate deficiency). May occur after partial or total gastrectomy, more commonly with increased number of post-operative years.8 Ηελιχοβαχτερ πψλορι colonisation appears to impair iron uptake and increase iron loss.

• •

• • • •

Excessive requirements for iron
• • Times of high demand for iron should be met by greater absorption from the diet. If the diet is not adequate, an intake that would otherwise be sufficient becomes inadequate. For example in: • • • Presentation Iron deficiency anaemia is often an incidental finding rather than a presenting feature. Chronic, slow blood loss can lead to compensation by the body and little in the way of symptoms. If symptoms occur, they can include: • Fatigue Times of rapid growth in children Pregnancy, especially with twins Exfoliative skin disease

• • • • • • • • •

Shortness of breath on exertion Παλπιτατιονσ Sore tongue and taste disturbance Changes in the hair/hair loss Πρυριτισ Ηεαδαχηε Τιννιτυσ Angina can occur if there is pre-existing coronary heart disease Very rarely, there may be dysphagia due to an oesophageal web with chronic iron deficiency. This is the Paterson-Brown-Kelly or Plummer-Vinson Syndrome and there is an association with oesophageal carcinoma.

Symptoms of severe anaemia (usually not occurring until Hb is <7 g/dL) include: shortness of breath at rest, angina and ankle swelling. These symptoms may occur at higher Hb levels if there is co-existing cardiorespiratory disease).4 History To look for potential causes, cover the following points: • • • • • • • • • Current/recent diet - could account for poor iron intake Drug history - NSAIDs, SSRIs, clopidogrel, corticosteroids could be a potential cause Any overt bleeding seen by patient - e.g. nosebleeds, rectal bleeding etc. History of recent blood donation Menstrual history in women History of recent illness - could suggest gastrointestinal bleeding, e.g. weight loss, change in bowel habit, dyspepsia History of previous gastrointestinal disease or surgery Travel history - e.g. hookworm infestation is possible if recent travel to the tropics Family history - including inherited haematological disorders such as thalassaemia; bleeding disorders and telangiectasia; iron deficiency anaemia (may indicate potential inherited disorder of iron absorption)

Examination • • • Examine the abdomen for abdominal masses, organomegaly, lymphadenopathy and any other features of intra-abdominal disease. Perform a rectal examination to look for signs of bleeding, malaena and masses. If menorrhagia is thought to be the cause: perform a vaginal/bimanual examination, examine the cervix and perform a cervical smear and swabs as appropriate (please refer to article on menorrhagia for further details).

Signs
• • • • • Pallor (best seen in the mucosa of tongue and mouth, especially in people with dark skin) Κοιλονψχηια (spoon shaped nails with longitudinal ridging) Ανγυλαρ χηειλιτισ (ulceration at the corners of the mouth) Ατροπηιχ γλοσσιτισ In marked anaemia there may be tachycardia, a flow murmur, cardiac enlargement, ankle oedema and heart failure. FPRIVATE "TYPE=PICT;ALT=KOILONYCHIA (OM985a.jpg)"

Note the spoon-shaped nail of koilonychia with the longitudinal ridges Other signs that may be seen include: • • • Stigmata of chronic liver disease, perhaps cirrhosis Multiple telangiectasia may be a feature of hereditary haemorrhagic telangiectasia, also known as Osler-Weber-Rendu Syndrome Pigmentation of the lips and oral mucosa may suggest Peutz-Jeghers syndrome

Confirming the diagnosis • Full blood count: shows a hypochromic microcytic anaemia (although there may be a mixed picture with coexistent B12 or folate deficiency). • Hypochromia means that there is as a low mean corpuscular haemoglobin

(MCH). • • • Microcytosis means that there is as a low mean corpuscular volume (MCV). Remember that a haemoglobinopathy will also cause a hypochromic microcytic anaemia.

Serum ferritin: should be measured to confirm iron deficiency (except during pregnancy). • • • • This correlates with total body iron stores. However, ferritin levels can be raised if infection or inflammation is present, even if iron stores are low.1 A ferritin level < 15 mcg/L confirms iron deficiency.5 If there is coexisting chronic inflammatory disease, the clinician should consider seeking specialist advice about other measures of iron status.

Blood film: anisocytosis (variation in size between red blood cells) and poikilocytosis (abnormally shaped red blood cells) can be seen.

Differential diagnosis Other causes of microcytic anaemia including: • • • • Thalassaemia Sideroblastic anaemia Αναεµια οφ χηρονιχ δισεασε Λεαδ ποισονινγ

Investigations The following groups of people do not usually require investigation before treatment is started:4 • • Otherwise healthy young people in whom the history clearly suggests a cause (e.g. regular blood donors). Menstruating young women without history of gastrointestinal symptoms nor family history of colorectal cancer (although some suggest coeliac disease screening in this group).9 Pregnant women - unless the anaemia is severe or the history/examination suggest another cause for the iron deficiency (e.g. inflammatory bowel disease), or there is no

response to iron supplementation. • • People who are terminally ill or unable to undergo invasive investigations. People who refuse further investigations.

However, consider investigations if there is a poor response to treatment or the anaemia recurs with no obvious cause. Otherwise, investigations that should be considered include: • • • • Urinalysis for blood (approximately 1% of patients with iron deficiency anaemia have a renal tract malignancy) Screening for coeliac disease (serology looking for anti-endomysial antibody or tissue transglutaminase antibody) Referral for upper and lower gastrointestinal investigations Stool examination looking for parasites if recent travel to endemic area

If menorrhagia is thought to be the cause of iron deficiency anaemia, please refer to the separate article on menorrhagia for details about appropriate investigations. Who should be referred to secondary care?4 • • • • If someone has profound anaemia and signs of acute heart failure, they should be admitted urgently to hospital. People of any age with dyspepsia and iron deficiency anaemia should be referred for endoscopy, or to a specialist in upper gastrointestinal cancer, within 2 weeks. Men of any age with unexplained iron deficiency anaemia and a haemoglobin of 11 g/dL or below, should be referred within 2 weeks to a gastroenterologist. Women who are not menstruating with unexplained iron deficiency anaemia and a haemoglobin of 10 g/dL or below should be referred within 2 weeks to a gastroenterologist.

Clinical judgement should be used in people with unexplained iron deficiency anaemia who do not fall into the above categories. They will still need referral for further investigation but the clinician will have to determine the urgency.

Sideroblastic Anaemia
Synonyms: Refractory anemia with ringed sideroblasts (RARS)

Sideroblastic anaemias are a heterogeneous group of refractory anaemias. They are characterized by the presence of abnormal ringed sideroblasts in bone marrow aspirate. The sideroblasts form due to reduced haemoglobin synthesis, resulting in the accumulation of iron within red blood cell precursors. Cases can, rarely, be congenital but are more usually acquired and sometimes represent a stage in the development of myelodysplastic syndromes. Epidemiology This accounts for 5-15% of all myelodysplastic syndromes.1 70% of all patients are aged >50years old. Hereditary forms of sideroblastic anaemia are X-linked and more common in males. Cases can be related to ataxia and the condition may not present until the fourth decade or later if mild.2 Aetiology In addition to the myelodysplastic syndromes, sideroblastic anaemia can also occur in other bone marrow diseases including: • • • • Myeloma Πολψχψτηαεµια ρυβρα ϖερα Μψελοσχλεροσισ Λευκαεµιασ

Secondary causes include: • • • • • • • • • • Inflammatory conditions e.g. rheumatoid arthritis Σψστεµιχ λυπυσ ερψτηεµατοσυσ Chronic infections ∆ρυγ τοξιχιτψ - e.g. chloramphenicol, cycloserine, isoniazid, linezolid, pyrazinamide Χηρονιχ αλχοηολισµ Ηαεµολψτιχ αναεµια Μαλαβσορπτιον syndromes Μψξοεδεµα Λεαδ ποισονινγ Πρεγνανχψ

Presentation Clinical features are those related to anaemia in general. Symptoms reflect the cytopenias, i.e. anaemia, infection, bruising and haemorrhage. There are no specific signs or symptoms related to sideroblastic anaemia alone. Investigations • • • • • A FBC usually shows a moderate anaemia. The MCV is normal or increased but can be low. High serum iron and transferring saturation also occur. The blood film shows a dimorphic population of both normal and hypochromic red blood cells. Diagnosis is made from bone marrow examination demonstrating the presence of ring sideroblasts with a generalized increase in iron stores.

Management

Non-Drug
• • Treatment is mainly supportive. Red cell transfusion is given for symptomatic anaemia.

Iron chelation with desferrioxamine should be considered after 20-25 units of red cells have been received.3 Anemia (AmE) or anæmia/anaemia (BrE), from the Greek (Ἀναιμία) (an-haîmia) meaning "without blood," is defined as a qualitative or quantitative deficiency of hemoglobin, a molecule found inside red blood cells (RBCs). Since hemoglobin normally carries oxygen from the lungs to the tissues, anemia leads to hypoxia (lack of oxygen) in organs. Since all human cells depend on oxygen for survival, varying degrees of anemia can have a wide range of clinical consequences. The three main classes of anemia include excessive blood loss (acutely such as a hemorrhage or chronically through low-volume loss), excessive blood cell destruction (hemolysis) or deficient red blood cell production (ineffective hematopoiesis). Anemia is the most common disorder of the blood. There are several kinds of anemia, produced by a variety of underlying causes. Anemia can be classified in a variety of ways, based on the morphology of RBCs, underlying etiologic mechanisms, and discernible clinical spectra, to mention a few. There are two major approaches of classifying anemias, the "kinetic" approach which involves evaluating production, destruction and loss[1], and the "morphologic" approach which groups anemia by red blood cell size. The morphologic approach uses a quickly

available and cheap lab test as its starting point (the MCV). On the other hand, focusing early on the question of production may allow the clinician more rapidly to expose cases where multiple causes of anemia coexist.

Contents
[hide] • • • 1 Signs and symptoms 2 ∆ιαγνοσισ 3 Χλασσιφιχατιον • • 3.1 Production vs. destruction or loss 3.2 Ρεδ βλοοδ χελλ σιζε • • • • • • • • • 3.2.1 Microcytic anemia 3.2.2 Νορµοχψτιχ ανεµια 3.2.3 Μαχροχψτιχ ανεµια 3.2.4 ∆ιµορπηιχ ανεµια 3.2.5 Ηεινζ βοδψ ανεµια

4 Specific anemias 5 Ποσσιβλε χοµπλιχατιονσ 6 Ανεµια δυρινγ πρεγνανχψ 7 Τρεατµεντσ φορ ανεµια • • 7.1 Blood transfusions for anemia 7.2 Ηψπερβαριχ Οξψγενατιον

• • • •

8 References 9 Βοοκσ 10 Σεε αλσο 11 Εξτερναλ λινκσ

[edit] Signs and symptoms
Anemia goes undetected in many people, and symptoms can be small and vague. Most commonly, people with anemia report a feeling of weakness or fatigue in general or during exercise, general malaise and sometimes poor concentration. People with more severe anemia often report dyspnea (shortness of breath) on exertion. Very severe anemia prompts the body to compensate by increasing cardiac output, leading to palpitations and sweatiness, and to heart failure. Pallor (pale skin, mucosal linings and nail beds) is often a useful diagnostic sign in moderate or severe anemia, but it is not always apparent. Other useful signs are cheilosis and koilonychia. Pica, the consumption of non-food such as dirt, paper, wax, grass, ice and hair, may be a symptom of iron deficiency, although it occurs often in those who have normal levels of hemoglobin. Chronic anemia may result in behavioral disturbances in children as a direct result of impaired neurological development in infants, and reduced scholastic performance in children of school age.

[edit] Diagnosis
Generally, clinicians request complete blood counts in the first batch of blood tests in the diagnosis of an anemia. Apart from reporting the number of red blood cells and the hemoglobin level, the automatic counters also measure the size of the red blood cells by flow cytometry, which is an important tool in distinguishing between the causes of anemia. Examination of a stained blood smear using a microscope can also be helpful, and is sometimes a necessity in regions of the world where automated analysis is less accessible. In modern counters, four parameters (RBC count, hemoglobin concentration, MCV and RDW) are measured, allowing others (hematocrit, MCH and MCHC) to be calculated, and compared to values adjusted for age and sex. Some counters estimate hematocrit from direct measurements. For adult men, a hemoglobin level less than 13.0 g/dl (grams per deciliter) is diagnostic of anemia, and for adult women, the diagnostic threshold is below 12.0 g/dl. Reticulocyte counts, and the "kinetic" approach to anemia, have become more common than in the past in the large medical centers of the United States and some other wealthy nations, in part because some automatic counters now have the capacity to include reticulocyte counts. A reticulocyte count is a quantitative measure of the bone marrow's production of new red blood cells. The reticulocyte production index is a calculation of the ratio between the level of anemia and the extent to which the reticulocyte count has risen in response. If the degree of anemia is significant, even a "normal" reticulocyte count actually may reflect an inadequate response.

If an automated count is not available, a reticulocyte count can be done manually following special staining of the blood film. In manual examination, activity of the bone marrow can also be gauged qualitatively by subtle changes in the numbers and the morphology of young RBCs by examination under a microscope. Newly formed RBCs are usually slightly larger than older RBCs and show polychromasia. Even where the source of blood loss is obvious, evaluation of erythropoiesis can help assess whether the bone marrow will be able to compensate for the loss, and at what rate. When the cause is not obvious, clinicians use other tests: ESR, ferritin, serum iron, transferrin, RBC folate level, serum vitamin B12, hemoglobin electrophoresis, renal function tests (e.g. serum creatinine). When the diagnosis remains difficult, a bone marrow examination allows direct examination of the precursors to red cells.

[edit] Classification
[edit] Production vs. destruction or loss
The "kinetic" approach to anemia yields what many argue is the most clinically relevant classification of anemia. This classification depends on evaluation of several hematological parameters, particularly the blood reticulocyte (precursor of mature RBCs) count. This then yields the classification of defects by decreased RBC production versus increased RBC destruction and/or loss. Clinical signs of loss or destruction include abnormal peripheral blood smear with signs of hemolysis; elevated LDH suggesting cell destruction; or clinical signs of bleeding, such as guiaic-positive stool, radiographic findings, or frank bleeding. Here is a simplified schematic of this approach: A n e m i a

Re tic

Reti culo

ulo cyt e pr od uct ion ind ex sh ow s ina de qu ate pr od uct ion res po ns e to an em ia.

cyte prod ucti on inde x sho ws appr opri ate resp onse to ane mia = ong oing hem olysi s or bloo d loss with out RB C prod ucti on prob lem.

No cli nic al fin din

C lin ica l fin din

Clin ical find ings and nor

gs co nsi ste nt wit h he mo lys is or blo od los s: pu re dis or der of pr od uct ion .

gs an d ab no rm al M C V: he mo lys is or los s an d chr oni c dis or der of pr od uct ion *.

mal MC V= acu te hem olys is or loss with out ade quat e time for bon e mar row pro duct ion to com pen sate **.

M a c r o c y t i

N o r m o c y t i

M icro cyti c ane mia (M CV <80

c c a n e m i a ( M C V > 1 0 0 ) a n e m i a ( 8 0 < M C V < 1 0 0 ) )

* For instance, sickle cell anemia with superimposed iron deficiency; chronic gastric bleeding with B12 and folate deficiency; and other instances of anemia with more than one cause. ** Confirm by repeating reticulocyte count: ongoing combination of low reticulocyte production index, normal MCV and hemolysis or loss may be seen in bone marrow failure or anemia of chronic disease, with superimposed or related hemolysis or blood loss.

[edit] Red blood cell size
In the morphological approach, anemia is classified by the size of red blood cells; this is either done automatically or on microscopic examination of a peripheral blood smear. The size is reflected in the mean corpuscular volume (MCV). If the cells are smaller than normal (under 80 fl), the anemia is said to be microcytic; if they are normal size (80-100 fl), normocytic; and if they are larger than normal (over 100 fl), the anemia is classified as macrocytic. This scheme quickly exposes some of the most common causes of anemia; for instance, a microcytic anemia is often the result of iron deficiency. In clinical workup, the MCV will be one of the first pieces of information available; so even among clinicians who consider the "kinetic" approach more useful philosophically, morphology will remain an important element of classification and diagnosis. Here is a schematic representation of how to consider anemia with MCV as the starting point:

An em ia

M acr oc yti c an em ia (M C V >1 00 )

No rm oc yti c ane mi a (80 < M CV <1 00)

Mi cr oc yti c an e mi a ( M C V <8 0)

Hi gh ret ic ul oc yt e co un t

L o w re tic ul oc yt e co un t

Other characteristics visible on the peripheral smear may provide valuable clues about a more specific diagnosis; for example, abnormal white blood cells may point to a cause in

the bone marrow.

[edit] Microcytic anemia Microcytic anemia is primarily a result of hemoglobin synthesis failure/insufficiency, which could be caused by several etiologies: • Heme synthesis defect • • • Iron deficiency anemia Ανεµια οφ χηρονιχ δισεασε (more commonly presenting as normocytic anemia)

Globin synthesis defect • • • • alpha-, and beta-thalassemia HbE syndrome HbC syndrome and various other unstable hemoglobin diseases

Sideroblastic defect • • • Hereditary sideroblastic anemia Acquired sideroblastic anemia, including lead toxicity Reversible sideroblastic anemia

Iron deficiency anemia is the most common type of anemia overall and it has many causes. RBCs often appear hypochromic (paler than usual) and microcytic (smaller than usual) when viewed with a microscope. • Iron deficiency anemia is caused by insufficient dietary intake or absorption of iron to replace losses from menstruation or losses due to diseases.[2] Iron is an essential part of hemoglobin, and low iron levels result in decreased incorporation of hemoglobin into red blood cells. In the United States, 20% of all women of childbearing age have iron deficiency anemia, compared with only 2% of adult men. The principal cause of iron deficiency anemia in premenopausal women is blood lost during menses. Studies[who?] have shown that iron deficiency without anemia causes poor school performance and lower IQ in teenage girls. Iron deficiency is the most prevalent deficiency state on a worldwide basis. Iron deficiency is sometimes the cause of abnormal fissuring of the angular (corner) sections of the lips (angular stomatitis).

Iron deficiency anemia can also be due to bleeding lesions of the gastrointestinal tract. Fecal occult blood testing, upper endoscopy and lower endoscopy should be performed to identify bleeding lesions. In men and post-menopausal women the chances are higher that bleeding from the gastrointestinal tract could be due to colon polyp or colorectal cancer. Worldwide, the most common cause of iron deficiency anemia is parasitic infestation (hookworm, amebiasis, schistosomiasis and whipworm).[3]

[edit] Normocytic anemia Normocytic anaemia occurs when the overall hemoglobin levels are always decreased, but the red blood cell size (Mean corpuscular volume) remains normal. Causes include: • • • • Acute blood loss Ανεµια οφ χηρονιχ δισεασε Απλαστιχ ανεµια (bone marrow failure) Ηεµολψτιχ ανεµια

[edit] Macrocytic anemia • Megaloblastic anemia, the most common cause of macrocytic anemia, is due to a deficiency of either vitamin B12, folic acid (or both). Deficiency in folate and/or vitamin B12 can be due either to inadequate intake or insufficient absorption. Folate deficiency normally does not produce neurological symptoms, while B12 deficiency does. • Pernicious anemia is an autoimmune condition thought to be due to a directed attack against intrinsic factor produced by the parietal cells of the stomach. Intrinsic factor is required to absorb vitamin B12 from food. Therefore, the destruction of intrinsic factor, leads to poor absorption of vitamin B12. Macrocytic anemia can also be caused by removal of the functional portion of the stomach, such as during gastric bypass surgery, leading to reduced vit B12/folate absorption. Therefore one must always be aware of anemia following this procedure.

• •

Alcoholism causes a macrocytosis, although not specifically anemia Μετηοτρεξατε, zidovudine, and other drugs that inhibit DNA replication.

Macrocytic anemia can be further divided into "megaloblastic anemia" or "nonmegaloblastic macrocytic anemia". The cause of megaloblastic anemia is primarily a failure of DNA synthesis with preserved RNA synthesis, which result in restricted cell division of the progenitor cells. The megaloblastic anemias often present with neutrophil hypersegmentation (6-10 lobes). The non-megaloblastic macrocytic anemias have different etiologies (i.e. there is unimpaired DNA globin synthesis,) which occur, for example in alcoholism. In addition to the non-specific symptoms of anemia, specific features of vitamin B12 deficiency include peripheral neuropathy and subacute combined degeneration of the cord with resulting balance difficulties from posterior column spinal cord pathology.[4] Other features may include a smooth, red tongue and glossitis. The treatment for vitamin B12-deficient anemia was first devised by William Murphy who bled dogs to make them anemic and then fed them various substances to see what (if anything) would make them healthy again. He discovered that ingesting large amounts of liver seemed to cure the disease. George Minot and George Whipple then set about to chemically isolate the curative substance and ultimately were able to isolate the vitamin B12 from the liver. All three shared the 1934 Nobel Prize in Medicine.[5]

[edit] Dimorphic anemia When two causes of anemia act simultaneously, e.g., macrocytic hypochromic, due to hookworm infestation leading to deficiency of both iron and vitamin B12 or folic acid [6] or following a blood transfusion more than one abnormality of red cell indices may be seen. Evidence for multiple causes appears with an elevated RBC distribution width (RDW), which suggests a wider-than-normal range of red cell sizes.

[edit] Heinz body anemia Heinz bodies are an abnormality that form on the cells in this condition. This form of anemia may be brought on by taking certain medications; it is also triggered in cats by eating onionsHYPERLINK \l "cite_note-6"[7] or acetaminophen (Tylenol). It can be triggered in dogs by ingesting onions or zinc, and in horses by ingesting dry red maple leaves.

[edit] Specific anemias
• • Anemia of prematurity occurs in premature infants at 2 to 6 weeks of age and results from diminished erythropoietin response to declining hematocrit levels Φανχονι ανεµια is an hereditary disorder or defect featuring aplastic anemia and various other abnormalities

Ηεµολψτιχ ανεµια causes a separate constellation of symptoms (also featuring jaundice and elevated LDH levels) with numerous potential causes. It can be autoimmune, immune, hereditary or mechanical (e.g. heart surgery). It can result (because of cell fragmentation) in a microcytic anemia, a normochromic anemia, or (because of premature release of immature red blood cells from the bone marrow), a macrocytic anemia. Ηερεδιταρψ σπηεροχψτοσισ is a hereditary defect that results in defects in the RBC cell membrane, causing the erythrocytes to be sequestered and destroyed by the spleen. This leads to a decrease in the number of circulating RBCs and, hence, anemia. Σιχκλε−χελλ ανεµια, a hereditary disorder, is due to homozygous hemoglobin S genes. Ωαρµ αυτοιµµυνε ηεµολψτιχ ανεµια is an anemia caused by autoimmune attack against red blood cells, primarily by IgG Χολδ αγγλυτινιν ηεµολψτιχ ανεµια is primarily mediated by IgM Περνιχιουσ ανεµια is a form of megaloblastic anaemia due to vitamin B12 deficiency dependent on impaired absorption of vitamin B12. Μψελοπητηισιχ ανεµια or Myelophthisis is a severe type of anemia resulting from the replacement of bone marrow by other materials, such as malignant tumors or granulomas.

• • • • •

[edit] Possible complications
Anemia diminishes the capability of individuals who are affected to perform physical activities. This is a result of one's muscles being forced to depend on anaerobic metabolism. The lack of iron associated with anemia can cause many complications, including hypoxemia, brittle or rigid fingernails, cold intolerance, and possible behavioral disturbances in children. Hypoxemia resulting from anemia can worsen the cardiopulmonary status of patients with pre-existing chronic pulmonary disease. Cold intolerance occurs in one in five patients with iron deficiency anemia, and becomes visible through numbness and tingling.[citation needed]

[edit] Anemia during pregnancy
Anemia affects 20% of all females of childbearing age in the United States. Because of the subtlety of the symptoms, women are often unaware that they have this disorder, as they attribute the symptoms to the stresses of their daily lives. Possible problems for the fetus include increased risk of growth retardation, prematurity, intrauterine death, rupture

of the amnion and infection. During pregnancy, women should be especially aware of the symptoms of anemia, as an adult female loses an average of two milligrams of iron daily. Therefore, she must intake a similar quantity of iron in order to make up for this loss. Additionally, a woman loses approximately 500 milligrams of iron with each pregnancy, compared to a loss of 4-100 milligrams of iron with each period. Possible consequences for the mother include cardiovascular symptoms, reduced physical and mental performance, reduced immune function, tiredness, reduced peripartal blood reserves and increased need for blood transfusion in the postpartum period.

[edit] Treatments for anemia
There are many different treatments for anemia and the treatment depends on severity and the cause. Iron deficiency from nutritional causes is rare in non-menstruating adults (men and postmenopausal women). The diagnosis of iron deficiency mandates a search for potential sources of loss such as gastrointestinal bleeding from ulcers or colon cancer. Mild to moderate iron deficiency anemia is treated by iron supplementation with ferrous sulfate or ferrous gluconate. Vitamin C may aid in the body's ability to absorb iron. Vitamin supplements given orally (folic acid) or subcutaneously (vitamin B-12) will replace specific deficiencies. In anemia of chronic disease, anemia associated with chemotherapy, or anemia associated with renal disease, some clinicians prescribe recombinant erythropoietin, epoetin alfa, to stimulate red cell production. In severe cases of anemia, or with ongoing blood loss, a blood transfusion may be necessary.

[edit] Blood transfusions for anemia
Doctors attempt to avoid blood transfusion in general, since multiple lines of evidence point to increased adverse patient clinical outcomes with more intensive transfusion strategies. The physiological principle that reduction of oxygen delivery associated with anemia leads to adverse clinical outcomes is balanced by the finding that transfusion does not necessarily mitigate these adverse clinical outcomes. In severe, acute bleeding, transfusions of donated blood are often lifesaving. Improvements in battlefield casualty survival is attributable, at least in part, to the recent improvements in blood banking and transfusion techniques.[citation needed] Transfusion of the stable but anemic hospitalized patient has been the subject of

numerous clinical trials, and transfusion is emerging as a deleterious intervention. Four randomized controlled clinical trials have been conducted to evaluate aggressive versus conservative transfusion strategies in critically ill patients. All four of these studies failed to find a benefit with more aggressive transfusion strategies. [8] [9] [10] [11] In addition, at least two retrospective studies have shown increases in adverse clinical outcomes with more aggressive transfusion strategies. [12] [13]

[edit] Hyperbaric Oxygenation
Treatment of exceptional blood loss (anemia) is recognized as an indication for hyperbaric oxygen (HBO) by the Undersea and Hyperbaric Medical Society.[14]HYPERLINK \l "cite_note-14"[15] The use of HBO is indicated when oxygen delivery to tissue is not sufficient in patients who cannot be transfused for medical or religious reasons. HBO may be used for medical reasons when threat of blood product incompatibility or concern for transmissible disease.[14] The beliefs of some religions (ex: Jehovah's Witnesses) may prohibit the receipt transfused blood products.[14] In 2002, Van Meter reviewed the publications surrounding the use of HBO in severe anemia and found that all publications report a positive result.[16] Macrocytic is from Greek words meaning "large cell." A macrocytic class of anemia is an anemia (defined as blood with an insufficient concentration of hemoglobin) in which the erythrocytes ("red blood cells" or RBCs) are larger than their normal volume. This normal RBC volume in humans is about 80 to 100 femtoliters (fL= 10-15 L). In slightly less correct metric terminology which does not use standard volume units, the size may be given in equivalent cubic micrometres (1 μm3 = 1 fL). The condition of having red cells which are on average too large, is called macrocytosis. In a macrocytic anemia the larger red cells are always associated with insufficient numbers of cells and often also insufficient hemoglobin content per cell, both factors which more than make up for the larger cell size, to produce a total blood hemoglobin concentration deficiency. Macrocytic anemia is not a disease, but a condition: a general classification of a set of pathologies. Many specific pathologies are known which result in macrocytic-type anemias, but which produce slightly different sets of appearances, some of which are detectable from red and white cell mophology, and others only from chemical tests on the blood.

Contents
[hide] • 1 Types of macrocytic anemias • • • • • 1.1 Megaloblastic anemias (DNA replication disorders) 1.2 Ρεδ χελλ µεµβρανε δισορδερσ προδυχινγ χοδοχψτεσ 1.3 Αλχοηολ 1.4 Ασσοχιατιον ωιτη ραπιδ ρεδ χελλ τυρνοϖερ ανδ ρετιχυλοχψτοσισ

2 References

[edit] Types of macrocytic anemias
[edit] Megaloblastic anemias (DNA replication disorders)
Especially common causes of macrocytic anemias are the so-called megaloblastic anemias, in which cells are larger because they cannot produce DNA quickly enough to divide at the right time as they grow, and thus grow too large before division. Causes for the DNA synthetic problem range from lack of certain vitamins needed to produce DNA (notably folate and B12), to poisons or inhibitors of DNA replication, such as some kinds of antiviral drugs and chemotherapeutic agents. Classically these megaloblastic types of anemias are associated also with more specific features, such as megaloblasts in the bone marrow, the presense of ovalocytes in the (peripheral) blood smear, and the pathognomonic presense of hypersegmented neutrophils.

[edit] Red cell membrane disorders producing codocytes
Other disorders which cause macrocytosis without DNA replication problems (i.e., nonmegaloblastic macrocytic anemias), are disorders associated with increased red cell membrane surface area, such as pathologies of the liver and spleen which produce codocytes or "target cells" which have a central collection of hemoglobin surrounded by a pallor (a thin area) then followed by a thicker collection of hemoglobin at the rim of the cell.

[edit] Alcohol
Round macrocytes which are not codocytes are produced in chronic alcoholism (which produces a mild macrocytosis even in the absence of vitamin deficiency), apparently as a direct toxic effect of alcohol specifically on the bone marrow.

[edit] Association with rapid red cell turnover and reticulocytosis
Mild macrocytocis is a common finding associated with rapid blood restoration or production, since in general, "fresh" or newly-produced red cells (reticulocytes) are larger than the mean (average) size, due to slow shrinkage of normal cells over a normal red cell circulating lifetime. Thus, chronic obstructive pulmonary disease (COPD), in which which red cells are rapidly produced in response to low oxygen levels in the blood, often produces mild macrocytosis. Also, rapid blood replacement from the marrow after a traumatic blood loss, or rapid red blood cell turnover from rapid hemolysis, also often produces mild macrocytosis in the associated anemia. [1].

Megaloblastic Anaemia
In this group of anaemias the erythroblasts in the bone marrow show a delay of the maturation of the nucleus relative to that of the cytoplasm. The delay in the maturation of the nucleus is due to defective DNA synthesis. This may be caused by: • • • • Vitamin B12 deficiency Φολατε δεφιχιενχψ Αβνορµαλιτιεσ οφ ϖιτ Β12 ορ φολατε µεταβολισµ Οτηερ δεφεχτσ οφ ∆ΝΑ σψντηεσισ

Both vitamin B12 and folate are required for the synthesis of DNA. Folate is needed in its tetrahydrofolate form (FH4) as a cofactor in DNA synthesis. Vitamin B12 is a cofactor required for the conversion of homocysteine to methionine which enables cells to receive FH4 for synthesis of methylene FH4, the coenzyme required for the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) in the formation of DNA. Vitamin B12 Deficiency The natural source of B12 is from the diet. Vitamin B12 is synthesised only by bacteria and is found in meat, fish, eggs, and milk, but not in plants, and it is not usually destroyed by cooking. A normal diet contains a large excess of B12 compared with daily needs. B12 is combined with intrinsic factor (IF), a glycoprotein synthesised by gastric parietal cells. The IF-B12 complex binds to a specific receptor protein for IF, cubulin, in the distal ileum, where B12 is then absorbed.

In Western countries, B12 deficiency is usually caused by pernicious anaemia, an autoimmune disorder. The majority of patients have IgG autoantibodies targeted against gastric parietal cells and IF, leading to atrophy of the gastric mucosa with consequent failure of IF production. Gastritis affecting the fundus is present with plasma cell and lymphoid infiltration. The parietal and chief cells are replaced by mucin-secreting cells. Achlorhydria (failure to produce hydrochloric acid) occurs and secretion of IF is absent or almost absent. Less commonly, it may also be caused by: • • • • • • • • veganism in which the diet lacks B12 gastrectomy ileal resection small intestinal lesions, as in Crohn's disease stagnant loop syndrome tropical sprue fish tapeworm congenital malabsorption

The deficiency takes at least 2 years to develop - i.e. the time needed for body stores to deplete at a rate of 1-2µg each day when there is no new B12 entering the body from the diet. Folate Deficiency Humans are unable to synthesise folate and so require preformed folate as a vitamin in the diet. It is found in green vegetables such as spinach broccoli, and offal, such as liver and kidney. Cooking causes loss of 60-90% of the folate. The main cause of folate deficiency is poor dietary intake, which may occur alone or with excessive utilisation or malabsorption (Table 1). It may also be caused by antifolate drugs. Poor Dietary Intake • • • • Old age Poor social conditions Starvation Alcohol excess • • Malabsorption • Small bowel disease - but effect is less than that of anorexia Gluten-induced enteropathy Tropical sprue

Anorexia:gastrointestinal disease - e.g. partial gastrectomy, coeliac disease, Crohn's disease; cancer Folate Antagonists • • • • • Anticonvulsants (phenytoin, primidone) Sulphasalazine Methotrexate Pyrimethamine Trimethoprim

Excess Utilisation • • • Pregnancy and lactation Haemolytic anaemia Myeloproliferative / malignant / inflammatory disorders

Excess Urinary Folate Loss • • Congestive cardiac failure Chronic dialysis

Mixed • • Liver disease Alcoholism

Table 1 Causes of folate deficiency

On a deficient diet, folate deficiency develops over about 4 months, but deficiency may develop more rapidly in patients who have both a poor intake and excess utilisation of folate, as in ITU patients. Abnormalities of Vitamin B12 or Folate Metabolism These include: • • • Congenital deficiencies of enzymes concerned in B12 or folate metabolism or of the serum transport protein for B12, transcobalamin II (TC II). Nitrous oxide anaesthesia Antifolate drug therapy, especially dihydrofolate (DHF) reductase inhibitors (e.g. methotrexate, pyrimethamine)

Other defects of DNA synthesis These include: • Congenital deficiency of one or other enzyme concerned in purine or pyrimidine synthesis, e.g. orotic aciduria

 

Drug therapy inhibiting purine and pyrimidine synthesis (e.g. hydroxyurea, cytosine arabinoside, 6-mercaptopurine, zidovudine (AZT)) Some forms of AML and myelodysplasia

Clinical Features             Onset: insidious Gradually progressive signs of anaemia Mild jaundice: excess Hb breakdown caused by ineffective erythropoiesis in bone marrow Glossitis Angular stomatitis Weight loss: malabsorption caused by epithelial abnormality Purpura: result of thrombocytopenia Neuropathy (vitamin B12 deficiency only) Sterility Neural tube defects in the fetus (vitamin B12 or folate deficiency) Widespread melanin pigmentation: rarely Cardiovascular disease: due to raised serum homocysteine levels

Investigations  Haematological findings:

Blood count: MCV (>96fl). May beHb, leucopenia, thrombocytopenia Peripheral blood film: oval macrocytes and hypersegmented neutrophils (due to retention of surplus nuclear material) with 6 lobes in the nucleus  Bone marrow aspirate:

Typical features of megaloblastic erythropoiesis The immature red cells show nuclear-cytoplasmic imbalance with enlarged abnormal nuclei and basophilic cytoplasm Not always necessary in straightforward megaloblastic anaemia and a low serum vitamin B12

•   

Serum bilirubin:  as a result of ineffective erythropoiesis or if destruction of developing red cells is increased Serum vitamin B12:  (<160ng/l). Very low in pernicious anaemia. Can be assayed using radioisotope dilution or immunological assays Serum folate: N / , and red cell folate is N /  owing to inhibition of normal folate synthesis Autoantibodies:

Parietal cell antibodies in serum IF antibodies in serum: diagnostic of pernicious anaemia Also detected in gastric juice Anti-gliadin and endomysial antibodies: folate deficiency  Vitamin B12 absorption tests: Schilling test - patient swallows B12 labelled with radioactive cobalt and absorption is usually measured in directly by quantifying urinary excretion. Normal subjects excrete >10% of the radioactive dose. The test is then repeated with IF added.

If excretion is now normal (malabsorption is corrected) = pernicious anaemia or gastrectomy If excretion is still abnormal = terminal ileum lesion or bacterial overgrowth.   Endoscopy or barium meal and follow through Duodenal biopsy

Treatment Most cases only require administering the appropriate vitamin (Table 2). However, it is important not to give folate in vitamin B12 deficiency since the neuropathy may be aggravated. B12 deficiency must be excluded before commencing large doses of folic acid. In the elderly, correct any heart failure with diuretics and oral potassium supplements given for 10 days. Avoid blood transfusion as it may cause circulatory overload. Vitamin B12 Deficiency Compound Hydroxycobalamin Route Dose IM, PO, SL 1000g Folate Deficiency Folic acid PO 5mg

Initial dose

6 x 1000g over 2-3 wks

Daily for 4 mths Depends on underlying disease; life-long therapy may be needed in chronic inherited haemolytic anaemias, myelofibrosis, renal dialysis

Maintenanc 1000g every 3 mths e

Prophylacti c Total gastrectomy Ileal resection

Pregnancy, severe haemolytic anaemias, dialysis, prematurity

Table 2 Treatment of megaloblastic anaemia

Course of Response to Correct Vitamin Therapy      24-48hrs: patient feels better with increased appetite and well-being 48hrs: marrow is normoblastic. However, giant metamyelocytes persist for up to 12 days 2-3 days: reticulocyte response begins. Peaks at 6-7 days 7-10 days: white cell and platelet counts return to normal Fortnight: Hb rises by 2-3g/dl each fortnight

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Non-Megaloblastic Macrocytic Anaemia
There are many non-megaloblastic causes of macrocytic anaemia. The exact mechanisms creating macrocytes in each of these conditions is not clear. Increased lipid deposition on the red cell membrane or alterations of erythrocyte maturation time in the marrow have been suggested. The causes of non-megaloblastic macrocytosis include:     Alcohol: most frequent cause of MCV in the absence of anaemia Liver disease Myxoedema Myelodysplastic syndromes

• • • • • • •

Cytotoxic drugs Aplastic anaemia Pregnancy Smoking Reticulocytosis Myeloma Neonatal

It is important to exclude B12 or folate deficiency before these diagnoses are made. White cell and platelet counts are normal unless the underlying marrow disease affects these. The red cells are circular rather than oval, hypersemented neutrophils are absent and the marrow is normoblastic. Red Cell Production and Anaemia Anaemia is defined as a reduction in haemoglobin concentration. This varies between sexes but is usually defined as a haemoglobin less than 13.5g/dl in males and 11.5 g/dl in females. The reduction in haemoglobin is generally accompanied by a fall in the red cell count and the packed cell volume or 'haematocrit'. Alterations in plasma volume will alter haemoglobin concentrations. A reduction in plasma volume, as in dehydration, will cause an artificial elevation of the haemoglobin concentration and may mask anaemia. An increase in plasma volume, as in pregnancy, may cause an apparent anaemia. Anaemia is not immediately apparent in acute major blood loss when the total blood volume is reduced. It generally takes over 24 hours before anaemia is evident. Clinical features of anaemia These are very variable and depend on the speed of onset of the anaemia and the coexistence of other medical conditions. In general, a slowly progressive anaemia may be relatively asymptomatic and the patient may be able to adapt. However, co-existent cardiac or pulmonary disease may exacerbate the symptoms. The symptoms that are defined include lethargy, shortness of breath, exacerbation of angina. The physical signs on examination of the patient are generally unreliable but it is possible that pallor of the mucous membranes or, very rarely, koilonychia (spooning of nails) may be observed. Classification of anaemia There are many different causes of anaemia and 2 major classification systems exist; in practice a combination of the two are used. A – a classification based on the cause of the anaemia: (i) those patients who have reduced production of red cells

(ii) patients whose red cells function poorly (iii) situations where there is increased loss or destruction of red cells. B – Classification of anaemia based on the size of red cells - the mean cell volume (MCV); the normal range for this parameter is 80-100fl. (i) macrocytic (large red cells) (ii) normocytic (normal sized red cells) (iii) microcytic (small red cells). The second classification is widely used. It is practical because the vast majority of peripheral blood counts measured in the United Kingdom are analysed on modern electronic cell counters. These counters identify a number of parameters related to red cell size, red cell number and the concentration of haemoglobin in red cells. The macrocytic anaemias Causes of a macrocytic anaemia (raised MCV) are listed below: B12 and folate deficiency Vitamin B12 and folic acid are closely involved in the production of DNA. Deficiency of either one of these vitamins causes a macrocytic anaemia. Vitamin B12 is absorbed from the ileum as a complex with intrinsic factor produced in the gastric parietal cells; folate on the other hand is absorbed in the duodenum and jejunum. Deficiencies of either can result from diseases of the site of absorption. Folic acid is widely distributed in foodstuffs but vitamin B12 is confined to meat products. Consequently, vitamin B12 deficiency can be seen in strict vegans. In non-vegans the main cause of vitamin B12 deficiency is pernicious anaemia, which is an auto-immune condition with antibodies being produced against gastric parietal cells in 90% and intrinsic factor in 70% of patients. Folic acid deficiency can often be related to a poor diet or to malabsorption within the gut, eg coeliac disease. Alcoholism and liver disease Many forms of liver disease, including alcoholic cirrhosis and, indeed, alcoholism per se, can lead to a macrocytic anaemia. There is often co-existent folate deficiency. Impaired red cell production Aplastic anaemia, where there is bone marrow failure or myelodysplasia, where there is ineffective red cell production, can both cause a macrocytic anaemia. The causes of aplastic anaemia are varied but can include certain viruses, eg hepatitis B, excessive doses of cytotoxic drugs or radiation, or idiosyncratic reactions to drugs. The treatment of aplastic anaemia is either bone marrow transplantation or immunotherapy. Myelodysplasia is a heterogeneous group of conditions which may be pre-leukaemic. There is no satisfactory treatment for these conditions other than blood product support,

eg red cell transfusion. In some patients, cytotoxic therapy or bone marrow transplantation may be indicated. Haemolytic anaemias There are many causes of haemolytic anaemia. Destruction of red cells may take place either within the circulation (intra-vascular haemolysis) or outside the circulation mainly in the spleen (extra-vascular haemolysis). In these conditions the reticulocyte count is usually raised. Reticulocytes are large red cells, and so their presence in increased numbers can cause a raised MCV. It is possible to have a haemolytic anaemia with a normal MCV; in these cases the degree of reticulocytosis is less. The aetiology of haemolytic anaemia may be divided into stimuli outside the red cell membrane, problems within the red cell membrane and defects within the red cell itself. An example of a haemolytic anaemia where the stimulus lies outside the red cell membrane is autoimmune haemolytic anaemia. In these cases the direct Coomb's test is positive; i.e. there is an antibody active against red cells, which is present in the plasma. This causes increased destruction of red cells in the spleen. Auto-immune anaemia can be idiopathic, i.e. without an identified precipitating cause or secondary to a lymphoma, an autoimmune disease, eg. rheumatoid arthritis or systemic lupus erythematosus, (but these diseases can also suppress red cell production); certain drugs induce auto-immune haemolytic anaemia; more rarely it may occur in association with an infection. An example of a haemolytic anaemia secondary to an inherent problem within the red cell membrane is hereditary spherocytosis. This is a congenital condition that has a Mendelian pattern of inheritance characterised by a chronic haemolytic anaemia but with a negative direct Coomb's test. It is best treated by splenectomy. An example of a chronic haemolytic anaemia due to an inherent problem within the red cell is glucose 6 phosphate dehydrogenase deficiency. This is an x-linked condition and therefore affects only males. It leads to a chronic haemolytic state which is exacerbated by certain drugs, infection and the ingestion of favar beans. Treatment is avoidance of precipitating agents. Normochromic anaemia Anaemia of chronic disease Most chronic coexistent medical conditions can cause such an anaemia. The mechanism is thought to be due to failure to use iron efficiently. Examples of chronic conditions include chronic inflammatory diseases such as rheumatoid arthritis, chronic infections including tuberculosis or malignancy. Some cases of anaemia of chronic disease are hypochromic, microcytic, ie, low MCH, low MCV but with a normal ferritin. Acute blood loss As mentioned previously, acute major blood loss will cause a normochromic, normocytic anaemia which becomes apparent after about 24 hours. Mixed deficiency anaemia

There are rare cases of a mixed deficiency anaemia, eg. combined iron deficiency with B12 or folate deficiency. The result is an anaemia which is normocytic. Bone marrow failure This may occur in individuals whose marrow is infiltrated by malignancy, are postchemotherapy or have chronic renal disease. Microcytic anaemias Causes of microcytic anaemia include: Iron deficiency anaemia This is the most common cause of anaemia in the UK. The most likely cause of iron deficiency anaemia is chronic blood loss. In women this may be due to excessive periods (menorrhagia) but overall it is usually due to chronic blood loss from the gastro-intestinal tract. This may be due to any bleeding pathology in the gut. Blood loss of 4ml per day will, in time, render an individual iron-deficient. The diagnosis of an iron deficiency anaemia is confirmed by a reduced serum ferritin. Once it has been ascertained that the patient has an iron deficient anaemia, then investigation to find the source of blood loss is required. This usually involves investigation of the G1 tract with barium studies or endoscopy. Treatment of the iron ferrous sulphate tablets, but it is important to remember that the cause of the anaemia must be found. Haemoglobinopathies, e.g., thalassaemia The thalassaemias are a complicated group of conditions which are inherited. They are prevalent in certain parts of the world including the Mediterranean basin, parts of Africa, the Middle East, Indian sub-continent and South-East Asia. In the severe forms of the disease the patient is chronically anaemic with a hypochromic, microcytic picture but a raised red cell count. Treatment is by repeated transfusion which can cause iron overload. Attention then needs to be given to the treatment of the iron overload, generally using Desferrioxamine. In some patients bone marrow transplantation can be curative. Other rare causes of a microcytic anaemia include lead poisoning and some types of sideroblastic anaemia Sideroblastic anaemia is a rare condition which may be either congenital when it usually occurs in males, or is secondary to certain drugs, particularly those used to treat tuberculosis. Anemia, like a fever, is a symptom of disease that requires investigation to determine the underlying etiology. Often, practicing physicians overlook mild anemia. This is similar to failing to seek the etiology of a fever. The purpose of this article is to provide a method of determining the etiology of an anemia. Anemia is strictly defined as a decrease in red blood cell (RBC) mass. Methods for measuring RBC mass are time consuming, are expensive, and usually require transfusion of radiolabeled erythrocytes. Thus, in practice, anemia is usually discovered and quantified by measurement of the RBC count, hemoglobin (Hb) concentration, and

hematocrit (Hct). These values should be interpreted cautiously because they are concentrations affected by changes in plasma volume. For example, dehydration elevates these values, and increased plasma volume in pregnancy can diminish them without affecting the RBC mass.

Pathophysiology
Erythroid precursors develop in bone marrow at rates usually determined by the requirement for sufficient circulating Hb to oxygenate tissues adequately. Erythroid precursors differentiate sequentially from stem cells to progenitor cells to erythroblasts to normoblasts in a process requiring growth factors and cytokines. This process of differentiation requires several days. Normally, erythroid precursors are released into circulation as reticulocytes. Reticulocytes remain in the circulation for approximately 1 day before reticulin is excised by reticuloendothelial cells with the delivery of the mature erythrocyte into circulation. The mature erythrocyte remains in circulation for about 120 days before being engulfed and destroyed by phagocytic cells of the reticuloendothelial system. Erythrocytes are highly deformable and increase their diameter from 7 µm to 13 µm when they traverse capillaries with a 3-µm diameter. They possess a negative charge on their surface, which may serve to discourage phagocytosis. Because erythrocytes have no nucleus, they lack a Krebs cycle and rely on glycolysis via the Embden-Meyerhof and pentose pathways for energy. Many enzymes required by the aerobic and anaerobic glycolytic pathways decrease within the cell as it ages. In addition, the aging cell has a decrease in potassium concentration and an increase in sodium concentration. These factors contribute to the demise of the erythrocyte at the end of its 120-day lifespan. RBCs contain fluid Hb encased in a lipid membrane supported by a cytoskeleton. Abnormalities of the membrane, the chemical composition of the Hb, or certain glycolytic enzymes can reduce the lifespan of RBCs to cause anemia. Basically, only 3 causes of anemia exist: blood loss, increased RBC destruction (hemolysis), and decreased production of RBCs. Each of these 3 causes includes a number of etiologies that require specific and appropriate therapy. Often, the etiology can be determined if the RBCs are altered in either size or shape or if they contain certain inclusion bodies. For example, Plasmodium falciparum malaria is suggested by the presence of more than one ring form in an RBC and produces pan-hemolysis of RBCs of all ages.

Frequency
United States The prevalence of anemia in population studies of healthy nonpregnant people depends

on the Hb concentration chosen for the lower limit of normal values. The World Health Organization chose 12.5 g/dL for both adult males and females. In the United States, limits of 13.5 g/dL for men and 12.5 g/dL for women are probably more realistic. Using these values, approximately 4% of men and 8% of women have values lower than those cited. A significantly greater prevalence is observed in patient populations. Less information is available regarding studies using RBC or Hct.

International The prevalence of anemia in Canada and northern Europe is believed to be similar to that in the United States. In underprivileged countries, limited studies of purportedly healthy subjects show the prevalence of anemia to be 2-5 times greater than that in the United States. Although geographic diseases, such as sickle cell anemia, thalassemia, malaria, hookworm, and chronic infections, are responsible for a portion of the increase, nutritional factors with iron deficiency and, to a lesser extent, folic acid deficiency play major roles in the increased prevalence of anemia. Populations with little meat in the diet have a high incidence of iron deficiency anemia because heme iron is better absorbed from food than inorganic iron.

Mortality/Morbidity
• The morbidity and mortality of anemias vary greatly depending on the etiology. • Acute hemorrhage has variable mortality depending on the site of bleeding (80% with aortic rupture, 30-50% with bleeding esophageal varices, approximately 1% with benign peptic ulcers). Anemia from gastrointestinal bleeding may be the first evidence of an intestinal malignancy. Sickle cell disease may be associated with frequent painful crises and a shortened lifespan, or patients with sickle cell disease may remain relatively asymptomatic with a nearly normal lifespan. Most patients with beta-0 homozygous thalassemia die during the second or third decade of life unless they undergo bone marrow transplantation. Ηερεδιταρψ σπηεροχψτοσισ either may present with a severe hemolytic anemia or may be asymptomatic with compensated hemolysis. Similarly, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency may manifest as chronic hemolytic anemia or exist without anemia until the patient receives an oxidant medication. The 2-year fatality rate for severe aplastic anemia is 70% without bone

• •

• • •

marrow transplantation or a response to immunosuppressive therapy. • Many symptoms associated with anemia are not caused by diminished RBC mass. Patients with pernicious anemia are often asymptomatic when they are detected incidentally with an Hb of 6 g/dL. In contrast, ice chewing, calf cramps, and diminished capability to perform muscular work occur in iron-deficiency anemia with an Hb of 10-11 g/dL because of depletion of iron-containing proteins other than Hb. In addition, tolerance of anemia is proportional to the anemia's rate of development. Symptoms and mortality associated with rapidly developing anemia are more profound than in slowly developing anemia.

• Race
• Certain races and ethnic groups have an increased prevalence of genetic factors associated with certain anemias. Examples are hemoglobinopathies, thalassemia, and G-6-PD deficiency. Each of these disorders has different morbidity and mortality in different populations due to differences in the genetic abnormality producing the disorder. For example, G-6-PD deficiency and thalassemia have less morbidity in African Americans than in Sicilians because of differences in the genetic fault. Conversely, sickle cell anemia has a greater morbidity and mortality in African Americans than among Saudi Arabians. Race is a factor in nutritional anemias and anemia associated with chronic untreated illnesses to the extent that socioeconomic advantages are distributed along racial lines in a given area. Socioeconomic advantages affect diet and the availability of health care and lead to a decreased prevalence of these types of anemia.1, 2, 3 For instance, iron deficiency anemia is much more prevalent in third world populations who have little meat in their diets than it is in populations of the United States and northern Europe. Similarly, anemia of chronic disorders is commonplace in populations with a high incidence of chronic infectious disease (eg, malaria, tuberculosis, AIDS), and this is at least in part worsened by the socioeconomic status of these populations and their access to adequate health care.

Sex
• • Overall, anemia is twice as prevalent in females as in males. This difference is significantly greater during the childbearing years due to pregnancies and menses. Approximately 65% of body iron is incorporated into circulating Hb. Each gram of Hb contains 3.46 mg of iron (1 mL of blood with Hb of 15 g/dL = 0.5 mg of iron). Each healthy pregnancy depletes the mother of approximately 500 mg of

iron. While a man must absorb about 1 mg of iron to maintain equilibrium, a premenopausal woman must absorb an average of 2 mg daily. Further, because women eat less food than men, they must be more than twice as efficient as men in the absorption of sufficient iron to avoid iron deficiency. • Women have a markedly lower incidence of anemia from X-linked anemias, such as G-6-PD deficiency and sex-linked sideroblastic anemias.

Age
• Severe genetically acquired anemias (eg, sickle cell disease, thalassemia, Fanconi syndrome) are more commonly found in children because they do not survive to adulthood. During the childbearing years, women are more likely to become iron deficient. Neoplasia increases in prevalence with each decade of life and can produce anemia from bleeding, from the replacement of bone marrow with tumor, or from the development of anemia associated with chronic disorders. Use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and Coumadin increases with age and can produce gastrointestinal bleeding.

• •

CLINICAL
Section 3 of 11 • • • • • • • • • • Authors and Editors Ιντροδυχτιον Χλινιχαλ ∆ιφφερεντιαλσ Ωορκυπ Τρεατµεντ Μεδιχατιον Φολλοω−υπ Μισχελλανεουσ Μυλτιµεδια

Ρεφερενχεσ

History
Carefully obtain a history and perform a physical examination in every patient with anemia because the findings usually provide important clues to the etiology of the underlying disorder. From the standpoint of the investigation of the anemia, asking questions in addition to those conventionally explored during a routine examination is important. Areas of inquiry found valuable are briefly described below. • Often, the duration of anemia can be established by obtaining a history of previous blood examination and, if necessary, by acquiring those records. Similarly, a history of rejection as a blood donor or prior prescription of hematinics provides clues that anemia was detected previously. Obtain a careful family history not only for anemia but also for jaundice, cholelithiasis, splenectomy, bleeding disorders, and abnormal Hbs. Carefully document the patient's occupation, hobbies, prior medical treatment, drugs (including over-the-counter medications and vitamins), and household exposures to potentially noxious agents. Patients are unlikely to volunteer exposures to tranquilizers, insecticides, paints, solvents, and hair dyes unless specifically queried. In searching for blood loss, carefully document pregnancies, abortions, and menstrual loss. Estimates of menstrual losses are notoriously inaccurate if only routine inquiry is made. Often, patients do not appreciate the significance of tarry stools. Changes in bowel habits can be useful in uncovering neoplasms of the colon. Hemorrhoidal blood loss is difficult to quantify, and it may be overlooked or overestimated from one patient to another. Obviously, seek a careful history of gastrointestinal complaints that may suggest gastritis, peptic ulcers, hiatal hernias, or diverticula. Abnormal urine color can occur in renal and hepatic disease and in hemolytic anemia. A thorough dietary history is important in a patient who is anemic. This history must include foods that the patient both eats and avoids as well as an estimate of their quantity. • A meal-by-meal description is necessary to obtain appropriate estimates.

• •

• •

Even then, patients frequently attempt to deceive the physician because of embarrassment regarding dietary idiosyncrasies or financial restrictions. In these circumstances, a close and concerned family member participating in the dietary history can often be helpful because this person is usually more objective than the patient. Specifically question patients regarding consumption of either clay or laundry starch. This history will not be provided spontaneously. These substances render iron less absorbable. Changes in body weight are important with regard to dietary intake and can suggest the presence of malabsorption or an underlying wasting disease of infectious, metabolic, or neoplastic origin.

Nutritional deficiencies may be associated with unusual symptoms that can be elicited by a history. • Patients with iron deficiencies frequently chew or suck ice (pagophagia). Occasionally, they complain of dysphasia, brittle fingernails, relative impotence, fatigue, and cramps in the calves on climbing stairs that are out of proportion to their anemia. In vitamin B-12 deficiency, early graying of the hair, a burning sensation of the tongue, and a loss of proprioception are common. Suspect a loss of proprioception if the patient stumbles in the dark or must look in order to put on pants in the morning. Paresthesia or unusual sensations frequently described as pain also occur in pernicious anemia. Patients with folate deficiencies may have a sore tongue, cheilosis, and symptoms associated with steatorrhea. Color, bulk, frequency, and odor of stools and whether the feces float or sink can be helpful in detecting malabsorption. More sensitive questions to detect steatorrhea include whether the toilet needs to be flushed more than once to rid it of stool and whether an oily substance is floating on the water surface after the first flush.

• • • • •

Obtain a history of fever or identify the presence of fever because infections, neoplasms, and collagen vascular disease can cause anemia. Similarly, the occurrence of purpura, ecchymoses, and petechiae suggest the occurrence of either thrombocytopenia or other bleeding disorders; this may be an indication either that more than one bone marrow lineage is involved or that coagulopathy is a cause of the anemia because of bleeding. Cold intolerance can be an important symptom of hypothyroidism or lupus

erythematosus, paroxysmal cold hemoglobinuria, and certain macroglobulinemias. • • The relation of dark urine to either physical activity or time of day can be important in march hemoglobinuria and paroxysmal nocturnal hemoglobinuria. Explore the presence or the absence of symptoms suggesting an underlying disease, such as cardiac, hepatic, and renal disease; chronic infection; endocrinopathy; or malignancy.

• Physical
• Too often, the physician rushes into the physical examination without looking at the patient for an unusual habitus or appearance of underdevelopment, malnutrition, or chronic illness. These findings can be important clues to the underlying etiology of disease and provide information related to the duration of illness. The skin and mucous membranes are often bypassed so that pallor, abnormal pigmentation, icterus, spider nevi, petechiae, purpura, angiomas, ulcerations, palmar erythema, coarseness of hair, puffiness of the face, thinning of the lateral aspects of the eyebrows, nail defects, and a usually prominent venous pattern on the abdominal wall are missed in the rush to examine the heart and the lungs. • Examine optic fundi carefully but not at the expense of the conjunctivae and the sclerae, which can show pallor, icterus, splinter hemorrhages, petechiae, comma signs in the conjunctival vessels, or telangiectasia that can be helpful in planning additional studies. Perform systematic examination for palpable enlargement of lymph nodes for evidence of infection or neoplasia. Bilateral edema is useful in disclosing underlying cardiac, renal, or hepatic disease, whereas unilateral edema may portend lymphatic obstruction due to a malignancy that cannot be observed or palpated. Carefully search for both hepatomegaly and splenomegaly. Their presence or absence is important, as are the size, the tenderness, the firmness, and the presence or the absence of nodules. In patients with chronic disorders, these organs are firm, nontender, and nonnodular. In patients with carcinoma, they may be hard and nodular. The patient with an acute infection usually has a palpably softer and more tender organ. A rectal and pelvic examination cannot be neglected because tumor or infection of these organs can be the cause of anemia. The neurologic examination should include tests of position sense and vibratory sense, examination of the cranial nerves, and testing for tendon reflexes. The heart should not be ignored because enlargement may provide evidence of the duration

• •

and the severity of the anemia, and murmurs may be the first evidence of a bacterial endocarditis that could explain the etiology of the anemia.

Causes
Causes of anemia are numerous and multifaceted. A family history may be useful in detecting hereditary etiology. Diet and exposure to drugs and chemicals can be useful. A geographic history and a thorough knowledge of the patient's health can be important in establishing an etiology. • Genetic • • • • • • • • • • Hemoglobinopathies Thalassemias Enzyme abnormalities of the glycolytic pathways Defects of the RBC cytoskeleton Congenital dyserythropoietic anemia Rh null disease Hereditary xerocytosis Abetalipoproteinemia Fanconi anemia

Nutritional • • • • Iron deficiency Vitamin B-12 deficiency Folate deficiency Starvation and generalized malnutrition

• • •

Hemorrhage Immunologic - Antibody-mediated abnormalities Physical effects • Trauma

• • • •

Burns Frostbite Prosthetic valves and surfaces

Drugs and chemicals • • Aplastic anemia Megaloblastic anemia

Chronic diseases and malignancies • • • • • Renal disease Hepatic disease Chronic infections Neoplasia Collagen vascular diseases

Infections • • • Viral - Hepatitis, infectious mononucleosis, cytomegalovirus Bacterial - Clostridia, gram-negative sepsis Protozoal - Malaria, leishmaniasis, toxoplasmosis

• • •

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

• DIFFERENTIALS
• Section 4 of 11 • • • Authors and Editors Ιντροδυχτιον Χλινιχαλ

• • • • • • • • •

∆ιφφερεντιαλσ Ωορκυπ Τρεατµεντ Μεδιχατιον Φολλοω−υπ Μισχελλανεουσ Μυλτιµεδια Ρεφερενχεσ

Aplastic Anemia Cooley Anemia Hemolytic Anemia Iron Deficiency Anemia Low LDL Cholesterol (Hypobetalipoproteinemia) Megaloblastic Anemia Myelophthisic Anemia Pernicious Anemia Sickle Cell Anemia Spur Cell Anemia Thalassemia, Alpha Thalassemia, Beta

• WORKUP
• Section 5 of 11 • • • • • • Authors and Editors Ιντροδυχτιον Χλινιχαλ ∆ιφφερεντιαλσ Ωορκυπ Τρεατµεντ

• • • • •

Μεδιχατιον Φολλοω−υπ Μισχελλανεουσ Μυλτιµεδια Ρεφερενχεσ

Lab Studies
• The first step in the diagnosis of anemia is detection with reliable accurate tests so that important clues to underlying disease are not overlooked and patients are not subjected to unnecessary tests for and treatment of nonexistent anemia. Detection of anemia involves the adoption of arbitrary criteria. • The World Health Organization's criterion for anemia in adults is Hb values less than 12.5 g/dL. Children aged 6 months to 6 years are considered anemic at Hb levels less than 11 g/dL, and children aged 6-14 years are considered anemic when Hb levels are less than 12 g/dL. The disadvantage of such arbitrary criteria is that a few healthy individuals fall below the reference range, and some people with an underlying disorder fall within the reference range for Hb concentration. Usually, US values are slightly higher. Anemia is suggested in males with Hb levels less than 13.5 g/dL and in females with Hb levels less than 12.5 g/dL. Higher values are anticipated in individuals living in altitudes significantly above sea level. Conditions with an increase in plasma volume, such as during the last trimester of pregnancy, are associated with lower values without an existent anemia because the red cell mass is normal.

Once the existence of anemia is established, investigate the pathogenesis. If an adequate history has been taken and a physical examination has been performed, the etiology may be obvious, and confirmatory studies and appropriate therapy can be undertaken with a minimum of investigation. If this is not the case, initiate a definite plan of investigation considering the cost to the patient along with a determination of the etiology of the abnormality. A rational approach is to begin by examining the peripheral smear and laboratory values obtained on the blood count. If the anemia is either microcytic (mean corpuscular volume [MCV], <84) or macrocytic (MCV, >96) or if certain abnormal RBCs or WBCs are observed in the blood smear, the investigative approach can be limited (see Table 1, Table 2, and Table 3).

Presently, RBC cellular indices are computer calculated and automatically placed on laboratory reports. The formulae for calculating these values follow (reference ranges are in parentheses). RBC is per million cells. • • • MCV = Hct X 10/RBC (84-96 fL) Mean corpuscular Hb (MCH) = Hb X 10/RBC (26-36 pg) Mean corpuscular Hb concentration (MCHC) = Hb X 10/Hct (32-36%)

A rapid method of determining whether cellular indices are normocytic and normochromic is to multiply the RBC and Hb by 3. The RBC multiplied by 3 should equal the Hb, and the Hb multiplied by 3 should equal the Hct. Deviation from the calculated values suggests microcytosis, macrocytosis, or hypochromia versus the presence of spherocytes (MCHC, >36). Table 1. Microcytic Hypochromic Anemia (MCV, <83; MCHC, <31)

• •

Conditi on

S eru m Iro n ⇓ ⇑

Total IronBinding Capacity (TIBC)

Bone Marr ow Iron

Comment

Iron deficien cy

0

Responsive to iron therapy

Chronic inflamm ⇓ ation Thalass emia major Thalass emia minor ⇑

++

Unresponsive to iron therapy

N

++++

Reticulocytosis and indirect bilirubinemia Elevation of A of fetal hemoglobin, target cells, and poikilocytosis Basophilic stippling of RBCs

N

N

++

Lead poisonin N g Siderobl ⇑ astic

N

++

N

++++

Ring sideroblasts in marrow

Hemogl obin •

N

N

++

Hemoglobin electrophoresis

⇑ = increased, ⇓ = decreased, N = normal, 0 = absent, +'s indicate amount of stainable iron in bone marrow specimens on a scale of 0-4. Table 2. Macrocytic Anemia (MCV, >95)

Megaloblastic bone marrow

Deficiency of vitamin B-12 Deficiency of folic acid Drugs affecting DNA synthesis Inherited disorders of DNA synthesis

Nonmegaloblastic bone marrow

Liver disease Hypothyroidism and hypopituitarism Accelerated erythropoiesis (reticulocytes) Hypoplastic and aplastic anemia Infiltrated bone marrow

Table 3. Various Forms of RBCs Macr ocyte Larger than normal (>8.5 µm diameter). See Table 2.

Micro Smaller than normal ( <7 µm diameter). See Table 1. cyte Hypo chro mic Spher ocyte Targe t cell Lepto cyte Ellipt Less hemoglobin in cell. Enlarged area of central pallor. See Table 1. Loss of central pallor, stains more densely, often microcytic. Hereditary spherocytosis and certain acquired hemolytic anemias. Hypochromic with central "target" of hemoglobin. Liver disease, thalassemia, hemoglobin D, postsplenectomy. Hypochromic cell with a normal diameter and decreased MCV. Thalassemia. Oval to cigar shaped. Hereditary elliptocytosis, certain anemias

ocyte

(particularly vitamin B-12 and folate deficiency).

Schist Fragmented helmet- or triangular-shaped RBCs. Microangiopathic ocyte anemia, artificial heart valves, uremia, malignant hypertension. Stom Slitlike area of central pallor in erythrocyte. Liver disease, acute atocyt alcoholism, malignancies, hereditary stomatocytosis, and artifact. e Tearshape Drop-shaped erythrocyte, often microcytic. Myelofibrosis and d infiltration of marrow with tumor. Thalassemia. RBCs Acant Five to 10 spicules of various lengths and at irregular interval on hocyt surface of RBCs. e Echin ocyte Sickl e cell • Evenly distributed spicules on surface of RBCs, usually 10-30. Uremia, peptic ulcer, gastric carcinoma, pyruvic kinase deficiency, preparative artifact. Elongated cell with pointed ends. Hemoglobin S and certain types of hemoglobin C and l. In microcytic hypochromic anemia, seek a source of bleeding. The appropriate laboratory tests are serum iron level and TIBC and either serum ferritin level or stain of bone marrow specimen for iron. If the serum iron level is decreased and TIBC is increased, a diagnosis of iron deficiency can be made, therapy can be initiated, and a search for the cause of the iron deficiency can be started. If this cannot be demonstrated, suspect each of the other causes of a microcytic anemia listed in Table 1, and the order of investigation can be influenced by findings in the history, physical examination, or peripheral smear. Similarly, a reasonable approach with macrocytic anemia is to determine if the bone marrow aspirate is megaloblastic. If so, attempt to incriminate either vitamin B-12 or folic acid deficiency with appropriate laboratory studies. Similar to the establishment of a diagnosis of iron deficiency anemia, a diagnosis of vitamin B12 or folic acid deficiency does not stop with an abnormal laboratory value for one of these vitamins. Prompt treatment can be instituted, but a continued search for an underlying cause of the vitamin deficiency is indicated (see Pernicious Anemia). When a normocytic normochromic anemia is encountered, classify the anemia into 3 possible etiologies (ie, blood loss, hemolysis, decreased production). In most anemias, one of these causes is the dominant factor. However, in certain anemias, more than a single cause may play an important role. For example, pernicious anemia is predominantly due to decreased production of erythrocytes,

but hemolysis adds significantly to the severity of anemia. • Blood loss • Obviously, significant hemorrhage produces anemia. Immediately after blood loss, the Hct cannot be used as a reliable method to determine the quantity of lost blood because the patient loses plasma as well as RBCs. After acute hemorrhage, the Hct falls for 24-48 hours until the plasma volume is replaced. At that time, anemia is normochromic and normocytic with normal cellular indices because the cells in the peripheral blood have been produced prior to bleeding (see Iron Deficiency Anemia). If the patient had adequate iron stores, accelerated production of RBCs occurs, so that 1 week after bleeding, a larger than normal number of young RBCs and reticulocytes are circulating in the peripheral blood. Because reticulocytes and young RBCs have a larger volume (MCV of approximately 120), macrocytes may be observed in the peripheral smear, and a slight increase in the MCV occurs. If hemorrhage was sufficient to deplete iron stores (1-2 L of blood, 5001000 mg of iron), newly formed erythrocytes are microcytic and hypochromic and gradually replace normal erythrocytes in the circulation that were produced prior to the induction of iron deficiency. Because RBCs normally survive for 120 days in circulation, maximal changes in the MCV and MCHC are not observed until that time. Iron deficiency and the depletion of iron stores can be detected several weeks after bleeding by measurements of the serum iron level and TIBC and/or special stains of bone marrow specimens showing an absence of storage iron. Diagnosis of iron deficiency anemia in an adult in the United States should be attributed to bleeding unless other causes can be proven. Aside from recent multiparity, other causes are relatively uncommon and include prolonged dietary idiosyncrasies (eg, clay eating, laundry starch consumption, protein deprivation for several years), urinary loss of iron due to intravascular hemolysis (eg, artificial aortic valves, paroxysmal nocturnal hemoglobinuria), gastrectomy, and other upper gastrointestinal surgery or disease. Diagnosis of iron deficiency anemia is made by demonstrating that the patient has low serum iron levels and elevated TIBC, absence of stainable iron in a bone marrow specimen, or both. A low serum ferritin level provides confirmation of the diagnosis. The presence of microcytosis and hypochromia is helpful but not diagnostic. Microcytic hypochromic anemia is observed with conditions other than iron deficiency anemia. Certain types of these disorders are ironoverloading states in which the administration of iron can be deleterious to

the patient (see Table 1). Similarly, low serum iron levels can be observed in chronic inflammatory states with normal body stores of iron. However, in the latter, the TIBC is usually decreased rather than increased, and stainable iron can be demonstrated in bone marrow aspirates. Whenever the diagnosis of iron deficiency anemia is in doubt, follow-up blood work after administration of iron to show correction of the anemia can be helpful in confirming the diagnosis. • The patient notices hemorrhage from most body organs. Epistaxis, hemoptysis, or hematuria of sufficient degree to cause anemia is usually reported to the physician long before iron deficiency ensues. However, bleeding from either the uterus or the gastrointestinal tract may be disregarded by the patient or be totally undetected until anemia becomes profound and symptomatic. Menstrual bleeding among healthy females varies monthly from 10-250 mL. Unless the patient observes a change in menses, she relates that menses are normal unless specific questions are asked. The presence of clots, abdominal cramps, excessive gushing of blood upon removal of tampons, the need for both tampons and pads, and the use of an unusual number of pads or tampons can be used to determine if menstrual bleeding may be sufficient to induce iron deficiency anemia. Gastrointestinal bleeding is the other occult cause of anemia due to blood loss. If hemorrhage is profuse, it is usually detected before evidence of iron deficiency anemia occurs because hematochezia or melena causes the patient to seek medical attention. However, if the bleeding occurs slowly, it is usually undetected until anemia ensues because stools appear normal. Every patient with iron deficiency anemia should have a stool examination for occult blood. A positive result necessitates a careful search of the gastrointestinal tract to identify the site of bleeding. Unfortunately, a negative result does not exclude gastrointestinal blood loss because bleeding can be intermittent and require several examinations for detection. Also, less than 20-30 mL of blood in the stool per day may go undetected due to the insensitivity of the test. The 2 methods used to detect small daily losses of blood from the gut are as follows: (1) placing the patient on a meat-free diet for several days and using more sensitive methods, such as a benzidine test, and (2) labeling the patient's RBCs with chromium 51 and collecting stool specimens for the detection of the radioisotope. Investigate gastrointestinal bleeding by endoscopy and radiographic studies (see Procedures).

• •

Hemolysis (increased RBC destruction)

A normal RBC survives in the circulation for 120 days. If the erythrocytic lifespan is shortened significantly ( <40 d), the patient has a hemolytic disorder that may be demonstrated by showing increased production of erythrocytes, increased destruction, or both. The former is revealed most readily by the presence of sustained reticulocytosis and the latter by the occurrence of indirect bilirubinemia (see Table 4, below). Other laboratory tests are available to detect hemolysis, but they are either more expensive or less reliable. Table 4. Classification of the Hemolytic Disorders

• • •

Hereditary Hereditary spherocytos is Hereditary elliptocytos is Hemoglobi nopathies Thalassemi Intraco as rpuscu Congenital lar dyserythrop defect oietic anemias Hereditary RBC enzymatic deficiencies Rarer hereditary abnormaliti es Extrac orpusc ular defect

Acquired

Vitamin B-12 and folic acid deficiency Paroxysmal nocturnal Hemoglobinuria Severe iron deficiency

Physical agents: Burns, cold exposure Traumatic: Prosthetic heart valves, march hemoglobinemia, DIC, graft rejection Chemicals: Drugs and venoms Infectious agents: Malaria, toxoplasmosis, mononucleosis, hepatitis, primary atypical pneumonia, clostridial infections, bartonellosis, leishmaniasis

Hepatic and renal disease Collagen vascular disease Malignancies: Particularly hematologic neoplasia Transfusion of incompatible blood Hemolytic disease of the newborn Cold hemagglutinin disease Autoimmune hemolytic anemia Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) • Anemia solely due to hemolysis does not occur until RBCs are being destroyed at 6-8 times the normal rate, reducing the mean RBC lifespan to less than 20 days because of the bone marrow's capacity to undergo 6-fold hypertrophy and hyperplasia. Thus, if the clinician relies on the presence of anemia to detect hemolytic states, the clinician misses most of them and, perhaps, an important clue to an underlying disorder. On the contrary, if reticulocytosis and indirect bilirubinemia are used to detect hemolytic states, they are usually found when the mean lifespan is less than 40-50 days. More sophisticated methods, such as measurements of RBC lifespan, are required to detect less severe shortening of erythrocyte lifespan (50100 d) and are only occasionally needed in clinical practice. All patients with both reticulocytosis and indirect bilirubinemia have a hemolytic disorder. All patients with sustained reticulocytosis have a hemolytic disorder. Unfortunately, the contrary is not the case, and significant hemolysis can occur without reticulocytosis if the bone marrow is unable to produce cells at an accelerated rate (eg, pernicious anemia, leukemia, aplasia). A single demonstration of an elevated reticulocyte count is insufficient to establish a diagnosis of hemolysis because transient reticulocytosis may occur without hemolysis (eg, in the treatment of iron deficiency anemia). Almost all patients with indirect bilirubinemia have a hemolytic disorder. In adults, the exception is patients with Gilbert disease. These patients can be distinguished from those with hemolytic disorders and those who have no other obvious stigmata of hemolysis (eg, anemia, reticulocytosis, Coombs test) by having the patient fast for 3 days. In Gilbert disease, indirect bilirubin doubles with starvation, whereas in hemolytic disorders, it does not. Once the presence of hemolysis has been established, the etiology of the increased rate of RBC destruction can be sought. All causes of hemolytic disorders are either hereditary or acquired. Similarly, they are due to either an intrinsic abnormality of the RBC (intracorpuscular defect) or external factors that shorten the erythrocyte lifespan (extracorpuscular). Using this nomenclature, only 4 groups of hemolytic disorders are possible—hereditary intracorpuscular, hereditary

extracorpuscular, acquired intracorpuscular, and acquired extracorpuscular. • All hereditary hemolytic disorders are due to intracorpuscular defects, and most acquired disorders are due to extracorpuscular abnormalities (see Table 4). Hereditary etiologies of hemolytic disease are suggested strongly in any patient with a family history of anemia, jaundice, cholelithiasis, or splenectomy. Whenever possible, family members, particularly parents, siblings, and children, should undergo a hematologic examination, including hemogram with reticulocyte count, indirect bilirubin determination, and careful examination of the peripheral smear. If a specific hereditary hemolytic disorder (eg, hereditary spherocytosis, hemoglobinopathy) is suggested in a patient, examine blood from family members for that entity by appropriate laboratory methods. Establishment of a hemolytic defect in other closely related family members permits a presumptive diagnosis of hereditary intracorpuscular hemolytic disorder in the patient. Showing a similar RBC abnormality (eg, spherocytes, abnormal Hb, G-6-PD deficiency) among family members establishes the basic etiology. Once the probability of a hereditary hemolytic disorder is established, a planned approach to determine the definitive abnormality is usually simple. A careful examination of the peripheral smear may reveal spherocytes in hereditary spherocytosis; ovalocytes in hereditary elliptocytosis; sickle cells in patients with major hemoglobinopathies associated with sickle Hb; target cells in patients with Hb C or E disease; and marked poikilocytosis with target cells, microcytes, and hypochromic RBCs in thalassemia. Even in certain rare disorders, abnormal erythrocyte morphology may provide an important clue. Examples are acanthocytosis in abetalipoproteinemia, stomatocytosis in the hereditary disorder of this name, and numerous target cells in lecithin cholesterol acyltransferase deficiency. Other laboratory studies of value in the hereditary hemolytic disorders include the following:4 • Hereditary spherocytosis - MCHC greater than 36%, incubated osmotic fragility studies autohemolysis in oxalate, and detection of the underlying molecular defect Hemoglobinopathies - Sickle cell preparation, Hb electrophoresis at one or more pH, heat denaturation test for unstable Hbs, oxygen disassociation for Hbs with abnormal oxygen affinity Thalassemia - A2 and fetal Hb, Hb electrophoresis, characterization of the molecular defect, quantification of alpha and beta chains

Congenital dyserythropoietic anemias - Demonstration of abnormalities of erythroid precursors in bone marrow aspirates, positive acid hemolysis (Ham) test with normal result of sucrose hemolysis test in one form of this disease (hereditary erythroblastic multinuclearity with a positive acidified serum test [HEMPAS]) Hereditary RBC enzymatic deficiencies - Specific RBC enzyme assay

• •

In clinical practice, approximately 90% of hereditary RBC enzymatic deficiencies with significant clinical manifestations are either G-6-PD deficiencies or abnormalities of pyruvic kinase. The age at which a hemolytic disorder is detected is not always helpful in determining whether the disorder is hereditary. Although the abnormality is inherited, congenital manifestations may be unusual. An infant with sickle cell anemia or beta thalassemia appears healthy at birth. Clinical manifestations usually do not occur in infants younger than 6 months because fetal Hb has not been replaced by adult Hb until that age. Most patients with G-6-PD deficiency have no manifestations of the erythrocyte enzymatic abnormality until they receive an oxidant drug. Usually, thalassemia minor is not detected until a routine hemogram is performed, and, then, it is often mistaken for iron deficiency anemia because of the microcytosis and hypochromia. Thus, the physician dealing with adult patients must be as aware of these disorders as the pediatrician. The most commonplace of the hereditary disorders is G-6-PD deficiency because it occurs in 10% of the African American population living in the United States. In this population, G-6-PD deficiency usually remains undetected until oxidant drugs are administered. Then, it produces a mildto-moderate hemolytic anemia that is transient in nature. In white populations of Mediterranean derivation, G-6-PD deficiency can produce a chronic hemolytic anemia without exposure to drugs. Exposure to oxidant drugs can produce lethal hemolysis. Acquired hemolytic disorders occur in a large number of disease states and can vary considerably in severity. In addition, hemolysis may be observed as a result of physical injury to the RBC or following exposure to drugs, chemicals, or venoms. In many patients, the etiology of the hemolytic disorder is apparent because of other manifestations of the disease (eg, infections, collagen vascular disease). A confirmed positive Coombs test result can be extremely helpful in this group of disorders. It provides assurance that the hemolytic disorder is an acquired extracorpuscular defect and limits it to the group of disorders associated with autoimmune hemolytic anemia. They include the following:

• • • •

Drug-dependent antibodies (eg, to penicillin, quinidine, alpha methyldopa) Coexistence of an underlying disease (eg, hematologic malignancies, lupus erythematosus, certain viral infections) Idiopathic groups in which an underlying disease cannot be demonstrated

Usually, the acquired hemolytic disorders with intracorpuscular defects are not difficult to diagnose. Vitamin B-12 and folic acid deficiencies are associated with macrocytic anemia, the presence of hypersegmented polymorphonuclear leukocytes in the peripheral smear, megaloblastic bone marrow, physical findings of the underlying cause of the deficiency state, and abnormal serum levels for the deficient vitamin. Iron deficiency in the United States is rarely of sufficient severity to cause significant hemolysis and is merely mentioned herein for the sake of completeness. Paroxysmal nocturnal hemoglobinuria is diagnosed only if the physician considers it in the differential diagnosis, and it may manifest by either a pancytopenia or a hemoglobinuria. However, a sugar-water test can help exclude this cause of hemolysis. The major diagnostic problem encountered with hemolytic disorders is when the known causes for hemolysis have been excluded by history, physical examination, and laboratory studies; the Coombs test result is negative; and not enough family members can be tested to differentiate between hereditary intracorpuscular hemolytic disorders and acquired extracorpuscular defects. A donor cell chromium survival study can be helpful in differentiating between a hereditary hemolytic disorder and an acquired hemolytic disorder. Labeled RBCs from a healthy blood donor of a compatible blood group allow for a normal survival rate in patients with hereditary hemolytic disease and a shortened lifespan in those with an acquired extracorpuscular defect.

Decreased RBC production • Diminished production of RBCs is suggested in all patients without evidence of either blood loss or hemolysis. Thus, a patient with anemia without evidence of bleeding or iron deficiency with normal indirect bilirubin and normal or decreased reticulocyte count probably has a defect in the production of erythrocytes. Many of these patients have pancytopenia or other abnormalities of the leukocytes or the platelets that can be detected with an examination of a peripheral smear. When this

group of disorders is suspected, the most important laboratory test is a bone marrow biopsy and aspiration (see Procedures). The bone marrow biopsy permits categorization of these disorders into 3 separate groups: (1) aplastic or hypoplastic, (2) hyperplastic, and (3) bone marrow replaced with nonhematopoietic elements (infiltration of bone marrow) (see Image 1). • Drugs or chemicals commonly cause the aplastic and hypoplastic group of disorders. Certain types of these causative agents are dose related and others are idiosyncratic. Any human exposed to a sufficient dose of inorganic arsenic, benzene, radiation, or the usual chemotherapeutic agents used for treatment of neoplastic diseases develops bone marrow depression with pancytopenia. Conversely, among the idiosyncratic agents, only an occasional human exposed to these drugs has an untoward reaction resulting in suppression of 1 or more of the formed elements of bone marrow (1:100 to 1:millions). With certain types of these drugs, pancytopenia is more common, whereas with others, suppression of one cell line is usually observed. Thus, chloramphenicol may produce pancytopenia, whereas a granulocytopenia is more frequently observed with toxicity to sulfonamides or antithyroid drugs. The idiosyncratic causes of bone marrow suppression include multiple drugs in each of the categories that can be prefixed with anti- (eg, antibiotics, antimicrobials, anticonvulsants, antihistamines). The other idiosyncratic causes of known etiology are viral hepatitis and paroxysmal nocturnal hemoglobinuria. In approximately one half of patients presenting with aplastic anemia, a definite etiology cannot be established, and the anemia must be regarded as idiopathic. Whenever possible, a cause for the aplastic anemia should be uncovered because cessation of exposure may lead to recovery. Identification of the offending agent is likewise important in determining the prognosis. Chances of survival are poorer for patients with idiosyncratic aplasia caused by chloramphenicol and viral hepatitis and better when paroxysmal nocturnal hemoglobinuria or anti-insecticides are the probable etiology. The prognosis for idiopathic aplasia lies between these 2 extremes, with an untreated mortality rate of approximately 60-70% within 2 years after diagnosis. Rare causes of anemia due to a hypoplastic bone marrow include familial disorders and the acquired pure red cell aplasias. The latter are characterized by a virtual absence of erythroid precursors in the bone marrow with normal numbers of granulocytic precursors and megakaryocytes. Among patients with a hyperplastic bone marrow and decreased production of RBCs, one group has an excellent prognosis, and the other is unresponsive, refractory to therapy, and has a relatively poor prognosis. The former includes patients with disorders of relative bone marrow failure due to nutritional deficiency in whom proper treatment with vitamin B-12, folic acid, or iron leads

to a correction of anemia once the appropriate etiology is established. Drugs acting as an antifolic antagonist or inhibitor of DNA synthesis can produce similar effects. The second group includes patients with an idiopathic hyperplasia that may respond partially to pyridoxine therapy in pharmacologic doses but, more frequently, does not. These patients have ringed sideroblasts in the bone marrow indicating an inappropriate use of iron in the mitochondria for heme synthesis. • • • Certain patients with marrow hyperplasia may have refractory anemia for years, but some of the group eventually develop acute myelogenous leukemia. Rare causes of diminished erythrocyte production with hyperplastic bone marrow include hereditary orotic aminoaciduria and erythremic myelosis. Infiltration of the bone marrow with fibrous tissue, neoplastic cells, or other cells that replace normal hematopoietic tissue can diminish the production of RBCs, granulocytes, and platelets. The diagnosis of myelofibrosis or neoplastic involvement of bone marrow is often suggested by evidence of myeloid metaplasia in the peripheral smear (ie, erythroid and granulocyte precursors). Replacement of bone marrow with nonhemopoietic cells leads to activation of fetal sites of blood production in organs, such as the liver and the spleen, with release of abnormally shaped erythrocytes and normoblasts, immature granulocytes and normoblasts, immature granulocytes, and large platelets into the peripheral blood. Myeloid metaplasia does not occur in aplastic disease. Thus, its presence in a patient who is anemic suggests bone marrow infiltration, even before the biopsy specimen is obtained.

• Imaging Studies
• Imaging studies are useful in the workup for anemia when a neoplastic etiology is suggested. They permit discovery of the neoplasm or centrally located adenopathy. Occasionally, they are useful in detecting or confirming the existence of splenomegaly.

• •

• Procedures
• Investigate gastrointestinal bleeding by endoscopy and radiographic studies to identify the bleeding site. However, even these methods may leave a source of gastrointestinal bleeding undetected because these procedures do not detect the bleeding site or the lesion if small. Examples of these causes include coagulation abnormalities induced by aspirin or platelet dysfunction, hookworm infestation, hemangiomas of the small bowel, lymphosarcoma and other tumors, adenomas of

the gallbladder, and self-administration of anticoagulants. • Bone marrow aspirates and biopsy findings are particularly useful in establishing the etiology of anemia in patients with decreased production of RBCs. They help differentiate aplasia; megaloblastic hyperplasia; and infiltration of marrow with neoplasia, myelodysplasia, and myelofibrosis. In addition, they lead to a definitive histologic diagnosis of leukemias, lymphomas, myelomas, and metastatic carcinomas. These procedures are less useful in detecting hemolytic anemia (except to detect lymphoma or leukemia), and they are less useful in diagnosing congenital dyserythropoietic anemia, in which they reveal the multinuclearity of erythroid precursors. Iron stains of the bone marrow aspirate can be used to document the existence of iron deficiency anemia or the sideroblastic anemias.

IRON DEFICIENCY ANAEMIA
LABORATORY FINDINGS Peripheral Blood • Normal or decreased reticulocytes reflect impaired marrow response to anaemia in absence of iron.

Sequential Stages in the Development of Iron Deficiency • • • Normal indices, no anaemia, and depleted iron stores, indicated by decreased serum ferritin and marrow haemosiderin - early iron deficiency Normocytic, normochromic anaemia follows complete depletion of iron stores; variable anisocytosis and poikilocytosis Microcytic, hypochromic anaemia indicates late iron deficiency.

Bone Marrow • • • Decreased or absent stainable iron (haemosiderin) is the earliest indicator of iron depletion; it precedes anaemia. Stainable marrow iron indicates storage iron. Variable cellularity - there is a poor correlation between the severity of anaemia and the degree of erythroid hyperplasia. Decreased sideroblasts, which are iron-containing normoblasts

Other Laboratory Findings* • Decreased serum ferritin - this is the earliest indicator of iron depletion, usually corresponding to marrow iron stores. This might be normal in the presence of accompanying chronic disease, liver disease, or malignant neoplasm.11

• • •

Increased iron binding capacity - this occurs only after storage iron is completely depleted. The iron binding capacity is a measure of serum transferrin. Decreased serum iron and transferrin saturation (<16% early, <10% late) Increased free erythrocyte protoporphyrin - this provides the same information as transferrin saturation but is a slower and more stable indicator of iron storage.

Laboratory Findings of Underlying Disease • • See diseases and conditions discussed above.

Megaloblastic Anaemia - Peripheral Blood

FOLIC ACID DEFICIENCY
top LABORATORY FINDINGS Peripheral Blood • Findings identical to those in vitamin B12 deficiency

Bone Marrow • Findings identical to those in vitamin B12 deficiency

Other Laboratory Findings • Decreased serum folate - this is the most sensitive indicator of folate deficiency, falling within a month of deficient intake (Fig. 8-1). This falls many weeks before megaloblastic anaemia appears. Serum folate levels may change abruptly with changes in diet.

Decreased RBC folate - this appears after 3 months - 4 months of folate deficiency (Fig. 8-1). RBC folate is an index of tissue folate stores. When folate stores are depleted, megaloblastic anaemia occurs. Findings of ineffective erythropoiesis - increased serum iron, unconjugated bilirubin, and LDH1 Normal gastric acid; normal Schilling test; normal serum vitamin B12

• • •

Laboratory Findings of Impaired Intestinal Absorption or Its Causes • • • • • Gluten enteropathy Lymphoma Amyloidosis Scleroderma Whipple's disease

ANAEMIA OF CHRONIC DISEASE
top LABORATORY FINDINGS Peripheral Blood • Normochromic, normocytic anaemia (8 g/dl - 12 g/dl; occasionally <7 g/dl); many patients have microcytosis (MCV < 80um3) and hypochromia (mean corpuscular haemoglobin concentration (MCHC) <31 g/dl) Usually normal reticulocyte count; may occasionally be reduced or slightly increased

Bone Marrow • • Normal cellularity and maturation Increased bone marrow RE iron - reflects impaired

marrow utilisation of stored iron. The increase in storage iron in the presence of decreased serum iron and marrow sideroblasts is characteristic of this disorder. • Decreased sideroblasts

Other Laboratory Findings • • Decreased serum iron - characteristic finding; precedes anaemia Decreased transferrin, which is usually measured as total iron binding capacity - occurs after the decrease in serum iron. This contrasts with increased total iron binding capacity in iron deficiency. Decreased transferrin saturation (mean 15% range 10% - 25%); not as low as in iron deficiency Normal or increased serum ferritin - because ferritin increases in inflammatory disorders, the level is disproportionately elevated for the amount of marrow iron.11 This contracts with decreased ferritin in iron deficiency.

• •

Laboratory Findings of Underlying Disease • See diseases discussed above.

ANAEMIA OF CHRONIC RENAL INSUFFICIENCY
top LABORATORY FINDINGS Peripheral Blood • • Normochromic, normocytic anaemia (haemoglobin 5 g/dl - 10 g/dl) - characteristic finding Microcytic anaemia occurs when there is iron deficiency due to bleeding seconary to various platelet dysfunctions. It may also be due to iron loss in haemodialysis fluid.

• • • •

Macrocytic anaemia - due to loss of folate in haemodialysis fluid Occasional burr or helmet cells Acanthocytes and schistocytes, especially in haemolytic-uremic syndrome Usually normal reticulocyte count; might be slightly decreaed; a moderate increase in reticulocytes may occur with higher blood urea nitrogen (BUN) levels.

Bone Marrow • Normal bone marrow appearance; might appear somewhat hypoplastic

Other Laboratory Findings • Usually normal serum iron, total iron binding capacity, transferring saturation; these may all be decreased if iron deficiency occurs. Laboratory findings of chronic renal insufficiency

ANAEMIA OF HYPOMETABOLISM
top LABORATORY FINDINGS • • • Normocytic, normochromic anaemia (>10 g/dl) characteristic of hypothyroidism Microcytic, hypochromic anaemia is a consequence of uterine bleeding in hypothyroidism Laboratory findings of anterior pituitary insufficiency, hypothyroidism, Addison's disease, or seconary testicular failure

HEREDITARY SPHEROCYTOSIS
top LABORATORY FINDINGS

Peripheral Blood • • Increased spherocytes with decreased cell diameter (microspherocytes) Normocytic, or slightly microcytic, hyperchromic (MCHC 36 g/dl - 40 g/dl) anaemia (haemoglobin {Hb} 9 g/dl - 12 g/dl) - the increased MCHC reflects cell membrane loss Increased reticulocytes (5% - 20%) - reflects marrow response to RBC destruction Macrocytes and polychromatophilia reflect reticulocytosis. Increased RBC distribution width and anisocytosis reflect two RBC populations.

• • •

Bone Marrow • • • Normoblastic hyperplasia Hypoplasia may occur in the presence of an aplastic crisis. Megaloblasts may occur with complicating folate deficiency, which may supervene in any severe chronic haemolytic anaemia. This is the result of accelerated folic acid utilisation and DNA synthesis in response to normoblastic hyperplasia. Moderate haemosiderin deposits

Other Laboratory Findings • Indicators of extravascular haemolysis - increased LDH (especially LDH1 and LDH2)1 unconjugated (indirect) bilirubin, urine haemosiderin; decreased or absent serum haptoglobin. Negative Coomb s' test

Increased Osmotic Fragility Test

Splenomegaly in Hereditary Spherocytosis

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY
top LABORATORY FINDINGS Diagnostic Laboatory Tests No Haematologic Findings in the Absence of haemolysis Haematologic Findings in the Prescence of Haemolysis Phase 1 • • Acute haemolysis (1 day - 3 days after oxidative drug exposure) Normocytic, normochromic anaemia - rapid occurrence, severe indicators of haemolysis - increased LDH, unconjugated bilirubin, reticulocytes; decreased haptoglobin Increased Heinz bodies (characteristic feature), basophillic stippling, polychromatophilia Fragmented RBC and spherocytes, if haemolysis is severe Marrow shows normoblastic hyperplasia.

• • •

Phase 2 • Recovery (5 days - 15 days after oxidative drug

exposure) • • • • Reticulocytosis (8% - 12%) Macrocytes reflect reticulocytosis. Increase in Hb and haematocrit over earlier values Absent haptoglobin reflects chronic haemolysis.

Phase 3 • • • Resistance (more than 7 days - 10 days after oxidative drug exposure) Haemolysis stops and anaemia disappears. Young cells produced in response to haemolysis have nearly normal levels of enzyme and are relatively resistance to haemolysis. This phase continues as long as the same dose of the drug is administered.

• Πψρυϖατε κινασε δεφιχιενχψ αν αυτοσοµαλ ρεχεσσιϖε δισορδερ χαυσινγ πολψχηροµασια, ανισοχψτοσισ, ποικιλοχψτοσισ ωιτη βυρρ χελλσ ανδ αχαντηοχψτεσ, ανδ ΝΡΒΧσ. Ρεδυχεδ ΑΤΠ φορµατιον χαυσεσ ΡΒΧ µεµβρανε ριγιδιτψ, ρεσυλτινγ ιν ηεµολψσισ. Σψµπτοµσ αρε υσυαλλψ µιλδ ασ ινχρεασεδ 2,3−∆ΠΓ χαυσεσ α ριγητ σηιφτ οφ τηε 02−δισσοχιατιον χυρϖε. Περσονσ ηοµοζψγοτε φορ ΠΚ δεφιχιενχψ σηοω σεϖερε ανεµια ανδ αρε υσυαλλψ δισχοϖερεδ ιν χηιλδηοοδ. Σπλενοµεγαλψ, χηολελιτηιασισ ανδ ϕαυνδιχε αρε φρεθυεντ.ΠΡΙςΑΤΕ ∀ΤΨΠΕ=ΠΙΧΤ;ΑΛΤ=∀0100090000034χ00000003001χ000 00000000400000003010600050000000χ025α1δδφ1707000 000φχ020000000000000000040000002δ01000008000000φ α0200000000000000000000040000002δ0101001χ000000φ β020χ00090000000000900100000000000202024δ53205361 6ε73205365726966000α0027008α0100000000φφφφφφφφ78 δ31300040000002δ010200030000000000 ΤΗΕ ΤΗΑΛΑΣΣΕΜΙΑΣ

ΗΨΠΕΡΛΙΝΚ ∴λ ∀τοπ∀0100090000034χ00000003001χ00000000000400000 003010600050000000χ029502110207000000φχ0200000000 00000000040000002δ01000008000000φα020000000000000 0000000040000002δ0101001χ000000φβ020χ000900000000 00900100000000000202024δ532053616ε732053657269660 00α0027008α0100000000φφφφφφφφ78δ31300040000002δ0 10200030000000000ΗΨΠΕΡΛΙΝΚ ∴λ ∀τοπ∀ΗΨΠΕΡΛΙΝΚ ∴λ ∀τοπ∀τοπ ∆εφινιτιον Ηερεδιταρψ δισορδερσ χηαραχτεριζεδ βψ δεφεχτιϖε προδυχτιον οφ ηεµογλοβιν, ωηιχη λεαδσ το ανεµια. Χαυσεσ ανδ ρισκσ Αν ιµβαλανχε ιν τηε αλπηα ανδ βετα προτειν γλοβιν χηαινσ νεχεσσαρψ φορ τηε προδυχτιον οφ ηεµογλοβιν ισ χαυσεδ βψ τηε ινηεριτανχε οφ α δεφεχτιϖε γενε. Τηερε αρε τωο τψπεσ, αλπηα τηαλασσεµια ανδ βετα τηαλασσεµια. Γενεσ µυστ βε ινηεριτεδ φροµ βοτη παρεντσ το αχθυιρε τηε δισεασε. Ιφ ονε γενε ισ ινηεριτεδ, τηε περσον ωιλλ βε α χαρριερ οφ τηε δισεασε βυτ ωιλλ νοτ ηαϖε σψµπτοµσ. Αλπηα τηαλασσεµιασ οχχυρσ ιν πεοπλε φροµ σουτηεαστ Ασια ανδ Χηινα, ανδ αρε χαυσεδ βψ δελετιον οφ α γενε ορ γενεσ φροµ τηε γλοβιν χηαιν. Τηε µοστ σεϖερε φορµ οφ αλπηα τηαλασσεµια χαυσεσ α στιλλβορν φετυσ ασ α ρεσυλτ οφ ηψδροπσ φεταλισ. Βετα τηαλασσεµια οχχυρσ ιν πεοπλε οφ Μεδιτερρανεαν οριγιν, ανδ το α λεσσερ εξτεντ, Χηινεσε, οτηερ Ασιανσ, ανδ βλαχκσ. Ιτ ισ χαυσεδ βψ α µυτατιον ιν τηε γλοβιν χηαιν. Αφφεχτεδ χηιλδρεν αρε νορµαλ ατ βιρτη βυτ δεϖελοπ ανεµια δυρινγ τηε φιρστ ψεαρ οφ λιφε. Γροωτη φαιλυρε, βονε δεφορµιτιεσ, ανδ ενλαργεδ λιϖερ ανδ σπλεεν αρε σοµε οφ τηε προβλεµσ τηατ χαν οχχυρ. Βλοοδ τρανσφυσιονσ µαψ µοδιφψ σοµε οφ τηε δισεασε µανιφεστατιον, βυτ ιρον οϖερλοαδ φροµ τηε τρανσφυσιονσ χαν χαυσε δαµαγε το τηε ηεαρτ, λιϖερ, ανδ ενδοχρινε σψστεµσ. Α µιλδερ φορµ οφ τηε δισεασε, τηαλασσεµια µινορ, προδυχεσ ιρον−δεφιχιεντ αππεαρινγ βλοοδ χελλσ, ωιτη νο

σψµπτοµσ. Ρισκ φαχτορσ ινχλυδε α φαµιλψ ηιστορψ οφ τηαλασσεµια ανδ αν ετηνιχ βαχκγρουνδ συσχεπτιβλε το τηε δισεασε. Τηε ινχιδενχε ϖαριεσ ωιδελψ τηρουγηουτ τηε ωορλδ. ΛΑΒΟΡΑΤΟΡΨ ΦΙΝ∆ΙΝΓΣ Βετα−τηαλασσεµια Μινορ Περιπηεραλ Βλοοδ • Ταργετ χελλσ, πολψχηροµατοπηιλια, βασοπηιλιχ στιππλινγ, οχχασιοναλ νυχλεατεδ ΡΒΧ, ανισοχψτοσισ, ποικιλοχψτοσισ • Σλιγητ ηψποχηροµιχ (ΜΧΗ 20 πγ−22πγ), µιχροχψτιχ (ΜΧς 50 υµ3 − 70 υµ3) αναεµια (ηαεµογλοβιν 9 γ/δλ − 11 γ/δλ), ωιτη νορµαλ το ινχρεασεδ ΡΒΧ (>5.7 µιλλιον/υλ) • Ινχρεασεδ ρετιχυλοχψτεσ (2% − 10%) Βονε Μαρροω • Σλιγητ νορµοβλαστιχ ηψπερπλασια; αβυνδαντ ιρον δεποσιτσ Οτηερ Λαβορατορψ Φινδινγσ • Ελεχτροπηορεσισ σηοωσ ινχρεασεδ ΗβΑ2 (3.5% − 8%); ινχρεασεδ ΗβΦ (1% − 5%) ιν 50% οφ πατιεντσ; ινχρεασεδ ΗβΑ2 ισ διαγνοστιχ • ∆εχρεασεδ οσµοτιχ φραγιλιτψ; τηισ ηασ βεεν υσεδ ασ α ραπιδ σχρεενινγ τεστ • Νορµαλ το ινχρεασεδ σερυµ ιρον; νορµαλ σερυµ φερριτιν

Image 1b Βετα−τηαλασσεµια Μαϕορ

Περιπηεραλ Βλοοδ • Μαρκεδ ανισοχψτοσισ, ποικιλοχψτοσισ, ταργετ χελλσ (10% − 35%), σπηεροχψτεσ, φραγµεντεδ ΡΒΧ; οχχασιοναλ νυχλεατεδ ΡΒΧ, βασοπηιλιχ στιππλινγ, σιδεροχψτεσ; ινχλυσιον βοδιεσ ρεπρεσεντινγ αγγρεγατεδ αλπηα χηαινσ • Μαρκεδ ηψποχηροµιχ, µιχροχψτιχ αναεµια (Ηβ 2.5 γ/δλ − 6.5 γ/δλ) • Ινχρεασεδ ρετιχυλοχψτεσ (4% − 10%) − τηισ ινχρεασε ισ λοωερ τηαν τηατ ωηιχη νορµαλλψ οχχυρσ ωιτη σεϖερε αναεµια ανδ ινδιχατεσ ιναδεθυατε µαρροω ρεσπονσε • Ινχρεασεδ ωηιτε βλοοδ χελλ (ΩΒΧ) χουντ (10,000/υλ − 25,000/υλ) ωιτη οχχασιοναλ ιµµατυρε γρανυλοχψτεσ • Οχχασιοναλ τηροµβοχψτοπενια − ρεφλεχτσ εφφεχτ οφ σεχονδαρψ ηψπερσπλενισµ Βονε Μαρροω • Μαρκεδ νορµοβλαστιχ ηψπερπλασια ωιτη ποορ ηαεµογλοβινισατιον; βασοπηιλιχ στιππλινγ; αβυνδαντ ιρον δεποσιτσ; ΡΒΧ χψτοπλασµιχ ινχλυσιονσ, ωηιχη αρε φρεε αλπηα χηαινσ; χλινιχαλ σεϖεριτψ χορρελατεσ ωιτη αµουντ οφ αλπηα−χηαιν πρεχιπιτατιον Οτηερ Λαβορατορψ Φινδινγσ • Ελεχτροπηορεσισ σηοωσ ΗβΦ 10% − 100% δεχρεασεδ ορ αβσεντ ΗβΑ; ΗβΑ2 1% − 8% • ∆εχρεασεδ οσµοτιχ φραγιλιτψ • Φινδινγσ οφ ηαεµολψσισ − ινχρεασεδ υνχονϕυγατεδ βιλιρυβιν, ινχρεασεδ Λ∆Η, δεχρεασεδ ηαπτογλοβιν • Ινχρεασεδ σερυµ ιρον ανδ τρανσφερριν σατυρατιον • ∆εχρεασεδ σερυµ φολατε − ρεφλεχτσ ινχρεασεδ µαρροω υτιλισατιον οφ φολατε ΗΨΠΕΡΛΙΝΚ ∀ηττπ://ωωω.βλοοδλινε.νετ/στοριεσ/στορψΡεαδερ∃2344 ∀Τηαλασσεµια Ιµαγε Σεριεσ(Λινκ το Ιµαγε σουρχε)ΒΛΟΟ∆ΛΙΝΕ

Haemoglobin H (Link to image source)The blood film shows hypchromia, microcytosis, and target cells. HbH disease is due to deletion of three out of four alpha globin genes, resulting in an anaemia which varies from mild to severe.

SICKLE-CELL DISEASE
top

Sickle cell disease is an inherited blood
disorder in which there is a substitutive defect in the formation of hemoglobin in the red blood cells, producing a distinctive disease process. This disease was first scientifically recorded in 1910 by Dr. James Herrick. While examining the blood of a young West Indian student, he observed that many of the red blood cells were elongated with a curved shape instead of the normal round configuration. It was after similar repeated observations by other investigators that the descriptive term "sickle cell anemia" was used to describe this disease. In sickle cell anemia, there is an alteration in the arrangement of the hemoglobin molecular structure. At the sixth position in each beta chain where the amino acid, glutamate should normally be incorporated, it is replaced by

another amino acid, valine. This small change in the molecule results in great changes in its physical and chemical characteristics, so that in certain stressful conditions when the body is deprived of oxygen, the red cells then assume a crescent, banana, or sickle shape. This particular shape of the red cells makes its travel through the smaller blood vessels extremely difficult, producings an obstruction by creating a "logjam", which may result in tissue and ultimately organ damage. Because of the abnormal hemoglobin and the shape of the red cells, they are quickly destroyed. This, combined with an inability of the body to produce sufficient numbers of new cells, produces a state of anemia. The term sickle cell disease refers to all the clinically significant sickling disorders, since the degree of anemia may be variable and many potentially dangerous episodes can occur without an increase in the severity of the anemia. ΠΡΙςΑΤΕ ∀ΤΨΠΕ=ΠΙΧΤ;ΑΛΤ=∀0100090000034χ00000003001χ000 00000000400000003010600050000000χ0254104117070000 00φχ020000000000000000040000002δ01000008000000φα0 200000000000000000000040000002δ0101001χ000000φβ02 0χ00090000000000900100000000000202024δ532053616ε7 3205365726966000α0027008α0100000000φφφφφφφφ78δ31 300040000002δ010200030000000000 Ωελχοµε το τηε ΗΨΠΕΡΛΙΝΚ ∀ηττπ://ωωω.δεπτ.µεδ.υµν.εδυ/µεδιχινε/Χλινιχαλ_σερϖι χεσ/Σιχκλε_Χελλ_∆ισεασε_Προγραµ/βοδψ_σιχκλε_χελ λ_δισεασε_προγραµ.ητµλ∀Σιχκλε Χελλ ∆ισεασε Προγραµ οφ τηε Υνιϖερσιτψ οφ Μιννεσοτα Ηεαλτη Σψστεµ (ΥΜΗΣ). ΛΑΒΟΡΑΤΟΡΨ ΦΙΝ∆ΙΝΓΣ Σιχκλε Χελλ Τραιτ (ΗβΑΣ ∆ισεασε) • Νορµαλ περιπηεραλ σµεαρ ανδ βονε µαρροω • Νο αναεµια • Ποσιτιϖε σιχκλε χελλ τεστ − ωηεν µορε τηαν 25% ΗβΣ ισ πρεσεντ, σιχκλινγ οφ ΡΒΧ µαψ βε

δεµονστρατεδ ιν α βλοοδ συσπενσιον βψ δεοξψγενατιον οφ τηε βλοοδ • Ποσιτιϖε σολυβιλιτψ τεστ φορ ΗβΣ − σιχκλε τεστ Ηβ ισ ινσολυβλε ιν α πηοσπηατε βυφφερ σολυτιον • Ηβ ελεχτροπηορεσισ − ΗβΑ 70% − 80%; ΗβΣ 30% − 40%; ΗβΦ <2%. Πρεπονδερανχε οφ ΗβΑ οϖερ ΗβΣ ισ α πρερεθυισιτε φορ τηισ διαγνοσισ. (Τηε ρεϖερσε οχχυρσ ιν σιχκλε χελλ βετα−τηαλασσεµια) • Λοω φιξεδ υρινε σπεχιφιχ γραϖιτψ ανδ ηαεµατυρια οχχυρ ασ α ρεσυλτ οφ ρεναλ µεδυλλαρψ µιχροινφαρχτσ. Σιχκλε Χελλ Αναεµια (ΗβΣΣ ∆ισεασε) Περιπηεραλ Βλοοδ • Σιχκλε χελλσ, οϖαλοχψτεσ, µαρκεδ ποικιλοχψτοσισ, ανισοχψτοσισ, νυχλεατεδ ΡΒΧ, Ηοωελλ−ϑολλψ βοδιεσ, ταργετ χελλσ, σπηεροχψτεσ, πολψχηροµατοπηιλια, στιππλεδ ΡΒΧ, σιδεροχψτεσ. Τηεσε αβνορµαλ χελλσ αππεαρ ιν τηε χιρχυλατιον βεχαυσε τηε ινφαρχτεδ σπλεεν ισ νο λονγερ αβλε το ρεµοϖε τηεµ φροµ τηε χιρχυλατιον. • Νορµοχψτιχ, νορµοχηροµιχ αναεµια (Ηβ 5 γ/δλ − 11 γ/δλ) • Ινχρεασεδ ρετιχυλοχψτεσ (5% − 30%) − δεχρεασεδ δυρινγ απλαστιχ χρισισ • Ινχρεασεδ ΩΒΧ ωιτη λεφτ σηιφτ (10,000/υλ − 30,000/υλ) − δοεσ νοτ νεχεσσαριλψ σιγνιφψ αν ινφεχτιον • Ινχρεασεδ πλατελετσ (300,000/υλ − 500,000/υλ− µαψ φαλλ δυρινγ αν ινφαρχτιϖε χρισισ Βονε Μαρροω • Ηψπερπλασια οφ αλλ ελεµεντσ βυτ εσπεχιαλλψ οφ ΡΒΧ πρεχυρσορσ • Ινχρεασεδ ιρον δεποσιτσ Οτηερ Λαβορατορψ Φινδινγσ • Ποσιτιϖε σιχκλε χελλ τεστ − ΡΒΧ τρανσφορµ το σιχκλεδ φορµ ιν αν οξψγεν−ποορ ενϖιρονµεντ • Ποσιτιϖε σολυβιλιτψ τεστ φορ ΗβΣ − σιχκλε χελλ Ηβ ισ ινσολυβλε ιν α πηοσπηατε βυφφερ σολυτιον • Ηβ ελεχτροπηορεσισ − ΗβΣ 80% − 100% − 100%, ΗβΦ 0% − 20%; βεχαυσε τηερε ισ νο νορµαλ βετα

πολψπεπτιδε χηαιν, τηερε ισ νο ΗβΑ. • Φινδινγσ οφ ηαεµολψσισ − ινχρεασεδ υνχονϕυγατεδ (ινδιρεχτ) βιλιρυβιν, Λ∆Η (εσπεχιαλλψ Λ∆Η1 ανδ Λ∆Η2), υρινε ηαεµοσιδεριν; δεχρεασεδ σερυµ ηαπτογλοβιν • ∆εχρεασεδ σεδιµεντατιον ρατε −ρεφλεχτσ φαιλυρε οφ σιχκλε χελλσ το υνδεργο ρουλεαυξ φορµατιον • ∆εχρεασεδ οσµοτιχ φραγιλιτψ− τηε σιχκλε ΡΒΧ ρεσιστ ηαεµολψσισ βψ ηψποτονιχ σαλτ σολυτιονσ • Ινχρεασεδ σερυµ αλκαλινε πηοσπηατασε− ρεσυλτ οφ βονε ανδ λιϖερ ινφαρχτσ • Ηαεµατυρια ανδ φιξεδ υρινε σπεχιφιχ γραϖιτψ (1.010−1.020)− δυε το ρεπεατεδ µιχροινφαρχτσ ιν τηε ρεναλ µεδυλλα • Λαβορατορψ φινδινγσ οφ χοµπλιχατιονσ: ινφαρχτιον οφ λυνγσ, σπλεεν, κιδνεψσ; οστεοµψελιτισ, υσυαλλψ δυε το σαλµονελλα; ιρον δεφιχιενχψ αναεµια (δεχρεασεδ φερριτιν ανδ ΜΧς) ΗβΣΧ ∆ισεασε • Περιπηεραλ βλοοδ−σιχκλε χελλσ, µαψ ταργετ χελλσ (20%−85%); ΗβΧ χρψσταλσ ιν 1%−2% οφ ΡΒΧ, εσπεχιαλλψ φολλοωινγ σπλενεχτοµψ • Μιλδ ανεµια • Σλιγητ ρετιχυλοχψτισισ (αβουτ 3%) • Ηαεµογλοβιν ελεχτροπηορεσισ− ΗβΣ 40%−50%, ΗβΧ 40% − 50%, ΗβΦ 2%−15%, • ΗβΑ αβσεντ Σιχκλε Χελλ Β−Τηαλασσεµια ∆ισεασε • Μανψ ταργετ χελλσ (20%−40%) • Ηψποχηροµιχ, µιχροχψτιχ αναεµια • Ηβ ελεχτροπηορεσισ−χοµπλετε βετα−χηαιν συππρεσσιον: ΗβΣ50%−80%, ΗβΦ 2%−30%,ΗβΑ2 >3.6%; ινχοµπλετε Βετα−χηαιν συππρεσσιον:ΗβΣ 50%−80%, ΗβΦ 2%−20%, ΗβΑ 15%−35%, ΗβΑ2 >3.6% • Οτηερ λαβορατορψ φινδινγσ αρε τηοσε οφ ΗβΣΣ δισεασε. ΗΑΕΜΟΓΛΟΒΙΝ Χ ∆ΙΣΕΑΣΕ

Haemoglobin C disease (link to image source)
Glutamine in the 6th position of the beta globin chain is replaced by lysine. In the homozygous state (HbC disease), mild anaemia and splenomegaly is present. The condition is found in Africa and the Middle East.

top LABORATORY FINDINGS HbAC Trait • • Peripheral blood- moderately increased number of target cells (5%-30%) Hb electrophoresis- HbA 55%-70%, HbC 30%-45%, HbA2 slightly increased

HbCC Disease Peripheral Blood • Many target cells (about 90%), variable microspherocytes,polychcromatophilia, a few RBC contain tetragonal HbC crystals. The cryatals increase up to 10% following splenectomy and after incubation in 3% NaCl. Mild normocytic anemia (Hb 8 g/dl-12 g/dl)

Bone Marrow • Normoblastic hyperplasia

Other Laboratory Findings • Haemoglobin electrophoresis - HbC 95% - 100%, HbF 0% - 5%, HbA absent

• •

Findings of slight haemolysis - increased reticulocytes (2% - 10%), LDH, unconjugated bilirubin Osmotic fragility test shows two cell populations; target cells have decreased fragility and microspherocytes have increased fragility.

HbSC Disease • See Sickle Cell Disease.

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