ANEMIA

is a deficiency of red blood cells (RBCs) and/or hemoglobin. This results in a reduced ability of blood to transfer oxygen to the tissues, causing tissue hypoxia. three main classes of anemia: i. excessive blood loss (acutely such as a hemorrhage or chronically through low-volume loss) ii. excessive blood cell destruction (hemolysis) iii. deficient red blood cell production (ineffective hematopoiesis) according to red cell indices (MCV), anemia is divided into: i. hypochromic microcytic with a low MCV. ii. normochromic normocytic with a normal MCV. iii. Macrocytic with a high MCV CLINICAL FEATURES Symptoms: fatigue headache faintness breathlessness palpitation (due to cardiac output) angina intermittent claudication general malaise Signs: pallor tachycardia systolic flow murmur cardiac failure rarely papilloedema and retinal hemorrhages after an acute bleeding (can be accompanied by blindness!) <specific signs> koilonychias (spoon-shaped nails; in iron deficiency anemia) cheilosis (syn: Angular cheilitis, perlche, or angular stomatitis) is an inflammatory lesion at the labial commissure, or corner of the mouth, and often occurs bilaterally.seen in B12 and iron-deficiency anemia. jaundice (in hemolytic anemia) bone deformities (in thalassemia major) leg ulcers (occur in assoc with sickle cell disease).

Iron deficiency anemia

dev when there is inadequate iron for Hb synthesis. a normal level of Hb is maintained for as long as possible after the iron stores are depleted; latent iron deficiency is said to be present during this period. Causes: blood loss (from uterus or GIT hookworm infestation) demands such as growth and pregnancy absorption poor intake Clinical features: brittle nails koilonychia atrophy of the papillae of the tongue angular stomatitis (cheilosis) brittle hair a syndrome of dysphagia and glossitis (Plummer-Vinson or Paterson-Brown-Kelly syndrome) Symptoms pallor fatigue weakness In severe cases, dyspnea can occur Unusual obsessive food cravings, known as pica, may develop. Hair loss and lightheadedness can also be associated with iron deficiency anemia. Other symptoms Constipation Tinnitus Palpitations Seeing Bright Colors Fainting, Feeling faint Depression Weakness Breathlessness Twitching Nerves, Tingling, Numbness Burning sensations Sleep apnea (rare)

Investigations: 1. blood count and film microcytic RBC (MCV < 80fL) and hypochromic ( MCV < 27 pg) poikilocytosis (diff shape) and anisocytosis (diff size) 2. serum iron and iron-binding capacity serum iron total iron-binding capacity (TIBC) transferrin saturation (serum iron / TIBC) falls below 19%. 3. serum ferritin low level of serum ferritin in acute-phase rxtn. Normal value: 30-300g/L (11.6-144 nmol/L) in males and 15-200g/L (5.8-96 nmol/L) in females. BUT, its levels in the presence of inflammatory or malignant diseases. 4. serum soluble transferrin receptors no. of transferring receptors 5. bone marrow erythroid hyperplasia with ragged normoblast. Treatment: ferrous sulphate, 200mg, 3x daily, orally - a total of 180mg ferrous iron - is best absorbed when the pt is fasting - if S/E, take drug with food! ferrous gluconate, 300mg, 2x daily, orally - is give if pt S/E such as nausea, diarrhea or constipation. commonest causes of failure of response to oral iron: - lack of compliance - continuing hemorrhages - incorrect Dx eg Thalassemia trait UUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUU If the cause is dietary iron deficiency, iron supplements, usually with iron (II) sulfate, ferrous gluconate, or iron amino acid chelate NaFeEDTA, will usually correct the anemia. Recent research suggests the replacement dose of iron, at least in the elderly with iron deficiency, may be as little as 15 mg per day of elemental iron. There can be a great difference between iron intake and iron absorption, also known as bioavailability. Scientific studies indicate iron absorption problems when iron is taken in conjunction with milk, tea, coffee and other substances. There are already a number of proven solutions for this problem, including:

Fortification with ascorbic acid, which increases bioavailability in both presence and absence of inhibiting substances, but which is subject to deterioration from moisture or heat. Ascorbic acid fortification is usually limited to sealed dried foods, but individuals can easily take ascorbic acid with basic iron supplement for the same benefits. Microencapsulation with lecithin, which binds and protects the iron particles from the action of inhibiting substances. The primary benefit over ascorbic acid is durability and shelf life, particularly for products like milk which undergo heat treatment. Using an iron amino acid chelate, such as NaFeEDTA, which similarly binds and protects the iron particles. A study performed by the Hematology Unit of the University of Chile indicates that chelated iron (ferrous bis-glycine chelate) can work with ascorbic acid to achieve even higher absorption levels. Separating intake of iron and inhibiting substances by a couple of hours. Using goats milk instead of cows milk.

Iron bioavailability comparisons require stringent controls, because the largest factor affecting bioavailability is the subject's existing iron levels. Informal studies on bioavailability usually do not take this factor into account, so exaggerated claims from health supplement companies based on this sort of evidence should be ignored. Scientific studies are still in progress to determine which approaches yield the best results and the lowest costs. If anemia does not respond to oral treatments, it may be necessary to administer iron parenterally (e.g., as iron dextran) using a drip or haemodialysis. Parenteral iron involves risks of fever, chills, backache, myalgia, dizziness, syncope, rash, anaphylactic shock and secondary iron overload. Epinephrine is used to counter anaphylactic shock, and Chelation therapy is used to manage secondary iron overload. A follow up blood test is essential to demonstrate whether the treatment has been effective.

Pernicious anemia
Pernicious anemia refers to a state of anemia due to vitamin B12 deficiency. Pernicious anemia is a chronic illness caused by impaired absorption of vitamin B-12 because of a lack of intrinsic factor (IF) in gastric secretions. Pernicious anemia occurs as a relatively common adult form of anemia that is associated with gastric atrophy and a loss of IF production and as a rare congenital autosomal recessive form in which IF production is lacking without gastric atrophy. Pathophysiology: Classic pernicious anemia is caused by the failure of gastric parietal cells to produce sufficient IF to permit the absorption of adequate quantities of dietary vitamin B-12. Other disorders that interfere with the absorption and metabolism of vitamin B-12 can produce cobalamin (Cbl) deficiency, with the development of a macrocytic anemia and neurological complications. Cbl is an organometallic substance containing a corrin ring, a centrally located cobalt atom, and various axial ligands (see Image 1). The basic structure known as vitamin B-12 is solely synthesized by microorganisms, but most animals are capable of converting vitamin B-12 into the 2 coenzyme forms, adenosylcobalamin and methylcobalamin. The former is required for conversion of L-methylmalonic acid to succinyl coenzyme A (CoA), and the latter acts as a methyltransferase for conversion of homocysteine to methionine. When either Cbl or folate is deficient, thymidine synthase function is impaired. This leads to megaloblastic changes in all rapidly dividing cells because DNA synthesis is diminished. In erythroid precursors, macrocytosis and ineffective erythropoiesis occur. Dietary Cbl is acquired mostly from meat and milk and is absorbed in a series of steps, which require proteolytic release from foodstuffs and binding to a gastric protein secreted by parietal cells that is known as IF. Subsequently, recognition of the IF-Cbl complex by specialized ileal receptors must occur for transport into the portal circulation to be bound by transcobalamin II (TC II), which serves as the plasma transporter. The Cbl-TC II complex binds to cell surfaces and is endocytosed. The transcobalamin (TC) is degraded within a lysozyme, and the Cbl is released into the cytoplasm. An enzyme-mediated reduction of the cobalt occurs with either cytoplasmic methylation to form methylcobalamin or mitochondrial adenosylation to form adenosylcobalamin. Defects of these steps produce manifestations of Cbl dysfunction. Most defects become

manifest in infancy and early childhood and result in impaired development, mental retardation, and a macrocytic anemia. Certain defects cause methylmalonic aciduria and homocystinuria (see Image 2). Pernicious anemia probably is an autoimmune disorder with a genetic predisposition. Pernicious anemia is more common than is expected in families of patients with pernicious anemia, and the disease is associated with human leucocyte antigen (HLA) types A2, A3, and B7 and type A blood group. Antiparietal cell antibodies occur in 90% of patients with pernicious anemia but in only 5% of healthy adults. Similarly, binding and blocking antibodies to IF are found in most patients with pernicious anemia. A greater association than anticipated exists between pernicious anemia and other autoimmune diseases, which include thyroid disorders, type I diabetes mellitus, ulcerative colitis, Addison disease, infertility, and acquired agammaglobulinemia. An association between pernicious anemia and Helicobacter pylori infections has been postulated but not clearly proven. Cbl deficiency may result from dietary insufficiency of vitamin B-12; disorders of the stomach, small bowel, and pancreas; certain infections; and abnormalities of transport, metabolism, and utilization (see Summary of causes of Cbl deficiency). Deficiency may be observed in strict vegetarians. Breastfed infants of vegetarian mothers also are affected. Severely affected infants of vegetarian mothers who do not have overt Cbl deficiency have been reported. Meat and milk are the main source of dietary Cbl. Because body stores of Cbl usually exceed 1000 mcg and the daily requirement is about 1 mcg, strict adherence to a vegetarian diet for more than 5 years usually is required to produce findings of Cbl deficiency. Classic pernicious anemia produces Cbl deficiency due to failure of the stomach to secrete IF (see Image 3). In adults, pernicious anemia is associated with severe gastric atrophy and achlorhydria, which are irreversible. Coexistent iron deficiency is common because achlorhydria prevents solubilization of dietary ferric iron from foodstuffs. Autoimmune phenomena and thyroid disease frequently are observed. Patients with pernicious anemia have a 2- to 3-fold increased incidence of gastric carcinoma. Causes of Cbl deficiency:

Inadequate dietary intake (ie, vegetarian diet) Atrophy or loss of gastric mucosa (eg, pernicious anemia, gastrectomy, ingestion of caustic material, hypochlorhydria, histamine 2 [H2] blockers) Functionally abnormal IF Inadequate proteolysis of dietary Cbl Insufficient pancreatic protease (eg, chronic pancreatitis, Zollinger-Ellison syndrome) Bacterial overgrowth in intestine (eg, blind loop, diverticula)

Disorders of ileal mucosa (eg, resection, ileitis, sprue, lymphoma, amyloidosis, absent IF-Cbl receptor, Imerslnd-Grasbeck syndrome, Zollinger-Ellison syndrome, TCII deficiency, use of certain drugs) Disorders of plasma transport of cobalamin (eg, TCII deficiency, R binder deficiency) Dysfunctional uptake and use of cobalamin by cells (eg, defects in cellular deoxyadenosylcobalamin [AdoCbl] and methylcobalamin [MeCbl] synthesis)

SIGNS AND SYMPTOMS:

General findings: Weight loss of 10-15 pounds occurs in about 50% of patients and probably is due to anorexia, which is observed in most patients. Low-grade fever occurs in one third of newly diagnosed patients and promptly disappears with treatment. Anemia: The anemia often is well tolerated in pernicious anemia, and many patients are ambulatory with hematocrit levels in the mid teens. However, the cardiac output is usually increased with hematocrits less than 20%, and the heart rate accelerates. Congestive heart failure and coronary insufficiency can occur, most particularly in patients with preexisting heart disease. Gastrointestinal findings: Approximately 50% of patients have a smooth tongue with loss of papillae. This is usually most marked along the edges of the tongue. The tongue may be painful and beefy red. Occasionally, red patches are observed on the edges of the dorsum of the tongue. Patients may report burning or soreness, most particularly on the anterior one third of the tongue. These symptoms may be associated with changes in taste and loss of appetite.
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Patients may report either constipation or having several semisolid bowel movements daily. This has been attributed to megaloblastic changes of the cells of the intestinal mucosa. Nonspecific gastrointestinal symptoms are not unusual and include anorexia, nausea, vomiting, heartburn, pyrosis, flatulence, and a sense of fullness. Rarely, patients present with severe abdominal pain associated with abdominal rigidity; this has been attributed to spinal cord pathology.

Nervous system: Neurological symptoms can be elicited in most patients with pernicious anemia, and the most common symptoms are paresthesias, weakness, clumsiness, and an unsteady gait. The 2 latter symptoms become worse in a dark room because they reflect the loss of proprioception in a patient who is unable to rely upon vision for compensation. These neurological symptoms are due to myelin degeneration and loss of nerve fibers in the dorsal and lateral columns of the spinal cord and cerebral cortex.

Neurological symptoms and findings may be present in the absence of anemia; this is more common in patients taking folic acid or on a highfolate diet. Patients who are older may present with symptoms suggesting senile dementia or Alzheimer disease; memory loss, irritability, and personality changes are commonplace. Megaloblastic madness is less common and can be manifested by delusions, hallucinations, outbursts, and paranoid schizophrenic ideation. Identifying the cause is important because significant reversal of these symptoms and findings can occur with vitamin B-12 administration.

Genitourinary system: Urinary retention and impaired micturition may occur because of spinal cord damage. This can predispose patients to urinary tract infections.

Physical: The finding of severe anemia in an adult patient whose constitutional symptoms are relatively mild and in whom weight loss is not a major symptom should arouse suspicion of pernicious anemia.

Typically, patients with pernicious anemia are described as having a stereotypic appearance.
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Patients have a lemon-yellow waxy pallor with premature whitening of the hair. They appear flabby, with a bulky frame that is generally incongruent with the severe anemia and weakness. While this characterization is useful in patients of northern European descent, it is less helpful among patients of other ethnic groups who develop Cbl deficiency.

Low-grade fever and mild icterus are commonplace but are usually mild and easily missed. A beefy, red, smooth tongue may be observed. In patients with dark complexions, blotchy skin pigmentation may be observed. Tachycardia often is present and may be accompanied by flow murmurs. Abnormal mentation and deterioration of vision and hearing may be observed. With severe anemia, dyspnea, tachypnea, and evidence of congestive heart failure may be present.

Retinal hemorrhages and exudates may accompany severe anemia. The liver may be enlarged in association with congestive heart failure. A splenic tip is palpable in about 20% of patients. A careful neurological assessment is important. In all megaloblastic disorders, hematological and epithelial manifestations occur, but only Cbl deficiency causes neurological deficits. Neurological findings may occur in the absence of anemia and epithelial manifestations of pernicious anemia, making it more difficult to identify the etiology. If left untreated, they can become irreversible.
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Central nervous system: Suspect pernicious anemia in all patients with recent loss of mental capacities. Somnolence, dementia, psychotic depression, and frank psychosis may be observed, which can be reversed or improved by treatment with Cbl. Perversion of taste and smell and visual disturbances, which can progress to optic atrophy, can likewise result from central nervous system Cbl deficiency. Combined system disease: A history of either paresthesias in the fingers and toes or difficulty with gait and balance should prompt a careful neurological examination. Loss of position sense in the second toe and loss of vibratory sense for a 256-Hz but not a 128-Hz tuning fork are the earliest signs of posterolateral column disease. If untreated, this can progress to spastic ataxia from demyelinization of the dorsal and lateral columns of the spinal cord.

Causes: An increased incidence of pernicious anemia in families suggests a hereditary component to the disease. Patients with pernicious anemia have an increased incidence of autoimmune disorders and thyroid disease, suggesting that an immunological component to the disease exists. Children who develop Cbl deficiency usually have a hereditary disorder, and the etiology of their Cbl deficiency is different from the etiology observed in classic pernicious anemia.

Congenital pernicious anemia is a hereditary disorder in which an absence of IF occurs without gastric atrophy. Other gastric disorders that cause Cbl deficiency are gastrectomy, gastric stapling, and bypass procedures for obesity and extensive infiltrative disease of the gastric mucosa. Usually, these disorders are associated with a decreased ability to mobilize Cbl from food rather than a malabsorption of Cbl. Thus, a patient with these disorders may exhibit a normal finding on Schilling test (stage I). Pancreatic insufficiency can produce Cbl deficiency. Nonspecific R binders chelate Cbl in the stomach, making it unavailable for binding to IF. Pancreatic proteases degrade the R binders and release the Cbl so that it can bind IF. The Cbl-IF complex is formed so that it can bind ileal receptors that enable uptake by

absorptive cells. Thus, patients with chronic pancreatitis may have impaired absorption of Cbl.

Cbl deficiency is reported in the Zollinger-Ellison syndrome. The mechanism is believed to be due to the acidic pH of the distal small intestine such that the CblIF complex cannot effectively bind the ileal receptors. Disorders of the ileum cause Cbl deficiency due to loss of the ileal receptors for the Cbl-IF complex. Thus, surgical loss of the ileum or diseases such as tropical sprue, regional enteritis, ulcerative colitis, and ileal lymphoma interfere with Cbl absorption. Genetic defects of the ileal receptors for IF (ie, Imerslnd-Grasbeck syndrome) and hereditary transcobalamin I (TC I) deficiency produce Cbl deficiency from birth and are usually discovered early in life. Many drugs impair Cbl uptake in the ileum but rarely are a cause of symptomatic vitamin B-12 deficiency because they are not taken long enough to deplete body stores of Cbl (eg, nitrous oxide, cholestyramine, para-aminosalicylic acid, neomycin, metformin, phenformin, colchicine). The clinical manifestations of inherited defects of Cbl transport and metabolism are usually observed in infancy and childhood. Thus, they are discussed only briefly in this article. Three hereditary disorders affect absorption and transport of Cbl, and another 7 alter cellular use and coenzyme production (see Image 2).
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The 3 disorders of absorption and transport are TC II deficiency and deficiencies of either IF or IF receptors. These defects produce developmental delay and a megaloblastic anemia, which can be alleviated with pharmacological doses of Cbl. Serum Cbl values are decreased in the IF abnormalities but may be within the reference range in TC II deficiency. The abnormalities of cellular use can be detected by the presence or absence of methylmalonic aciduria and homocystinuria. The presence of only methylmalonic aciduria indicates a block in conversion of methylmalonic CoA to succinyl CoA and results in either a genetic deficit in the methylmalonyl CoA mutase that catalyzes the reaction or a defect in synthesis of its CoA Cbl (Cbl A and Cbl B). The presence of only homocystinuria results either from poor binding of Cbl to methionine synthase (Cbl E) or from producing methylcobalamin from Cbl and S adenosylmethionine (Cbl G). This results in a reduction in

methionine synthesis, with pronounced homocystinemia and homocystinuria.

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Methylmalonic aciduria and homocystinuria occur when the metabolic defect impairs reduction of Cbl III to Cbl II (Cbl C, Cbl D, Cbl F). This reaction is essential for formation of both methylmalonic acid and homocystinuria. Early detection of these rare disorders is important because most patients respond favorably to large doses of Cbl. However, some of these disorders are less responsive than others, and delayed diagnosis and treatment are less efficacious.

Abnormalities in the intestinal lumen may produce Cbl deficiency. Individuals with blind intestinal loops, stricture, and large diverticula may develop bacterial overgrowth, which sequesters dietary Cbl for their metabolic needs. Tapeworm infestation with Diphyllobothrium latum occurs from eating poorly cooked lake fish that are infected and causes Cbl deficiency because the parasites have a high requirement for Cbl.

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Symptoms
Symptoms of pernicious anemia are variable from case to case, but often include: shortness of breath fatigue loss of appetite diarrhea tingling and numbness of hands and/or feet sore mouth bleeding gums. Those individuals who experience fatigue often also undergo problems with loss of concentration and extreme irritability.

FOLIC ACID-DEFICIENCY ANEMIA

Folate-deficiency anemia is a decrease in red blood cells (anemia) caused by folate deficiency. Definition Folic acid deficiency, an abnormally low level of one of the B vitamins, results in anemia characterized by red blood cells that are large in size but few in number. Description Folic acid is necessary for growth and cellular repair, since it is a critical component of DNA and RNA as well as essential for the formation and maturation of red blood cells. Folic acid deficiency is one of the most common of all vitamin deficiencies. Although it occurs in both males and females, folic acid deficiency anemia most often affects women over age 30. It becomes increasingly common as age impedes the body's ability to absorb folic acid, a water-soluble vitamin that is manufactured by intestinal bacteria and stored for a short time in the liver. Folic acid deficiency has also been implicated as a cause of neural tube defects in the developing fetus. Recent research has shown that adequate amounts of folic acid can prevent up to one-half of these birth defects, if women start taking folic acid supplements shortly before conception. Research from China in 2004 showed that women who were low in B vitamins and folate before conception, though not technically anemic, still had increased risk of lower birth weight babies and adverse pregnancy outcome. A healthy adult needs at least 400 mcg of folic acid every day. Requirements at least double during pregnancy, and increase by 50% when a woman is breastfeeding. The average American diet, high in fats, sugar, and white flour, provides about 200 mcg of folic acid, approximately the amount needed to maintain tissue stores of the substance for six to nine months before a deficiency develops. Most of the folic acid in foods (with the exception of the folic acid added to enriched flour and breakfast cereals) occurs as folate. Folate is only about pne-half as available for the body to use as is the folic acid in pills and supplements. Folate also is easily destroyed by sunlight, overcooking, or the storing of foods at room temperature for an extended period of time. Good dietary sources of folate include:

leafy green vegetables liver

mushrooms oatmeal peanut butter red beans soy wheat germ

Causes, incidence, and risk factors Folate, also called folic acid, is necessary for red blood cell formation and growth. can get folate by eating from green leafy vegetables and liver. Some medications, such as phenytoin (Dilantin), interfere with the absorption of this vitamin. Because folate is not stored in the body in large amounts, a continual dietary supply of this vitamin is needed. In folate-deficiency anemia, the red cells are abnormally large and are called megalocytes, or megaloblasts in the bone marrow. Subsequently, this anemia may be referred to as megaloblastic anemia Causes of this anemia are poor dietary intake of folic acid, malabsorption diseases such as celiac disease (sprue), and certain medications. A relative deficiency due to increased need for folic acid may occur in the third trimester of pregnancy. Risk factors include: poor diet (seen frequently in the poor, the elderly, and in people who do not eat fresh fruits or vegetables) eating overcooked food alcoholism (which interferes with the absorption of folate) history of malabsorption diseases pregnancy birth control pills, anticonvulsant therapy, sulfa antibiotics, and certain other medications smoking stress illness

U The disease occurs in about 4 out of 100,000 people. Symptoms

Tiredness Headache Pallor

Fatigue anorexia nervosa paranoia rapid heart beat sore, inflamed tongue weakness weight loss

Signs and tests

Low red blood cell folate level. A complete blood count (CBC) shows anemia and large red blood cells. A bone marrow examination is rarely necessary, but shows megaloblasts.

Treatment Folic acid supplements are usually prescribed, and self-care includes avoiding:

alcohol non-herbal tea, antacids, and phosphates (contained in beer, ice cream, and soft drinks), which restrict iron absorption tobacco

A person with folic acid deficiency anemia should rest as often as necessary until restored energy levels make it possible to resume regular activities. A doctor should be seen if fever, chills, muscle aches, or new symptoms develop during treatment, or if symptoms do not improve after two weeks of treatment. Alternative treatment Alternative therapies for folic acid deficiency anemia may include reflexology concentrated on areas that influence the liver and spleen. Increasing consumption of foods high in folate is helpful. Eating a mixture of yogurt (8 oz) and turmeric (1 tsp) also may help resolve symptoms. A physician should be contacted if the tongue becomes slick or smooth or the patient:

bruises or tires easily feels ill for more than five days feels weak or out of breath looks pale or jaundiced