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Hematologic manifestations of celiac disease
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Abstract
Celiac disease is a common systemic disorder that can have multiple hematologic manifestations. Patients with celiac disease may present to hematologists for evaluation of various hematologic problems prior to receiving a diagnosis of celiac disease. Anemia secondary to malabsorption of iron, folic acid, and/or vitamin B12 is a common complication of celiac disease and many patients have anemia at the time of diagnosis. Celiac disease may also be associated with thrombocytosis, thrombocytopenia, leukopenia, venous thromboembolism, hyposplenism, and IgA deficiency. Patients with celiac disease are at increased risk of being diagnosed with lymphoma, especially of the T-cell type. The risk is highest for enteropathy-type T-cell lymphoma (ETL) and B-cell lymphoma of the gut, but extraintestinal lymphomas can also be seen. ETL is an aggressive disease with poor prognosis, but strict adherence to a gluten-free diet may prevent its occurrence.
Introduction
Celiac disease (CD), or gluten-sensitive enteropathy, is a systemic disorder with protean manifestations. It is a common disease, previously described mainly in children but is now increasingly being diagnosed in persons of all ages.1 In the past, CD was usually considered only in patients who had frank malabsorption characterized by diarrhea, steatorrhea, weight loss, or failure to thrive or in the patient with multiple deficiencies of macronutrients and micronutrients. This could be termed the classic form. It has become clear that many, if not most, patients can present with much more subtle symptoms, often called atypical celiac disease, and often without the classic malabsorption syndrome or even diarrhea. Some, if not many, patients may have silent celiac disease wherein they have no symptoms at all. Dermatitis herpetiformis (DH) is an intensely pruritic immunologic skin disorder that is characterized by gluten sensitivity and, like CD, it responds to withdrawal of gluten from the diet.2
While CD has been considered a relatively rare disease, recent population-screening studies have suggested that it may affect as much as 1% of the population.3⇓⇓–6 The purpose of this review is to summarize the associations of CD with both common and uncommon conditions that may be of interest to hematologists and internists and to provide guidance as to the appropriate means of investigation to aid in identifying CD in a timely fashion.
CD is a common cause of various hematologic disorders, the most common of which is anemia. The anemia of CD is usually due to malabsorption of micronutrients such as iron, folic acid, and vitamin B12. CD is also frequently implicated in the etiology of other blood-count abnormalities, splenic hypofunction, and intestinal lymphomas.7 The hematologic manifestations of DH are less well described but DH has been associated with anemia and splenic dysfunction, and patients with DH have been found to be at increased risk of contracting malignant lymphoma. Additionally, some of the drugs used in the treatment of DH (primarily dapsone) have been associated with side effects such as hemolysis and methemoglobinemia. The hematologic manifestations of CD are summarized in Table 1.
Hematologic manifestations of CD
Diagnosis of celiac disease
The diagnosis of CD is usually made with the aid of a small-bowel biopsy. Pathologic diagnosis based on finding villous atrophy of the small-bowel mucosa is still considered the gold standard of diagnosis.8,9 Serologic testing is based on identifying IgA antibodies against gliadin, endomysium, and tissue transglutaminase. Antigliadin antibodies are less used due to their low sensitivity and specificity.10 A recent systematic review of the diagnostic accuracy of the various available antibody assays revealed that the sensitivity of antiendomysial antibodies (anti-EMAs) and anti–tissue-transglutaminase (anti-tTG) antibodies is more than 90%.11 The pooled sensitivity of the anti-EMA was between 90% and 97%, and anti-tTG antibodies had a pooled sensitivity of 90% to 98%, depending on the methods used and the population studied. Anti-tTG antibodies are the most practical test and is now widely used for diagnosing CD. The co-occurrence of IgA deficiency in 3% to 5% of CD patients poses certain difficulties in using serologic methods for diagnosis. Thus it may be appropriate to measure total IgA levels before concluding that negative serologic tests have excluded CD. Serologic testing using IgG-type anti-tTG antibodies appears to be helpful in diagnosing CD patients with concomitant IgA deficiency.12 A practical diagnostic algorithm is depicted in Figure 1. Patients with a high risk of having CD, such as those with the malabsorption syndrome, should have both serologic tests and an upper endoscopy with intestinal biopsy performed. Patients with a lower risk of having CD, such as patients with anemia only or anemia associated with other subtle features of CD (such as infertility, diarrhea, or type 1 diabetes), may be evaluated with serologic tests initially, followed by intestinal biopsy if the serology is positive.
Diagnosis of celiac disease.
Anemia
Anemia is a frequent finding in patients with CD and may be the presenting feature.13,14 The anemia may be the only abnormality identified.14,15 Anemia was particularly common in patients with untreated CD in the past but is still frequently encountered in undiagnosed adults.15,16 The anemia is usually hypoproliferative, reflecting impaired absorption of essential nutrients like iron and various vitamins. The prevalence of anemia varies greatly according to different reports and has been found in 12% to 69% of newly diagnosed patients with CD.14⇓⇓⇓–18 DH has also been associated with anemia that can be secondary to malabsorption of iron or vitamins or related to the pharmacologic management of DH, especially therapy with dapsone.19,20
Iron-deficiency anemia
Iron-deficiency anemia (IDA) is the most commonly encountered anemia in humans and is usually due to either increased iron loss or impaired absorption of iron.21 IDA is very common in the setting of CD and has been reported in up to 46% of cases of subclinical CD, with a higher prevalence in adults than children.15 Iron deficiency has also been reported in patients with DH.22,23 Iron is absorbed in the proximal small intestine and the absorption is dependent upon several factors, including an intact mucosal surface and intestinal acidity.21 IDA usually manifests as microcytic, hypochromic anemia and patients characteristically have low serum iron levels, elevated total iron-binding capacity, and low ferritin levels.24 Measurements of soluble transferrin receptors (sTfRs) can also be valuable in the evaluation of IDA, and the ratio of sTfR to ferritin may indicate CD in children with refractory IDA.25,26 Iron deficiency that is refractory to therapy can be the sole manifestation of CD, especially in pediatric patients.27⇓–29 The prevalence of CD in patients with refractory IDA may be as high as 20%.30
The iron deficiency in celiac disease primarily results from impaired absorption of iron but there may also be occult blood loss in the gastrointestinal (GI) tract.31,32 Occult gastrointestinal bleeding was detected in 25% to 54% of patients with CD, depending on the degree of villous atrophy, in 1 study.33 Occult GI blood loss was seen in 26.7% of children with CD and appears to respond to treatment with a gluten-free diet GFD, according to another study.34 More-recent studies have, however, suggested that occult GI bleeding in patients with CD may be much less common.35,36
CD is frequently diagnosed in patients referred for evaluation of anemia, and subclinical CD appears to be a relatively common cause of IDA.15,37⇓–39 Studies using serologic tests and small-bowel biopsies in patients referred for evaluation of IDA have reported CD in 0% to 8.7% of patients (Table 2)37⇓⇓⇓⇓⇓⇓⇓⇓–46 These studies are heterogeneous in design and used different methods for diagnosis of CD, often in selected referral populations.
Prevalence of celiac disease in patients with anemia
Two studies evaluated only patients with IDA and 1 of them did not use serologic testing. Biopsy-proven CD was reported in 2.6% to 5% of patients.37,42 Three other studies included patients with anemia other than IDA but the vast majority in all 3 studies suffered from IDA.39,43,44 Serologic evidence of CD was observed in 2.3% to 10.9% of these anemic patients. In 2 of the studies, biopsies were performed on the patients with positive serology, and the prevalence of biopsy-proven CD was 2.3% to 4.7%.39,44
Four studies evaluated the role of upper endoscopy in the evaluation of iron deficiency (Table 2).40,41,45,46 In only 1 of these studies were biopsies performed on all patients evaluated, and 8.7% of patients were found to have CD.45 The other 3 studies showed lower prevalence of CD in patients with IDA, ranging from 0% to 5.7%.40,41,46 One of the studies suggested that history of chronic diarrhea predicted CD as the cause for the anemia.46 Clinicians should consider CD as a possible cause of anemia in all subjects with unexplained IDA, including menstruating women.
Endoscopic markers of CD in patients with IDA have been shown to lack sensitivity for diagnosis and have limited utility in selecting patients for a small-bowel biopsy.47 Duodenal biopsies should be performed even if the duodenal mucosa appears normal to the endoscopist. One recent study has shown that many patients undergoing an endoscopy for anemia do in fact not have a small-bowel biopsy performed.48
In conclusion, IDA is common in CD, and CD is frequently found in patients presenting with IDA. The treatment of IDA associated with CD is primarily a GFD and iron supplementation until the iron stores have been restored. This process can take as long as a year for the hemoglobin to normalize and 2 years for the iron stores to be replete.
Folate deficiency
Folic acid is an essential element of amino acid and nucleic acid metabolism and metabolic regulation.49 Adequate folic acid is required for normal hematopoiesis and development of the nervous system. Folic acid is primarily absorbed in the jejunum, and malabsorption is frequent in diseases of the small intestines.49,50 Deficiency of folic acid usually presents as macrocytic and megaloblastic anemia, but abnormalities of the other cell lines are common. Concomitant iron deficiency as can be seen in CD can result in atypical findings on the blood smear, and patients with deficiencies of folate and vitamin B12 may not present with the characteristic macrocytosis. Examination of the blood smear may reveal a dimorphic picture reflecting the effects of both deficiencies. Severe folic-acid deficiency can result in a decrease in both leukocytes and platelets and even manifest as severe pancytopenia. The diagnosis is usually made by measuring serum folate and red-cell folate levels. Serum folate is highly dependent on folate intake and is frequently increased in patients with deficiency of vitamin B12.51 Red-cell folate is not specific for folate deficiency, as it can be decreased in patients with vitamin B12 deficiency, but red-cell folate is less subject to transient changes secondary to variations in folate intake.51 Elevated serum homocysteine level can be helpful in diagnosing folate deficiency but its sensitivity is somewhat less for vitamin B12 deficiency.52,53
Previous studies have shown that many untreated patients with CD are folate deficient.13,54 Two small studies found that folate deficiency is a common finding in children but it does not usually result in anemia.55,56 More-recent studies have confirmed that folic-acid deficiency continues to be a frequent finding in subjects with newly diagnosed CD and even in adolescents and young adults with CD detected by screening.44,57,58 Folate deficiency has also been reported in association with DH.23,59 Homocysteine levels are commonly elevated in patients with CD at the time of diagnosis and may serve as a diagnostic clue.60 We recommend folate supplementation in conjunction with a GFD for treatment of these patients.
Vitamin B12 deficiency
Vitamin B12 is an essential cofactor and a coenzyme in multiple biochemical pathways, including the pathways of DNA and methionine synthesis. While the main site of vitamin B12 absorption is the distal ileum (where it is absorbed bound to intrinsic factor), a small proportion is also absorbed passively along the entire small bowel.61 Deficiency of vitamin B12 is common in CD and frequently results in anemia. Malabsorption of vitamin B12 resulting in anemia has also been described in patients with DH.20 The cause of the vitamin B12 deficiency in CD is not known but may include decreased gastric acid, bacterial overgrowth, autoimmune gastritis, decreased efficiency of mixing with transfer factors in the intestine, or perhaps subtle dysfunction of the distal small intestine.62,63
Recent studies suggested that 8% to 41% of previously untreated subjects with CD were deficient in vitamin B12.64,65 This is in accordance with an older study that reported 11% incidence of vitamin B12 deficiency in 50 consecutively diagnosed patients with CD.54 Vitamin B12 deficiency should be considered in all CD patients with hematologic and neurologic abnormalities. Measurements of vitamin B12 levels can be misleading and difficult to interpret, especially if the results fall within the lower range of normal or if there is a coexisting deficiency of folic acid.66 Elevated levels of serum methylmalonic acid (MMA) may enhance the diagnostic accuracy under these circumstances.67 Patients with vitamin B12 deficiency should receive therapy with parenteral vitamin B12. Even though studies have suggested that oral vitamin B12 may be as effective as parenteral vitamin B12, no such studies have been performed in patients with vitamin B12 deficiency secondary to CD.68
Deficiency of other micronutrients
The anemia seen in CD can also result from malabsorption of various micronutrients necessary for normal hematopoiesis. Copper deficiency has been described in adults and children with CD and may result in anemia and thrombocytopenia.69⇓⇓–72 We have recently diagnosed adult CD patients with symptomatic copper deficiency (T.R.H. and J.A.M., unpublished data, October 2006). Deficiencies in vitamin B6, pantothenic acid, and riboflavin have also been suggested as etiologic factors in patients with CD but recent data are lacking.13
Thrombocytopenia and thrombocytosis
Thrombocytopenia has rarely been reported in patients with CD and may be autoimmune in nature.72⇓⇓⇓⇓–77 Thrombocytopenia associated with CD has been reported in association with keratoconjunctivitis and choroidopathy, suggesting an autoimmune pathophysiology.73,74 The best therapy for thrombocytopenia in association with CD is uncertain, given the rarity of the problem, but a GFD may result in normalization of the platelet count in some cases.72
Thrombocytosis in association with CD appears to be more common than thrombocytopenia, occurring in up to 60% of patients.78⇓⇓–81 The exact etiology of the thrombocytosis is unknown but it may be secondary to inflammatory mediators or, in some cases, secondary to iron-deficiency anemia or functional hyposplenia.82 The thrombocytosis may resolve after institution of a GFD.79,80
Leukopenia/neutropenia
Abnormally low white-blood count has been reported in a few children with CD.72 These findings appear to be rare, and deficiencies of both folate and copper have been implicated as possible etiology for the leukopenia.69,70,83 The data on treatment of these patients are extremely limited but we recommend initiating a GFD and supplementing these patients' diets with oral copper sulfate if there is evidence of copper deficiency.
Venous and arterial thromboembolism
Venous thrombosis has been reported in CD and may be the presenting feature. Hyperhomocysteinemia is a frequent finding in CD and may be related to an increased tendency to form clots.60 Increased levels of thrombin-activatable fibrinolysis inhibitor (TAFI) have recently been reported in patients with inflammatory bowel disease and CD.84 Elevated levels of TAFI have been shown to be a risk factor for venous thromboembolism.85 Decreased levels of the K vitamin–dependent anticoagulant proteins, protein S and C, has recently been suggested as a causative factor in thrombosis associated with CD.86 Not all studies support the link between CD and hypercoagulability, however.87 The clinical spectrum of thromboembolism observed in patients with CD is variable, but most cases appear to involve the venous circulation.88⇓–90 Only a few case reports have included patients with thrombosis on the arterial side of the circulation, and in those cases the role of CD in the mechanism of the thrombosis was uncertain.91⇓–93
Coagulopathy
CD can be associated with abnormalities in coagulation factors resulting in an abnormal bleeding tendency. Malabsorption of vitamin K is common in chronic gastrointestinal disorders. A decrease in K vitamin–dependent coagulation factors results in prolongation of coagulation assays such as the prothrombin time (PT), international normalized ratio (INR), and the activated partial thromboplastin time (aPTT).94,95 A recent study found that 18.5% of untreated CD patients had prolongation of PT and these patients were also more likely to present with anemia and abnormal iron proteins.96 Symptomatic patients were also more likely to present with a prolonged PT. Patients with CD occasionally present with hemorrhagic diathesis as their first symptom. The resulting hemorrhage can be minimal to severe.97⇓–99 Therapy is initially parenteral vitamin K, but occasionally plasma products may be needed in bleeding patients. Malabsorption of vitamin K is very uncommon in CD patients who do not have ongoing malabsorption of other nutrients.96 The treatment primarily consists of initiating a GFD and correcting the vitamin K deficiency.
Splenic dysfunction
Splenic atrophy in patients suffering from malabsorption secondary to nontropical sprue was first described in 1923.100 Multiple cases of splenic atrophy in association with malabsorption and CD or DH were subsequently published.101,102 Unsuspected CD may be found when patients with evidence of hyposplenism are investigated for the condition.103 Splenic hypofunction can be demonstrated using scintigraphy and measurements of the clearance of labeled heat-damaged red cells.101 A commonly used method of assessing splenic function in patients with CD is to count “pitted” erythrocytes by interference contrast microscopy.104 This method has the advantage of being simple to perform but unfortunately it is labor intensive and many laboratories do not routinely offer this test. A pitted-erythrocyte count of more than 2% to 4% is indicative of hyposplenism.104⇓–106 The presence of Howell-Jolly bodies, acanthocytes, and target cells is suggestive of hyposplenism but may not be apparent in patients with milder forms of hyposplenism (Figure 2).107,108
Blood smear showing characteristic findings of hyposplenism such as Howell-Jolly bodies, acanthocytes, and target cells. Image was observed using an Olympus Provis AX70 microscope equipped with an Olympus PlanApo 60 ×/1.40 numerical aperture oil objective (Olympus, Tokyo, Japan). Resolve high-viscosity immersion oil was used as imaging medium, and cells were stained with Wright-Giemsa. Image was acquired using a Nikon DXM 1200 digital camera and Nikon ACT-1 software version 2.62 (Nikon, Melville, NY).
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