Introduction

Haematological complications in anorexia nervosa (AN) are common and most often result from bone marrow hypometabolism secondary to undernutrition. Anaemia is found in 16.7–39% of cases, leucopenia in 7.9–36% of cases, and thrombocytopenia in 8.9–11.3% of cases [1, 2]. The severity of these conditions is correlated with the intensity and duration of undernutrition, and they are usually reversible with appropriate renutrition. Nevertheless, recommendations for caloric needs and refeeding strategies for AN patients are highly variable in the literature [3, 4]. We report here the case of a 16-year-old anorexic girl, hospitalized for severe undernutrition, who presented severe, prolonged neutropenia in the course of refeeding in a specialized care unit.

Case presentation

A 16-year-old adolescent girl of Franco-Japanese origin suffering from AN was hospitalized for a situation of terminal cachexia in a multidisciplinary specialized medical unit for eating disorders (EDs). On admission, BMI was 11.96 kg/m2 (29.5 kg/1.57 m) with various signs of adaptation to undernutrition such as bradycardia (40/min), hypotension (80/40 mmHg) and hypothermia (36 °C) but without any signs of multi-organ decompensation. There were no signs of confusion, but there were anorexic cognitions such as denial of weight loss and dysmorphophobia. No purgative behaviours, physical hyperactivity or toxic consumption were found in the medical interview. The anamnesis and physical examination did not reveal any evidence of an intricate somatic comorbidity. Initial blood tests showed disturbances, with leukopenia [2200/mm3 (normal range 4000–10,000)] and neutropenia [620/mm3 (normal range 1700–7000)]. Haemoglobin [12 g/dl (normal range 12–17)] and platelet count [240,000/mm3 (normal range 150,000–450,000)] were within the normal range. All other tests including blood ionogram, serum calcium, phosphorus, creatinine, transaminases, albumin, and CRP yielded normal levels. The patient's previous history was prematurity at 28 weeks of amenorrhea in a context of maternal uterine malformation, with a birth weight of 1800 g (birth height not specified). The patient's maximum weight before the anorexic episode was 43 kg for 1.55 m at the age of 14 years (BMI 17.8 kg/m2) and there was secondary amenorrhea. During the summer before hospitalisation, the patient had been on a humanitarian mission for 1 month and returned home early because of relational difficulties within the group. Her family and friends then noticed significant weight loss and a change in eating behaviours, switching to a vegetarian diet. The situation worsened at the beginning of the school year with a sudden weight loss of 10 kg in the 3 months preceding hospitalisation. In view of the severity of the undernutrition and neutropenia observed at admission, exclusive enteral nutrition by nasogastric tube was started at 300 kcal/day or 10 kcal/kg/day, with an increase of 300–400 kcal per week (Fig. 1). Polyvitamin substitution was also administered at the time of enteral nutrition: a single dose of 10 mg of vitamin K1, 1200 mg/day potassium, 25 drops/day of polyvitamin hydrosol and 1600 mg/day of phosphorus. After the third week of hospitalization, her weight progression became favourable with an increase of 1 kg per week. Moderate, declining oedemas were found on clinical examination in the first 2 months of renutrition, with no sign of heart failure. Despite weight gain, the haematological parameters deteriorated, falling to a haemoglobin level of 9.4 g/dl (normal range 12–17), a leucocyte level of 1520/mm3 (normal range 4000–10,000) and a neutrophil level of 280/mm3 (normal range 1700–7000/mm3), without associated thrombocytopenia, at the end of the sixth week of hospitalisation (Fig. 1). The patient remained apyretic and CRP was negative (normal range < 1 mg/l). Specialized haematological advice was sought to deal with this severe neutropenia. It was recommended that protective isolation should not be instated as the total monocyte and neutrophil counts remained above the critical threshold of 500/mm3. Further aetiological exploration found slightly decreased ferritinemia at 39 μmol/l (N 47–110), increased vitamin B12 at 950 ng/l (N 197–771) and normal serum folate at 925 μg/l (N 523–1257). HIV 1 and 2, EBV, CMV and Parvovirus B19 serology tests were negative. Iron (66 mg/day po) and folate (5 mg/day po) replacement therapy was initiated, but the anaemia continued to worsen. An osteomedullary biopsy was performed at 7 weeks from admission to rule out gelatinous transformation of the bone marrow (GTBM). The osteomedullary biopsy showed slightly overall decreased cellularity for the patient’s age, in favour of bone marrow hypometabolism. During the eighth week of hospitalization, the neutrophil count normalized to 1750/mm3 without replacement therapy using granulocyte-cell stimulating factor (G-CSF). Meals were reintroduced at this time (initial oral intake of 450 kcal/day) alongside the maintenance of enteral renutrition, which provided 2000 kcal/day (Fig. 1); the patient's weight then reached 32.4 kg with a BMI of 13.1 (Fig. 2). The nasogastric tube was definitively stopped 4 months after the start of hospitalization. During the five and a half months corresponding to the total duration of the inpatient management, there was no refeeding syndrome (normal phosphoremia), only moderate cytolysis was observed 6 weeks after admission with maximum levels of ASAT at 66 U/l (N 10–45) and ALAT at 104 U/l (N 10–35). An individual and family psychiatric approach was initiated at admission and anxiolysis using Cyamemazine (20 mg daily) was introduced in the second week, because of significant sleep disturbances. Major depressive disorder was diagnosed and antidepressant treatment with Sertraline was prescribed at the start of the third month and increased to 75 mg daily. The patient presented a generalized convulsive seizure at the end of the third month, with no apparent triggering factor, apart from the state of undernutrition and psychotropic treatments which are known to lower the epileptogenic threshold. A post-critical EEG showed generalized epileptiform abnormalities. The diagnosis retained, after neurological advice, was generalized idiopathic epilepsy, which probably pre-dated AN condition. Treatment with Lamotrigine was initiated at 25 mg and increased to 75 mg daily. At the end of hospitalization, the patient’s weight gain was 15.4 kg in 5.5 months, and her weight at discharge was 44.9 kg (BMI 18.2 kg/m2) (Fig. 2) with a normalized blood count (leukocytes: 3810/mm3 and neutrophils: 1930/mm3). After discharge, the patient was regularly monitored in outpatient follow-up with a favourable initial evolution in the course of the first year without any recurrence of neutropenia, in a context of relative weight stability and resumption of menses. A re-aggravation of anorexic and depressive symptoms was observed 15 months later with a decrease in weight (BMI 15.4 kg/m2) and the reappearance of moderate leuco-neutropenia at 1556/mm3 without anaemia or thrombocytopenia.

Fig. 1
figure 1

Neutrophil count (/mm3) and total caloric intake (kcal/day)

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Fig. 2
figure 2

Neutrophil count (/mm3) evolution and weight (kg)

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Discussion

Neutropenia is the most common leukocyte line affected in undernourished AN patients and is thought to occur in up to 16.3% of patients [5]. Defective haematopoiesis is thought to be the result of an alteration in the bone marrow microenvironment that affects cell differentiation, but the exact pathophysiological mechanism remains unknown [1, 5]. In most cases, weight restoration combined with adequate refeeding enables ad integrum correction of haematological disturbances [5, 6]. Nevertheless, in the most serious situations of massive, rapid weight loss, the existence of severe neutropenia associated with pancytopenia should raise concern about GTBM, which is associated with a very poor pronostic [6]. In the case reported, we were challenged by the severity and unusual duration of the neutropenia, but above all by the discrepancy between a weight evolution considered satisfactory and a progressive degradation of the haematological parameters. The unfavourable outcome profile of this bicytopenia in this context of severe caloric-protein undernutrition led us to fear an evolution towards GTBM. This risk justified a bone marrow biopsy which showed bone marrow hypometabolism, thus eliminating GTBM [6]. Furthermore, the persistence of neutropenia has led us to fear an increased risk of sepsis with late diagnosis, given the low reliability of infection usual markers in this context of immune dysregulation associated with AN [7]. In the absence of an infectious event and in view of the maintenance of a cumulative level of monocytes and neutrophils above the critical threshold of 500/mm3, treatment with G-CSF or erythropoietin was not initiated, unlike strategies detailed in a few clinical cases reported in the literature [8]. Haematological parameters improved progressively and spontaneously in the course of the usual multidisciplinary institutional treatment without further specific medication. The question of the factors involved in the aetiopathogenesis of this neutropenia remains subject to discussion, and the aetiological assessment of this bicytopenia was negative. The iatrogenic hypothesis was not retained. Indeed, no haematotoxicity for Cyamemazine was evidenced and antidepressant treatment was started once the neutropenia episode had been resolved. The hypothesis of ethnic vulnerability remains unlikely, as to our knowledge, mild ethnic neutropenia has not been described among patients of Japanese or Caucasian origin [9]. We could also envisage the existence of individual vulnerability resulting in part from the rapid, massive weight loss and the particular nutritional status induced by the vegetarian diet adopted by the patient. We also wondered about the nutritional factors that could have contributed to this surprisingly prolonged state of neutropenia. Adolescence is associated with specific energy needs and this may have increased the caloric requirements during the refeeding stage. In addition, the questions of the efficacy of refeeding and the quality of the weight gain observed at the beginning of hospitalization were raised. There was a slight initial hydrosodic inflation, as evidenced by mild renutrition oedemas during the first 2 months of hospitalization, but there were no elements suggesting a major overestimation of weight gain from intentional hyperhydration.

In addition, we found that the speed of weight gain increased from the seventh week of hospitalization (1.2 kg/week compared to 0.8 kg/week at the beginning of hospitalization), indicating more effective refeeding, also evidenced by the regression of cytolysis. An overall improvement in the situation and nutritional status was observed in the second part of hospitalization, when total caloric intake exceeded 2300 kcal/day. Over the past decades, consensual refeeding strategies have recommended the adoption of “start low and go slow” to avoid complications of overly aggressive renutrition, in particular refeeding syndrome [10]. In the case of our patient with severe undernutrition, an individualized nutritional approach was thus initiated taking into account the severity of the undernutrition and the patient’s physiological and psychological tolerance, in accordance with the philosophy of transdisciplinary care [11]. In recent years, we have witnessed a paradigm shift in therapeutic refeeding strategies [12, 13]. Recent publications have focused on several drawbacks of overly cautious renutrition, such as prolonged hospitalization and insufficient weight gain, exposing patients to undernutrition complications, which some authors have termed the “underfeeding syndrome” [3, 11]. This has sparked interest in more aggressive renutrition strategies called “higher calorie refeeding” with an initial caloric intake starting at 1400 kcal/day and an increase in the range of 67–250 kcal/day. These studies suggest adopting this new refeeding strategy, which could provide significant benefits in terms of length of hospital stay and nutritional restoration while preserving patient safety [14, 15]. Indeed, the rapid restoration of weight in adolescents suffering from eating disorders could be associated with a better prognosis for psychological symptoms [12]. We suggest that an episode of severe neutropenia occurring during and despite “conventional” renutrition process is a stigma of the undernutrition syndrome, which is a complication of overly cautious renutrition strategies. Furthermore, it seems important to retain the perfect clinical tolerance of this severe but reversible neutropenia, with the pursuit of effective renutrition without the need for another specific treatment. A more aggressive renutrition strategy would probably have been beneficial for the haematological aspects, the infectious risks, the iatrogenic aspects (repeated blood tests, invasive and costly over-investigations such as an osteo-medullary biopsy) and for the neuropsychic aspects [14]. Thus, an episode of severe and evolving neutropenia occurring in spite of conventional treatment should lead to a re-appraisal of the traditional methods of refeeding for adolescents suffering from anorexia nervosa. We suggest that teams specialized in the management of eating disorders facing situations of severe undernutrition should consider the benefits of more aggressive renutrition, which could reduce many of the complications, particularly haematological disturbances, inherent in the occurrence of an underfeeding syndrome.

What is already known on this subject?

Mild neutropenia is a frequent and adaptive consequence of undernutrition in anorexia nervosa. Severe neutropenia associated with pancytopenia is a severity criteria that may evolve to gelatinous bone marrow.

What does this study add?

Isolated severe neutropenia can occur during refeeding, despite regular weight gain. This situation should suggest an underfeeding syndrome and a more aggressive initial refeeding strategy.