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UEDI1064-02661532-530XEating Disorders, Vol. 18, No. 2, jan 2010: pp. 0–0Eating Disorders

Interpreting the Complete Blood Count in Anorexia Nervosa

Interpreting the Complete Blood Count in Anorexia NervosaB. S. Cleary et al.

BARBARA S. CLEARY, JENNIFER L. GAUDIANI, and PHILIP S. MEHLER

Department of Internal Medicine, University of Colorado Health Sciences Center and Denver Health Medical Center, Denver, Colorado, USA

Anemia, leukopenia and thrombocytopenia are frequent complications of anorexia nervosa. The complete blood count provides useful information to diagnose and characterize these findings. Anemia tends to be normocytic and normochromic. Leukopenia manifests as a deficiency of lymphocytes or neutro- phils. Thrombocytopenia, if severe, may confer a bleeding risk. A careful history and physical examination should be performed to evaluate for other possible etiologies of cytopenias. Cell line deficiencies related solely to anorexia nervosa often resolve with nutritional rehabilitation. Knowledge of these potential findings and their expected outcomes may help avoid costly and potentially invasive procedures in patients with anorexia nervosa.

INTRODUCTION

Anorexia Nervosa occurs in 0.9% of women and 0.3% of men in the United States (Hudson, Hiripi, Pope & Kessler, 2007) and is associated with exten- sive medical complications that can affect almost every organ system (Mehler & Krantz, 2003). The bone marrow is frequently affected, and patients with anorexia nervosa may present with anemia (low hemoglobin and hematocrit), leukopenia (low white blood cell count) or thrombocy- topenia (low platelet count) in a pattern involving one, two or all three cell lines simultaneously (Hütter, Ganepola & Hofmann, 2009).

Address correspondence to Philip S. Mehler, M.D., Department of Internal Medicine, University of Colorado Health Sciences Center/Denver Health Medical Center, 660 Bannock Street, MC 0278, Denver, CO 80204, USA. E-mail: pmehler@dhha.org

Interpreting the Complete Blood Count in Anorexia Nervosa 133

Along with a thorough history and physical examination, a complete blood count (CBC) provides baseline diagnostic information about hemato- logic medical issues encountered in the patient with anorexia nervosa. With a basic understanding of the typical findings on the CBC in the patient with anorexia nervosa, excessive worry and more invasive and costly tests such as bone marrow biopsy may be avoided. Reference ranges for normal CBC values are listed in Table 1.

ANEMIA

Red blood cells (RBCs) are made in the bone marrow and are responsible for distributing oxygen throughout the body. Anemia is an abnormally low number of RBCs or low levels of hemoglobin in the blood. Symptoms and examination findings of anemia may include fatigue and paleness. If oxy- gen distribution is inadequate shortness of breath, cardiovascular collapse and death may ensue. In general, people become anemic because they lose RBCs due to blood loss or hemolysis (destruction of RBCs while cir- culating), or they fail to produce RBCs due to nutritional deficiencies or other factors that affect production of RBCs in the bone marrow (Table 2) (Hillman, 1998).

Approximately 21–39% of those with anorexia nervosa are anemic (Hütter et al., 2009). The anemia may be mild, moderate or even severe enough to necessitate a blood transfusion. Bone marrow failure is thought to be the most likely etiology of anemia in those with anorexia nervosa, although there have been anorectic patients with normal bone marrow who are anemic as well (Hütter et al., 2009).

The mean corpuscular volume (MCV), an index reflecting the size of the RBCs, serves to classify anemia (Bergin, 1985). The MCV may be low (microcytic anemia), normal (normocytic anemia) or high (macrocytic ane- mia) and corresponds to potential etiologies of anemia (Table 3). Addition- ally, information about the morphology and pallor of cells may be obtained by examining a peripheral smear (Bergin, 1985). An anemic patient with anorexia nervosa tends to have a normocytic anemia (Miller et al., 2005; Misra et al., 2004) with cells of normal pallor (normochromic) (Hütter et al., 2009).

TABLE 1 References Ranges for CBC Values

White blood cell 4.5–10.0 k/μl Hematocrit 38%–52% Hemoglobin 13–18 g/dl Mean corpuscular volume 80–100 fl Platelet 150–400 k/μl

134 B. S. Cleary et al.

Although one might expect vitamin deficiencies in patients with anor- exia nervosa, levels of Vitamin B12 and folic acid, both necessary to make RBCs, are frequently normal. Van Binsbergen et al. (1988) studied 10 anorectics, 10 lean and 10 normal weight females and found that women with anorexia nervosa actually had the highest serum vitamin B12 levels and that folate levels were similar among groups. McLoughlin et al. (2000) also found normal to elevated levels of B12 and folate in their cohort of inpatient anorectic patients with skeletal myopathies. It is not exactly clear

TABLE 2 Etiologies of Anemia1

Blood Loss Gastrointestinal losses Surgical losses Trauma

Hemolysis Hemoglobin abnormalities (Sickle cell, Thalassemia, Methemoglobinemia)

G6PD deficiency Antibody related Thrombotic thrombocytopenia purpura Hemolytic uremic syndrome Toxic (spider bite, metals) Low phosphorous during refeeding2

Low bone marrow production

Iron deficiency anemia (blood loss, malabsorption, pregnancy, hookworm, inadequate diet)

Medications (antiepileptics, antipsychotics, antimicrobials) Alcohol Infection (viral, fungal) Anemia of chronic disease Anemia of renal disease Hypometabolic state (anorexia nervosa, hypothyroid, liver disease)

Ineffective bone marrow production

Vitamin B12 deficiency (terminal ileum disorders, fish tapeworm, inadequate diet)

Folate deficiency (inadequate diet, pregnancy, medications) Myelodysplastic syndrome

1Adapted from Hillman, 1998. 2Kaiser & Barth, 2001.

TABLE 3 Anemia Classified by MCV1

Low MCV Normal MCV High MCV

Iron deficiency anemia Chronic disease Vitamin B12 deficiency Thalassemia Acute blood loss Folic acid deficiency Chronic disease Mixed deficiency Myelodysplastic syndrome Fragmentation Renal disease Alcohol

Anorexia nervosa2 Hypothyroid

1Adapted from Bergin, 1985. 2Hütter, Ganepola, & Hofmann, 2009.

Interpreting the Complete Blood Count in Anorexia Nervosa 135

why these severely malnourished and anemic patients have normal or even elevated levels of B12 and folate. However, one possible explanation may be the tendency for increased vitamin supplementation that occurs in those with anorexia nervosa (Misra et al., 2006).

Iron deficiency anemia is also uncommon in patients with anorexia nervosa (Hütter et al., 2009). Kennedy et al. (2004) studied 12 women admitted to the hospital for anorexia nervosa and found that iron levels were normal in 11 of 12 patients. Ferritin levels (a marker of iron storage) were also normal to increased in all 12 patients despite 9 of 12 being ane- mic at some point in their admission. The authors speculate that relative increased iron storage due to contraction of circulating blood volume and decreased iron loss due to the commonly found amenorrhea contribute to normal iron levels in patients with anorexia nervosa.

LEUKOPENIA

Two lines of white blood cells, lymphocytes and neutrophils, are pro- duced in the bone marrow and work together to help defend against infection. The CBC provides information about the white blood cell count as well as a differential that reports the percentages of lymphocytes, neu- trophils and subtypes of neutrophils. Leukopenia means an abnormally low number of white blood cells in the blood. In general, white blood cells may be low because of decreased production in the bone marrow or increased destruction in circulating white blood cells (Table 4) (Holland & Gallin, 1998).

Approximately 22–34% of outpatients (Miller et al., 2005; Misra et al., 2004) and as many as 75% of hospitalized patients (McLoughlin et al., 2000) with anorexia nervosa are leukopenic. Lymphopenia (low lympho- cyte count) is common in patients with anorexia nervosa; however, sev- eral examples of neutropenia (low neutrophil count) have been noted as well. Although usually mild, the leukopenia can be severe (white blood count < 1,000), but typically resolves with adequate nutrition (Hütter et al., 2009).

Although one might expect to see increased rates of infection in those with anorexia nervosa and leukopenia, the literature reveals mixed results. Devuyst et al. (1993) found an increased risk for severe infections in leuko- penic patients with anorexia nervosa who were hospitalized Brown et al. (2005) evaluated hospitalized anorectics with concurrent bacterial infections and found that the overall leukocyte count was actually elevated, but noted an increased concentration of neutrophils and low concentration of lymphocytes. In general, the majority of those with anorexia nervosa and leukopenia seem to remain free from infectious complications (Misra et al., 2004).

136 B. S. Cleary et al.

THROMBOCYTOPENIA

Platelets are produced in the bone marrow and help control bleeding after injuries to blood vessel walls. The CBC provides information about the actual platelet count. Thrombocytopenia is an abnormally low number of platelets in the blood. In general, patients may be thrombocytopenic because of decreased marrow production, increased peripheral destruction or splenic sequestration of circulating platelets (Table 4) (Handin, 1998).

Although less commonly observed than anemia and leukopenia, mild to severe thrombocytopenia has been reported in those with anorexia ner- vosa (Hütter et al., 2009), and purpura (bruising) and increased bleeding have been reported in the cases of severe thrombocytopenia (Saito, Kita, Morioka & Watanabe, 1999). Decreased bone marrow production is thought to be the main etiology of thrombocytopenia in those with anorexia ner- vosa. Most reported cases resolved within a few weeks of improved nutri- tion (Saito et al., 1999).

BONE MARROW CHANGES

Cytopenias (low cell line counts measured on the CBC) are thought to be secondary to bone marrow failure in patients with anorexia nervosa. Serous fat atrophy or gelatinous degeneration of the bone marrow is described in those with anorexia nervosa and seems to be related specifically to the lack of carbohydrate in the diet of anorectics (Mehler, 1995). Abella et al. (2002) looked at the bone marrow in 44 patients with anorexia nervosa and found normal bone marrow in 11%, hypoplastic or aplastic (low or zero blood cell

TABLE 4 Etiologies of Leukopenia and Thrombocytopenia1

Decreased production in bone marrow

Medications (antipsychotics, antiepileptics, antimicrobials) Vitamin B12 deficiency Folic acid deficiency Bone marrow infiltration (tumor, infection) Infection (many viruses, tuberculosis, brucellosis) Anorexia nervosa2

Increased destruction in peripheral circulation

Autoimmune processes (platelet or neutrophil antibodies, systemic lupus erythematosus, rheumatoid arthritis)

Disseminated intravascular coagulation Sepsis Medication associated antibodies3

Sequestration Splenic sequestration (infiltrative process in spleen, liver disease)

1Adapted from Holland & Gallin, 1998, and Handin, 1998. 2Hütter, Ganepola, & Hofmann, 2009. 3Heparin associated with heparin induced thrombocytopenia.

Interpreting the Complete Blood Count in Anorexia Nervosa 137

precursors) bone marrow in 39% and partial or complete gelatinous degen- eration in the remaining 50%. The authors found that the degree of weight loss correlated with the severity of bone marrow changes. Although cytope- nias were present more frequently when the bone marrow had undergone gelatinous transformation, peripheral cell counts did not always reflect the severity of bone marrow changes. Gelatinous degeneration of the bone marrow generally recovers with adequate nutrition (Abella et al., 2002; Hütter et al., 2009).

DISCUSSION

Anemia, leukopenia and thrombocytopenia are frequent complications of anorexia nervosa. The CBC, in addition to a thorough history and physical examination, provides useful information to both diagnose and characterize these cell line deficiencies.

The anemia occurring in anorexia nervosa tends to be normocytic and normochromic. Accordingly, patients with anorexia nervosa presenting with anemia and an abnormal MCV or cells of abnormal pallor warrant further evaluation. B12 and folic acid deficiency are uncommon; however, if a CBC reveals an elevated MCV (macroctyosis), or if there are conditions that pre- dispose to vitamin deficiency such as concurrent alcohol abuse, further diagnostics should include blood serum measurements of B12 and RBC folate. It is also uncommon that an anorectic patient with anemia is iron deficient. However, if ongoing bleeding is a concern, or if the MCV is low (microcytosis) and the cells are hypochromic, the diagnosis of iron defi- ciency should be pursued by checking serum iron, total iron binding capac- ity and ferritin levels.

Leukopenia may manifest as a deficiency of lymphocytes or neutro- phils. It is still unclear if low white blood cells confer an infection risk in the severe anorectic, but clinicians must remain vigilant, as those with anorexia nervosa are frequently hypothermic and have low heart rates, findings that may mask ongoing infectious complications. Although leukopenia is com- mon in patients with anorexia nervosa and improves with nutrition, it is important to consider other potential causes especially if the leukopenia does not resolve. Several classes of medications such as antiepileptic and antipsychotic agents which are both frequently used in treatment of the patient with anorexia nervosa may also cause leukopenia.

Although less common, thrombocytopenia also occurs and in severe cases may confer a bleeding risk. As with leukopenia, multiple drugs and coexisting conditions can predispose to thrombocytopenia and must be considered when platelet counts are low.

The cytopenias of anorexia nervosa are thought to be secondary to bone marrow failure, and indeed, those with cytopenias frequently have

138 B. S. Cleary et al.

either hypoplasia or partial or complete gelatinous degeneration of their bone marrow on bone marrow biopsy. These changes typically resolve with nutritional rehabilitation, and evaluation of the bone marrow by bone mar- row biopsy should not routinely be considered in the patient with anorexia nervosa prior to nutritional rehabilitation unless compelling evidence for an alternative diagnosis exists.

Cell line deficiencies related solely to anorexia nervosa tend to resolve with nutritional rehabilitation, and regular monitoring of the CBC is war- ranted to ensure normalization of the CBC. Knowledge of potential CBC findings and the expected outcomes may help avoid costly and potentially invasive procedures in patients with anorexia nervosa.

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Bergin, J. J. (1985). Evaluation of anemia: Getting the most out of the MCV, RDW, and other tests. Postgraduate Medicine, 77, 253–269.

Brown, R. F., Bartrop, R., Beumont, P., & Birmingham, C. L. (2005). Bacterial infec- tions in anorexia nervosa: Delayed recognition increases complications. Inter- national Journal of Eating Disorders, 37, 261–265.

Devuyst, O., Lambert, M., Rodhain, J., Lefebvre, C., & Coche, E. (1993). Haemato- logical changes and infectious complications in anorexia nervosa: A case- control study. Quarterly Journal of Medicine, 86, 791–799.

Handin, R. I. (1998). Bleeding and thrombosis. In A. S. Fauci, E. Braunwald, K. J. Isselbacher, J. D. Wilson, J. B.Martin, D. L. Kasper et al. (Eds), Harrison’s principles of internal medicine (14th ed., pp. 39–345). New York: McGraw-Hill Health Professions Division.

Hillman, R. S. (1998). Anemia. In A. S. Fauci, E. Braunwald, K. J. Isselbacher, J. D. Wilson, J. B. Martin, D. L. Kasper et al. (Eds), Harrison’s principles of internal medicine (14th ed., pp. 334–339). New York: McGraw-Hill Health Professions Division.

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Interpreting the Complete Blood Count in Anorexia Nervosa 139

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