Postscript

Introduction

Anorexia nervosa is a serious psychiatric illness that leads to medical complications which can adversely affect multiple organ systems, including:
- Hematologic
- Metabolic
- Cardiac
- Hormonal
- Neurologic
Hematological abnormalities are commonly seen in patients with anorexia nervosa, including:
- Anemia
- Leukopenia
- Thrombocytopenia
- Bone marrow changes:
  - Atrophy
  - Hypocellularity
  - Gelatinous transformation
The extent of hematologic abnormalities in anorexia nervosa depends on the severity of caloric deprivation.
Hematological abnormalities typically resolve with nutritional rehabilitation after a variable length of time.

From: Pediatrics 2021 Jan;147(1):e2020040279

Definition of anorexia nervosa

DSM-5 criteria:
- Restriction of energy intake relative to requirements, leading to a significantly low body weight in the context of age, sex, developmental trajectory, and physical health. Significantly low weight is defined as a weight that is less than minimally normal or, for children and adolescents, less than that minimally expected.
- Intense fear of gaining weight or of becoming fat, or persistent behavior that interferes with weight gain, even though at a significantly low weight.
- Disturbance in the way in which one’s body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or persistent lack of recognition of the seriousness of the current low body weight.
Even if all the DSM-5 criteria for anorexia are not met, a serious eating disorder can still be present. Atypical anorexia includes those individuals who meet the criteria for anorexia but who are not underweight despite significant weight loss. Research studies have not found a difference in the medical and psychological impacts of anorexia and atypical anorexia.

Types of anorexia nervosa

Restricting type:
- During the last 3 months, the individual has not engaged in recurrent episodes of binge eating or purging behavior (i.e., self-induced vomiting or the misuse of laxatives, diuretics, or enemas). This subtype describes presentations in which weight loss is accomplished primarily through dieting, fasting, and/or excessive exercise.
Binge-eating/purging type:
- During the last 3 months, the individual has engaged in recurrent episodes of binge eating or purging behavior (i.e., self-induced vomiting or the misuse of laxatives, diuretics, or enemas).

Level of severity

Severity of anorexia nervosa depends on body mass index (BMI):
- Mild – BMI > 17 kg/m2
- Moderate – BMI 16-16.99 kg/m2
- Severe – BMI 15-15.99 kg/m2
- Extreme – BMI < 15 kg/m2

Hematological changes in anorexia nervosa

Hematological alterations anorexia nervosa include:
- Anemia:
  - Occurs in about 1/3 of patients.
  - Typically:
    - Normocytic
    - Normochromic
    - Hypoproliferative (inappropriately low reticulocyte count)
  - May be partially masked by low plasma volume.
  - May be associated with acanthocytes on peripheral smear.¹
  - Rarely associated with:
    - Iron deficiency
    - B12 deficiency
    - Folate deficiency
  - Serum ferritin is usually normal or elevated.
  - Although anemia itself is considered not to be the immediate cause of death in most cases, anemia is one of the predictors of mortality for patients with anorexia nervosa ²
- Leukopenia:
  - Occurs in about 30 to 40% of patients.
  - Typically characterized by lymphocytopenia and/or neutropenia.
- Thrombocytopenia:
  - Occurs in about 5 to 10% of patients.
- Pancytopenia:
  - Occurs in 1% of outpatients.
  - Occurs in 25% of inpatients with severe anorexia nervosa.
- Changes in the bone marrow:
  - The main morphological alterations consist of bone marrow hypoplasia to aplasia or gelatinous degeneration of bone marrow (GDBM), either focal or diffuse up to complete atrophy of the bone marrow.
    - Mild cases of anorexia nervosa may be associated with:
      - Focal or diffuse bone marrow hypoplasia
      - An increase in bone marrow adipocyte size and number
    - Moderate cases may involve bone marrow aplasia in which the hematopoietic cellularity is replaced completely by large adipocytes.
    - Severe cases may present with gelatinous transformation (GMT):
      - Also known as serous atrophy.
      - Diagnosed by bone marrow aspirate/biopsy (though some have reported on the use of bone marrow magnetic resonance imaging).
      - Reported tp occur with/in:
        
        Anorexia nervosa (about 20% of cases)
        
        Tumors
        
        Infections
      - Characterized by extracellular deposits of a gelatin-like substance of amorphous appearance that can be identified histochemically as hyaluronic acid.
      - Associated with reduced:
        
        Hematopoietic cells
        
        Fat cells
      - Peripheral blood cytopenias are more common in patients with evidence of GMT.
      - Presence of GMT correlates with:
        
        Deficiency of carbohydrates and calories, which represent the source of marrow fat
        
        Reduced total fat mass index
      - Reversible with adequate food intake

From: Am J Clin Pathol 2002;118:582-588.

Hematological alterations in anorexia nervosa are rarely associated with micronutrient deficiencies such as vitamins and iron.

Patient cohorts

In a study of 214 women (outpatients) with anorexia nervosa:
- Anemia in 39%:
  - MCV normal in 94% of those with anemia
  - No correlation between anemia and ideal body weight
- Leukopenia in 34%
- Thrombocytopenia in 5% (lowest 114 k/μL)
In a study of 53 men (11%) and women (89%) admitted to hospital with severe anorexia nervosa:
- Red blood cells:
  - Anemia in 83% of patients at some point during hospitalization
  - Iron deficiency in 15% (3 of the 4 patients had anemia)
  - Macrocytosis (> 100 fL) in 13%
  - Microcytosis (< 80 fL) in 6% (2 of the 3 patients were iron deficient)
  - Anisocytosis (elevated RDW) in 30%
  - Folate and B12 deficiency not found in any patient
  - Significant positive correlation between degree of anemia and nadir body mass index (BMI)
- White blood cells:
  - Leukopenia in 79%
    - White blood cell count not correlated with BMI
  - Neutropenia (ANC < 1000 cells/μL)
    - Present in in 29%
    - Resolved in 87% prior to discharge
    - Patients with neutropenia had a significantly lower BMI than patients without neutropenia
- Platelets:
  - Thrombocytopenia in 25%
    - Nadir platelet count:
      - Median nadir platelet count 103,000/μL
      - Reached on hospital day 8
    - Patients with thrombocytopenia had a significantly lower BMI than patients without thrombocytopenia
  - Thrombocytosis in 34%
    - 44 % of patients who developed thrombocytosis also had neutropenia.
    - 100 % resolved their neutropenia by discharge.
    - Patients who developed thrombocytosis had a significantly lower BMI than those without thrombocytosis.
- Pancytopenia in 23%
In a study of 318 female outpatients with anorexia nervosa:
- Cytopenias included:
  - Anemia in 16.7%
  - Neutropenia in 7.9%
  - Thrombocytopenia in 8.9%
  - Anemia and neutropenia in 3.8%
  - Anemia and thrombocytopenia in 2.6%
  - Neutropenia with thrombocytopenia in 2.3%
  - Pancytopenic in 1.1%
- High serum ferritin levels were shown in 33% of patients.
In a study of 799 patients with anorexia nervosa:
- Patients subtypes:
  - 415 patients with restricting subtype (AN-R) subtype
  - 383 patients with binge-eating/purging subtype (AN-BP subtype)
- Hematological findings:
  - Anemia present in:
    - 16.4% of patients with AN-R
    - 20.2% of patients with AN-B/P
  - Microcytosis present in:
    - 1.3% of patients with AN-R
    - 3.8% of those with AN-B/P
  - Macrocytosis present in:
    - 6.9% of those with AN-R
    - 5.8% of those with AN-B/P
  - Leukopenia present in:
    - 50.5% of those with AN-R
    - 36.8% of patients with AN-B/P
  - Thrombocytopenia found in:
    - 7.4% of those with AN-R
    - 5.2% of those with AN-B/P
In a study of 44 patients (40 females, 4 males) with anorexia nervosa:
- Anemia in 15 cases
- Leukopenia in 13 cases
- Thrombocytopenia in 5 cases
- Acanthocytes observed in 8 cases
- Bone marrow aspiration showed:
  - Increased proportion of adipocytes in 48%
  - Decreased hematopoietic cellularity in 70%
  - Complete absence of hematopoietic cellularity in 16%
  - Pink stromal material in 45%
  - Histologic characteristics:
    - Normal in 11%
    - Hypoplastic or aplastic in 39%
    - preGDBM in 30%
    - GDBM in 20%
  - Note: GDBM was defined as the absence of normal hematopoietic cellularity, the presence of scanty degenerated adipocytes, and the presence of a hyaluronic acid matrix confirmed by alcian blue stain. Alternating areas of preserved or hypoplastic bone marrow and GDBM was called focal GDBM or pre-GDBM.
  - Peripheral blood cytopenias tended to appear more frequently in GDBM, but more than half of these patients did not have cytopenias, despite extensive alterations in bone marrow. The authors concluded: “Consequently, peripheral blood findings are not good predictors of the degree of bone marrow involvement in anorexia nervosa”.

Effects of refeeding

Most studies concerning hematological abnormalities in patients with anorexia nervosa have used hematological values at outpatient clinics or upon admission. The lowest hematological values, however, are observed during the refeeding period, ~1 week after admission.³
In a study of 55 patients admitted to hospital with anorexia nervosa and severe malnutrition (body mass index, 13.4±3.4):
- Initial hemoglobin value of 12.1±2.7 g/dl decreased by 22.3% to 9.4±2.5 g/dl 10.1±9.2 days after admission.
- Initial white cell count was 5387±3474/μl, which decreased by 33.6% to 3576±1440/μl 10.1±9.2 days after admission.
- Initial platelet count of 226±101×1000/μl decreased by 24.3% to 171±80×1000/μl 5.5±4.9 days after admission..
- All nadir levels were observed during the refeeding period from the fifth to tenth day of hospitalization.
- 41.7% of patients who received red blood cell transfusion during hospitalization showed normal hemoglobin levels upon admission.
Refeeding syndrome (RFS)
- A serious complication that occurs during treatment of anorexia nervosa.
- The hallmark findings in RFS are fluid and electrolyte dysregulation including:
  - Hypophosphatemia
  - Hypokalemia
  - Hypomagnesemia
  - Abnormalities in glucose metabolism
  - Vitamin (e.g., thiamine)
  - Trace element deficiencies
- Hypophosphatemia:
  - Results from cellular uptake of phosphorus (shift of phosphate into muscle and liver cells to initiate anabolic metabolism)
  - Hypophosphatemia leads to a decrease in erythrocyte ATP and subsequent hemolysis (ATP is needed to maintain the integrity of the erythrocyte membrane).

Pathophysiology

Hematological deficiencies of patients with anorexia nervosa result from bone marrow hypoplasia characterized by serous atrophy of bone marrow (atrophy of the fatty marrow and loss of hematopoietic cells) that is replaced by an accumulation of gelatinous material (gelatinous marrow transformation).
No evidence for role of:
- Iron deficiency
  - No evidence
  - Ferritin levels normal or elevated
- Vitamin B12 or folate deficiency
  - Rarely found in patients in anorexia nervosa

Diagnosis

There is generally no role for extensive hematologic work ups with bone marrow biopsies for cytopenias.⁴

Treatment

Treatment is supportive, including careful refeeding and transfusions as needed.
There is generally no role for the use of costly growth factors such as granulocyte stimulating factor, since leukopenia resolves with weight gain over the course of just a few weeks or months.⁵
Ultimately, all hematologic and morphological alterations disappear completely and rapidly after sufficient refeeding.

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