Anemia

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Vol. 95 No. 2 February 2003

ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY MEDICAL MANAGEMENT UPDATE

Editor: Donald Falace

Anemia Scott S. DeRossi, DMD,a and Sree Raghavendra, DMD,b Philadelphia, Pa UNIVERSITY OF PENNSYLVANIA SCHOOL OF DENTAL MEDICINE

(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:131-41)

Anemia is a disease resulting from a decrease in the normal amount of circulating hemoglobin. A variety of factors cause this decrease, including iron deficiency, hemolysis, a decrease in the production of red blood cells (RBCs), folic acid deficiency, or a combination of these entities. Many types of anemia have oral manifestations, and the disease itself or its medical management can affect the provision of dental care. This article will discuss some of the more common anemias, their systemic and oral manifestations, and suggested modifications for dental care. CLASSIFICATION/ETIOLOGY Anemia can be classified by pathogenesis into bloodloss anemias, hemolytic anemias, hemoglobinopathies, and hypoproliferative anemias. This classification of anemia is summarized in Table I. Anemia also can be classified by the appearance of the RBC on the peripheral blood smear by virtue of its size (microcytic, normocytic, or macrocytic) or by the concentration of hemoglobin (hypochromic, normochromic).1 This article will discuss some of more common anemias, including iron deficiency anemia, hemolytic anemias, glucose-6 phosphate dehydrogenase (G-6-P-D) deficiency, sickle cell anemia, thalassemia, anemias caused by vitamin Bl2 deficiency and folic acid deficiency, and aplastic anemia (Table II). a

Assistant Professor, Department of Oral Medicine, University of Pennsylvania School of Dental Medicine. b Oral Medicine Resident, Department of Oral Medicine, University of Pennsylvania School of Dental Medicine. Received for publication Apr 8, 2002; returned for revision ????; accepted for publication Sept 5, 2002. © 2003, Mosby, Inc. 1079-2104/2003/$30.00 ⫹ 0 doi:10.1067/moe.2003.13

Table I. Classification of anemia by pathogenesis Blood loss anemia Hemolytic anemias

Hemoglobinopathies or disorders of hemoglobin Hypoproliferative anemias

Iron deficiency anemia; PlummerVinson syndrome Glucose-6-phosphate dehydrogenase deficiency; druginduced; immune mediated Sickle cell anemia; thalassemia; Cooley’s anemia Vitamin B12 deficiency; pernicious anemia; folic acid deficiency; aplastic anemia

Blood loss anemias Iron deficiency anemia. Iron deficiency anemia is the most common of all anemias, affecting approximately 30% of the world population and accounting for up to 500 million cases worldwide.2 In the United States, 5% to 11% of women and 1% to 4% of men are iron deficient, and 5% of women and 2% of men have iron deficiency anemia.3 In individuals of Southeast Asian background, there is an increased prevalence, suggesting a cultural component to this anemia. Specifically, a diet of milk, rice and soup, with a lack of meat, and prolonged bottle-feeding are suggested causes of iron deficiency anemia in this population.4 Other causes of iron deficiency anemia include chronic blood loss such as menstrual or menopausal bleeding, parturition, bleeding hemorrhoids, or a bleeding malignant ulcer in the gastrointestinal tract. Malabsorption of iron can also cause this anemia, such as is seen in subtotal or complete gastrectomy, a habit of eating clay (pica), or as part of a malabsorption syndrome. Pica, which is the craving of unusual foodstuffs, is associated with iron deficiency anemia, especially pagophagia or the craving for ice, which is the most common kind of pica. Up to 58% of patients with iron 131

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Table II. Manifestations and treatment of anemia Kind of anemia Blood loss anemia Iron deficiency anemia

Manifestations

Treatment

Pica, especially pagophagia Impaired motor and mental development in children Pallor: Koilonychia Atrophic tongue Glossodynia Dysphagia; xerostomia Depapillated tongue Koilonychia Angular stomatitis Pallor and fatigue dyspnea Prevalence of oral and pharyngeal carcinoma

FeSO4 200mg 3⫻/d Treatment of celiac disease

Hemolytic anemia G-6-P-D deficiency

Icteric sclera skin, soft palate and floor of the mouth Increased trabeculation of bone

Avoid oxidative drugs

Hemoglobinopathies Sickle cell anemia

Painful crisis Frequent bacterial infection Chronic leg ulcers Hepatomegaly Hematuria PICA Pallor: jaundice Hypoplasia of dentition Delayed eruption of teeth Ladder-like appearance of alveolar bone Distinct and dense lamina dura Thick diploe Paresthesia Areas of sclerosis Hemosiderosis Marrow expansion “chipmunk” facies Bimaxillary protrusion spacing of teeth; open bite prominent malar bone saddled nose; retracted upper lip Thinning cortical bone Cranial nerve palsies Discoloration of teeth

Blood transfusion in crisis Deferoxamine to decrease iron overload Hydroxyurea to decrease painful episodes Allogeneic BMT— severe cases

Plummer-Vinson syndrome

Thalassemia ␣ Thalassemia ␤ Cooley’s anemia

deficiency anemia manifest pica as a symptom.5 Celiac disease, which is a common disorder of the small bowel, can cause both occult blood loss and iron deficiency anemia.6 In one study, gastric achlorhydria and atrophy as seen in atrophic gastritis was shown to cause iron deficiency anemia in 20% of patients.7 Another recent study has reported an association of Helicobacter pylori infection and iron deficiency anemia, suggesting that infection with H pylori may impair iron absorption or increase iron demand because the organism uses iron as an essential growth factor.8 Diagnosis of this anemia is especially important in children because it has profound effects on the central nervous system and has been associated with impaired mental and motor development.9,10 To diagnose iron deficiency anemia, a lowered hemoglobin level in routine blood counts is needed along with the finding of microcytic hypochromic cells on a peripheral blood smear. In advanced stages, this anemia

Thalassemia major— blood transfusion

also causes a decrease in the mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, and an increased RBC distribution width. In addition, low-serum iron levels are noted, with a high-serum iron-binding capacity and markedly reduced serum ferritin levels. Mild iron deficiency anemia in children can now be diagnosed by measuring levels of serum-circulating transferring receptor and reticular cellular indices. Reticulocyte hemoglobin content is a good predictor of iron deficiency anemia in children whereas ferritin is a good predictor in adults.11 Measuring iron stores in the bone marrow is the gold standard for diagnosing iron deficiency but may not be diagnostic in cases of iron overload, since iron stores can be also be found in other organs like the liver.12 Occult blood loss is often manifested as iron deficiency anemia and thus should be ruled out when determining the cause of the deficiency,6 especially since most cases of anemia in men in the Western

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Table II. (Continued) Kind of anemia Hypoproliferative Vitamin B12 deficiency

Pernicious anemia

Folic acid deficiency

Aplastic anemia

Fanconi’s anemia

Manifestations Development delay Weakness Irritability Failure to thrive Paresthesia Sensory deficits Loss of deep tendon reflexes Seizures; dementia Glossodynia Atrophic glossitis Dysphangia Taste aberrations Spina bifida Anencephaly Down’s syndrome Pharyngitis Ulcerative stomatitis Angular chelitis Fatigue; lassitude; shortness of breath Chest pain; epistaxis Gingival bleeding; Bacterial sepsis Fungal infections Hypoplasia of the kidney and spleen Brown discoloration of the skin

Treatment Cobalamin administration

Folate replacement from 1 mg/dL to 5 mg/dL Avoid chemotherapeutic drugs in pregnancy Bone marrow transplantation Androgens Perioperative antibiotics if ANC ⬍1000 Platelet transfusion if platelet count ⬍60,000

Absent or hypoplastic thumb or radius Microcephaly Mental and sexual retardation Oral petechiae Gingival hyperplasia Increased incidence of herpetic lesions Spontaneous gingival bleeding

hemisphere result from chronic blood loss from the gastrointestinal tract.13 Hemolytic anemias Anemia due to hemolysis results from the decreased survival of erythrocytes, either from an intracorpuscular (hereditary) or extracorpuscular factor. Considerable hemolysis must take place before an anemia can be detected because the bone marrow has the capability to increase the production of erythrocytes by up to 8-fold in response to reduced erythrocyte survival. This will not hold true in cases where there is a short survival of the RBC or when marrow toxicity or suppression is present. Jaundice is often seen in patients with hemolysis, except in cases of minor hemolysis, because the liver is incapable of excreting the excess amount of bilirubin. In hereditary spherocytosis, a disorder that is transmitted as an autosomal dominant trait, the RBCs exhibit an abnormal spherical shape, thus becoming less deformable and

vulnerable to splenic sequestration and destruction. Characteristic laboratory findings with hemolytic anemia are reticulocytosis, decreased hemoglobin, and increased unconjugated serum bilirubin with normochromic, normocytic cells on a peripheral smear. Measuring the erythrocyte survival time can often help identify extracorpuscular or intracorpuscular etiology. A small number of the patient’s RBCs are tagged with radioactive chromium (51Cr) and reinjected into the patient. An extracorpuscular factor can be identified when similarly tagged RBCs from a donor are cleared as quickly as the patient’s own cells. When donor cells survive longer, an intracorpuscular factor can be identified as the cause. When hemolysis occurs, haptoglobins— globulins that bind to hemoglobin— bind to the RBCs and form a haptoglobin-hemoglobin complex, which is rapidly removed from the system. Hemolytic anemias therefore have lowered serum haptoglobin levels. In hereditary spherocytosis, the cells show an in-

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creased hemolytic activity in hypotonic solutions. When an immune-mediated hemolysis is suspected, the Coomb’s test is used to detect antibodies to erythrocytes.14 In the direct Coomb’s test, incomplete antibodies to the erythrocytes are identified, and antihuman globulin is required to produce hemolysis, whereas in the indirect Coomb’s test, antibodies (usually IgGl and IgG3) directed against RBCs are identified, which activate complement. The X-linked hereditary glucose-6-phosphate dehydrogenase (G-6-P-D) deficiency is the most common metabolic disorder of the RBC. More than 400 genetic variants of this disorder have been described, but most of these variants have not been associated with the disease. Africans and people of Mediterranean descent are most frequently affected.15 As with sickle cell anemia, affected individuals have the advantage of resisting malaria,16 which may explain the increased prevalence in endemically affected areas. The RBC and its membrane are sensitive to injury by oxidants normally inactivated by intracellular glutathione. Glucose-6phosphate deficient cells have impairment in the regeneration of glutathione. Patients with this deficiency have reduced levels of glutathione; thus, under oxidative stress, the hemoglobin sulfhydryl groups and the cell membranes themselves undergo oxidation and form a precipitate eventually leading to lysis of the cell. The glucose-6-phosphate deficient erythrocyte has denatured hemoglobin, and this in conjunction with stromal proteins forms Heinz bodies. Heinz bodies circulate through the spleen and liver with difficulty and are removed, resulting in a hemolytic anemia. Hemolytic crisis may be precipitated by taking oxidative drugs such as sulfonamides, by ingesting fava beans, or by infections like hepatitis or pneumonitis. Although much attention has been given to drug-induced hemolytic crisis, infections cause the majority of crises.15 Hemoglobinopathies Sickle cell anemia. Sickle cell anemia falls under a broad entity of diseases known as hemoglobinopathies, which are a group of disorders characterized by the presence of structurally abnormal hemoglobin, resulting in qualitative abnormalities. Sickle cell anemia is an autosomal recessive disorder and is characterized by an abnormality in the ␤ chain of hemoglobin. A single amino acid substitution of valine for glutamic acid occurs at the sixth position of the ␤ chain and produces sickle hemoglobin. When the RBC is subjected to a lowered oxygen tension or decreased blood pH, the hemoglobin will form a sickle-shaped crystal (tactoid) within the erythrocyte.17 This leads to abnormally functioning and irregularly shaped RBCs. Diminished blood flow and stasis occurs because of

ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY February 2003

altered shape, while increased sequestration is seen in the spleen with resulting hemolysis. Stasis leads to even lower oxygen tension, lower pH, and further sickling. This cycle continues and is eventually responsible for “crisis” in these individuals. Hypoxia, dehydration, acidosis, hypotension, or hypothermia can precipitate a crisis in individuals with the disease. The normal hemoglobin molecule is made of 2 ␣ and 2 ␤ chains (hemoglobin A), thus making the formula AlB2. In cells with sickle characteristics, because of the amino acid change, the formula becomes A2B26 valine. Fetal hemoglobin is designated as hemoglobin F and is abnormal when present in adults. In sickle cell anemia, the majority of the hemoglobin (⬃75% to 100%) is hemoglobin S, and the remainder is hemoglobin F. In the heterozygous trait, only 20% to 45% of the hemoglobin is hemoglobin S, and the rest is normal hemoglobin A. In the heterozygous trait, one of the ␤ chains is abnormal, whereas in the disease (homozygous) both ␤ chains are abnormal. Patients with the trait usually lead a normal life with no symptoms of the disease, except when subjected to abnormally low oxygen levels, such as in an unpressurized airplane or under general anesthesia. Patients with the disease demonstrate marked clinical manifestations including chronic anemia, recurrent attacks of painful crises, frequent bacterial infections, and gradual deterioration of tissue and organ function. Acute crisis is manifested as extreme pain in muscles, joints, and abdomen as a result of localized intravascular sickling, stasis, and eventual vascular occlusion. Later complications include chronic leg ulcers, infarction, shrinkage of the spleen, hepatomegaly, aseptic necrosis of the bone, hematuria, pulmonary infarction and central nervous complications. Pica, with a craving for paper, foam and powders, has also been associated with sickle cell disease but is not used as a specific marker for this condition.18,19 Diagnosis of sickle cell anemia cannot be made from a peripheral smear, as the cells don’t undergo sickling until the oxygen tension is lowered. In the past, a sickle-cell preparation was used for diagnosis: fresh blood was sealed in a chamber with the reducing agent sodium metabisulfite for 1 hour and then the cells were observed for sickling. Currently, the more effective and less expensive hemoglobin electrophoresis is used to make the diagnosis. This test identifies various abnormal hemoglobins in the blood by measuring the differences in their rates of migration in an applied electric field. Thalassemia. The thalassemias, recognized as the most common monogenic diseases in humans, are a group of hereditary disorders characterized by a decreased synthesis of the globin chains. They include

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␣ thalassemia and ␤ thalassemia. In ␣ thalassemia there is a decreased production of the ␣-globin chain. In ␤ thalassemia, mutations lead to a deficient production of the ␤ chain (␤⫹ thalassemia) or an absence of production of the ␤ chain (␤° thalassemia). In ␤ thalassemia, the heterozygous individual will have the trait (thalassemia minor) and the homozygous individual will have ␤ thalassemia major or Cooley’s anemia, a severe congenital hemolytic anemia. Approximately 200 different mutations have been described with ␤ thalassemia.20,21 As opposed to the hemoglobinopathies, there is a quantitative abnormality in this group of disorders. Patients with thalassemia minor may be mildly symptomatic or even asymptomatic whereas patients with thalassemia major have severe hemolytic anemia. Thalassemia is more common among Mediterranean, Middle Eastern, and African populations and is particularly prevalent in India and Thailand. As in sickle cell anemia, the high prevalence is probably related to the protective effect against malaria, which is endemic in these areas.20 In thalassemia major, the excess ␤ chains aggregate and form inclusion bodies. This defect results in the impaired permeability of the RBCs; thus, these cells are trapped and removed from the circulation by phagocytosis or lysis. Compensation occurs by expansion of the marrow compartments, extramedullary hematopoiesis, and formation of hemoglobin F. Ineffective erythropoiesis is the hallmark of ␤ thalassemia.20 Heterozygous carriers of thalassemia (or thalassemia minor) are clinically normal and are often not aware of their genetic condition.17 Severe ␤ thalassemia is usually diagnosed during the first year of life, when there is a decline in the synthesis of fetal hemoglobin, and a lack of shift from fetal to adult hemoglobin is evident.20 Diagnosis of thalassemia major is made by the presence of hypochromic and microcytic cells in the peripheral smear. These cells vary in shape and size and are characteristic for this disease. Hemoglobin electrophoresis shows an increased amount of hemoglobin F and variable amounts of hemoglobin A. In at risk fetuses, DNA analysis of the amniotic fluid detects this prenatally and helps in counseling parents. Hypoproliferative anemias Vitamin B12 (cobalamin) deficiency anemia. Vitamin B12 deficiency, along with folic acid deficiency anemia, falls under a group of anemias called megaloblastic anemias. Foods of animal origin are the primary dietary sources of cobalamin. Cobalamin deficiency takes 2 to 5 years to develop as the body stores relatively large amounts in comparison to the daily requirements. Cobalamin is necessary for DNA synthesis, and a deficiency prevents cell division in the marrow, lead-

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ing to the production of large erythrocytes.22 These cells have small immature nuclei and large mature cytoplasm (poikilocytosis), which characterize all megaloblastic anemias. Vitamin B12 deficiency most often results from malabsorption; however dietary deficiency as a cause is almost always found in strict vegetarians. Pernicious anemia (PA) is the most common cause of vitamin B12 deficiency and is associated with chronic atrophic gastritis.23 Malabsorption occurs secondary to the inadequate gastric production or defective functioning of intrinsic factor, which is necessary to absorb vitamin B12. In developed countries, a deficiency of vitamin B12 implies PA unless proven otherwise. Other conditions that can lead to vitamin B12 deficiency include gastrectomy, small bowel bacterial overgrowth, diverticulosis, blind intestinal loops, scleroderma, tapeworm, tropical sprue, celiac disease, Crohn’s disease, alcoholism, HIV, and medications such as neomycin and colchicine. Pernicious anemia develops because atrophic changes in the gastric mucosa result in a lack of intrinsic factor production. Intrinsic factor is necessary for the absorption of vitamin Bl2 because it binds to the Bl2 molecule, forms a complex that can cross the ileal mucosa, and protects the vitamin from proteolysis. Autoimmune reaction to the gastric parietal cells or to intrinsic factor itself can cause the disease. In 85% of patients, serum antibodies to the gastric parietal cells are noted, and in 60% of patients, serum antibodies to intrinsic factor have also been noted. Often, PA is seen with other autoimmune conditions like Grave’s disease, Hashimoto’s thyroiditis, Addison’s disease, insulin dependent diabetes mellitus, vitiligo, and myasthenia gravis, further strengthening the case for PA as an autoimmune disease.23-30 In children, decreased intake, abnormal absorption, or inborn errors of vitamin B12 transport and metabolism cause vitamin B12 deficiency.31 Diagnosis of PA is made by the presence of macrocytic, normochromic cells on the peripheral blood smear. Mean corpuscular volume and mean corpuscular hemoglobin will be elevated while the mean corpuscular hemoglobin concentration remains normal. Other features include varying shapes of the RBCs, abnormally large platelets, and hypersegmented neutrophils. Serum assay for B12 and folate is also necessary, as these megaloblastic changes can also be seen in folic acid deficiency anemia. Definitive diagnosis is made by the Schilling test. In this test, the patient is given a small amount of radioactive vitamin B12 orally, followed by a large flushing dose of parenteral nonradioactive vitamin B12. This excess of vitamin B12 will cause an overload of the

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kidneys, and the excess will appear in the urine within 24 hours. The amount of radioactive B12 in the urine will be proportional to the amount administered orally. In the normal patient 7% to 30% of the radioactive B12 will be seen in the urine, whereas in the patient with PA only 3% is excreted. Recently, by-products of cobalamin metabolism (ie, methylmalonic acid and homocysteine) have been used to differentiate megaloblastic anemias such as vitamin B12 deficiency and folate deficiency. Methylmalonic acid and homocysteine are by-products of cobalamin metabolism, and an elevation of both by-products is seen in cobalamin deficiency. In contrast, in patients with folate deficiency, only levels of homocysteine are elevated. An increase in the levels of these metabolites usually precedes the development of hematologic abnormalities and thus can potentially identify this disorder in the absence of hematologic abnormalities.22,31,23 These tests can therefore be used to diagnose an underlying deficiency before the progression to hematologic manifestations. Folic acid deficiency anemia. Folates are widely distributed in the diet, occurring mostly in vegetables, fruits, cereals, and dairy products. The body’s stores of folates are relatively low, thus making daily folate supplementation necessary.22 Folic acid deficiency anemia is seen in patients with an increased requirement for folic acid, such as pregnant women and young children, as well as in patients with a dietary deficiency of leafy vegetables, such as alcoholics and drug abusers. Cancer chemotherapeutics, such as methotrexate, azathioprine, 5-FU, 6 mercaptopurine, and cytosinearabinoside, can also cause this deficiency. Folate deficiency can also be caused by inborn errors of metabolism affecting folate transport and hereditary folate malabsorption, which is a rare genetic disorder.25 Hematologic changes in folic acid deficiency anemia are similar to those found in PA. With the exception of a normal Schilling test and normal B12 levers, there is a decrease in the serum levels of folic acid and the presence of neutropenia, lymphopenia, hypersegmented neutrophils, and large platelets. Measurement of serum folate levels is nonspecific. Recently, determination of RBC folate levels has been advocated, as folate levels in the RBC are less sensitive to short-term dietary effects.22 Aplastic anemia. Aplastic anemia, most common in young adults and the elderly, is caused by total bone marrow failure, the cause of which is often not know. In about half of the cases, a chemical substance like paint solvents, benzol, and chloramphenicol; chemotherapy; or exposure to high levels of x-radiation is implicated as the offending agent. The term aplastic anemia is actually a misnomer because with total bone marrow failure all

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3-cell lines of the marrow are depleted. Acquired aplastic anemia is relatively uncommon in children, affecting 2 in 100,000 children each year. In recent years prognosis for this anemia has greatly improved, with approximately 80% of children becoming long-term survivors.26 Fanconi’s anemia, a subset of inherited aplastic anemia, manifests in early childhood. A rare autosomal recessive disease with a variable penetration, it causes multiple congenital abnormalities, bone marrow failure, and increased susceptibility to cancer.11 Aplastic anemia is quite alarming, as it often presents as severe pancytopenia in otherwise previously healthy young individuals.28 Patients with aplastic anemia often present with symptoms of fatigue and lassitude, which are typical for most anemias. In addition, shortness of breath or chest may be seen, especially in the elderly. Other manifestations include sudden onset of alarming bleeding, usually as epistaxis, or gingival bleeding, or increased bruising.28 High risk of infection, bacterial sepsis, and fungal infections are the most serious complications in this disease and occur due to the absence of neutrophils. Bone marrow changes include an acellular marrow with a decrease in hematopoiesis and replacement of the marrow with fat.28 Recent research indicating that the physiology of acquired aplastic anemia entails the destruction of the stem cell compartment by lymphocytes29 suggests an autoimmune pathophysiology involving T-lymphocytes. The pathophysiologic theory involving T-lymphocytes is supported by the fact that immunosuppressive therapy has been effective in treating this anemia. Etiologies range from idiopathic to posthepatitis aplastic anemia to pharmaceutically induced aplastic anemia. PHYSICAL AND ORAL MANIFESTATIONS Iron deficiency anemia Iron deficiency anemia is the most common of all anemias. A common finding in patients with this anemia is pallor, which can be observed in the nail beds and palpebral conjunctiva as well as in the oral mucosa, especially the soft palate, tongue, and sublingual tissues. Jaundice is usually not evident. Koilonychia (ie, spoon-shaped fingernails) is also found, as well as an atrophic tongue as a result of depapillation and loss of filiform and fungiform papillae. Glossodynia is a common complaint. Plummer-Vinson syndrome Plummer-Vinson syndrome is a type of iron deficiency anemia characterized by dysphagia and microcytic hypochromic anemia. Physical findings include sore depapillated tongue, xerostomia, koilonychia, and angular stomatitis. The atrophic changes are not limited

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to the oral cavity, but are also found in the pharynx, upper esophagus, and vulva, rendering these tissues inelastic and dry. Other symptoms of anemia including fatigue, pallor, and dyspnea. The dysphagia is impressive in these patients and results from muscular degeneration in the esophagus and stenosis or webs of the esophageal mucosa. An important consequence is the prevalence of oral and pharyngeal carcinoma in patients with this syndrome. Frequent follow-up for the development of malignant lesions is imperative in treating patients with this syndrome. Glucose-6-phosphate dehydrogenase deficiency Unlike factor deficiency anemia, one of the most common manifestations of G-6-P-D deficiency is jaundice because of the presence of hyperbilirubinemia, which is caused by destruction of the erythrocytes. The sclera, skin, soft palate, and the floor of the mouth may become icteric. Radiographic changes include an increase in the trabeculation of the bone, creating an increased radiolucency. This is secondary to the hyperplasia of the erythroid elements of the bone marrow. Sickle cell anemia Sickle cell disease causes marked underdevelopment, and a majority of sickle cell patients die before 40 years of age. As with hemolytic anemia, patients develop pallor and jaundice as a result of hemolysis and also develop cardiac failure secondary to the basic anemia. Necrosis is evident as a result of stasis of the blood and vaso-occlusion, causing splenic infarcts, chronic leg ulcers, priapism, strokes, and pain crisis. Sickle cell crisis can be triggered by infection, hypersensitivity reactions, or unknown causes. Patients in crisis become acutely ill, and the production of RBCs stops. Hemoglobin levels thus fall to dangerously low levels. Patients with sickle cell disease are also at increased risk for developing infections with Streptococcus pneumoniae, Haemophilus influenzae type b, Salmonella species, Escherichia coli, and Klebsiella species.30 In addition to pallor and jaundice, hypoplasia of the dentition and delayed eruption of teeth are common. Ladder-like appearance of the alveolar bone between the roots of teeth is evident on dental radiographs as a result of increased trabeculation, secondary to increased erythropoietic activity. The lamina dura is dense and distinct. Skull films reveal a thickened diploe, and the trabeculae are coarse and run parallel to the inner and outer tables, giving the characteristic appearance of “hair on end.” Areas of sclerosis are present on dental radiographs and can either represent previous areas of thromboses or osteomyelitis. Rarely, paresthesia or temporary numbness of the mental nerve has

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been reported, secondary to vascular occlusion resulting in a decrease in blood supply to the nerve. Thalassemia Severe ineffective erythropoiesis is the hallmark of thalassemia and causes marrow expansion to as much as 30 times the normal level. “Chipmunk facies” is a common finding in patients with thalassemia; notable features include bimaxillary protrusion, spacing of teeth, marked open bite, prominent malar bones, saddled nose, and retracted upper lip. Delayed pneumatization of the maxillary sinuses is also common. Radiographic bony changes include generalized rarefaction of the alveolar bone, thinning of the cortical bone, enlarged marrow spaces, and coarse trabeculae. As in sickle cell anemia, the bones of the skull have a “hair on end” appearance. Extramedullary hematopoiesis can cause pressure on nerves and may result in cranial nerve palsies. Discoloration of the teeth occurs in ␤ thalassemia from deposition of iron in the dentin and enamel of deciduous and permanent teeth. Affected teeth can have up to 5 times the iron concentration of normal teeth. Vitamin B12 (cobalamine) deficiency/pernicious anemia In children, vitamin B12 deficiency often presents with nonspecific symptoms such as developmental delay, weakness, irritability, and failure to thrive. Neurological manifestations include paresthesias, sensory deficits, loss of deep tendon reflexes, developmental regression, hypotonia, seizures, dementia, paralysis, and neuropsychiatric changes. Other symptoms include abnormal skin pigmentation, systolic flow murmurs, anorexia, vomiting, constipation, diarrhea, and icterus.31 In adults, glossodynia, which may be accompanied by glossitis, is a common finding. The tongue may be atrophic with loss of the filiform papillae; in advanced disease, the tongue loses normal muscle tone. As a result, the tongue appears “beefy red” and inflamed with erythematous macular lesions on the tip and margins.23 Dysphagia and taste aberrations are also common. The oral mucosa becomes thin and may cause discomfort to denture wearers. When patients present with glossodynia, it also is important to rule out other causes like diabetes, candidiasis, and parafunctional habits.32 Folic acid deficiency anemia Neural tube defects including spina bifida, anencephaly, and even Down’s syndrome have been linked to folate deficiency in pregnancy. Vitamin B12 has also been implicated independently in causing these neural tube defects.31 Manifestations of folic acid deficiency anemia include pharyngitis, ulcerative stomatitis in severe cases, and, commonly, angular chelitis. As op-

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posed to PA, folic acid deficiency causes a severe anemia but does not cause the neurological symptoms. Aplastic anemia Several characteristics of this anemia are brown discoloration of the skin, hypoplasia of the kidney and spleen, absent or hypoplastic thumb or radius, microcephaly, and mental and sexual retardation. Many of these manifestations are developmental changes if the patient is affected during fetal development and infancy. Oral manifestations include oral petechiae, gingival hyperplasia, spontaneous gingival bleeding, and increased incidence of herpetic lesions.33 MEDICAL AND DENTAL MANAGEMENTS OF PATIENTS WITH ANEMIA It is important to obtain a complete blood count in patients with anemia or those who present with signs and symptoms of anemia. If a low hemoglobin count is found, referral to the patient’s physician is necessary for a more thorough history and physical examination, laboratory diagnosis, and treatment. Elective surgical procedures should be deferred, as there is an increased potential for bleeding and poor wound healing with hemoglobin levels less than 10 gm/dL. General anesthesia is contraindicated unless the hemoglobin level is above 10 gm/dL. Specific treatment and dental management issues for each specific anemia is discussed as follows (Table III). Iron deficiency anemia Most patients with iron deficiency anemia respond to oral iron therapy.6 Oral ferrous sulfate, 200 mg 3 times a day, is the standard therapy and is very cost-effective. Ascorbic acid has been showed to enhance the absorption of iron and should be considered as a supplement in patients demonstrating a poor response to iron supplementation alone. Parenteral iron therapy should be reserved for patients who are intolerant to oral iron therapy or when compliance is an issue.34 Patients with iron deficiency anemia as a result of celiac disease are refractory to oral iron therapy, and treatment of the underlying disease in this case will cure the anemia.13 Glucose-6-phosphate dehydrogenase deficiency In patients with G-6-P-D deficiency, a determination of the severity of the anemia is necessary as the hemoglobin levels can reach 3 to 4 gm/dL during a hemolytic crisis. Drugs like dapsone, sulfasalazine, and phenacetin can induce hemolysis and should be avoided. Drug-induced hemolysis is reversible, and complete recovery follows completion of treatment. In severe cases, blood transfusions may be necessary prior to treatment. Therefore, thorough and effective treatment planning is necessary. Dentists should use caution in prescribing medications,

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Table III. Dental management considerations for patients with anemia Before treatment ● CBC with differential if patient presents with signs and symptoms of anemia ● Consultation with a physician if low hemoglobin levels are found ● Assessment of the severity of the underlying anemia in conjunction with the patient’s physician or hematologist ● Possible blood transfusions if the underlying anemia is severe ● Avoidance of elective treatment in patients who are in a “crisis,” as occurs in sickle cell anemia ● In patients receiving blood transfusions, a thorough history and physical examination to determine the potential risk of acquiring hepatitis or HIV ● Judicious use of general anesthesia if hemoglobin levels are below optimal levels ● If deemed necessary, administration of antibiotic prophylaxis prior to treatment for appropriate anemias During treatment ● Short appointments ● Cautious use of nitrous oxide analgesia in patients with sickle cell anemia and in patients with poorly controlled vitamin B12 deficiency ● Primary closure ● Aggressive management of infections After treatment ● Avoidance of prescription drugs that can precipitate a crisis or cause hemolysis in patients with hemolytic anemias ● Emphasis of impeccable oral hygiene techniques/ recommendation of prophylactic antibiotics if poor wound healing is anticipated ● Cautious use of respiratory depressant analgesics with Hgb/dL

avoiding medications known to cause hemolysis (Table IV). Because infection is a major cause of hemolytic crisis, aggressive elimination of oral infection is indicated. Sickle cell anemia Medical treatment of sickle cell anemia is palliative; there is no cure. Blood transfusions are given only in an aplastic crisis. Hemosiderosis is a complication of transfusions, and a risk of acquiring hepatitis and HIV may be present. Oral iron chelators like deferoxamine are used to decrease the iron overload caused by frequent blood transfusions.17 Long-term blood transfusions in children with sickle cell disease have resulted in a decrease in the incidence of stroke to 10%.35 Hydroxyurea is given to patients with painful episodes because it increases the level of hemoglobin F and thus reduces the frequency of painful episodes.44 For severely affected young individuals, allogeneic bone marrow transplant is an option. Optimal hemoglobin levels are desirable prior to treatment (7-10 gm/dL in adults and 10-12 gm/dL in children). Oral infections should be treated early and aggressively with antibiotics as they can precipitate a crisis.37 In poorly controlled patients,

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Table IV. Medications known to cause hemolysis Drugs used in dentistry that can precipitate a hemolytic event in G-6-P-D deficiency ● ASA ● Sulfonamides ● Chloramphenicol ● Acetophenetidin ● Dapsone ● Ascorbic acid ● Vitamin K Dietary product that can cause hemolysis ● Fava beans Drugs used in dentistry that have a lesser link to hemolysis in G-6-P-D deficiency ● Penicillin ● Streptomycin ● Isoniazid

elective dental and surgical procedures should be deferred, and general anesthesia must be used judiciously because it can precipitate hypoxic events that can result in cerebral or myocardial thrombosis. Perioperative antibiotic prophylaxis is commonly recommended prior to surgical treatment to minimize postoperative wound infection and osteomyelitis, although no controlled clinical trials have been performed to substantiate this practice. Dental modifications also include short appointments, avoiding elective treatment during an episode of crisis, and the cautious use of nitrous oxide analgesia thus to avoid hypoxia.38 There is no good evidence demonstrating that vasoconstrictor-containing local anesthetics are contraindicated; thus they can be used with caution. Thalassemia In patients with thalassemia minor, no medical treatment is necessary. With thalassemia major, however, survival depends on blood transfusions. Hemoglobin levels are kept above 10 gm/dL in order for normal development and survival. Hemosiderosis is a complication that leads to other systemic conditions, such as cardiac insufficiency, diabetes, pituitary hypofunction, and liver disease that result from the deposition of excess iron in these tissues. Hemosiderosis can be avoided by a continuous injection of deferiprone, a chelator of iron. Splenectomy is common in this subset of patients and is performed in an attempt to prolong RBC survival. Poor wound healing is again a common problem encountered in this population. Dental radiographic changes as discussed in the section on physical manifestations must be identified and documented. Vitamin B12 deficiency Recent research has indicated that oral administration and parenteral administration are equally effective

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in treatment of vitamin Bl2 deficiency in adults.39 However, in PA, parenteral cobalamin must be administered for the lifetime of the patient. There is a 100% recurrence of the anemia with cessation of Bl2 therapy. Vitamin Bl2 administration will arrest the neurologic symptoms of PA, but will not reverse them. Folic acid also reverses the hematologic changes of PA, but will not arrest the neurologic symptoms. If concurrent iron deficiency is present, there may be an incomplete response or no response to vitamin BI2 repletion.22 Nitrous oxide has been shown to deplete bioavailable cobalamin and may precipitate acute neurologic decompensation and pancytopenia.40,41 Modifications necessary for dental treatment include (1) avoiding nitrous oxide sedation in patients with vitamin B12 deficiency anemia that is not treated or in patients in whom a deficiency is suspected and (2) ruling out vitamin B12 deficiency or PA as a cause of glossodynia. Dental plaque has been shown to harbor H pylori, and the eradication of gastric H pylori does not necessarily eradicate H pylori in dental plaque. With a strong association of H pylori and vitamin B12 deficiency anemia, it is imperative to encourage good oral hygiene techniques.42-44 Folic acid deficiency Folic acid deficiency anemia is treated by replacement therapy with doses ranging from 1 mg/dL to up to a maximum of 5 mg/dL. Drugs like methotrexate, trimethoprim, triamterene, carbamezapine, phenytoin, phenobarbital, and primidone, all folic acid antagonists, may increase neural-tube defects, cardiovascular defects, oral clefts, and urinary tract defects when given in pregnancy. Folate supplementation may help reverse some of these adverse effects.45 Consumption of 400 ␮g of folic acid daily before conception and during early pregnancy reduces the occurrence of neural tube defects.46 Folate deficiency has also been associated with lymphopenia and neutropenia, as folate is critical for synthesis of DNA and a deficiency results in B and T cell incompetence.25 Patients with folate deficiency may be at a risk for increased oral infections secondary to B- and T-cell incompetence. Patients with known folate deficiency should have a complete blood count with differential prior to surgical procedures. Aplastic anemia Severe aplastic anemia is successfully treated with immunosuppressive therapy,47 but bone marrow transplantation is still widely regarded to be the treatment of choice when possible. Androgens have been used as effective alternative therapy in patients with partial marrow failure. Transfusions are used in a limited fashion because they can adversely affect the outcome of future stem cell trans-

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plantation, as patients can develop antibodies to antigens in the donor blood.28 Because bone marrow transplantation is possible in fewer than 30% of patients, immunosuppressive therapy is gaining popularity.26 Aplastic anemia constitutes a pancytopenia, and thus infection and bleeding are 2 major issues. Oral infections should be treated aggressively because they can be fatal in these patients. Antibiotic prophylaxis and platelet transfusions may be needed depending on the severity of the pancytopenia.33 Systemic (aminocaproic acid and tranexamic acid) and local hemostatic agents might be needed to control gingival bleeding. Chlorhexidine mouth rinses reduce the number of plaque microorganisms. Intramuscular injections and nerve blocks should be avoided because of thrombocytopenia and increased bleeding tendency, but the use of intraligamentary injections is generally safe. CONCLUSION Anemia is a symptom complex that can be caused by numerous diseases. Proper recognition of symptoms may help in the diagnosis of underlying systemic disease. In addition, anemias have oral manifestations that dentists must be able to recognize. The anemia or its medical management may affect the dental management in an outpatient setting. Special consideration for the prevention and treatment of infection is necessary. Proper understanding of each entity that causes anemia is imperative. Understanding of the mechanisms in each disease process and its implications can help aid in the proper dental care of these patients. REFERENCES 1. Ravel R. Clinical laboratory medicine. St Louis: Mosby Inc; 1994. p. 9-60. 2. Cook JD, Skikne BS, Baynes RD. Iron deficiency: the global perspective. Adv Exp Med Biol 1994;356:219-28. 3. Locker A, Dallman P, Carroll M, et al. Prevalence of iron deficiency in the United States. JAMA 1997;277:973-6. 4. Kwiatkowski JL, West TB, Heidary N, Smith-Whitley K, Cohen AR. Severe iron deficiency anemia in young children. J Pediatr 1999;135:514-6. 5. Marinella MA. “Tomatophagia” and iron-deficiency anemia. N Engl J Med 1999;341:60-1. 6. Rockey D. Primary Care: Occult Gastrointestinal Bleeding. N Engl J Med 1999;341: 38-46 7. Dickey W, Kenny BD, McMillan SA, Porter KG, McConnell JB. Gastric as well as duodenal biopsies may be useful in the investigation of iron deficiency anaemia. Scand J Gastroenterol 1997; 32:469-72. 8. Annibale B, Marignani M, Monarca B, Antonelli G, Marcheggiano A, Martino G, et al. Reversal of iron deficiency anemia after Helicobacter pylori eradication in patients with asymptomatic gastritis. Ann Intern Med 1999;131:668-72. 9. Cohen AR. Choosing the best strategy to prevent childhood iron deficiency. JAMA 1999;281:2247-8. 10. Buchanan G. The tragedy of iron deficiency anemia during infancy and early childhood. J Pediatr 1999;135:413-5. 11. Brugnara C, Zurakowski D, DiCanziot J, Boyd T, Platt O. Reticulocyte hemoglobin content to diagnose iron deficiency in children. JAMA 1999;281:2225-30. 12. Hogan WJ, Kay NE. 87-year-old man with macrocytic anemia. Mayo Clin Proc 2001;76:201-4.

ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY February 2003 13. Navab F, Yantiss R. Weekly clinicopathological exercises: Case 5-2001: a 52-year-old man with chronic anemia and sudden severe abdominal pain. N Engl J Med 2001;344: 510-7. 14. Steensma DP, Tefferi A, Weiler CR. Autoimmune hemolytic anemia in a patient with autosomal dominant chronic mucocutaneous candidiasis. Mayo Clin Proc 2000;75:853-5. 15. Steensma DP, Hoyer JD, Fairbanks VF. Hereditary red blood cell disorders in middle eastern patients. Mayo Clin Proc 2001;76: 285-93. 16. McMullin MF. The molecular basis of disorders of red cell enzymes. J Clin Pathol 1999;52:241-4. 17. Mentzer WC, Kan YW. Prospects for research in hematologic disorders: sickle cell disease and thalassemia. JAMA 2001;285: 640-2. 18. Ivascu NS, Sarnaik S, McCrae J, Whitten-Shurney W, Thomas R, Bond S. Characterization of pica prevalence among patients with sickle cell disease. Arch Pediatr Adolesc Med 2001;155: 1243-7. 19. Roberts-Harewood M, Davies SC. Pica in sickle cell disease: “She ate the headboard.” Arch Dis Child 2001;85:510. 20. Olivieri NF. The beta-thalassemias. N Engl J Med 1999;341:99109. 21. Clarke GM, Higgins TN. Laboratory investigation of hemoglobinopathies and thalassemias: review and update. Clin Chem 2000;46:1284-90. 22. Snow C. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med 1999;159:1289-98. 23. Toh B, van Driel, Ian R. Mechanisms of disease: pernicious anemia. N Engl J Med 1997;337:1441-8. 24. Rasmussen SA, Fernhoff PM, Scanlon KS. Vitamin B12 deficiency in children and adolescents. J Pediatr 2001;138:10-7. 25. Geller J, Kronn D, Jayabose S, Sandoval C. Hereditary folate malabsorption: family report and review of the literature. Medicine 2002;81:51-68. 26. Pitcher LA, Hann IM, Evans JP, Veys P, Chessells JM, Webb DK. Improved prognosis for acquired aplastic anaemia. Arch Dis Child 1999;80:158-62. 27. Dupuis-Girod S, Gluckman E, Souberbielle JC, Brauner R. Growth hormone deficiency caused by pituitary stalk interruption in Fanconi’s anemia. J Pediatr 2001;138:129-33. 28. Young NS. Acquired aplastic anemia. JAMA 1999;282:271-8. 29. Young NS. Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med 1997;336:1365-72. 30. Magnus SA, Hambleton IR, Moosdeen F, Serjeant GR. Recurrent infections in homozygous sickle cell disease. Arch Dis Child 199;80:537-41. 31. Palekar AG. Preconceptional intake of folate and vitamin B12 in the prevention of neural tube defects and Down syndrome. Am J Obstet Gynecol 2001;184:517. 32. Carrington J, Getter L, Brown RS. Diabetic neuropathy masquerading as glossodynia. J Am Dent Assoc 2001;132:1549-51. 33. Brennan MT, Sankar V, Baccaglini L, Pillemer SR, Kingman A, Nunez O, et al. Oral manifestations in patients with aplastic anemia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:503-8. 34. Goddard AF, McIntyre AS, Scott BB. Guidelines for the management of iron deficiency anaemia. Gut 2000;46 (Suppl 3-4): IV1-5. 35. Adams RJ. Stroke prevention and treatment in sickle cell disease. Arch Neurol 2001;58:565-8. 36. Wang W, Wynn L, Rogers Z, Scott JP, Peter A, Ware RE. A two-year pilot trial of Hydroxyurea in very young children with sickle-cell anemia. J Pediatr 2001;139: 790-96. 37. Steinberg M. Drug therapy: management of sickle cell disease. N Engl J Med 1999;340:1021-30. 38. Garel HJ. Management of sickle cell disease for the dental patient. J Mo Dent Assoc 1982;62:26-8. 39. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP. Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92:1191-8. 40. Felmet K, Robins B, Tilford D, Hayflick SJ. Acute neurologic

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decompensation in an infant with cobalamin deficiency exposed to nitrous oxide. J Pediatr 2000;137:427-8. Smith I. Nitrous oxide and vitamin B12. Arch Dis Child 2001; 85:510. Avcu N, Avcu F, Beyan C, Ural AU, Kaptan K, Ozyurt M, et al. The relationship between gastric-oral Helicobacter pylori and oral hygiene in patients with vitamin B12-deficiency anemia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92: 166-9. Stopeck A. Links between Helicobacter pylori infection, cobalamin deficiency, and pernicious anemia. Arch Int Medicine 2000;160:1229-30. Kaptan K, Beyan C, Ural AU, Cetin T, Avcu F, Gulsen M, et al. Helicobacter pylori--is it a novel causative agent in Vitamin B12 deficiency? Arch Intern Med 2000;160:1349-53. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol 2001;153:961-8.

46. Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 2001;285:2981-6. 47. Tichelli A, Socie G, Henry-Amar M, Marsh J, Passweg J, Schrezenmeier H, et al. Effectiveness of immunosuppressive therapy in older patients with aplastic anemia. European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party. Ann Intern Med 1999;130:193-201.

Reprint requests: Scott S. DeRossi, MDD University of Pennsylvania School of Dental Medicine 240 S. 40th Street Philadelphia, PA 19104