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Anemia and nutritional deficiency in the acutely ill hospitalized patients
CLINICAL NUTRITION
0025-7125/93 $0.00 + .20
ANEMIA AND NUTRITIONAL DEFICIENCY IN THE ACUTELY ILL HOSPITALIZED PATIENTS Richard R. Streiff, MD
Nutritional deficiencies and accompanying symptoms are often directly or indirectly related to the medical problems which precipitate the patient's admission to the hospital. Patients most often bring with them mild to severe nutritional deficiencies which have been developing over a period of time. Rarely does a nutritional deficiency of great consequence develop during a short hospital stay. On the other hand, long hospitalizations or chronic custodial care provide the opportunity for nutritional deficiencies to become manifest, again most frequently related to the basic physical or behavioral disease problem. FOLIC ACID
Deficiencies in folic acid are common enough in North America to be one of the top three causes of nutritional anemia and its deficiency is being implicated in a number of other chronic and acute illnesses. Folic acid is a water soluble vitamin which is widely found in vegetables as well as most animal products. The prevalence of folic acid in food suggests that deficiency should be rare, but this is not the case. 21 Because folate is heat labile and water soluble, much of the vitamin is lost in preparation or preservation of food. Many patients' diet preferences exclude fresh uncooked vegetables or fruit but include mostly cooked vegetables and meats. In many cases, this approximates the experimental low-folic diet devised by Herbert l2 in which he cooked the food in large quantities of water and discarded the water. Alcohol as well as some prescription drugs inhibit folate absorption or metabolism further, increasing the possibility of folic deficiency in a significant group of patients. HyperFrom the Hematology/Oncology Division, University of Florida College of Medicine, Gainesville, Florida MEDICAL CLINICS OF NORTH AMERICA VOLUME 77· NUMBER 4· JULY 1993
911
912
STREIFF
thyroid ism, hemolytic anemia, and some cancers cause increased folic acid requirements, whereas alcohol intake and some intestinal diseases cause malabsorption of folic acid. A portion of the patient population of many hospitals, particularly those of large metropolitan areas, are deprived of access to appropriate nutrition to the point that their nutritional status approximates that of individuals in some of the deprived areas of the world. Several large nutritional surveys have shown that folic acid deficiency is quite common among nonhospitalized patients from rural areas as well as the inner city.2 The number of deficiencies found in populations of low socioeconomic level is higher, but deficiencies are not exclusive to the underprivileged group.7 Causes of Folic Acid Deficiency
Folic acid deficiency can usually be traced back to one of four primary causes: (1) dietary deficiency, (2) increased requirements, (3) malabsorption, and (4) inhibition of folate metabolism. 23 A diet lacking folate is generally a result of poverty or to inappropriately prolonged cooking time. Food faddism or inappropriate diets because of personal idiosyncrasies can derange a person's food intake to a point where folate is all but excluded. Alcoholism is a significant cause of folic acid deficiency because alcohol contains no folate and it can cover many of the caloric requirements for the individual but adds no important nutrients. 23 Increased folate requirements are commonly caused by pregnancy, hemolytic anemia, hyperthyroidism, and some forms of cancer. Supplementation with folate is necessary as well as treatment of the basic problem. 16, 23 Malabsorption is an insidious cause of folic acid deficiency developing slowly after the basic gastrointestinal problem starts. Conditions causing intestinal malabsorption of folate include sprue, gluten enteropathy, blind loop syndrome, and druginduced malabsorption. 16 Substances that inhibit folic acid metabolism or utilization can in some cases cause almost immediate folate deficiency. These include folic acid antagonists such as methotrexate, frequently used in cancer chemotherapy; several antibiotics; and triamterene, a diuretic which can cause less serious problems. 25 Alcohol ingestion and severe liver disease can also inhibit folate metabolism.9, 14,24 Signs and Symptoms of Folic Acid Deficiency
The classic symptom of folic acid deficiency is macrocytic anemia, This is often accompanied by low platelet count as well as low white count in the more severely deficient patients.>' Patients are usually folic acid deficient for 12 or more weeks before the anemia develops.13 Mucosal changes such as smooth tongue and cytologic abnormalities noted on pap smears can be abnormal before frank folic acid deficiency anemia is noted. Recent observations suggest that cervical dysplasia is more common among women who have low tissue folic acid levels as measured by red cell folate analysis. 3 Folic acid deficiency in pregnant women early in the first trimester is being correlated with an increased incidence of birth defects in their children. 22 Establishing the Diagnosis
Dietary history, complete blood count, serum, and red cell folic acid measurements are the cornerstones of a diagnosis of folic acid deficiency. A
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general history as well as a dietary history can give the physician a strong suspicion that the patient is at risk for a folate deficiency. Questions concerning food intake, particularly uncooked vegetables such as salads and fresh fruit, are very important. If a patient's blood count indicates a macrocytic anemia, the serum folic acid level should be checked. It is important to make a very specific diagnosis of nutritional deficiency whenever possible, particularly in the case of folic acid because vitamin B'2 deficiency can cause a macrocytic anemia identical to that of folic acid deficiency. With a specific deficiency the patient can be advised as to vitamin supplementation and diet changes necessary because a normal diet supplies enough folic acid to maintain normal health except in instances of malabsorption or significantly increased requirements. Therapy
One milligram of folic acid orally is sufficient in most instances except where malabsorption or increased requirement is present, when up to 4 mg of folic acid can be used. Folic acid causes no side effects except in patients who are deficient in vitamin B'2 where it can mask the condition and lead to increased neuropathy. In pregnant women, folic acid should be administered in the form of a multivitamin from the first indication of pregnancy. In women who have had children with malformations in the past or whose families had frequent malformations, folic acid therapy should best be started before attempts at conception. In patients who are not taking oral medications, intravenous folic acid may be administered at 1 mg per day. VITAMIN B'2 DEFICIENCY
Vitamin B'2 deficiency due to pernicious anemia is quite common in the white population of North America. The incidence approaches 1 per 1000. Pernicious anemia is a disease primarily of the elderly with the peak incidence in the 7th decade. 26 Pernicious anemia, though the most frequent, is not the only cause of vitamin B'2 deficiency. IS Surgical removal of part of the distal small intestine, part of the stomach, or severe malabsorption can also cause vitamin B'2 deficiency.17 Recently, dietary B'2 deficiency has become more common with larger numbers of people following a strict vegetarian diet. 10 Signs and Symptoms
Classic signs of vitamin B'2 deficiency from any of the above causes include a macrocytic anemia, which can include leukopenia and thrombocytopenia, mucosal changes with a smooth tongue, abnormal gastric cytology, or abnormal pap smear. 8 These signs and symptoms are identical to those of folic acid deficiency. In addition to symptoms seen in folate deficiency, however, vitamin B'2 deficiency has neurologic symptoms of combined system disease which involves the posterior and lateral columns of the spinal cord giving primarily sensory changes in the long tracts of the legs and the arms.23 Deficits in the first cranial nerve as well as memory deficits are also commonly noted. After appropriate treatment with vitamin B,2 , the hematologic abnormalities quickly return to normal whereas the neurologic changes improve over a period of months but frequently do not return completely to normal.
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Within the last 10 years it has been noted by a number of investigators that a significant number of patients present with very subtle but definite findings attributable to vitamin B12 deficiency.s This group of patients in almost all cases are elderly and present with little or no anemia but frequently have neurologic abnormalities such as memory loss or subtle peripheral neurologic findings. 21 Several investigators have reported patients who have been found to have normal or near normal vitamin B12 levels but had definite biochemical signs of vitamin B12 deficiency when their homocystine or methylmalonate excretion was measured. uo Both of these compounds are metabolites found in vitamin B12-dependent reactions and accumulate in the case of insufficient vitamin B12 . Hospitalized patients can have vitamin B12 deficiency of the classical type with typical macrocytic anemia and the neurologic findings; however, most of these patients receive a diagnosis and are treated before they enter the hospital and are not admitted for treatment of vitamin B12 deficiency unless they are extremely anemic or have marked thrombocytopenia or leukopenia along with other problems. It is much more common to find patients admitted for another reason to have incidental subtle vitamin B12 deficiency as described above. Subclinical vitamin B12 deficiency can go unnoticed for some time unless significant anemia or neuropathy develops. Other complicating problems such as blood loss, surgical operations, or cancer could conceivably stress the patient with borderline vitamin B12 deficiency to the point that definite symptoms appear in a short period of time. In the elderly population, vitamin B12 deficiency has to be considered very seriously in patients with even mild anemias or those who have mild to moderate neuropathy with no anemia. It should also be considered in patients with "leukemia" who may, in fact, have B12 deficiency to account for the immature forms. A normal or near normal vitamin B12 serum level should not dissuade one from making the diagnosis. It can be worthwhile to try a therapeutic trial with vitamin B12 for 3 or 4 months and observe the patient closely for biochemical or hematologic improvement or possibly even neurologic changes, although these frequently require more time. I do not advocate that vitamin B12 be administered without reason, but with the appearance of patients who have very subtle vitamin B12 deficiencies it is prudent to use a therapeutic trial to rule out deficiency if your suspicion is sufficiently strong. The measurement of homocystine or methylmalonate excretion can be very helpful to identify this group of patients; currently, these measurements are not widely available. Clinicians know that vitamin B12 deficiency is predominantly a problem of the elderly; however, patients in their 20s or 30s who enter with a neuropathy and/or a mild macrocytic anemia should be questioned about their dietary habits, particularly about strict vegetarian habits. In these patients, the diagnosis of vitamin B12 deficiency needs to be entertained until proven otherwise. 20 If you prove that the patient does have vitamin B12 deficiency because of decreased dietary intake, therapy with oral vitamin B12 is simple and effective. Patients with small intestinal disease, malabsorption, or pancreatic abnormalities are good candidates for vitamin B12 deficiency. In many instances, the workup of the patient's immediate problem can relegate a mild or moderate B12 deficiency far into the background. It is not that vitamin B12 deficiency is hiding under every stone, but it does occur frequently enough that it must be considered in the elderly with neuropathies with or without significant ane!flia and in younger patients who have a macrocytic anemia with or without a neuropathy and a history of malabsorption or vegetarian habits.
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Diagnosis
The cornerstone of diagnosis of vitamin Bl2 is still the serum vitamin B12 level and a complete blood count with primary focus on the red cell size and the number of lobes in the mature granulocytes. Because vitamin B'2 and folic acid deficiency anemia cannot be separated from each other on morphologic grounds, it is important to measure both serum vitamin B'2 and folic acid. In order to test the patient's ability to absorb vitamin Bm a Schilling test is very helpful particularly in patients who have a history or symptoms of other types of malabsorption or in cases with a history of intestinal or gastric surgery. A bone marrow examination is helpful to document the presence of megaloblasts and to evaluate the presence of megakaryocytes and white cell precursors when leukopenia or thrombocytopenia are present. If available, homocystine excretion or methylmalonate excretion is helpful in cases of subtle vitamin B'2 deficiency but a therapeutic trial with observation may suffice if these assays are not available. It is important to remember that a Schilling test involves the injection of vitamin B'2 as well as the oral tracer dose; therefore, the patient is treated during the administration of the test and all vitamin Bl2 levels and other tests including bone marrow should be complete before the Schilling test. In any case, it is important to observe the patient's response to vitamin Bl2 therapy since many patients with myelodysplasia can present with a moderate macrocytosis and even hypersegmentation of the polymorph leukocytes. These patients, however, do not respond to vitamin B12 therapy.
Treatment
In all cases of vitamin B12 deficiency caused by malabsorption, such as in pernicious anemia, vitamin Bl2 malabsorption due to surgery of the stomach or the small intestine or malabsorption secondary to pancreatitis or other intestinal problems, treatment is with parenteral vitamin B12 . Patients should initially receive at least 3 or 4 injections of 1000 fLg subcutaneously during the first week to 10 days to adequately replenish the vitamin Bl2 body stores; maintenance therapy should be 1000 fLg of vitamin Bl2 subcutaneously once per month. Some authors have suggested that in patients with severe neuropathy, more frequent vitamin Bl2 injections are necessary. To receive vitamin Bl2 injections twice a month or even once a week for a period of time in patients with severe neuropathy seems reasonable, even without proof that more vitamin Bl2 is necessary, because there are no side effects to vitamin B12 . For the few patients who are suffering from vitamin Bl2 deficiency due to dietary deficiency, oral vitamin B12 tablets of 100 mg per day are more than sufficient. One hundred micrograms a day is more than necessary but if a patient is instructed to take one tablet a week you can be assured that compliance would be poor.
IRON DEFICIENCY
The most common nutritional deficiency anemia is iron deficiency. Iron deficiency in adults is almost always caused by blood loss. Nutritional iron deficiency, that is, insufficient intake of iron, is extremely rare. Blood loss causing iron deficiency is in most cases lost in the gastrointestinal tract due to gastric or duodenal ulcers, gastritis, or gastric tumors. Tumors of the colon and
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diverticular or hemorrhoidal bleeding are also significant sources of blood loss. Women of child-bearing age are most commonly iron deficient because of menstrual blood loss. Nutritional iron deficiency should only be considered as a possible diagnosis in infants or very young children who are growing rapidly and whose diet provides insufficient amounts of iron. Hospitalized patients with acute illnesses and with anemia should be considered as suffering from iron deficiency particularly if the red cell size, the mean corpuscular volume, is decreased in the range of 65 to 75 f.lm 3 • It is very important to diagnose the source of bleeding in cases where iron deficiency is documented. Diagnosis
Diagnosis of iron deficiency must begin with a thorough history of the patient: questions should specifically inquire about gastrointestinal blood loss, the frequency and duration of menstrual periods, hematuria, and hemorrhoidal blood loss. If on physical examination the patient is pale, has mucosal changes such as a smooth tongue, and spooning of the nails, suspicion of iron deficiency should be very high. Complete blood count with serum iron and iron binding capacity will tell you if there are microcytic hypochromic red cells as well as low serum iron and elevated total iron binding capacity as is typical in established iron deficiency. A serum ferritin is a good measure of the patients' iron stores; however, it is an acute phase reactant and can be significantly elevated during inflammation or infection. After establishing the presence of iron deficiency, it is necessary to identify and correct the source of the blood loss. This is pursued by testing the stool for occult blood, doing appropriate upper and lower endoscopy, and radiographic contrast studies. Some athletes are also at risk for iron deficiency anemia secondary to gastrointestinal blood loss during running and hemolysis from heavy impact on the pavement. Treatment
Most patients respond very well to oral iron supplements in the form of ferrous sulfate at 325 mg per tablet three times a day administered with meals. Ferrous sulfate on an empty stomach is much more likely to cause gastrointestinal discomfort and noncompliance. Some patients experience gastrointestinal distress with ferrous sulfate tablets so that different forms of iron such as ferrous gluconate are administered. Very few cases require parenteral iron therapy. ANEMIAS FREQUENTLY CONFUSED WITH IRON DEFICIENCY
In evaluating a patient who has small, pale red cells, it is important not to start therapy before the diagnostic studies are complete. Thalassemia is a rather common inherited abnormality in a number of racial groups found in the United States and can appear in the heterozygote form as a mild to moderate microcytic hypochromic anemia. In almost every case, these patients will have elevated iron levels and additional iron will not correct the anemia. Actually,
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iron therapy will be detrimental and cause iron overload if the patient does not already have excess iron levels. Patients who enter the hospital and have a chronic disease, such as a chronic infection, cancer, or inflammatory disease, frequently have an anemia related to their chronic disease. This is usually a mild anemia with a hematocrit reading between 30 and 35 and the red cells are most commonly normochromic normocytic. A slightly to moderately depressed serum iron is usually present along with a decreased iron-binding capacity. In contrast, serum ferritin may be normal or very high. Iron therapy for patients with anemia of chronic disease is not indicated and will not improve the patient's blood counts. Treating the basic disease is the appropriate treatment for this particular anemia. VITAMIN K DEFICIENCY
Vitamin K is a fat-soluble vitamin supplied by a normal diet. Green leafy vegetables are a particularly rich source. Homologues of vitamin K are synthesized by bacteria which normally inhabit the small intestine. Vitamin K is necessary for the hepatic synthesis of the clotting factors II, VII, IX, and X. Deficiencies of those clotting factors are associated with a prolonged prothrombin time and in severe deficiencies, also the activated partial thromboplastin time. 1 Vitamin K deficiency is quite uncommon in individuals on a normal diet but patients with malnutrition from any cause frequently have moderate or significant deficiency often with abnormal clotting studies. Recent reports emphasize the frequency of hospitalized patients who develop abnormal clotting studies due to vitamin K deficiency. This can occur in some patients 7 to 10 days after hospital admission. Patients most at risk are those who enter malnourished and receive antibiotics for 7 or more days.6 Malnourished patients on admission frequently have decreased vitamin K stores or are frankly deficient. Antibiotic therapy frequently kills the bacteria in the small intestine which make vitamin K homologues, further complicating the situation for the patient with already decreased vitamin K stores. Some patients who enter the hospital with normal or near normal vitamin K levels can develop deficiency if they have surgical procedures which make it necessary to include nasogastric drainage and intravenous antibiotics. Anorexia due to the patient's primary illness or medication such as chemotherapy can lead to vitamin K deficiency within a relatively short time. The incidence of vitamin K deficiency in the type of patient described is sufficiently frequent to entertain this as the cause of an unexpected abnormal coagulation test, prothrombin and activated partial thromboplastin times. Those patients respond well to intravenous vitamin K with oral vitamin K as follow up. SUMMARY
Hospitalized patients may present with nutritional deficiencies or develop them during the hospitalization. The physician should remain alert to the presence of these readily correctable conditions. References 1. Alpevin JE: Coagulopathy caused by Vitamin K deficiency in critically ill, hospitalized patients. JAMA 258:1916-1919, 1987
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2. Bailey LB, Wagner PA, Christakis GL et al: Folacin and iron status and hematologic findings in predominately black elderly persons from urban low-income households. Am J Clin Nutr 32:2346-2353, 1979 3. Butterworth CE Jr, Hatch KO, Macaluso M, et al: Folate deficiency and cervical dysplasia. JAMA 267:528-533, 1992 4. Carmel R: Subtle and atypical deficiency states. Am J Hematol 34:108-114, 1990 5. Carmel R, Karnaze OS: The deoxyuridine suppression test identifies subtle cobalamin deficiency in patients without typical megaloblastic anemia. JAMA 253:1284-1287, 1985 6. Cohen H, Scott SO, et al: The development of hypoprothrombinemia following antibiotic therapy in malnourished patients with low serum Vitamin K levels. Br J Haematol 68:63-66, 1988 7. Daniel WA Jr, Gaines EG, Bennett DL: Dietary intakes and plasma concentrations of folate in healthy adolescents. Am J Clin Nutr 28:363-370, 1975 8. Dawson AA, Ogston 0, Fullerton HW: Evaluation of diagnostic significance of certain symptoms and physical signs in anemic patients. Br Med J iii:436-439, 1969 9. Eichner ER, Hillman RS: The evolution of anemia in alcoholic patients. Am J Med 50:218-232, 1971 10. Ellis RR, Montegriffo VME: Veganism, clinical findings and investigations. Am J Clin Nutr 23:249-255, 1970 11. Halstead CH: Intestinal absorption and malabsorption of folates. Ann Rev Med 28:854-857, 1980 12. Herbert V: A palatable diet for producing folate deficiencies in man. Am J Clin Nutr 12:17-20, 1963 13. Herbert V: Experimental nutritional folate deficiency in man. Trans Assoc Am Physicians 75:307-320, 1962 14. Hermos JA, Adams WH, et al: Mucosa of the small intestine in folate deficient alcoholics. Ann Intern Med 76:957-965, 1972 15. Hippe E, Jensen KB: Hereditary factors in pernicious anaemia and their relation to serum-immunoglobulin levels and age at diagnosis. Lancet ii:721-724, 1969 16. Hoffbrand AV: Anaemia in adult coeliac disease. Clin Gastroenterol 3:71-89, 1974 17. Lenz K: The effect of the site of lesion and extent of resection on duodenal bile acid concentrate and Vitamin B12 absorption in ulcerative colitis. Scand J Gastroenterol 11:769-775, 1975 18. Lindenbaum 1, Healton EB, Savage DG, et al: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 318:720728, 1988 19. Mehta BM, Rege DV, Satoskav RS: Serum vitamin B12 and folic acid activity in lactovegetarian and non vegetarian healthy adult Indians. Am J Nutr 15:17-84, 1964 20. Norman El, Martelo 01, Denton MD: Cobalamin deficiency detection by urinary methylmalonic acid quantitation. Blood 59:1128-1131, 1982 21. Senti FR, Pilch SM: Analysis of folate data from the (NHANES). J Nutr 115:13981402, 1985 22. Smithells RW, Sheppard S, Schorah CJ: Vitamin levels and neural tube defects. Arch Dis Children 51:944-950, 1959 23. Streiff RR: Folic acid deficiency anemia. Semin Hematol 7:23-39, 1970 24. Sullivan LW, Herbert V: Suppression of hematopoiesis by ethanol. J Clin Invest 43:2048-2062, 1964 25. Waxman S, Corcino JJ, Herbert V: Drugs, toxins and dietary amino acids affecting Vitamin B'2 or folic acid absorption or utilization. Am J Med 48:599-608, 1970 26. Willett WC: Folic acid and neural tube defect: Can't we come to closure? Am J Public Health 82:666-668, 1992
Address reprint requests to Richard R. Streiff, MD Hematology/Oncology Section College of Medicine University of Florida Box 100277 Gainesville, FL 32610-0277
0025-7125/93 $0.00 + .20
ANEMIA AND NUTRITIONAL DEFICIENCY IN THE ACUTELY ILL HOSPITALIZED PATIENTS Richard R. Streiff, MD
Nutritional deficiencies and accompanying symptoms are often directly or indirectly related to the medical problems which precipitate the patient's admission to the hospital. Patients most often bring with them mild to severe nutritional deficiencies which have been developing over a period of time. Rarely does a nutritional deficiency of great consequence develop during a short hospital stay. On the other hand, long hospitalizations or chronic custodial care provide the opportunity for nutritional deficiencies to become manifest, again most frequently related to the basic physical or behavioral disease problem. FOLIC ACID
Deficiencies in folic acid are common enough in North America to be one of the top three causes of nutritional anemia and its deficiency is being implicated in a number of other chronic and acute illnesses. Folic acid is a water soluble vitamin which is widely found in vegetables as well as most animal products. The prevalence of folic acid in food suggests that deficiency should be rare, but this is not the case. 21 Because folate is heat labile and water soluble, much of the vitamin is lost in preparation or preservation of food. Many patients' diet preferences exclude fresh uncooked vegetables or fruit but include mostly cooked vegetables and meats. In many cases, this approximates the experimental low-folic diet devised by Herbert l2 in which he cooked the food in large quantities of water and discarded the water. Alcohol as well as some prescription drugs inhibit folate absorption or metabolism further, increasing the possibility of folic deficiency in a significant group of patients. HyperFrom the Hematology/Oncology Division, University of Florida College of Medicine, Gainesville, Florida MEDICAL CLINICS OF NORTH AMERICA VOLUME 77· NUMBER 4· JULY 1993
911
912
STREIFF
thyroid ism, hemolytic anemia, and some cancers cause increased folic acid requirements, whereas alcohol intake and some intestinal diseases cause malabsorption of folic acid. A portion of the patient population of many hospitals, particularly those of large metropolitan areas, are deprived of access to appropriate nutrition to the point that their nutritional status approximates that of individuals in some of the deprived areas of the world. Several large nutritional surveys have shown that folic acid deficiency is quite common among nonhospitalized patients from rural areas as well as the inner city.2 The number of deficiencies found in populations of low socioeconomic level is higher, but deficiencies are not exclusive to the underprivileged group.7 Causes of Folic Acid Deficiency
Folic acid deficiency can usually be traced back to one of four primary causes: (1) dietary deficiency, (2) increased requirements, (3) malabsorption, and (4) inhibition of folate metabolism. 23 A diet lacking folate is generally a result of poverty or to inappropriately prolonged cooking time. Food faddism or inappropriate diets because of personal idiosyncrasies can derange a person's food intake to a point where folate is all but excluded. Alcoholism is a significant cause of folic acid deficiency because alcohol contains no folate and it can cover many of the caloric requirements for the individual but adds no important nutrients. 23 Increased folate requirements are commonly caused by pregnancy, hemolytic anemia, hyperthyroidism, and some forms of cancer. Supplementation with folate is necessary as well as treatment of the basic problem. 16, 23 Malabsorption is an insidious cause of folic acid deficiency developing slowly after the basic gastrointestinal problem starts. Conditions causing intestinal malabsorption of folate include sprue, gluten enteropathy, blind loop syndrome, and druginduced malabsorption. 16 Substances that inhibit folic acid metabolism or utilization can in some cases cause almost immediate folate deficiency. These include folic acid antagonists such as methotrexate, frequently used in cancer chemotherapy; several antibiotics; and triamterene, a diuretic which can cause less serious problems. 25 Alcohol ingestion and severe liver disease can also inhibit folate metabolism.9, 14,24 Signs and Symptoms of Folic Acid Deficiency
The classic symptom of folic acid deficiency is macrocytic anemia, This is often accompanied by low platelet count as well as low white count in the more severely deficient patients.>' Patients are usually folic acid deficient for 12 or more weeks before the anemia develops.13 Mucosal changes such as smooth tongue and cytologic abnormalities noted on pap smears can be abnormal before frank folic acid deficiency anemia is noted. Recent observations suggest that cervical dysplasia is more common among women who have low tissue folic acid levels as measured by red cell folate analysis. 3 Folic acid deficiency in pregnant women early in the first trimester is being correlated with an increased incidence of birth defects in their children. 22 Establishing the Diagnosis
Dietary history, complete blood count, serum, and red cell folic acid measurements are the cornerstones of a diagnosis of folic acid deficiency. A
ANEMIA AND NUTRITIONAL DEFICIENCY
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general history as well as a dietary history can give the physician a strong suspicion that the patient is at risk for a folate deficiency. Questions concerning food intake, particularly uncooked vegetables such as salads and fresh fruit, are very important. If a patient's blood count indicates a macrocytic anemia, the serum folic acid level should be checked. It is important to make a very specific diagnosis of nutritional deficiency whenever possible, particularly in the case of folic acid because vitamin B'2 deficiency can cause a macrocytic anemia identical to that of folic acid deficiency. With a specific deficiency the patient can be advised as to vitamin supplementation and diet changes necessary because a normal diet supplies enough folic acid to maintain normal health except in instances of malabsorption or significantly increased requirements. Therapy
One milligram of folic acid orally is sufficient in most instances except where malabsorption or increased requirement is present, when up to 4 mg of folic acid can be used. Folic acid causes no side effects except in patients who are deficient in vitamin B'2 where it can mask the condition and lead to increased neuropathy. In pregnant women, folic acid should be administered in the form of a multivitamin from the first indication of pregnancy. In women who have had children with malformations in the past or whose families had frequent malformations, folic acid therapy should best be started before attempts at conception. In patients who are not taking oral medications, intravenous folic acid may be administered at 1 mg per day. VITAMIN B'2 DEFICIENCY
Vitamin B'2 deficiency due to pernicious anemia is quite common in the white population of North America. The incidence approaches 1 per 1000. Pernicious anemia is a disease primarily of the elderly with the peak incidence in the 7th decade. 26 Pernicious anemia, though the most frequent, is not the only cause of vitamin B'2 deficiency. IS Surgical removal of part of the distal small intestine, part of the stomach, or severe malabsorption can also cause vitamin B'2 deficiency.17 Recently, dietary B'2 deficiency has become more common with larger numbers of people following a strict vegetarian diet. 10 Signs and Symptoms
Classic signs of vitamin B'2 deficiency from any of the above causes include a macrocytic anemia, which can include leukopenia and thrombocytopenia, mucosal changes with a smooth tongue, abnormal gastric cytology, or abnormal pap smear. 8 These signs and symptoms are identical to those of folic acid deficiency. In addition to symptoms seen in folate deficiency, however, vitamin B'2 deficiency has neurologic symptoms of combined system disease which involves the posterior and lateral columns of the spinal cord giving primarily sensory changes in the long tracts of the legs and the arms.23 Deficits in the first cranial nerve as well as memory deficits are also commonly noted. After appropriate treatment with vitamin B,2 , the hematologic abnormalities quickly return to normal whereas the neurologic changes improve over a period of months but frequently do not return completely to normal.
914
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Within the last 10 years it has been noted by a number of investigators that a significant number of patients present with very subtle but definite findings attributable to vitamin B12 deficiency.s This group of patients in almost all cases are elderly and present with little or no anemia but frequently have neurologic abnormalities such as memory loss or subtle peripheral neurologic findings. 21 Several investigators have reported patients who have been found to have normal or near normal vitamin B12 levels but had definite biochemical signs of vitamin B12 deficiency when their homocystine or methylmalonate excretion was measured. uo Both of these compounds are metabolites found in vitamin B12-dependent reactions and accumulate in the case of insufficient vitamin B12 . Hospitalized patients can have vitamin B12 deficiency of the classical type with typical macrocytic anemia and the neurologic findings; however, most of these patients receive a diagnosis and are treated before they enter the hospital and are not admitted for treatment of vitamin B12 deficiency unless they are extremely anemic or have marked thrombocytopenia or leukopenia along with other problems. It is much more common to find patients admitted for another reason to have incidental subtle vitamin B12 deficiency as described above. Subclinical vitamin B12 deficiency can go unnoticed for some time unless significant anemia or neuropathy develops. Other complicating problems such as blood loss, surgical operations, or cancer could conceivably stress the patient with borderline vitamin B12 deficiency to the point that definite symptoms appear in a short period of time. In the elderly population, vitamin B12 deficiency has to be considered very seriously in patients with even mild anemias or those who have mild to moderate neuropathy with no anemia. It should also be considered in patients with "leukemia" who may, in fact, have B12 deficiency to account for the immature forms. A normal or near normal vitamin B12 serum level should not dissuade one from making the diagnosis. It can be worthwhile to try a therapeutic trial with vitamin B12 for 3 or 4 months and observe the patient closely for biochemical or hematologic improvement or possibly even neurologic changes, although these frequently require more time. I do not advocate that vitamin B12 be administered without reason, but with the appearance of patients who have very subtle vitamin B12 deficiencies it is prudent to use a therapeutic trial to rule out deficiency if your suspicion is sufficiently strong. The measurement of homocystine or methylmalonate excretion can be very helpful to identify this group of patients; currently, these measurements are not widely available. Clinicians know that vitamin B12 deficiency is predominantly a problem of the elderly; however, patients in their 20s or 30s who enter with a neuropathy and/or a mild macrocytic anemia should be questioned about their dietary habits, particularly about strict vegetarian habits. In these patients, the diagnosis of vitamin B12 deficiency needs to be entertained until proven otherwise. 20 If you prove that the patient does have vitamin B12 deficiency because of decreased dietary intake, therapy with oral vitamin B12 is simple and effective. Patients with small intestinal disease, malabsorption, or pancreatic abnormalities are good candidates for vitamin B12 deficiency. In many instances, the workup of the patient's immediate problem can relegate a mild or moderate B12 deficiency far into the background. It is not that vitamin B12 deficiency is hiding under every stone, but it does occur frequently enough that it must be considered in the elderly with neuropathies with or without significant ane!flia and in younger patients who have a macrocytic anemia with or without a neuropathy and a history of malabsorption or vegetarian habits.
ANEMIA AND NUTRITIONAL DEFICIENCY
915
Diagnosis
The cornerstone of diagnosis of vitamin Bl2 is still the serum vitamin B12 level and a complete blood count with primary focus on the red cell size and the number of lobes in the mature granulocytes. Because vitamin B'2 and folic acid deficiency anemia cannot be separated from each other on morphologic grounds, it is important to measure both serum vitamin B'2 and folic acid. In order to test the patient's ability to absorb vitamin Bm a Schilling test is very helpful particularly in patients who have a history or symptoms of other types of malabsorption or in cases with a history of intestinal or gastric surgery. A bone marrow examination is helpful to document the presence of megaloblasts and to evaluate the presence of megakaryocytes and white cell precursors when leukopenia or thrombocytopenia are present. If available, homocystine excretion or methylmalonate excretion is helpful in cases of subtle vitamin B'2 deficiency but a therapeutic trial with observation may suffice if these assays are not available. It is important to remember that a Schilling test involves the injection of vitamin B'2 as well as the oral tracer dose; therefore, the patient is treated during the administration of the test and all vitamin Bl2 levels and other tests including bone marrow should be complete before the Schilling test. In any case, it is important to observe the patient's response to vitamin Bl2 therapy since many patients with myelodysplasia can present with a moderate macrocytosis and even hypersegmentation of the polymorph leukocytes. These patients, however, do not respond to vitamin B12 therapy.
Treatment
In all cases of vitamin B12 deficiency caused by malabsorption, such as in pernicious anemia, vitamin Bl2 malabsorption due to surgery of the stomach or the small intestine or malabsorption secondary to pancreatitis or other intestinal problems, treatment is with parenteral vitamin B12 . Patients should initially receive at least 3 or 4 injections of 1000 fLg subcutaneously during the first week to 10 days to adequately replenish the vitamin Bl2 body stores; maintenance therapy should be 1000 fLg of vitamin Bl2 subcutaneously once per month. Some authors have suggested that in patients with severe neuropathy, more frequent vitamin Bl2 injections are necessary. To receive vitamin Bl2 injections twice a month or even once a week for a period of time in patients with severe neuropathy seems reasonable, even without proof that more vitamin Bl2 is necessary, because there are no side effects to vitamin B12 . For the few patients who are suffering from vitamin Bl2 deficiency due to dietary deficiency, oral vitamin B12 tablets of 100 mg per day are more than sufficient. One hundred micrograms a day is more than necessary but if a patient is instructed to take one tablet a week you can be assured that compliance would be poor.
IRON DEFICIENCY
The most common nutritional deficiency anemia is iron deficiency. Iron deficiency in adults is almost always caused by blood loss. Nutritional iron deficiency, that is, insufficient intake of iron, is extremely rare. Blood loss causing iron deficiency is in most cases lost in the gastrointestinal tract due to gastric or duodenal ulcers, gastritis, or gastric tumors. Tumors of the colon and
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diverticular or hemorrhoidal bleeding are also significant sources of blood loss. Women of child-bearing age are most commonly iron deficient because of menstrual blood loss. Nutritional iron deficiency should only be considered as a possible diagnosis in infants or very young children who are growing rapidly and whose diet provides insufficient amounts of iron. Hospitalized patients with acute illnesses and with anemia should be considered as suffering from iron deficiency particularly if the red cell size, the mean corpuscular volume, is decreased in the range of 65 to 75 f.lm 3 • It is very important to diagnose the source of bleeding in cases where iron deficiency is documented. Diagnosis
Diagnosis of iron deficiency must begin with a thorough history of the patient: questions should specifically inquire about gastrointestinal blood loss, the frequency and duration of menstrual periods, hematuria, and hemorrhoidal blood loss. If on physical examination the patient is pale, has mucosal changes such as a smooth tongue, and spooning of the nails, suspicion of iron deficiency should be very high. Complete blood count with serum iron and iron binding capacity will tell you if there are microcytic hypochromic red cells as well as low serum iron and elevated total iron binding capacity as is typical in established iron deficiency. A serum ferritin is a good measure of the patients' iron stores; however, it is an acute phase reactant and can be significantly elevated during inflammation or infection. After establishing the presence of iron deficiency, it is necessary to identify and correct the source of the blood loss. This is pursued by testing the stool for occult blood, doing appropriate upper and lower endoscopy, and radiographic contrast studies. Some athletes are also at risk for iron deficiency anemia secondary to gastrointestinal blood loss during running and hemolysis from heavy impact on the pavement. Treatment
Most patients respond very well to oral iron supplements in the form of ferrous sulfate at 325 mg per tablet three times a day administered with meals. Ferrous sulfate on an empty stomach is much more likely to cause gastrointestinal discomfort and noncompliance. Some patients experience gastrointestinal distress with ferrous sulfate tablets so that different forms of iron such as ferrous gluconate are administered. Very few cases require parenteral iron therapy. ANEMIAS FREQUENTLY CONFUSED WITH IRON DEFICIENCY
In evaluating a patient who has small, pale red cells, it is important not to start therapy before the diagnostic studies are complete. Thalassemia is a rather common inherited abnormality in a number of racial groups found in the United States and can appear in the heterozygote form as a mild to moderate microcytic hypochromic anemia. In almost every case, these patients will have elevated iron levels and additional iron will not correct the anemia. Actually,
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iron therapy will be detrimental and cause iron overload if the patient does not already have excess iron levels. Patients who enter the hospital and have a chronic disease, such as a chronic infection, cancer, or inflammatory disease, frequently have an anemia related to their chronic disease. This is usually a mild anemia with a hematocrit reading between 30 and 35 and the red cells are most commonly normochromic normocytic. A slightly to moderately depressed serum iron is usually present along with a decreased iron-binding capacity. In contrast, serum ferritin may be normal or very high. Iron therapy for patients with anemia of chronic disease is not indicated and will not improve the patient's blood counts. Treating the basic disease is the appropriate treatment for this particular anemia. VITAMIN K DEFICIENCY
Vitamin K is a fat-soluble vitamin supplied by a normal diet. Green leafy vegetables are a particularly rich source. Homologues of vitamin K are synthesized by bacteria which normally inhabit the small intestine. Vitamin K is necessary for the hepatic synthesis of the clotting factors II, VII, IX, and X. Deficiencies of those clotting factors are associated with a prolonged prothrombin time and in severe deficiencies, also the activated partial thromboplastin time. 1 Vitamin K deficiency is quite uncommon in individuals on a normal diet but patients with malnutrition from any cause frequently have moderate or significant deficiency often with abnormal clotting studies. Recent reports emphasize the frequency of hospitalized patients who develop abnormal clotting studies due to vitamin K deficiency. This can occur in some patients 7 to 10 days after hospital admission. Patients most at risk are those who enter malnourished and receive antibiotics for 7 or more days.6 Malnourished patients on admission frequently have decreased vitamin K stores or are frankly deficient. Antibiotic therapy frequently kills the bacteria in the small intestine which make vitamin K homologues, further complicating the situation for the patient with already decreased vitamin K stores. Some patients who enter the hospital with normal or near normal vitamin K levels can develop deficiency if they have surgical procedures which make it necessary to include nasogastric drainage and intravenous antibiotics. Anorexia due to the patient's primary illness or medication such as chemotherapy can lead to vitamin K deficiency within a relatively short time. The incidence of vitamin K deficiency in the type of patient described is sufficiently frequent to entertain this as the cause of an unexpected abnormal coagulation test, prothrombin and activated partial thromboplastin times. Those patients respond well to intravenous vitamin K with oral vitamin K as follow up. SUMMARY
Hospitalized patients may present with nutritional deficiencies or develop them during the hospitalization. The physician should remain alert to the presence of these readily correctable conditions. References 1. Alpevin JE: Coagulopathy caused by Vitamin K deficiency in critically ill, hospitalized patients. JAMA 258:1916-1919, 1987
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2. Bailey LB, Wagner PA, Christakis GL et al: Folacin and iron status and hematologic findings in predominately black elderly persons from urban low-income households. Am J Clin Nutr 32:2346-2353, 1979 3. Butterworth CE Jr, Hatch KO, Macaluso M, et al: Folate deficiency and cervical dysplasia. JAMA 267:528-533, 1992 4. Carmel R: Subtle and atypical deficiency states. Am J Hematol 34:108-114, 1990 5. Carmel R, Karnaze OS: The deoxyuridine suppression test identifies subtle cobalamin deficiency in patients without typical megaloblastic anemia. JAMA 253:1284-1287, 1985 6. Cohen H, Scott SO, et al: The development of hypoprothrombinemia following antibiotic therapy in malnourished patients with low serum Vitamin K levels. Br J Haematol 68:63-66, 1988 7. Daniel WA Jr, Gaines EG, Bennett DL: Dietary intakes and plasma concentrations of folate in healthy adolescents. Am J Clin Nutr 28:363-370, 1975 8. Dawson AA, Ogston 0, Fullerton HW: Evaluation of diagnostic significance of certain symptoms and physical signs in anemic patients. Br Med J iii:436-439, 1969 9. Eichner ER, Hillman RS: The evolution of anemia in alcoholic patients. Am J Med 50:218-232, 1971 10. Ellis RR, Montegriffo VME: Veganism, clinical findings and investigations. Am J Clin Nutr 23:249-255, 1970 11. Halstead CH: Intestinal absorption and malabsorption of folates. Ann Rev Med 28:854-857, 1980 12. Herbert V: A palatable diet for producing folate deficiencies in man. Am J Clin Nutr 12:17-20, 1963 13. Herbert V: Experimental nutritional folate deficiency in man. Trans Assoc Am Physicians 75:307-320, 1962 14. Hermos JA, Adams WH, et al: Mucosa of the small intestine in folate deficient alcoholics. Ann Intern Med 76:957-965, 1972 15. Hippe E, Jensen KB: Hereditary factors in pernicious anaemia and their relation to serum-immunoglobulin levels and age at diagnosis. Lancet ii:721-724, 1969 16. Hoffbrand AV: Anaemia in adult coeliac disease. Clin Gastroenterol 3:71-89, 1974 17. Lenz K: The effect of the site of lesion and extent of resection on duodenal bile acid concentrate and Vitamin B12 absorption in ulcerative colitis. Scand J Gastroenterol 11:769-775, 1975 18. Lindenbaum 1, Healton EB, Savage DG, et al: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 318:720728, 1988 19. Mehta BM, Rege DV, Satoskav RS: Serum vitamin B12 and folic acid activity in lactovegetarian and non vegetarian healthy adult Indians. Am J Nutr 15:17-84, 1964 20. Norman El, Martelo 01, Denton MD: Cobalamin deficiency detection by urinary methylmalonic acid quantitation. Blood 59:1128-1131, 1982 21. Senti FR, Pilch SM: Analysis of folate data from the (NHANES). J Nutr 115:13981402, 1985 22. Smithells RW, Sheppard S, Schorah CJ: Vitamin levels and neural tube defects. Arch Dis Children 51:944-950, 1959 23. Streiff RR: Folic acid deficiency anemia. Semin Hematol 7:23-39, 1970 24. Sullivan LW, Herbert V: Suppression of hematopoiesis by ethanol. J Clin Invest 43:2048-2062, 1964 25. Waxman S, Corcino JJ, Herbert V: Drugs, toxins and dietary amino acids affecting Vitamin B'2 or folic acid absorption or utilization. Am J Med 48:599-608, 1970 26. Willett WC: Folic acid and neural tube defect: Can't we come to closure? Am J Public Health 82:666-668, 1992
Address reprint requests to Richard R. Streiff, MD Hematology/Oncology Section College of Medicine University of Florida Box 100277 Gainesville, FL 32610-0277