Articles

Anemia

Introduction

Anemia has been defined as a reduction in red cell mass. It is often described as a decrease in the number of red blood cells (RBC) per mm3, or as a decrease in the hemoglobin concentration in blood to a level below the normal physiologic requirement that is necessary for adequate tissue oxygenation. (1) Anemia represents a problem with RBC production, an accelerated loss of RBC mass, or a symptom of some other pathological condition such as infection, chronic renal disease, or malignancy. It can be associated with nutritional deficiencies, acute and chronic diseases, and may be drug induced.

If the anemia is due to decreased red cell production, it may be the result of disturbances in stem-cell proliferation or differentiation. Anemias due to increased red cell destruction may be secondary to hemolysis, while increased red cell loss may be caused by acute or chronic bleeding. (2)

Anemias can be classified on the basis of morphology of the RBC, etiology, or pathophysiology. Morphology classifies anemias based upon physical appearance of the red blood cell’s size (microcytic, normocytic, or macrocytic) and hemoglobin content (hypochromic, normochromic, hyperchromic). Macrocytic anemias include the megaloblastic anemias caused by vitamin B12 deficiency and folic acid deficiency. Iron deficiency anemia is considered a hypochromic, microcytic anemia, as are genetic anomalies such as sickle cell anemia and thalassemia. Normocytic anemias include those caused by recent blood loss, hemolysis, bone marrow failure, anemias of chronic disease, renal failure, endocrine disorders, and myeloplastic anemias.

Classification by etiology uses three fundamental mechanisms as its basis:

    Deficiency - Iron, Vitamin B12, Folic Acid, or Pyridoxine. Central mechanism - caused by bone marrow impairment (anemia of chronic disease, anemia of the elderly, malignant bone marrow disorders) and Peripheral mechanisms - bleeding, hemolysis. Pathophysiology - trauma, disease, hereditary disorder, malignancy, nutrient deficiency, etc.

In adults, RBCs are formed in the marrow of the vertebrae, ribs, sternum, clavicle, pelvic (iliac) crest, and the proximal epiphyses of the long bones. In children, most bone marrow space is hemopoietically active to meet increased RBC requirements. (3) Production of RBCs is initiated by the hormone erythropoietin (EPO), 90 percent of which is produced in the kidneys in response to a decrease in tissue oxygen concentration. When EPO is released into the plasma, the following events occur: stem cells are stimulated to differentiate into proerythroblasts; the rate of mitosis is increased; the release of reticulocytes from marrow is increased; and hemoglobin formation is induced.

When hemoglobin synthesis is accelerated, the critical hemoglobin concentration necessary for maturity is reached more rapidly. A feedback mechanism stops further RBC nucleic acid synthesis such that the last mitotic division is skipped, causing an earlier release of reticulocytes. Early appearance of reticulocytes, in larger quantities in the peripheral circulation, is another indication that RBC production is being stimulated. (4)

Iron deficiency anemia, anemia of chronic disease, and anemias associated with acute bleeding account for roughly 75 percent of all anemias. (5) Iron deficiency anemia occurs in approximately 25 percent of patients with anemia. Common causes include inadequate dietary intake, inadequate absorption from the GI tract (as in certain malabsorption syndromes, unrelenting diarrhea, or the presence of certain food or drugs), increased iron demands (as in pregnancy, adolescence, infancy, old age, or during exercise), blood loss, and certain diseases. Dietary deficiencies most frequently result from decreased consumption of animal protein and ascorbic acid, (6) as a consequence of chronic alcoholism, food faddism, prolonged illness with anorexia, or poor nutrition.

The average adult body contains about 4 grams of iron, approximately two-thirds of which exists in the form of hemoglobin. Another 13 percent exists as myoglobin, while the same percentage exists as a combination of ferritin and hemosiderin. Because inorganic iron is quite toxic, the body has an intricate system for iron absorption, transport, storage, assimilation, and elimination. (7)

Megaloblastic anemias are the results of interference in the folic acid- and vitamin B12 -interdependent nucleic acid synthesis in the immature erythrocyte. The result is a slowing of DNA and RNA synthesis, with one or more of the mitotic divisions being skipped and resulting in an abnormally large cell.

Vitamin B12 deficiency anemia or pernicious anemia is most frequently found as an adult onset anemia most often caused by either an inadequate intake of vitamin B12, decreased absorption, or inadequate utilization. There is a sharp increase in the incidence with increasing age, suggesting that it is a consequence of gastric epithelial aging. Inadequate dietary consumption is very rare in the United States, as the typical western diet contains close to 20mcg of Vitamin B12. It is a water-soluble vitamin found primarily in meats and dairy products that is an essential component in the synthesis of DNA. It is also important in metabolic reactions involving folic acid, and is essential in maintaining the integrity of the neurologic system. Body stores of vitamin B12 range from 2-5mg.

Decreased absorption occurs in people with a deficiency of intrinsic factor and can be diagnosed by using the Schilling test. If there is a decrease in production of intrinsic factor, the patient has acquired pernicious anemia, while true dysfunction of intrinsic factor causes congenital pernicious anemia. Other factors that affect the absorption of Vitamin B12 are conditions such as regional enteritis, Crohn’s disease, and intestinal resections. In these conditions, there is injury or removal of ileal receptor sites where vitamin B12 and intrinsic factor are absorbed. Patients may also have an overgrowth of bacteria in the bowel that utilize vitamin B12. Blind-loop syndrome, fish-tapeworm infestations, and tropical sprue may all contribute to Vitamin B12 deficiency.

Other patients may have adequate vitamin B12 levels and still have a deficiency if they lack transcobalamin II. In portal blood, vitamin B12 is bound to this transport protein for delivery to utilization and storage sites. Consequently, the patient has a normal B12 level but clinical evidence of frank B12 deficiency.

Folic acid deficiency anemia is another of the megaloblastic anemias, causing the development of large functionally immature erythrocytes. Folic acid is a heat-labile vitamin necessary for the production of nucleic acids, proteins, amino acids, purines, and thymine, and hence DNA and RNA. (8) Humans are unable to synthesize total daily folate requirements and must rely upon dietary sources. These sources include fresh vegetables and fruits, yeast, mushrooms, and animal organs such as the liver and kidney.

The minimum daily requirement of folic acid is 50-100mcg, though the body demands are high due to RBC synthesis and turnover. The normal body can store 10-20mg of folate, so cessation of intake of dietary folate would deplete body stores in a few months. Major causes of folic acid deficiency include inadequate intake, underutilization, hyperutilization, and decreased absorption. It is seen frequently in patients with poor eating habits such as the elderly, food faddists, and alcoholics. It is also seen in the poverty stricken, as well as patients with chronic disease or demented states.

Decreased absorption of folic acid occurs in patients with malabsorption syndromes or after administration of certain drugs. Celiac disease is a common cause of malabsorption of folate, but other conditions such as Crohn’s disease and extensive small bowel resection can also reduce absorption. (9) Alcohol interferes with folic acid absorption, utilization at the cellular level, decreases folic acid stores in the liver, and as mentioned before, alcoholism often results in a diet deficient in folic acid.

Pregnancy and growth spurts seen in infancy and adolescence are states in which the rate of cellular division is increased. Hyperutilization of folic acid may be seen during these times and may only be of significance if dietary intake is borderline, resulting in inadequate replacement of folate stores. Certain malignancies, chronic inflammatory disorders such as Crohn’s disease, rheumatoid arthritis, or psoriasis are examples of disease states that also involve an enhanced rate of cell division and may cause hyper-utilization of folic acid.

Several drugs are known to cause a folic acid deficiency megaloblastic anemia either by interfering with folate absorption, or inhibiting the enzyme necessary for conversion to its active form.

Anemia of chronic disease is a hypoproliferative anemia that has traditionally been associated with infectious, inflammatory, or neoplastic diseases lasting more than one or two months. (10) , (11) It is thought that various cytokines released during these illnesses inhibit the production or action of erythropoietin or inhibit RBC production. (12) Pathologically, the life span of the RBC is shortened and the bone marrow’s capacity to respond to EPO is inadequate to maintain normal hemoglobin concentrations.

There are several mechanisms involved in the anemia of chronic renal failure. Decreased EPO production by the kidneys is the primary mechanism of severe anemia associated with end stage renal disease. (13) The uremic environment created by chronic renal failure has a tendency to decrease the life span of RBCs. This creates a demand for increased production, which cannot be met due to the decreased level of serum erythropoietin. Many CRF patients also become iron deficient due to losses from hemodialysis.

Anemia is one of the most common clinical problems seen in the elderly. There is a progressive decrease in bone marrow reserve with age and a decrease in hormonal response to hematologic stress. (14) One major factor that is often overlooked that may contribute to the presence of anemia in the older population is nutritional status. While rarely encountered in affluent elderly communities, in lower socioeconomic circumstances where other dietary deficiencies are found, anemia is a much more frequent occurrence. The principle reason for inadequate nutrition status in the elderly is poor dentition.

Hemolytic anemia results from decreased survival time of RBCs secondary to destruction in the spleen or circulation processes. The life span of the typical RBC has been determined to be approximately 120 days; therefore, destruction of the RBC prior to that time indicates a probable alteration in one of three areas. These areas have been defined as changes in membrane integrity, hemoglobin solubility or stability, and cell metabolism. These changes can occur as a result of extrinsic or intrinsic defects. Intrinsic defects are often genetically determined, and include such disorders as sickle cell anemia, thalassemia, and certain enzyme deficiencies. Extrinsic defects are often acquired and include autoimmune hemolytic anemia and anemia caused by exposure to oxidants.

Laboratory findings show hemolytic anemia to be a normocytic, normochromic anemia. Peripheral smear may reveal sickle cells, target cells, spherocytes, elliptocytes, and fragmented RBCs.

Statistic

Centers for Disease Control- MMWR- Recommendations to Prevent and Control Iron Deficiency in the United States April 03, 1998 / 47(RR-3);1-36

    Iron deficiency is the most common known form of nutritional deficiency. Its prevalence is highest among young children and women of childbearing age (particularly pregnant women). About 15 to 20 milligrams of iron is lost every menstrual period. Women with heavy menses and women who wear intrauterine devices (IUDs) may lose twice that much.

Centers for Disease Control, 2000.

    Iron deficiency, the most common nutritional deficiency worldwide, has negative effects on work capacity and on motor and mental development in infants, children, and adolescents, and maternal iron deficiency anemia might cause low birthweight and preterm delivery. Although iron deficiency is more common in developing countries, a significant prevalence was observed in the United States during the early 1990s among certain populations, such as toddlers and females of childbearing age.

Signs and Symptoms

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Anemia can develop from several different causes. Most anemias are asymptomatic or have vague, general signs and symptoms. The symptoms have an insidious onset, which often makes early diagnosis difficult. Iron deficiency anemia is one type of anemia whose symptoms appear when the hemoglobin falls below 8 or 9 Gm/100ml. Several common symptoms include koilonychias, glossitis, angular stomatitis and pica.

Vitamin B12 anemia may present with gastric mucosal atrophy and neuropsychiatric abnormalities as a result of a combined degeneration of the spinal cord and brain. The most frequent neurologic symptoms are paresthesias and ataxia. Other common symptoms include glossitis, diminished vibratory sensation in the lower extremities, muscle weakness, dysphagia, anorexia, irritability, dementia and psychosis.

A folic acid deficiency presents with symptoms similar to vitamin B12 deficiency with the exception of the neurologic symptoms.

Iron deficiency anemia

  • May be asymptomatic or have vague, general signs and symptoms associated with most anemias
  • Symptoms appear with hemoglobin below 8 or 9 Gm/100ml
  • Koilonychia (spooning of the nails)
  • Glossitis
  • Angular stomatitis
  • Pica (a craving for susubstances such as clay, ice, or cornstarch)

Vitamin B12 anemia

  • May present with gastric mucosal atrophy
  • Neuropsychiatric abnormalities as a result of combined degeneration of the spinal cord and brain
  • Most frequent neurologic symptoms are paresthesias and ataxia
  • Glossitis
  • Diminished vibratory sensation in the lower extremities
  • Muscle weakness
  • Dysphagia
  • Anorexia
  • Irritability
  • Dementia
  • Psychosis

Folic acid deficiency

    Symptoms similar to vitamin B12 deficiency with the absence of neurologic symptoms Symptoms have an insidious onset, which often makes early diagnosis difficult

Treatment Options

Conventional

Treatment of iron deficiency anemia usually consists of dietary supplementation of iron preparations. Iron is, of course, available in the diet; however, absorption varies greatly with different foods. Iron is poorly absorbed from vegetables, grain products, dairy products, and eggs and is best absorbed from meat, fish, and poultry. Substitution of meat for eggs, milk, or cheese in a mixed meal has been reported to quadruple the absorption of iron from an entire meal. (15) Studies have determined that beverages have an effect on iron absorption. Drinking milk or tea with a meal may cut iron absorption by as much as one half, while drinking orange juice can double iron absorption.

In most cases of iron deficiency anemia, oral iron therapy with soluble ferrous iron salts is sufficient. The preferred iron preparation is a non-enteric coated ferrous salt. This preference is due to the fact that the greatest absorption of iron occurs in the duodenum. The alkaline medium of the small intestine causes iron to form insoluble complexes; therefore, slow-release or sustained release forms do not undergo extensive dissolution until reaching the small intestine, causing significantly reduced absorption. The dose depends upon the patient’s ability to tolerate iron, but the normally recommended dose is 200mg of elemental iron daily, delivered in two to three divided doses. One of the chronic problems with traditional iron repletion is that it may constipate the individual. This has lead to the use of other sources of iron to be sought out by consumers.

Parenteral iron therapy may be necessary in patients intolerant to oral iron, or patients with iron malabsorption. Iron dextran, containing 50mg of iron/ml, may be given intravenously or by intramuscular injection. When administered IV, it may be given by slow IV push, or diluted in an IV infusion. The IM injection is given by z-track method to avoid staining of the skin. Another form of treatment is blood transfusions; however, this form of therapy should be used with extreme caution.

According to the author of one study, iron supplementation should continue for 6 months after reaching normal hemoglobin levels in order to insure that that total iron stores have been adequately restored. It is suggested that follow-up testing be done to ensure that iron levels remain in the normal range and that the initial diagnosis was correct. (16)

Vitamin B12 deficiency anemia is commonly treated with parenteral cyanocobalamin. Doses range from 800-1,000mcg daily for one to two weeks, then decreased to 100-1,000mcg one time weekly until normalization of the hemoglobin and hematocrit occur. Thereafter, monthly injections should be administered. In the rare cases of nutritional deficiency, oral administration of cobalamin may be used. It is also used effectively against pernicious anemia, but in much larger doses than those used to treat vitamin B12 deficiency.

Folic acid deficiency is treated by exogenous folic acid administration. For replenishment of folate stores, therapy is generally initiated at 1-5mg daily. The 1mg daily dose is usually sufficient in most patients, even those with documented absorption problems. Therapy is usually continued for about four months. Once the deficiency is corrected, therapy can be discontinued. It is also recommended that patients with folic acid deficiency be placed on diets high in folic acid. Long-term therapy may be necessary for patients in hemolytic states, refractory malabsorption, and myelofibrosis.

Anemia of chronic disease is somewhat less specific than treatment of other anemias. Usually, recovery of anemia is related to recovery of the underlying process. Exogenous EPO has been used to stimulate erythropoiesis in patients with chronic diseases. Red cell transfusions are also effective, but should be limited to situations where oxygen transport is inadequate due to concomitant medical problems.

Anemia of chronic renal failure results from an inability to produce EPO, and many of these patients are transfusion dependent. The use of exogenous epoetin has become the mainstay of therapy.

Nutritional Supplementation


Vitamin B6

Some hemodialysis patients with normal serum ferritin levels developed hypochromic, microcytic anemia, which responded to pyridoxine at a dosage of 60 mg three times daily for 20 weeks. (17)

Vitamin B6 may also be therapeutically useful for patients with sickle cell anemia. In one study, plasma pyridoxal phosphate (PLP) concentrations were substantially lower in patients with sickle cell anemia compared to controls. Patients who took 50 mg of pyridoxine twice daily for 2 months exhibited increased plasma and erythrocyte PLP levels along with minor, but not significant, improvements in the number of erythrocytes, hemoglobin, and hematocrit. One subject also reported a substantial reduction in the frequency and duration of painful sickle cell crises, which previously required hospitalization. These authors report that pyridoxal and PLP have been shown to have anti-sickling properties in vitro, and the results of this human trial suggest that pyridoxine supplementation may also be of therapeutic benefit in the treatment of sickle cell anemia. (18)


Copper

Copper deficiency anemia can occur due to over consumption of zinc, (19) malabsorption due to gastrectomy, (20) or long-term enteral feeding. (21) Copper deficiency can prevent the release of iron from storage sites, resulting in what appears to be iron-deficiency anemia. This condition is non-responsive to iron supplementation, and occurs even though adequate iron reserves are available. (22)


Vitamin C

Vitamin C deficiency can result in the development of a normochromic, normocytic or macrocytic anemia, and occasionally a megaloblastic anemia has also been reported. (23) Vitamin C also has the ability to enhance the absorption of non-heme iron making it useful in the prevention and treatment of iron-deficiency anemia. In the acidic gastric pH, vitamin C binds with dietary ferric iron and then the more alkaline pH in the small intestine solubilizes this complex, which releases the iron so that the body can utilize it. (24)


Vitamin E

Vitamin E supplementation may be effective in the prevention of a hemolytic anemia that often develops in infants who are born with low tissue levels of tocopherol. (25) Vitamin E supplementation could also be beneficial for patients with sickle cell anemia because sickle erythrocytes are more susceptible to peroxidation than are normal erythrocytes. On the other hand, vitamin E deficiency in patients with sickle cell anemia enhances the susceptibility of erythrocytes to peroxidation, which promotes a destructive cycle of damage to red blood cells. (26)


Vitamin A

Vitamin A deficiency has also been reported as a possible factor in anemia. (27) The authors of one study state that nearly fifty percent of the pregnant women in developing countries suffer from iron-deficiency anemia, which is usually treated with iron supplements such as ferrous sulfate. However, studies reveal that administering vitamin A with ferrous sulfate increases the iron-induced hematopoietic effect. Studies with animals reveal no difference among various routes of vitamin A administration, which lead researchers to conclude that the therapeutic effect of vitamin A in iron-deficiency anemia is probably not due to its influence on iron absorption from the gastrointestinal tract. (28)

Herbal Supplementation


Ashwagandha

Ashwagandha is rich in iron, which may increase hemoglobin and red blood cell count in anemic individuals. (29) This agent should be used in moderation in men with known cardiovascular risk because iron may potentially accelerate this risk.

Ashwaghandha is an adaptogen, or substance that helps protect the body against various emotional, physical, and environmental stresses. Ashwagandha is reported to have tonic or adaptogenic effects similar to panax ginseng. (30) Ashwagandha reportedly prevented myelosuppression in mice treated with three immunosuppressive drugs with a significant increase in hemoglobin concentration. (31) Ashwagandha was also reported to have immunostimulatory activity, because treatment was accompanied by significant increases in hemolytic antibody responses towards human erythrocytes.


Dong Quai

Dong quai also reportedly promotes circulatory activity and has blood building properties, while reducing the viscosity of the blood. (32) , (33) The root contains about 750-880ppm of elemental iron, and has been used traditional for anemia and increasing red blood cell counts. (34)

Traditional Chinese Medicine

Anemia

Extensive information regarding the treatment of this health condition using Traditional Chinese Medicine is available through the link above.

Diet & Lifestyle

Excess Zinc: Long-term consumption of pharmacologic doses of zinc can induce a severe copper deficiency, which can enable the development of sideroblastic anemia. (35)

Hydrochloric acid: Gastric secretion of hydrochloric acid influences iron absorption. Patients with hydrochloric acid deficiency are more likely to have reduced iron absorption as well as intestinal bacterial overgrowth, which can also hinder digestion and absorption of nutrients.

Clinical Lab Assessment

Some of the following laboratory testing can provide information necessary for diagnosis and treatment. In addition, the tests listed may also give insight to functional metabolism and functional nutrient status in the body.

Thyroid Profile

Anemia is often the first sign of hypothyroidism. Anemias are diagnosed in 20-60% patients with hypothyroidism. Values of the extent of anemia are estimated by radioisotopic analysis due to the lower volume of plasma in hypothyroidism, which causes false readings of high levels of hemoglobin in blood. Diagnosis of hypothyroidism should be considered in every case of anemia with uncertain etiology because sometimes signs of overt hypothyroidism needn't necessarily be evident.

CBC

A CBC may suggest the involvement of secondary infections, inflammation, and/or nutrient deficiencies. Mean corpuscular volume (MCV) may not be sufficient to assess iron status. Analysis of serum iron, total iron binding capacity, and ferritin may be indicated. Anemia may appear as low hemoglobin, moderately low mean corpuscular hematocrit (MCHC), and elevated reticulocyte percentage. The CBC includes screening for leukopenia (low WBC) and thrombocytopenia (low platelet count).

Mineral Analysis

The evaluation of essential and/or toxic elements can be of use in the evaluation of many clinical conditions. Essential mineral imbalances can affect nearly any tissue and organ resulting in a myriad of disorders. Trace element deficiencies can disproportionately affect enzyme systems that are used in regulatory substrates resulting in dysfunctional metabolic pathways. Toxic elements can be damaging as a result of toxicity responses, enzyme binding, and toxic inhibition of enzyme-substrate complexes, which can result in inhibition of essential nutrient-dependent mechanisms.

Iron, Serum

This inorganic ion, most commonly in hemoglobin, carries oxygen to the tissues and returns carbon dioxide to the lungs. Iron is stored in the liver and reticuloendothelial tissue as ferritin and hemosiderin. It is released on demand for metabolic processes.

Total Iron Binding Capacity (TIBC)

This test enables a differentiation of anemia secondary to iron deficiency from other diseases associated with cellular oxidation variations (chronic inflammatory disorders). TIBC is the maximum amount of iron that can be bound to transferrin.

Transferrin

Transferrin (a.k.a. siderophilin) is an iron transport protein formed in the liver, found in plasma, with a seven-day half-life. It will decrease more rapidly than will albumin. It may be used to evaluate nutritional status.

Transferrin Saturation

Transferrin is capable of binding more than its own weight in iron. In normal individuals, iron saturation of transferrin is between 20-45%. Transferrin saturation by iron has a diurnal variation, with a peak in the morning and a depression in the evening. Transferrin Saturation is calculated by the formula (Serum Iron/TIBC) x 100 = Transferrin Saturation.

References

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