Anemias due to Essential Nutrient Deficiencies

Transcription

1 Nutrition for Disease States Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp DOI: / Anemias due to Essential Nutrient Deficiencies Sally P. Stabler Division of Hematology, School of Medicine, University of Colorado, Aurora, Colo., USA Key Words Anemia Iron deficiency Vitamin B 12 Folate Key Messages Iron deficiency results from decreased intake in the setting of increased loss due to menstruation, childbirth or gastrointestinal bleeding. Diets low in animal source foods are deficient in both iron and vitamin B 12. Atrophic gastritis (pernicious anemia) and other malabsorption syndromes are the major cause of vitamin B 12 deficiency megaloblastic anemia. Folate deficiency megaloblastic anemia is often the result of alcoholism, drug therapy or malabsorption syndromes. Vitamin B 12 deficiency causes elevated methylmalonic acid levels, and both B 12 deficiency and folate deficiency cause elevated homocysteine levels S. Karger AG, Basel Introduction Anemia is defined as hemoglobin (Hgb) less than 13 g/dl for males and 12 g/dl for females. There are many factors influencing Hgb such as sex, age, race, altitude of residence and presence of common hemoglobinopathies such as thalassemia minor and Hgb E which also affect a population s normal values. Anemia may be accompanied by other cytopenias such as leukopenia and thrombocytopenia. Anemia impacts many aspects of health such as growth and development, perinatal health and even survival in seniors with chronic conditions. Anemias due to nutritional deficiencies are easily treated; thus, prompt diagnosis is important. Often, such anemias are a sign of other medical conditions that require investigation. Iron deficiency is the most common cause of anemia worldwide, especially in women due to the difficulty of replacing iron lost from menstruation and childbearing [1]. Iron is most readily absorbed when bound to heme, as found in animal foods; thus, nutritional iron deficiency is common in populations who do not eat meat. Iron deficiency anemia arises in occult bleeding of the gastrointestinal tract, and thus can be an early sign of malignancy or a consequence of aspirin and/or anticoagulant drug therapy. Both vitamin B 12 (cobalamin) and folate deficiency cause megaloblastic anemia, and the former also causes a demyelinating disorder of the nervous system. Mixed nutrient deficien-

2 cies frequently coexist because diets containing little animal protein are also deficient in both iron and B 12, and gastrointestinal disorders may cause malabsorption of all three nutrients as well as occult blood loss. I r o n D e f i c i e n c y The largest quantity of iron is bound to Hgb in red blood cells. Absorbed iron is bound to serum transferrin and is delivered to all tissues including the bone marrow. The percent saturation of transferrin is a useful test in the diagnosis of iron deficiency. Iron that is not needed for heme synthesis is stored in ferritin, another useful measurement of iron status. Daily losses of iron are approximately 1 mg in men, which is compensated by absorption of 1 mg of iron per day in males who store about 800 mg of iron in Western countries. Menstruating women have higher iron requirements, needing to absorb mg of iron daily. A total of 1,000 mg of iron may be required during pregnancy and childbirth. The bioavailability of dietary iron is much lower from plant foods as compared to the heme iron found in animal foods. Small intestinal gastrointestinal diseases cause iron malabsorption. In developed countries, however, the major cause of iron deficiency is bleeding. Besides peptic disease and cancer, the widespread use of aspirin and warfarin is associated with recurrent episodes of iron deficiency anemia. Diagnosis of Iron Deficiency After depletion of stored iron, there is iron-deficient erythropoiesis and eventually microcytic (mean cell volume, MCV <80 fl) and hypochromic anemia with occasional thrombocytosis. A fall in MCV levels in a patient known to be at risk for iron deficiency is a sign that iron supplementation should begin. Laboratory Testing in Iron Deficiency Serum ferritin <12 ng/ml is indicative of decreased iron stores ( table 1 ). Unfortunately, ferritin is an acute-phase reactant and may be in the normal range or actually high in patients with iron deficiency and inflammation. Seniors may have absent iron stores with ferritin values as high as 50 ng/ml [2]. Serum iron, the saturation of transferrin, and total iron-binding capacity are also useful tests, best obtained in the fasting state. A low serum iron (<50 μg/dl) and a high total iron-binding capacity (>450 μg/dl) translates into a low transferrin saturation level, i.e. <15%. If malabsorption of iron supplements is suspected, the patient may have the serum iron measured before and after ingestion, where a rise in serum iron of 100 μg/dl after 2 h should be expected. Treatment of Iron Deficiency One ml unit of packed red blood cells contains 1 mg of iron; thus, 1 unit of transfused blood contains 250 mg of iron, which will raise Hgb levels by 1 g/dl. Therefore, a patient with 7 g/dl of Hgb will require 1,500 mg of absorbed iron. Iron salts such as ferrous sulfate, gluconate, and fumerate are used for oral supplementation; they contain between 30 and 60 mg of elemental iron, although only about 15 mg is usually absorbed ( table 1 ). Continue supplements for 2 3 months after resolution of the anemia in order to replace stores. In patients with ongoing bleeding, the final maximum Hgb and MCV values should be noted and used to guide retreatment. There are excellent, safe, intravenous preparations of iron that should be used in intolerant patients, especially when bleeding is brisk, and it is unlikely that oral supplementation will be adequate [3]. The reformulated iron dextran can be used in large doses, up to 1,000 mg administered i.v. over 4 h. There are also three new i.v. iron preparations: iron gluconate, iron sucrose and Nutritional Anemias 165

3 ferumoxytol. Iron sucrose is dosed at mg, iron gluconate at 125 mg/dose and ferumoxytol as high as 500 mg i.v. over 90 s, but the latter only has approval in the United States for dialysis patients. Iron deficiency anemia is undertreated. Regular monitoring for a fall in red cell MCV and aggressive replacement with oral or i.v. iron will prevent needless blood transfusion and hospitalization for acute anemia as well as maintain quality of life and productivity [1]. Table 1. Iron deficiency anemia Causes Bleeding, lack of animal-based food products Laboratory tests (1) Hypochromic, microcytic anemia or fall in MCV (2) Serum ferritin <12 ng/ml (<50 in seniors) (3) Serum iron <50 μg/dl; TIBC >450 μg/dl; saturation <15% Treatment (1) Iron salts, mg tablets 1 3/day (2) i.v. iron dextran, iron sucrose or iron gluconate, 1,000, 300 or 125 mg/session, respectively (3) Correct bleeding problem Megaloblastic Anemia due to Vitamin B 12 or Folate Deficiency Megaloblastic anemia is caused by a defect in DNA synthesis which leads to the production of larger cells than usual (macrocytosis and hypersegmented neutrophils) and apoptosis and destruction of red blood cells in the bone marrow (ineffective erythropoiesis). Both vitamin B 12 and folate deficiency cause identical megaloblastic anemia, which can be confused with acute leukemia or hemolytic syndromes when severe [4]. Table 2. Clinical abnormalities in vitamin B 12 or folate deficiency Megaloblastic anemia in B 12 or folate deficiency Macrocytic red blood cells, high MCV Hypersegmentated granulocytes High lactate dehydrogenase High indirect bilirubin Low haptoglobin Hypercellular bone marrow with increased erythroblasts Neurologic disease in vitamin B 12 deficiency Paresthesia, ataxia, loss of position sense Spongy degeneration of spinal cord or brain Inverse relationship with anemia Causes of Vitamin B 12 Deficiency Plants do not require vitamin B 12 ; thus, the sources of B 12 in the human diet are all animal-based including meats, dairy products and seafood, and especially shellfish. Low meat consumers and vegetarians are at risk for vitamin B 12 deficiency [4, 5]. Although the RDA for vitamin B 12 is 2.4 μg/day, diets containing 4 6 μg show improved status over lower quantities [5]. The most severe vitamin B 12 deficiency is seen in pernicious anemia which is caused by a lack of intrinsic factor secreted by gastric parietal cells due to autoimmune attack. Intrinsic factor normally carries bound B 12 to the ileum, where it is absorbed. Thus, surgical removal or bypass of the stomach or the distal ileum will also cause severe B 12 deficiency. The breastfed infant of a B 12 -deficient mother may develop severe B 12 deficiency with failure to thrive and severe developmental disability. Diagnosis of Vitamin B 12 Deficiency Vitamin B12 deficiency should be suspected in patients with anemia or pancytopenia of unclear etiology, especially with macrocytosis and other autoimmune diseases such as autoimmune thyroid disease or vitiligo ( table 2 ). 166 Stabler

4 Table 3. Vitamin B 12 deficiency vs. folate deficiency Vitamin B 12 deficiency Causes Diet poor in meat Pernicious anemia Gastric or ileal surgery or bypass Lack of gastric acid Diagnosis Low serum B 12, positive intrinsic factor antibodies High methylmalonic acid and homocysteine Treatment CN-cobalamin 1 mg/month i.m. or 1 2 mg/day oral Folate deficiency Diet poor in vegetables Alcoholism, drugs, small bowel disease or hemolysis Low serum folate High homocysteine Normal methylmalonic acid Folic acid 1 mg/day oral Correct the underlying cause Values of serum B 12 <100 or >400 pg/ml are usually diagnostic. However, the vitamin B 12 level has poor specificity and sensitivity in the intermediate ranges. Assays of methylmalonic acid and/or total homocysteine prior to treatment with vitamin B 12 will confirm or eliminate the diagnosis of vitamin B 12 deficiency [6]. Intrinsic factor blocking antibodies will confirm pernicious anemia; however, they are present in only 50% of cases. About 30% of patients with pernicious anemia will present with predominant neurologic signs and symptoms, especially paresthesia, loss of proprioception, and ataxic gait. The severity of the neurologic findings is inversely related to the severity of the megaloblastic anemia, leading to delay in diagnosis [7]. Treatment with vitamin B 12 will halt the progression of these lesions but often recovery is incomplete. Treatment of Vitamin B 12 Deficiency Dietary deficiency can be treated with multivitamin supplements, which contain between 6 and 100 μg of vitamin B 12. However, since most patients have malabsorption of vitamin B 12, either parenteral administration or high-dose (1 2 mg) oral tablets must be used. One can inject 1 mg cyanocobalamin i.m. daily for several days in cases of severe deficiency, followed by weekly administration for the next 4 8 doses, then monthly for life [5]. A randomized trial showed that serum vitamin B 12 levels were higher and methylmalonic acid levels were lower at 2 months with high-dose oral supplementation as compared to injections [8]. The most common problem in pernicious anemia is that treatment is discontinued; thus, patient education is an essential part of the management of this disorder. Causes of Folate Deficiency In contrast to vitamin B 12, a diet rich in fruits, vegetables and organ meats will supply an adequate amount of folate. Folates are absorbed in the jejunum, and some drugs and alcohol as well as diseases of the small intestine will interfere with absorption. Alcoholics have a higher than normal requirement for folate. Persons with hemolysis also require more folate. Table 3 provides an overview of the causes, diagnosis, and treatment of folate deficiency versus vitamin B 12 deficiency. Nutritional Anemias 167

5 Folates appear to play a role in preventing neural tube defects. Thus, the United States, Canada and many other countries mandated folate fortification of grain products as early as 1998 in order to prevent these tragic birth defects. As a result, folate deficiency has become rare with the exception of patients in the above-mentioned groups. There have been population-wide increases in the levels of serum folate and decreases in serum total homocysteine [9]. Diagnosis and Treatment of Folate Deficiency Low serum folate (<3 ng/ml) indicates folate deficiency with the following caveats: serum folate can be depressed in vitamin B 12 deficiency and after a short period of poor dietary intake. Red blood cell folate assays are not recommended. There are strong inverse correlations between serum folate levels and serum total homocysteine [9]. Elevated total homocysteine levels can be used to diagnose folate deficiency prior to treatment [6]. Most patients can be treated with an oral folate supplement of 1 mg. Women of childbearing age are recommended to take a supplement of at least 400 μg/day and/or prenatal vitamins, since neural tube formation occurs prior to knowledge of the pregnancy. It is essential to avoid treating the vitamin B 12 -deficient patient with folic acid alone. The megaloblastic anemia in vitamin B 12 deficiency may respond to folate treatment, but any other neurologic disease will remain untreated and may progress. Conclusions Iron deficiency is common and suspected when red blood cells are microcytic and hypochromic. Either oral or i.v. iron replacement is safe and effective. Vitamin B12 deficiency causes both megaloblastic anemia and demyelinating neurologic disease curable with replacement. High-dose oral B 12 (1 2 mg/day) is as effective as parenteral treatment. Food folate fortification has improved population folate status and decreased neural tube birth defects in many countries. References 1 Boccio JR, Iyengar V: Iron deficiency: causes, consequences, and strategies to overcome this nutritional problem. Biol Trace Elem Res 2003; 94: Joosten E, Pelemans W, Hiele M, et al: Prevalence and causes of anaemia in a geriatric hospitalized population. Gerontology 1992; 38: Auerbach M, Ballard H: Clinical use of intravenous iron: administration, efficacy, and safety. Hematology Am Soc Hematol Educ Program 2010; 2010: Stabler SP: Vitamin B 12 deficiency. N Engl J Med 2013; 368: Bor MV, von Castel-Roberts KM, Kauwell GP, et al: Daily intake of 4 to 7 microg dietary vitamin B-12 is associated with steady concentrations of vitamin B-12-related biomarkers in a healthy young population. Am J Clin Nutr 2010; 91: Savage DG, Lindenbaum J, Stabler SP, Allen RH: Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994; 96: Healton EB, Savage DG, Brust JC, et al: Neurologic aspects of cobalamin deficiency. Medicine 1991; 70: Kuzminski AM, Del Giacco EJ, Allen RH, et al: Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998; 92: Pfeiffer CM, Caudill SP, Gunter EW, et al: Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey Am J Clin Nutr 2005; 82: Stabler