Pediatric and Developmental Pathology 17, 470–473, 2014 DOI: 10.2350/14-05-1489-CR.1 ª 2014 Society for Pediatric Pathology

CASE REPORTS

A Rare Association of Celiac Disease and Aplastic Anemia: Case Report of a Child and Review of Literature RAMA KUMARI BADYAL,1 MAN UPDESH SINGH SACHDEVA,1* NEELAM VARMA,1 1 2

AND

BABU RAM THAPA2

Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India Department of Pediatric Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Received May 19, 2014; accepted July 15, 2014; published online July 30, 2014.

ABSTRACT An association between severe aplastic anemia and other autoimmune diseases is rare and has been described in adults for eosinophilic fasciitis, thymomas, systemic lupus erythematosus, and thyroid disorders. Herein we report a patient with celiac disease who was not strictly following a gluten-free diet and presented with progressive pallor, fever, and weakness of 1 month’s duration. On investigation, he had pancytopenia, which on subsequent evaluation revealed aplastic anemia. An association between aplastic anemia and celiac disease has rarely been reported. To the best of author’s knowledge, only 1 pediatric case of celiac disease associated with aplastic anemia has been published. This is the second report to suggest such an association in children. Key words: aplastic anemia, celiac disease, child, glutenfree diet

INTRODUCTION Celiac disease (CD), or gluten-sensitive enteropathy, is a systemic disorder with protean manifestations. Once considered a rare childhood disorder, CD is now known to be a common condition that may have multiple complications. Silent/atypical CD, in the absence of gastrointestinal symptoms, is increasingly recognized, and patients may present with generalized symptoms, such as malaise and fatigue, which are easily attributable to aplastic anemia (AA) [1]. The diagnosis of CD should always be kept in mind when a patient presents with unexplained and isolated hematological findings. Many hematological abnormalities, mostly related to nutritional deficiencies, have been commonly associated with CD

*Corresponding author, e-mail: [email protected]

[2]; however, the occurrence of AA is extremely rare. We present a patient with CD who developed AA.

CASE HISTORY A 9-year-old boy, diagnosed with CD at age 2 years and with an immunoglobulin A (IgA) tissue transglutaminase level of 105 IU/mL (normal: ,20 IU/mL), was referred to the pediatric gastroenterology department with progressive pallor and fever of 1 month’s duration, which was associated with excessive weakness and lethargy. The patient was not following a gluten-free diet (GFD) strictly. He had a history of multiple episodes of melena. On examination, he was smaller than normal, with a height of 121 cm (,3rd percentile) and a weight of 21.2 kg (,3rd percentile). The child had severe pallor and multiple petechiae all over his body. There was no lymphadenopathy or organomegaly. Investigations revealed hemoglobin of 62 g/L, total leukocyte count of 2.4 3 109/L, absolute neutrophil count of 0.4 3 109/L, platelet count of 8 3 109/ L, and reticulocyte count of 0.2%. The peripheral smear examination confirmed findings of cytopenias. Liver function tests were within normal limits and showed total protein of 6.4 g/dL with albumin of 3.2 g/dL. Renal function tests were within normal limits, and a urine examination did not reveal any abnormality. Blood culture was sterile, and rapid card test for malarial antigen, Widal test, and serology for dengue did not reveal any infection. Ultrasonographic examination of abdomen was normal. In view of the unexplained fever with pancytopenia, a bone marrow aspirate and biopsy were performed. The bone marrow examination revealed markedly hypocellular bone marrow spaces with occasional pockets of hematopoietic cells comprising mainly erythroid colonies accompanied by scattered lymphocytes and plasma cells (Fig. 1). Bone marrow iron was increased, as revealed on Perls stain (Fig. 1b).

Figure 1. a. Bone marrow aspirate smear showing relatively increased plasma cells (arrow) and mast cells (arrowhead). Small inset on the lower right side shows mast cell (arrowhead) with metachromatic granules (May-Grunwald-Giemsa, 3400). b. Bone marrow iron 4+ (Perls stain, 3400). c. Trephine biopsy section showing hypocellular marrow spaces with cellularity ,10%, (hematoxylin and eosin, 3200). d. Hypocellular bone marrow showing extensive fatty replacement (hematoxylin and eosin, 3400). e. Few marrow pockets showing erythroid colonies and scattered lymphocytes (hematoxylin and eosin, 3200). f. High-power view showing preserved foci of lymphocytes and an occasional megakaryocyte (hematoxylin and eosin, 3400).

Investigation for short stature revealed that the patient’s IgA tissue transglutaminase levels were 104 IU/ mL, confirming the previously diagnosed CD. However, his thyroid profile was normal. Duodenal biopsy could not be done because of low platelet counts and active gastrointestinal bleeding. Chromosome breakage studies did not reveal increased sensitivity to mitogens. Flow cytometry, done for screening of paroxysmal nocturnal hemoglobinuria (PNH) using fluorescein-labeled proaerolysin (FLAER) and CD24 on CD15-gated neutrophils and FLAER and CD14 on CD33-gated monocytes, revealed a PNH clone in 6.7% of granulocytes and 8% of monocytes, respectively. He was managed with antibiotics, packed red cells, and platelet support and was supplemented with multivitamins. The child was planned for bone marrow transplantation. However, because of financial constraints, the family refused bone

marrow transplantation. The parents were counseled about the nature of the disease and treatment modalities. The child was then started on equine antithymocyte globulins 400 mg/kg/day for 4 days, along with steroids. However, he discontinued treatment and did not follow a GFD strictly. One year later, he was readmitted to an outside hospital with fresh complaints of nasal and gastrointestinal bleeding with hemoglobin of 1.0 g/L, total leukocyte count of 2.8 3 109/L, and platelet count of 68 3 109/L. He was managed symptomatically with blood transfusions and platelet support. Unfortunately, he died of continued bleeding and shock.

DISCUSSION CD is an autoimmune disorder that occurs in genetically predisposed individuals as the result of an immune response to gluten [3]. It is present in approximately 1%

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Table 1.

Comparison of all studies on patients with celiac disease and aplastic anemia Grey-Davies and colleagues [9]

Salmeron and colleagues [10]

Maheshwari and colleagues [11]

Kumar and colleagues [12]

Present study, 2013

No. of cases Age (years) Gender Infection

5 NA NA NA

1 13 Male No history of infection present

1 10 Male No history of infection present

1 9 Male No history of infection present

No history of autoimmune disorders in family

No history of autoimmune disorders in family

No history of autoimmune disorders in family

Small intestinal biopsy

Partial, subtotal, and total villous atrophy

CD, IBD, CVID, ITP, AIHA, collagenous colitis, Grave’s disease, pancytopenia Subtotal villous atrophy

Total villous atrophy

Subtotal villous atrophy

IgA-tTG PNH/CBS

Levels not mentioned Only one patient was positive for PNH clone; normal cytogenetic study Aplastic anemia

NA Two patients were positive for PNH clone; normal cytogenetic study Aplastic anemia

.205 IU/L Normal

100 IU/L Normal

Biopsy not done because of active GI bleed and low platelet counts .105 IU/L Positive for PNH clone; normal cytogenetic study

Aplastic anemia

Not done; peripheral Aplastic anemia pancytopenia

Study

3 47, 37, 23 All female One patient had Aspergillus and Pseudomonas infection and died Other autoimmune One patient had disorder/s in history of CD in 3 proband or family maternal cousins

Bone marrow examination and biopsy

NA indicates not available; CD, celiac disease; IBD, inflammatory bowel disease; CVID, common variable immunodeficiency; ITP, idiopathic thrombocytopenia; AIHA, autoimmune hemolytic anemia; IgA, gamma A immunoglobulin; tTG, tissue transglutaminase; PNH, paroxysmal nocturnal hemoglobinuria; CBS, chromosomal breakage study; GI, gastrointestinal.

of the population in Northwestern India. Due to recognition of its varied presentations, diarrhea has become a less common mode of presentation (,50% of cases) than it once was [4]. Other presentations include iron-deficiency anemia, osteoporosis, dermatitis herpetiforme, and neurologic and endocrine disorders [5]. Anemia remains the most common hematological manifestation of CD due to many mechanisms and can be the sole presenting symptom. Other hematological manifestations include thrombocytosis and thrombocythemia, leukopenia, thromboembolism, increased bleeding tendency, IgA deficiency, splenic dysfunction, and lymphoma [2,6]. Reviews of the hematological manifestations of CD have highlighted various manifestations; the extremely rare association of CD and AA has not been mentioned [2,6]. Associations between AA and other autoimmune diseases, particularly Graves’ disease, fasciitis, thymoma, or CD, have rarely been reported [7,8]. Table 1 compares the various studies done on the CD-AA association. A total of 10 cases (8 adult and 2 pediatric) of CD associated with AA have been reported in the literature [9–12]. Of the 8 adult cases reported, 5 were diagnosed with CD and AA simultaneously. Three cases had already been diagnosed with CD, and despite a GFD, these patients developed AA. In both the pediatric cases, CD and AA were diagnosed simultaneously; however, in the second case, the diagnosis of AA is doubtful, since a bone marrow

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examination was not done, although cytopenias were present [12]. The age ranges in adult and pediatric cases were 23–47 years and 9–13 years, respectively. All the adult cases were females, and all the pediatric cases were males. Among the adults, of the 3 cases reported by Grey-Davies et al., only one had recurrent bacterial and fungal infections [9]. In the pediatric cases, there was no history of any infection. In a study conducted by Salmeron et al., there was history of multiple autoimmune disorders in family members or in the proband, as shown in Table 1 [10]. A PNH clone was detected in 6.7% of granulocytes and 8% of monocytes in our patient. This was also documented in the studies of Gray-Davies et al. and Salmeron et al. [9,10]. PNH clones are characterized by a deficiency of glycophosphatidylinositol-anchored proteins (CD55 and CD59) on the cell surface due to acquired mutation of the PIG-A gene in one or more hematopoietic stem cells. It may develop de novo (primary PNH) or in the context of other bone marrow disorders such as AA (secondary PNH). About 40%–50% cases of AA have a PNH clone detected at the time of diagnosis. CD has been associated with multiple autoimmune disorders. Autoantibodies can lead to underexpression of the GPI-1–anchored proteins CD55 and CD59 on the cell surface. Acquired deficiencies of complement regulatory molecules in human autoimmune diseases might play a role in the mechanism of cell destruction in PNH [13].

CD is associated with inflammation that is not only intestinal but also systemic. Thus, the hematologic manifestations of the disease likely reflect the interplay between local and systemic factors. The anemia is usually attributable to malabsorption of iron, folic acid, vitamin B12, and other micronutrients, with additional features of anemia of chronic disorders. Deficiencies in vitamin B6, pantothenic acid, and riboflavin have also been suggested as etiologic factors in patients with CD [2]. Copper deficiency has been described in adults and children with CD and may result in anemia and thrombocytopenia [14]. Leukopenia has been reported, with the etiology suggested to be deficiencies of folate, vitamin B12, and copper [15]. Thrombocytopenia may be autoimmune in nature. Severe folic acid and vitamin B12 deficiencies can result in leukopenia, thrombocytopenia, and even as severe pancytopenia [5]. A link with AA is in keeping, as it shares an underlying immune pathological mechanism, with autoreactive T-cells mediating tissue-specific destruction. Constitutional T-regulatory cell (Treg) deficit has been associated with various autoimmune diseases, including cytopenia and autoimmune enteropathy. Mutation in the forkhead box protein P3 is associated with a severe immune disorder: immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome [16]. An acquired Treg deficit has been reported in AA [17]. Inadvertent gluten ingestion can lead to absent or incomplete clinical response, resulting in refractory celiac sprue. Other potential causes, such as autoimmune enteropathy, pancreatic insufficiency, concomitant collagenous colitis, and lymphoma, should be ruled out. In the present case, the long-standing immune dysregulation caused by poor adherence to a GFD might have led to bone marrow suppression. We postulate that the etiology of AA in CD is multifactorial and that there is intricate interplay among various factors, such as autoimmunity and systemic inflammation. Future studies addressing the role of immune dysregulation and the degree of inflammation contributing to the anemia associated with CD are necessary. To conclude, AA, although uncommon in patients with CD, should be suspected with onset of multiple

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A rare association of celiac disease and aplastic anemia: case report of a child and review of literature.

An association between severe aplastic anemia and other autoimmune diseases is rare and has been described in adults for eosinophilic fasciitis, thymo...
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