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.

Table 1

Hematologic manifestations of CD

Problem Frequency Comments 
Anemia: iron deficiency, folate deficiency, vitamin B12 deficiency, and other nutritional deficiencies Common The anemia is most commonly secondary to iron deficiency but may be multifactorial in etiology. Low serum levels of folate and vitamin B12 without anemia are frequently seen. Anemia due to other deficiencies appears to be rare. 
Thrombocytopenia Rare May be associated with other autoimmune phenomena 
Thrombocytosis Common May be secondary to iron deficiency or hyposplenism 
Thromboembolism Uncommon Etiology is unknown but may be related to elevated levels of homocysteine or other procoagulants. 
Leukopenia/neutropenia Uncommon Can be autoimmune or secondary to deficiencies of folate, vitamin B12, or copper 
Coagulopathy Uncommon Malabsorption of vitamin K 
Hyposplenism Common Rarely associated with infections 
IgA deficiency Common May be related to anaphylactic transfusion reactions 
Lymphoma Uncommon The risk is highest for intestinal T-cell lymphomas 
Problem Frequency Comments 
Anemia: iron deficiency, folate deficiency, vitamin B12 deficiency, and other nutritional deficiencies Common The anemia is most commonly secondary to iron deficiency but may be multifactorial in etiology. Low serum levels of folate and vitamin B12 without anemia are frequently seen. Anemia due to other deficiencies appears to be rare. 
Thrombocytopenia Rare May be associated with other autoimmune phenomena 
Thrombocytosis Common May be secondary to iron deficiency or hyposplenism 
Thromboembolism Uncommon Etiology is unknown but may be related to elevated levels of homocysteine or other procoagulants. 
Leukopenia/neutropenia Uncommon Can be autoimmune or secondary to deficiencies of folate, vitamin B12, or copper 
Coagulopathy Uncommon Malabsorption of vitamin K 
Hyposplenism Common Rarely associated with infections 
IgA deficiency Common May be related to anaphylactic transfusion reactions 
Lymphoma Uncommon The risk is highest for intestinal T-cell lymphomas 

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.

Figure 1

Diagnosis of celiac disease.

Figure 1

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.

Table 2

Prevalence of celiac disease in patients with anemia

Study and year published No. of patients Positive by serology, % Positive on biopsy, % Comments 
McIntyre and Long,38  1993 114 n/a 2.6 IDA. Not all patients were biopsied. 
Corazza et al,37  1995 200 IDA. All patients with positive serology were biopsied. 
Unsworth et al,42  2000 483 6.6 4.6 Four hundred eighty-three of 1380 blood donors with anemia were offered serologic screening; the majority of anemic CD patients had IDA. Not all seropositive patients were biopsied. 
Haslam et al,43  2001 216 2.3 n/a Pregnant women with anemia. Four of 5 anemic women with positive serology had IDA. 
Howard et al,44  2002 258 10.9 4.7 The majority of patients had IDA. Four percent had folate deficiency. Not all seropositive patients were biopsied. 
Ransford et al,39  2002 484 3.5 2.3 All patients with hypochromic and microcytic anemia. Not all seropositive patients were biopsied. 
Studies using endoscopy and small-bowel biopsies in patients with IDA     
    Bini et al,41  1998 186 n/a No patient was diagnosed with CD. 
    Kepczyk and Kadakia,40  1995 70 n/a 5.7 Not all patients were biopsied. 
    Grisolano et al,45  2004 103 n/a 8.7 All patients were biopsied. 
    Mandal et al,46  2004 504 n/a 1.8 Not all patients were biopsied. 
Study and year published No. of patients Positive by serology, % Positive on biopsy, % Comments 
McIntyre and Long,38  1993 114 n/a 2.6 IDA. Not all patients were biopsied. 
Corazza et al,37  1995 200 IDA. All patients with positive serology were biopsied. 
Unsworth et al,42  2000 483 6.6 4.6 Four hundred eighty-three of 1380 blood donors with anemia were offered serologic screening; the majority of anemic CD patients had IDA. Not all seropositive patients were biopsied. 
Haslam et al,43  2001 216 2.3 n/a Pregnant women with anemia. Four of 5 anemic women with positive serology had IDA. 
Howard et al,44  2002 258 10.9 4.7 The majority of patients had IDA. Four percent had folate deficiency. Not all seropositive patients were biopsied. 
Ransford et al,39  2002 484 3.5 2.3 All patients with hypochromic and microcytic anemia. Not all seropositive patients were biopsied. 
Studies using endoscopy and small-bowel biopsies in patients with IDA     
    Bini et al,41  1998 186 n/a No patient was diagnosed with CD. 
    Kepczyk and Kadakia,40  1995 70 n/a 5.7 Not all patients were biopsied. 
    Grisolano et al,45  2004 103 n/a 8.7 All patients were biopsied. 
    Mandal et al,46  2004 504 n/a 1.8 Not all patients were biopsied. 

n/a indicates not available.

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 

Figure 2

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).

Figure 2

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).

The prevalence of hyposplenism in patients with CD is not well known. Croese et al78  found evidence of hyposplenism in 15 (21%) of 70 of their patients with CD. Other investigators have reported an incidence of 30% to 60% in adults with CD.108-111  Hyposplenism appears to be more common when CD coexists with other autoimmune disorders such as insulin-dependent diabetes mellitus, autoimmune thyroiditis, and connective-tissue disorders and when CD is complicated by lymphoma, refractory CD, or ulcerative jejunitis (59%-80%) than uncomplicated CD (19%), according to a recent report from Italy (Di Sabatino et al112 ). O'Grady et al113  studied 177 patients with CD using pitted-erythrocyte counts. Seventy-six percent were found to have hyposplenism as manifested by the presence of pitted erythrocytes. Higher counts were found in older patients and in patients who had more-pronounced morphologic findings on a small-bowel biopsy. Adherence to a GFD was associated with a decrease in pitted-erythrocyte counts, suggesting that the hyposplenism may be reversible in some patients who maintain such a diet. Other investigations have not supported this and have, on the contrary, suggested that splenic hypofunction may be irreversible in adult patients with CD.114  Hyposplenism appears to be much less common in children with CD, as reported by Corazza et al.115  In their report of 37 children with CD, none were found to have the elevated pitted-erythrocyte count suggestive of hyposplenism. Various autoantibodies including antinuclear antibodies, anti–smooth-muscle antibodies, and antimitochondrial antibodies have been found in patients with CD and hyposplenism.116 

The risks associated with hyposplenism in patients with CD are unknown. Infectious complications appear to be uncommon, given the reported frequency of hyposplenism. Several case reports of severe and even fatal bacterial infections in such patients have, however, been published.117-119  Cavitating lesions in mesenteric lymph nodes and the lungs have also been reported in patients with CD and hyposplenism and can be associated with significant mortality, presumably due to an overwhelming infection.120-123  The etiology of these cavitating lesions is unknown but some authors have suggested that immune complexes result in endothelial damage leading to intranodal hemorrhagic necrosis.123,124 

It is not known whether immunizations against encapsulated bacteria prevent infectious complications in CD patients with splenic dysfunction, and no firm conclusions can be drawn regarding routine immunizations in these patients. It seems reasonable to evaluate patients with CD for evidence of hyposplenism as manifested by characteristic blood-smear findings such as Howell-Jolly bodies, acanthocytes, and target cells. The blood-smear examination lacks sensitivity for detecting hyposplenism but can easily be performed in most laboratories. Patients with signs of hyposplenism should be treated in a similar fashion as patients who are asplenic because of other reasons such as elective or emergency splenectomy. Immunization against the encapsulated bacteria Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis is recommended.125-127  Younger patients should be considered for prophylactic therapy with antibiotics and all patients should receive education on the infectious complications associated with hyposplenism.125-127  A small study has suggested that the antibody response to the polyvalent pneumococcal vaccine is intact in patients with CD.128 

IgA deficiency

CD and selective IgA deficiency are associated more often than expected by chance alone. Approximately 2% to 3% of CD patients have IgA deficiency, and up to 8% of IgA-deficient individuals may have CD.12,129,130  Partial IgA deficiency has recently been described in 2 patients with DH.131  Patients with IgA deficiency have up to a 10-fold higher risk of suffering from CD, and the prevalence of IgA deficiency among CD patients is 10- to 16-fold what is to be expected in the general population.129,132  The importance of the association is 2-fold. Firstly, IgA-deficient individuals are prone to other enteric conditions such as inflammatory bowel disease or chronic parasite infections, especially giardiasis, which could mimic CD. Secondly, patients with IgA deficiency are at risk of developing anaphylactic transfusion reactions that may be life threatening if the recipient has anti-IgA antibodies.133 

Lymphoma

The association of CD and intestinal lymphoma is well known.7,134  This association was first described in 1937 by Fairley and Mackie.174  Initially it was thought that the enteropathy and malabsorption that occurred was secondary to the lymphoma itself, a concept that persisted for many decades until it became apparent that the CD preceded the lymphoma.134  Later reports suggested that lymphoma involving the GI tract was relatively common and possibly a major cause of death in patients with CD.135-137  Multiple studies now support the association of CD and lymphomas.138-149  The association between CD and intestinal T-cell non-Hodgkin lymphoma (NHL), called enteropathy-associated T-cell lymphoma (EATL), appears to be particularly strong but these aggressive lymphomas are rare. The current World Health Organization (WHO) classification of lymphomas has recommended the term enteropathy-type T-cell lymphoma (ETL).7  In this article we use the terms ETL and EATL synonymously.

ETLs are rare lymphomas accounting for less than 1% of all NHL.150  ETL frequently presents as multifocal lymphoma with ulcerative lesions and commonly results in bowel perforation or other abdominal emergencies.151,152  The malignant cells of ETL appear to arise as clonal proliferations of phenotypically abnormal intraepithelial lymphocytes (IELs).153,154  Loss of CD8 expression by IELs is characteristic for early ETL. Patients with refractory CD have been found to harbor clonal IELs that share a similar immunophenotype to ETL, but there can be substantial heterogeneity in the phenotype of IELs.154-156  The IELs seen in refractory CD have been shown to express cytosolic CD3 (cCD3) and to be monoclonal when T-cell receptor gene-rearrangement studies are performed.157,158  Loss of CD8 expression by IELs is characteristic for early ETL.156,157  Interleukin-15 appears to be an important signaling molecule in driving the expansion of the IELs.159  The monoclonal IELs seem to be neoplastic, and accumulation of these phenotypically aberrant IELs appears to be the first step in the pathogenesis of ETL.154  The etiology of this increase in monoclonal IELs is unknown but may be secondary to chromosomal gains or mutations of tumor-suppressor genes.154  ETL cells typically express CD3, CD7, and CD103; they may express CD30 but are usually negative for CD4, CD5, and CD8.154  Sometimes the ETL cells lack CD3 expression.160  Immunostaining for CD3, CD8, and CD4 may be helpful for initial screening, but molecular-clonality analysis is required for confirmation in the cases suspected to have early ETL.

The risk of developing an NHL as a complication of CD is not fully known, but recent epidemiologic studies suggest a relative risk ranging from 2.1 to 6.6.144,145,148,149,161-164  The risk of contracting lymphoma in the setting of DH appears to be increased to a similar degree.145,162,165  Other studies have indicated that there may be a much higher risk, ranging from a 15-fold up to 100-fold increase.136,138-140,166  Ascertainment bias may account for some of the difference noted in these studies. There is a strong relationship between CD and ETL. One study showed that the odds ratio (OR) of being diagnosed with ETL was 19.2 among patients with CD.144  A more recent Swedish study (Smedby et al148 ) showed the standardized incidence ratio (SIR) for ETL to be 51. Even though the relative risk of developing ETL is most significantly increased in CD patients, non-ETLs, including B-cell NHL and extraintestinal T-cell NHL, are more common in aggregate than ETL in these patients.148,149,163 

Several recent studies on the relationship between NHL and CD deserve special mention. Catassi et al144  reported the results of a case-control study attempting to quantify the risk of NHL in patients with CD. The study included 653 patients with NHL. Six of the patients had CD: 3 had lymphoma of B-cell origin and 3 had lymphoma of T-cell origin. The control group in this series consisted of 5720 adults participating in 2 mass CD-screening studies. The researchers were able to calculate the age- and sex-adjusted OR for developing lymphoma in patients with CD. The OR for developing NHL at any primary site was 3.1. The ORs for primary gut lymphoma and T-cell lymphoma were substantially higher, at 16.9 and 19.2, respectively.144  These calculations were based on very low numbers of lymphoma cases, however.

Using a different approach, Askling et al145  observed an SIR of 5.9 for developing a lymphoma among CD patients. Their study evaluated 11 019 hospitalized CD patients identified through the national Swedish hospital inpatient registry. Forty-four cases of lymphoma were diagnosed in these patients, using a linkage between the inpatient registry and the national cancer and death registries. Patients with incident cancers occurring within 12 months from hospital dismissal were excluded from the analysis. Patients hospitalized at a younger age had a lower risk of being diagnosed with lymphoma in the subsequent years than the patients hospitalized at an older age.145  The relative risk also decreased over calendar time, perhaps suggesting that early institution of a GFD may decrease the risk of contracting lymphoma secondary to CD. Given the fact that these patients were hospitalized, they may not represent the group of CD patients with milder forms of the disease. A recently published 30-year population-based study from Finland (Viljamaa et al162 ) followed 1147 patients diagnosed with CD or DH at a single medical center over 17 245 person-years. This study reported an SIR of 3.2 and 6.0 for developing NHL in patients diagnosed with CD or DH, respectively. The SIR was slightly lower than in other reports, and the study provided further support to the theory that compliance with a GFD protects against the development of lymphoma in patients with CD.

A large population-based case-control study undertaken in both Denmark and Sweden (Smedby et al161 ) assessed the risk of NHL in patients with a variety of autoimmune disorders, including CD. Participants including 3055 patients with NHL identified through a national hospital and tumor registries and 3187 matched controls were surveyed regarding a history of autoimmune disorders. Nineteen patients with NHL and 9 controls reported a previous diagnosis of CD. CD was associated with a doubled risk of NHL with an OR of 2.1. The OR for diffuse large B-cell lymphoma (DLBCL) was 2.8 in contrast to an OR of 17 for T-cell lymphoma. Ten lymphomas were extranodal, including 5 involving the GI tract. The OR for GI NHL was estimated to be 12 in comparison with an OR of 1.7 for non-GI NHL. Another study published earlier this year reports a similar magnitude of risk for CD patients contracting NHL.163  This European, prospective, multicenter case-control study identified 1446 patients with newly diagnosed NHL who were willing to be screened for CD by serology and subsequently be evaluated with a small-bowel biopsy. Thirteen patients had previously been diagnosed with CD and an additional 4 patients were found to have CD after the diagnosis of NHL was made. After adjusting for age and sex, the OR for contracting NHL in the setting of CD was 2.6. Of the 17 patients, 8 had ETL and another 8 had DLBCL. The OR for small-bowel NHL and ETL were 11.8 and 28, respectively. Table 3 summarizes the findings of several recent studies evaluating the increased risk of being diagnosed with a lymphoma in patients with CD.

Table 3

Recent studies evaluating the risk of lymphoma in patients with celiac disease

Study and year published Risk of being diagnosed with lymphoma
 
Suggestion that GFD may be protective 
All NHL ETL Other NHL 
Catassi et al,144  2002 OR = 3.1 NR Gut NHL: OR = 16.9; Any T-cell NHL: OR = 19.2 NR 
Askling et al,145  2002 SIR = 5.9 NR NR Yes 
Green et al,149  2003 SMR = 5.3-9.1 NR NR No 
Card et al,164  2004 SIR = 5.8 NR Gut NHL: SIR = 40.5 NR 
Smedby et al,148  2005 SIR = 6.6 NR Gut NHL: SIR = 24; Any T-cell NHL: SIR = 51; Non-GI NHL: SIR = 3.6 NR 
Mearin et al,163  2006* OR = 2.6 OR = 28 Gut NHL: OR = 11.8 NR 
Viljamaa et al,162  2006 SIR = 3.2 NR NR Yes 
Smedby et al,161  2006 OR = 2.1 NR Gut NHL: OR = 12; Any T-cell NHL: OR = 17; DLBCL: OR = 2.8 No 
Study and year published Risk of being diagnosed with lymphoma
 
Suggestion that GFD may be protective 
All NHL ETL Other NHL 
Catassi et al,144  2002 OR = 3.1 NR Gut NHL: OR = 16.9; Any T-cell NHL: OR = 19.2 NR 
Askling et al,145  2002 SIR = 5.9 NR NR Yes 
Green et al,149  2003 SMR = 5.3-9.1 NR NR No 
Card et al,164  2004 SIR = 5.8 NR Gut NHL: SIR = 40.5 NR 
Smedby et al,148  2005 SIR = 6.6 NR Gut NHL: SIR = 24; Any T-cell NHL: SIR = 51; Non-GI NHL: SIR = 3.6 NR 
Mearin et al,163  2006* OR = 2.6 OR = 28 Gut NHL: OR = 11.8 NR 
Viljamaa et al,162  2006 SIR = 3.2 NR NR Yes 
Smedby et al,161  2006 OR = 2.1 NR Gut NHL: OR = 12; Any T-cell NHL: OR = 17; DLBCL: OR = 2.8 No 

GFD indicates gluten-free diet; NHL, non-Hodgkin lymphoma; ETL, enteropathy-type T-cell lymphoma; SIR, standardized incidence ratio; SMR, standardized morbidity ratio; NR, not reported; and DLBCL, diffuse large B-cell lymphoma.

*

There was a marked difference in the observed odds ratio for lymphoma between centers in this multicenter European study.

Multiple studies suggest that there may be a reduction of risk with long-term adherence to a GFD.138,139,142,143,145,146,162  A GFD may also reduce the risk in patients with DH.167,168  The benefit of a GFD may be slow in accruing in those who are diagnosed later in life and, in at least 1 study, the risk of NHL seemed to persist.149 

The risk of being diagnosed with an NHL is thus clearly increased in patients with CD but the risk appears less than earlier reports suggested. The highest increase in risk relates to T-cell intestinal lymphomas (ETLs), but these uncommon lymphomas constitute a minority of all CD-related lymphomas. The risk of acquiring a B-cell lymphoma of the gut or extraintestinal T-cell lymphoma is also increased in CD patients but less than with ETL, and collectively the non-ETLs account for the majority of CD-associated lymphomas.

Therapy for CD-associated lymphoma is not different from the therapy used in similar lymphomas in patients without CD. However, the presence of CD may raise issues of malnutrition, an increased risk of infection due to concomitant hyposplenism, and increased likelihood of diarrhea or other consequences of CD. Combination chemotherapy is most frequently used, and the choice of regimen depends on the lineage of the lymphoma. B-cell lymphomas are usually treated with combinations such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with rituximab. T-cell–derived lymphomas have been more challenging to treat. Case series of patients with NHL associated with CD have yielded variable results but suggested that selected patients may enjoy prolonged survival.148,151,152,169,170  One study suggested that the prognosis of stage IV NHL was worse in patients with CD compared with those without CD.169 

Therapy of ETL is currently unsatisfactory, with a 5-year survival ranging from 11% to 20% in 2 studies and a 2-year survival of 28% according to another study.151,152,171  Survival of patients with T-cell intestinal lymphoma appears to be inferior to the survival of patients with intestinal B-cell lymphoma and patients with other types of peripheral T-cell lymphomas.171,172  The chemotherapy regimens that have been used for treatment of CD-associated T-cell lymphomas are very heterogeneous, mostly involving CHOP or similar anthracycline-based regimens.151  A recent study evaluated the efficacy of CHOP with the addition of etoposide (CHOEP) and reported a disappointingly low response rate and significant toxicities.173 

Conclusion

Celiac disease is a frequent cause of hematologic disorders. Anemia and hyposplenism may be the most common hematologic complications. The anemia is most commonly secondary to iron deficiency but deficiencies of folate, vitamin B12, and other micronutrients have been implicated as well. It seems reasonable to obtain a small-bowel biopsy in all patients with iron-deficiency anemia undergoing an upper endoscopy, regardless of the endoscopic findings. The hyposplenism complicating CD is rarely associated with serious infectious complications but it is appropriate to immunize patients against encapsulated bacteria if there is evidence of splenic hypofunction. The risk of lymphoma associated with CD has been overestimated in the past but current estimates suggest that the relative risk is between 3 and 6. The risk is highest for T-cell lymphomas of the gastrointestinal tract (EATL) and other non-Hodgkin lymphomas of the GI tract.

Conflict-of-interest disclosure: the authors declare no competing financial interests.

Contribution: J.A.M. provided the concept; T.R.H., M.R.L., and J.A.M. designed the review; T.R.H. wrote the first draft; and T.R.H., M.R.L., and J.A.M. edited the revision and gave final approval.

Acknowledgments

Thanks to David J. Inwards, MD, and Ahmet Dogan, MD, PhD, for reviewing the section on lymphoma.

This work was supported by National Institutes of Health (NIH) grants DK 71003 and DK 57892 (J.A.M.).

References

References
1
Green PH and Jabri B. Coeliac disease.
Lancet
2003
;
362
:
383
–391.
2
Nicolas ME, Krause PK, Gibson LE, Murray JA. Dermatitis herpetiformis.
Int J Dermatol
2003
;
42
:
588
–600.
3
Maki M, Mustalahti K, Kokkonen J, et al. Prevalence of celiac disease among children in Finland.
N Engl J Med
2003
;
348
:
2517
–2524.
4
Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
Arch Intern Med
2003
;
163
:
286
–292.
5
West J, Logan RF, Hill PG, et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England.
Gut
2003
;
52
:
960
–965.
6
Bingley PJ, Williams AJ, Norcross AJ, et al. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study.
BMJ
2004
;
328
:
322
–323.
7
Brousse N and Meijer JW. Malignant complications of coeliac disease.
Best Pract Res Clin Gastroenterol
2005
;
19
:
401
–412.
8
Green PHR and Jabri B. Celiac disease.
Annu Rev Med
2006
;
57
:
207
–221.
9
Jones RB, Robins GG, Howdle PD. Advances in celiac disease.
Curr Opin Gastroenterol
2006
;
22
:
117
–123.
10
Green PH, Rostami K, Marsh MN. Diagnosis of coeliac disease.
Best Pract Res Clin Gastroenterol
2005
;
19
:
389
–400.
11
Rostom A, Dube C, Cranney A, et al. The diagnostic accuracy of serologic tests for celiac disease: a systematic review.
Gastroenterology
2005
;
128
:
S38
–S46.
12
Lenhardt A, Plebani A, Marchetti F, et al. Role of human-tissue transglutaminase IgG and anti-gliadin IgG antibodies in the diagnosis of coeliac disease in patients with selective immunoglobulin A deficiency.
Dig Liver Dis
2004
;
36
:
730
–734.
13
Hoffbrand AV. Anaemia in adult coeliac disease.
Clin Gastroenterol
1974
;
3
:
71
–89.
14
Unsworth DJ, Lock FJ, Harvey RF. Iron-deficiency anaemia in premenopausal women.
Lancet
1999
;
353
:
1100
.
15
Bottaro G, Cataldo F, Rotolo N, Spina M, Corazza GR. The clinical pattern of subclinical/silent celiac disease: an analysis on 1026 consecutive cases.
Am J Gastroenterol
1999
;
94
:
691
–696.
16
Kolho KL, Farkkila MA, Savilahti E. Undiagnosed coeliac disease is common in Finnish adults.
Scand J Gastroenterol
1998
;
33
:
1280
–1283.
17
Hin H, Bird G, Fisher P, Mahy N, Jewell D. Coeliac disease in primary care: case finding study.
BMJ
1999
;
318
:
164
–167.
18
Lo W, Sano K, Lebwohl B, Diamond B, Green PH. Changing presentation of adult celiac disease.
Dig Dis Sci
2003
;
48
:
395
–398.
19
Gawkrodger DJ, Ferguson A, Barnetson RS. Nutritional status in patients with dermatitis herpetiformis.
Am J Clin Nutr
1988
;
48
:
355
–360.
20
Kastrup W, Mobacken H, Stockbrugger R, Swolin B, Westin J. Malabsorption of vitamin B12 in dermatitis herpetiformis and its association with pernicious anaemia.
Acta Med Scand
1986
;
220
:
261
–268.
21
Andrews NC. Disorders of iron metabolism and heme synthesis. In Greer JP, Foerster J, Lukens JN, Rodgers GM, Paraskevas F, Glader B (Eds.).
Wintrobe's Clinical Hematology
2004
; 11th ed Philadelphia, PA Lippincott Williams & Wilkins Vol
1
: pp.
979
–1009.
22
Kastrup W, Magnusson B, Mobacken H, Swolin B, Solvell L. Iron absorption in patients with dermatitis herpertiformis.
Acta Derm Venereol
1977
;
57
:
407
–412.
23
Fry L, Keir P, McMinn RM, Cowan JD, Hoffbrand AV. Small-intestinal structure and function and haematological changes in dermatitis herpetiformis.
Lancet
1967
;
2
:
729
–733.
24
Cook JD. Diagnosis and management of iron-deficiency anaemia.
Best Pract Res Clin Haematol
2005
;
18
:
319
–332.
25
Labbe RF and Dewanji A. Iron assessment tests: transferrin receptor vis-a-vis zinc protoporphyrin.
Clin Biochem
2004
;
37
:
165
–174.
26
De Caterina M, Grimaldi E, Di Pascale G, et al. The soluble transferrin receptor (sTfR)-ferritin index is a potential predictor of celiac disease in children with refractory iron deficiency anemia.
Clin Chem Lab Med
2005
;
43
:
38
–42.
27
Garrido C, Gaya J, Liompart A, et al. [Prevalence of monosymptomatic celiac disease in patients with iron deficiency anemia].
Gastroenterol Hepatol
1997
;
20
:
172
–174.
28
Mody RJ, Brown PI, Wechsler DS. Refractory iron deficiency anemia as the primary clinical manifestation of celiac disease.
J Pediatr Hematol Oncol
2003
;
25
:
169
–172.
29
Economou M, Karyda S, Gombakis N, Tsatra J, Athanassiou-Metaxa M. Subclinical celiac disease in children: refractory iron deficiency as the sole presentation.
J Pediatr Hematol Oncol
2004
;
26
:
153
–154 author reply 154.
30
Carroccio A, Iannitto E, Cavataio F, et al. Sideropenic anemia and celiac disease: one study, two points of view.
Dig Dis Sci
1998
;
43
:
673
–678.
31
de Vizia B, Poggi V, Conenna R, Fiorillo A, Scippa L. Iron absorption and iron deficiency in infants and children with gastrointestinal diseases.
J Pediatr Gastroenterol Nutr
1992
;
14
:
21
–26.
32
Kosnai I, Kuitunen P, Siimes MA. Iron deficiency in children with coeliac disease on treatment with gluten-free diet: role of intestinal blood loss.
Arch Dis Child
1979
;
54
:
375
–378.
33
Fine KD. The prevalence of occult gastrointestinal bleeding in celiac sprue.
N Engl J Med
1996
;
334
:
1163
–1167.
34
Shamir R, Levine A, Yalon-Hacohen M, et al. Faecal occult blood in children with coeliac disease.
Eur J Pediatr
2000
;
159
:
832
–834.
35
Logan RF, Howarth GF, West J, Shepherd K, Robinson MH, Hardcastle JD. How often is a positive faecal occult blood test the result of coeliac disease?
Eur J Gastroenterol Hepatol
2003
;
15
:
1097
–1100.
36
Mant MJ, Bain VG, Maguire CG, Murland K, Yacyshyn BR. Prevalence of occult gastrointestinal bleeding in celiac disease.
Clin Gastroenterol Hepatol
2006
;
4
:
451
–454.
37
Corazza GR, Valentini RA, Andreani ML, et al. Subclinical coeliac disease is a frequent cause of iron-deficiency anaemia.
Scand J Gastroenterol
1995
;
30
:
153
–156.
38
McIntyre AS and Long RG. Prospective survey of investigations in outpatients referred with iron deficiency anaemia.
Gut
1993
;
34
:
1102
–1107.
39
Ransford RA, Hayes M, Palmer M, Hall MJ. A controlled, prospective screening study of celiac disease presenting as iron deficiency anemia.
J Clin Gastroenterol
2002
;
35
:
228
–233.
40
Kepczyk T and Kadakia SC. Prospective evaluation of gastrointestinal tract in patients with iron-deficiency anemia.
Dig Dis Sci
1995
;
40
:
1283
–1289.
41
Bini EJ, Micale PL, Weinshel EH. Evaluation of the gastrointestinal tract in premenopausal women with iron deficiency anemia.
Am J Med
1998
;
105
:
281
–286.
42
Unsworth DJ, Lock RJ, Harvey RF. Improving the diagnosis of coeliac disease in anaemic women.
Br J Haematol
2000
;
111
:
898
–901.
43
Haslam N, Lock RJ, Unsworth DJ. Coeliac disease, anaemia and pregnancy.
Clin Lab
2001
;
47
:
467
–469.
44
Howard MR, Turnbull AJ, Morley P, Hollier P, Webb R, Clarke A. A prospective study of the prevalence of undiagnosed coeliac disease in laboratory defined iron and folate deficiency.
J Clin Pathol
2002
;
55
:
754
–757.
45
Grisolano SW, Oxentenko AS, Murray JA, Burgart LJ, Dierkhising RA, Alexander JA. The usefulness of routine small bowel biopsies in evaluation of iron deficiency anemia.
J Clin Gastroenterol
2004
;
38
:
756
–760.
46
Mandal AK, Mehdi I, Munshi SK, Lo TC. Value of routine duodenal biopsy in diagnosing coeliac disease in patients with iron deficiency anaemia.
Postgrad Med J
2004
;
80
:
475
–477.
47
Oxentenko AS, Grisolano SW, Murray JA, Burgart LJ, Dierkhising RA, Alexander JA. The insensitivity of endoscopic markers in celiac disease.
Am J Gastroenterol
2002
;
97
:
933
–938.
48
Harewood GC, Holub JL, Lieberman DA. Variation in small bowel biopsy performance among diverse endoscopy settings: results from a national endoscopic database.
Am J Gastroenterol
2004
;
99
:
1790
–1794.
49
Gregory JF 3rd and Quinlivan EP. In vivo kinetics of folate metabolism.
Annu Rev Nutr
2002
;
22
:
199
–220.
50
Pawson R and Mehta A. Review article: the diagnosis and treatment of haematinic deficiency in gastrointestinal disease.
Aliment Pharmacol Ther
1998
;
12
:
687
–698.
51
Carmel R. Megaloblastic anemias: disorders of impaired DNA synthesis. In Greer JP, Foerster J, Lukens JN, Rodgers GM, Paraskevas F, Glader B (Eds.).
Wintrobe's Clinical Hematology
2004
;Philadelphia, PA Lippincott Williams & Wilkins Vol
1
: pp.
1367
–1395.
52
Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies.
Am J Med
1994
;
96
:
239
–246.
53
Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician.
Arch Intern Med
1999
;
159
:
1289
–1298.
54
Bode S and Gudmand-Hoyer E. Symptoms and haematologic features in consecutive adult coeliac patients.
Scand J Gastroenterol
1996
;
31
:
54
–60.
55
Pittschieler K. [Folic acid concentration in the serum and erythrocytes of patients with celiac disease].
Padiatr Padol
1986
;
21
:
363
–366.
56
Stevens D. Nutritional anaemia in childhood coeliac disease [abstract].
Proc Nutr Soc
1979
;
38
:
102A
.
57
Kemppainen TA, Kosma VM, Janatuinen EK, Julkunen RJ, Pikkarainen PH, Uusitupa MI. Nutritional status of newly diagnosed celiac disease patients before and after the institution of a celiac disease diet: association with the grade of mucosal villous atrophy.
Am J Clin Nutr
1998
;
67
:
482
–487.
58
Haapalahti M, Kulmala P, Karttunen TJ, et al. Nutritional status in adolescents and young adults with screen-detected celiac disease.
J Pediatr Gastroenterol Nutr
2005
;
40
:
566
–570.
59
Hoffbrand AV, Douglas AP, Fry L, Stewart JS. Malabsorption of dietary folate (Pteroylpolyglutamates) in adult coeliac disease and dermatitis herpetiformis.
Br Med J
1970
;
4
:
85
–89.
60
Saibeni S, Lecchi A, Meucci G, et al. Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: role of B12, folate, and genetics.
Clin Gastroenterol Hepatol
2005
;
3
:
574
–580.
61
Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin.
Blood
1998
;
92
:
1191
–1198.
62
Gillberg R, Kastrup W, Mobacken H, Stockbrugger R, Ahren C. Gastric morphology and function in dermatitis herpetiformis and in coeliac disease.
Scand J Gastroenterol
1985
;
20
:
133
–140.
63
Dickey W and Hughes DF. Histology of the terminal ileum in coeliac disease.
Scand J Gastroenterol
2004
;
39
:
665
–667.
64
Dahele A and Ghosh S. Vitamin B12 deficiency in untreated celiac disease.
Am J Gastroenterol
2001
;
96
:
745
–750.
65
Dickey W. Low serum vitamin B12 is common in coeliac disease and is not due to autoimmune gastritis.
Eur J Gastroenterol Hepatol
2002
;
14
:
425
–427.
66
Ward PC. Modern approaches to the investigation of vitamin B12 deficiency.
Clin Lab Med
2002
;
22
:
435
–445.
67
Klee GG. Cobalamin and folate evaluation: measurement of methylmalonic acid and homocysteine vs vitamin B(12) and folate.
Clin Chem
2000
;
46
:
1277
–1283.
68
Vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency.
Cochrane Database Syst Rev
2005
; CD004655.
69
Goyens P, Brasseur D, Cadranel S. Copper deficiency in infants with active celiac disease.
J Pediatr Gastroenterol Nutr
1985
;
4
:
677
–680.
70
Jameson S, Hellsing K, Magnusson S. Copper malabsorption in coeliac disease.
Sci Total Environ
1985
;
42
:
29
–36.
71
Rodriguez A, Soto G, Torres S, Venegas G, Castillo-Duran C. Zinc and copper in hair and plasma of children with chronic diarrhea.
Acta Paediatr Scand
1985
;
74
:
770
–774.
72
Fisgin T, Yarali N, Duru F, Usta B, Kara A. Hematologic manifestation of childhood celiac disease.
Acta Haematol
2004
;
111
:
211
–214.
73
Mulder CJ, Pena AS, Jansen J, Oosterhuis JA. Celiac disease and geographic (serpiginous) choroidopathy with occurrence of thrombocytopenic purpura.
Arch Intern Med
1983
;
143
:
842
.
74
Eliakim R, Heyman S, Kornberg A. Celiac disease and keratoconjunctivitis: occurrence with thrombocytopenic purpura.
Arch Intern Med
1982
;
142
:
1037
.
75
Stenhammar L and Ljunggren CG. Thrombocytopenic purpura and coeliac disease.
Acta Paediatr Scand
1988
;
77
:
764
–766.
76
Kahn O, Fiel MI, Janowitz HD. Celiac sprue, idiopathic thrombocytopenic purpura, and hepatic granulomatous disease: an autoimmune linkage?
J Clin Gastroenterol
1996
;
23
:
214
–216.
77
Stene-Larsen G, Mosvold J, Ly B. Selective vitamin B12 malabsorption in adult coeliac disease: report on three cases with associated autoimmune diseases.
Scand J Gastroenterol
1988
;
23
:
1105
–1108.
78
Croese J, Harris O, Bain B. Coeliac disease: haematological features, and delay in diagnosis.
Med J Aust
1979
;
2
:
335
–338.
79
Nelson EW, Ertan A, Brooks FP, Cerda JJ. Thrombocytosis in patients with celiac sprue.
Gastroenterology
1976
;
70
:
1042
–1044.
80
Patwari AK, Anand VK, Kapur G, Narayan S. Clinical and nutritional profile of children with celiac disease.
Indian Pediatr
2003
;
40
:
337
–342.
81
Carroccio A, Giannitrapani L, Di Prima L, Iannitto E, Montalto G, Notarbartolo A. Extreme thrombocytosis as a sign of coeliac disease in the elderly: case report.
Eur J Gastroenterol Hepatol
2002
;
14
:
897
–900.
82
Schafer AI. Thrombocytosis.
N Engl J Med
2004
;
350
:
1211
–1219.
83
Pittschieler K. Neutropenia, granulocytic hypersegmentation and coeliac disease.
Acta Paediatr
1995
;
84
:
705
–706.
84
Saibeni S, Bottasso B, Spina L, et al. Assessment of thrombin-activatable fibrinolysis inhibitor (TAFI) plasma levels in inflammatory bowel diseases.
Am J Gastroenterol
2004
;
99
:
1966
–1970.
85
van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis.
Blood
2000
;
95
:
2855
–2859.
86
Thorburn D, Stanley AJ, Foulis A, Campbell Tait R. Coeliac disease presenting as variceal haemorrhage.
Gut
2003
;
52
:
758
.
87
Miehsler W, Reinisch W, Valic E, et al. Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism?
Gut
2004
;
53
:
542
–548.
88
Zenjari T, Boruchowicz A, Desreumaux P, Laberenne E, Cortot A, Colombel JF. Association of coeliac disease and portal venous thrombosis.
Gastroenterol Clin Biol
1995
;
19
:
953
–954.
89
Marteau P, Cadranel JF, Messing B, Gargot D, Valla D, Rambaud JC. Association of hepatic vein obstruction and coeliac disease in North African subjects.
J Hepatol
1994
;
20
:
650
–653.
90
Grigg AP. Deep venous thrombosis as the presenting feature in a patient with coeliac disease and homocysteinaemia.
Aust N Z J Med
1999
;
29
:
566
–567.
91
Morello F, Ronzani G, Cappellari F. Migraine, cortical blindness, multiple cerebral infarctions and hypocoagulopathy in celiac disease.
Neurol Sci
2003
;
24
:
85
–89.
92
Lee ES and Pulido JS. Nonischemic central retinal vein occlusion associated with celiac disease.
Mayo Clin Proc
2005
;
80
:
157
.
93
McNeill A, Duthie F, Galloway DJ. Small bowel infarction in a patient with coeliac disease.
J Clin Pathol
2006
;
59
:
216
–218.
94
Krasinski SD, Russell RM, Furie BC, Kruger SF, Jacques PF, Furie B. The prevalence of vitamin K deficiency in chronic gastrointestinal disorders.
Am J Clin Nutr
1985
;
41
:
639
–643.
95
Jacobs P and Wood L. Macronutrients.
Dis Mon
2004
;
50
:
46
–115.
96
Cavallaro R, Iovino P, Castiglione F, et al. Prevalence and clinical associations of prolonged prothrombin time in adult untreated coeliac disease.
Eur J Gastroenterol Hepatol
2004
;
16
:
219
–223.
97
Granel B, Rossi P, Frances Y, Henry JF. Bilateral massive adrenal haemorrhage revealing coeliac disease.
QJM
2005
;
98
:
70
–71.
98
Hussaini SH, Ahmed S, Heatley RV. Celiac disease and hypoprothrombinemia.
Nutrition
1999
;
15
:
389
–391.
99
Lubel JS, Burrell LM, Levidiotis V. An unexpected cause of macroscopic haematuria.
Med J Aust
2005
;
183
:
321
–323.
100
Blumgart HL. Three fatal cases of malabsorption of fat with emaciation and anemia, and in two acidosis and tetany.
Arch Intern Med
1923
:
113
–128.
101
Marsh GW and Stewart JS. Splenic function in adult coeliac disease.
Br J Haematol
1970
;
19
:
445
–457.
102
Pettit JE, Hoffbrand AV, Seah PP, Fry L. Splenic atrophy in dermatitis herpetiformis.
Br Med J
1972
;
2
:
438
–440.
103
Ferguson A, Hutton MM, Maxwell JD, Murray D. Adult coeliac disease in hyposplenic patients.
Lancet
1970
;
1
:
163
–164.
104
Corazza GR, Bullen AW, Hall R, Robinson PJ, Losowsky MS. Simple method of assessing splenic function in coeliac disease.
Clin Sci (Lond)
1981
;
60
:
109
–113.
105
Pearson HA, Gallagher D, Chilcote R, et al. Developmental pattern of splenic dysfunction in sickle cell disorders.
Pediatrics
1985
;
76
:
392
–397.
106
Pearson HA, Johnston D, Smith KA, Touloukian RJ. The born-again spleen: return of splenic function after splenectomy for trauma.
N Engl J Med
1978
;
298
:
1389
–1392.
107
Corazza GR, Ginaldi L, Zoli G, et al. Howell-Jolly body counting as a measure of splenic function: a reassessment.
Clin Lab Haematol
1990
;
12
:
269
–275.
108
Robertson DA, Bullen AW, Hall R, Losowsky MS. Blood film appearances in the hyposplenism of coeliac disease.
Br J Clin Pract
1983
;
37
:
19
–22.
109
Robertson DA, Swinson CM, Hall R, Losowsky MS. Coeliac disease, splenic function, and malignancy.
Gut
1982
;
23
:
666
–669.
110
Corazza GR, Zoli G, Di Sabatino A, Ciccocioppo R, Gasbarrini G. A reassessment of splenic hypofunction in celiac disease.
Am J Gastroenterol
1999
;
94
:
391
–397.
111
Robinson PJ, Bullen AW, Hall R, Brown RC, Baxter P, Losowsky MS. Splenic size and function in adult coeliac disease.
Br J Radiol
1980
;
53
:
532
–537.
112
Di Sabatino A, Rosado MM, Cazzola P, et al. Splenic hypofunction and the spectrum of autoimmune and malignant complications in celiac disease.
Clin Gastroenterol Hepatol
2006
;
4
:
179
–186.
113
O'Grady JG, Stevens FM, Harding B, O'Gorman TA, McNicholl B, McCarthy CF. Hyposplenism and gluten-sensitive enteropathy: natural history, incidence, and relationship to diet and small bowel morphology.
Gastroenterology
1984
;
87
:
1326
–1331.
114
Trewby PN, Chipping PM, Palmer SJ, Roberts PD, Lewis SM, Stewart JS. Splenic atrophy in adult coeliac disease: is it reversible?
Gut
1981
;
22
:
628
–632.
115
Corazza GR, Lazzari R, Frisoni M, Collina A, Gasbarrini G. Splenic function in childhood coeliac disease.
Gut
1982
;
23
:
415
–416.
116
Bullen AW, Hall R, Gowland G, Rajah S, Losowsky MS. Hyposplenism, adult coeliac disease, and autoimmunity.
Gut
1980
;
22
:
28
–33.
117
Johnston SD and Robinson J. Fatal pneumococcal septicaemia in a coeliac patient.
Eur J Gastroenterol Hepatol
1998
;
10
:
353
–354.
118
O'Donoghue DJ. Fatal pneumococcal septicaemia in coeliac disease.
Postgrad Med J
1986
;
62
:
229
–230.
119
Parnell N and Thomas P. Fatal pneumococcal septicaemia in a coeliac patient.
Eur J Gastroenterol Hepatol
1998
;
10
:
899
–900.
120
Matuchansky C, Colin R, Hemet J, et al. Cavitation of mesenteric lymph nodes, splenic atrophy, and a flat small intestinal mucosa: report of six cases.
Gastroenterology
1984
;
87
:
606
–614.
121
Stevens FM, Connolly CE, Murray JP, McCarthy CF. Lung cavities in patients with coeliac disease.
Digestion
1990
;
46
:
72
–80.
122
Howat AJ, McPhie JL, Smith DA, et al. Cavitation of mesenteric lymph nodes: a rare complication of coeliac disease, associated with a poor outcome.
Histopathology
1995
;
27
:
349
–354.
123
Schmitz F, Herzig KH, Stuber E, et al. On the pathogenesis and clinical course of mesenteric lymph node cavitation and hyposplenism in coeliac disease.
Int J Colorectal Dis
2002
;
17
:
192
–198.
124
Keller CE, Gamboa ET, Hays AP, et al. Fatal CNS vasculopathy in a patient with refractory celiac disease and lymph node cavitation.
Virchows Arch
2006
;
448
:
209
–213.
125
Melles DC and de Marie S. Prevention of infections in hyposplenic and asplenic patients: an update.
Neth J Med
2004
;
62
:
45
–52.
126
Castagnola E and Fioredda F. Prevention of life-threatening infections due to encapsulated bacteria in children with hyposplenia or asplenia: a brief review of current recommendations for practical purposes.
Eur J Haematol
2003
;
71
:
319
–326.
127
American Academy of Pediatrics. Immunization in special clinical circumstances: immunocompromised children. In Pickering LK, Baker CJ, Long SS, McMilland JA (Eds.).
Red Book: 2006 Report of the Committee on Infectious Diseases
2006
; 27th ed Elk Grove Village, IL American Academy of Pediatrics pp.
71
–85.
128
McKinley M, Leibowitz S, Bronzo R, Zanzi I, Weissman G, Schiffman G. Appropriate response to pneumococcal vaccine in celiac sprue.
J Clin Gastroenterol
1995
;
20
:
113
–116.
129
Cataldo F, Marino V, Ventura A, Bottaro G, Corazza GR. Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study. Italian Society of Paediatric Gastroenterology and Hepatology (SIGEP) and “Club del Tenue” Working Groups on Coeliac Disease.
Gut
1998
;
42
:
362
–365.
130
Meini A, Pillan NM, Villanacci V, Monafo V, Ugazio AG, Plebani A. Prevalence and diagnosis of celiac disease in IgA-deficient children.
Ann Allergy Asthma Immunol
1996
;
77
:
333
–336.
131
Samolitis NJ, Hull CM, Leiferman KM, Zone JJ. Dermatitis herpetiformis and partial IgA deficiency.
J Am Acad Dermatol
2006
;
54
:
S206
–S209.
132
Collin P, Maki M, Keyrilainen O, Hallstrom O, Reunala T, Pasternack A. Selective IgA deficiency and coeliac disease.
Scand J Gastroenterol
1992
;
27
:
367
–371.
133
Vassallo RR. Review: IgA anaphylactic transfusion reactions, part I: laboratory diagnosis, incidence, and supply of IgA-deficient products.
Immunohematol
2004
;
20
:
226
–233.
134
Catassi C, Bearzi I, Holmes GK. Association of celiac disease and intestinal lymphomas and other cancers.
Gastroenterology
2005
;
128
:
S79
–S86.
135
Holmes GK, Stokes PL, Sorahan TM, Prior P, Waterhouse JA, Cooke WT. Coeliac disease, gluten-free diet, and malignancy.
Gut
1976
;
17
:
612
–619.
136
Harris OD, Cooke WT, Thompson H, Waterhouse JA. Malignancy in adult coeliac disease and idiopathic steatorrhoea.
Am J Med
1967
;
42
:
899
–912.
137
Cooper BT, Holmes GK, Ferguson R, Cooke WT. Celiac disease and malignancy.
Medicine (Baltimore)
1980
;
59
:
249
–261.
138
Corrao G, Corazza GR, Bagnardi V, et al. Mortality in patients with coeliac disease and their relatives: a cohort study.
Lancet
2001
;
358
:
356
–361.
139
Logan RF, Rifkind EA, Turner ID, Ferguson A. Mortality in celiac disease.
Gastroenterology
1989
;
97
:
265
–271.
140
Cooper BT, Holmes GK, Cooke WT. Lymphoma risk in coeliac disease of later life.
Digestion
1982
;
23
:
89
–92.
141
Nielsen OH, Jacobsen O, Pedersen ER, et al. Non-tropical sprue: malignant diseases and mortality rate.
Scand J Gastroenterol
1985
;
20
:
13
–18.
142
Holmes GK, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease: effect of a gluten free diet.
Gut
1989
;
30
:
333
–338.
143
Collin P, Reunala T, Pukkala E, Laippala P, Keyrilainen O, Pasternack A. Coeliac disease: associated disorders and survival.
Gut
1994
;
35
:
1215
–1218.
144
Catassi C, Fabiani E, Corrao G, et al. Risk of non-Hodgkin lymphoma in celiac disease.
JAMA
2002
;
287
:
1413
–1419.
145
Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, Ekbom A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis.
Gastroenterology
2002
;
123
:
1428
–1435.
146
Peters U, Askling J, Gridley G, Ekbom A, Linet M. Causes of death in patients with celiac disease in a population-based Swedish cohort.
Arch Intern Med
2003
;
163
:
1566
–1572.
147
Freeman HJ. Lymphoproliferative and intestinal malignancies in 214 patients with biopsy-defined celiac disease.
J Clin Gastroenterol
2004
;
38
:
429
–434.
148
Smedby KE, Akerman M, Hildebrand H, Glimelius B, Ekbom A, Askling J. Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma.
Gut
2005
;
54
:
54
–59.
149
Green PH, Fleischauer AT, Bhagat G, Goyal R, Jabri B, Neugut AI. Risk of malignancy in patients with celiac disease.
Am J Med
2003
;
115
:
191
–195.
150
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma: the Non-Hodgkin's Lymphoma Classification Project.
Blood
1997
;
89
:
3909
–3918.
151
Gale J, Simmonds PD, Mead GM, Sweetenham JW, Wright DH. Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center.
J Clin Oncol
2000
;
18
:
795
–803.
152
Egan LJ, Walsh SV, Stevens FM, Connolly CE, Egan EL, McCarthy CF. Celiac-associated lymphoma: a single institution experience of 30 cases in the combination chemotherapy era.
J Clin Gastroenterol
1995
;
21
:
123
–129.
153
Daum S, Weiss D, Hummel M, et al. Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue.
Gut
2001
;
49
:
804
–812.
154
Isaacson PG and Du MQ. Gastrointestinal lymphoma: where morphology meets molecular biology.
J Pathol
2005
;
205
:
255
–274.
155
Farstad IN, Johansen FE, Vlatkovic L, et al. Heterogeneity of intraepithelial lymphocytes in refractory sprue: potential implications of CD30 expression.
Gut
2002
;
51
:
372
–378.
156
Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma: French Coeliac Disease Study Group.
Lancet
2000
;
356
:
203
–208.
157
Bagdi E, Diss TC, Munson P, Isaacson PG. Mucosal intra-epithelial lymphocytes in enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease constitute a neoplastic population.
Blood
1999
;
94
:
260
–264.
158
Cellier C, Patey N, Mauvieux L, et al. Abnormal intestinal intraepithelial lymphocytes in refractory sprue.
Gastroenterology
1998
;
114
:
471
–481.
159
Mention JJ, Ben Ahmed M, Begue B, et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease.
Gastroenterology
2003
;
125
:
730
–745.
160
Meijer JW, Mulder CJ, Goerres MG, Boot H, Schweizer JJ. Coeliac disease and (extra)intestinal T-cell lymphomas: definition, diagnosis and treatment.
Scand J Gastroenterol Suppl
2004
;
241
:
78
–84.
161
Smedby KE, Hjalgrim H, Askling J, et al. Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype.
J Natl Cancer Inst
2006
;
98
:
51
–60.
162
Viljamaa M, Kaukinen K, Pukkala E, Hervonen K, Reunala T, Collin P. Malignancies and mortality in patients with coeliac disease and dermatitis herpetiformis: 30-year population-based study.
Dig Liver Dis
2006
;
38
:
374
–380.
163
Mearin ML, Catassi C, Brousse N, et al. European multi-centre study on coeliac disease and non-Hodgkin lymphoma.
Eur J Gastroenterol Hepatol
2006
;
18
:
187
–194.
164
Card TR, West J, Holmes GK. Risk of malignancy in diagnosed coeliac disease: a 24-year prospective, population-based, cohort study.
Aliment Pharmacol Ther
2004
;
20
:
769
–775.
165
Collin P, Pukkala E, Reunala T. Malignancy and survival in dermatitis herpetiformis: a comparison with coeliac disease.
Gut
1996
;
38
:
528
–530.
166
Selby WS and Gallagher ND. Malignancy in a 19-year experience of adult celiac disease.
Dig Dis Sci
1979
;
24
:
684
–688.
167
Lewis HM, Reunala TL, Garioch JJ, et al. Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis.
Br J Dermatol
1996
;
135
:
363
–367.
168
Hervonen K, Vornanen M, Kautiainen H, Collin P, Reunala T. Lymphoma in patients with dermatitis herpetiformis and their first-degree relatives.
Br J Dermatol
2005
;
152
:
82
–86.
169
Howdle PD, Jalal PK, Holmes GK, Houlston RS. Primary small-bowel malignancy in the UK and its association with coeliac disease.
QJM
2003
;
96
:
345
–353.
170
Sonet A, Theate I, Delos M, et al. Clinical and pathological features of 14 non-Hodgkin's lymphomas associated with coeliac disease.
Acta Clin Belg
2004
;
59
:
143
–151.
171
Daum S, Ullrich R, Heise W, et al. Intestinal non-Hodgkin's lymphoma: a multicenter prospective clinical study from the German Study Group on Intestinal non-Hodgkin's Lymphoma.
J Clin Oncol
2003
;
21
:
2740
–2746.
172
Savage KJ, Chhanabhai M, Gascoyne RD, Connors JM. Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification.
Ann Oncol
2004
;
15
:
1467
–1475.
173
Wöhrer S, Chott A, Drach J, et al. Chemotherapy with cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone (CHOEP) is not effective in patients with enteropathy-type intestinal T-cell lymphoma.
Ann Oncol
2004
;
15
:
1680
–1683.
174
Fairley NH and Mackie FP. The clinical and biochemical syndrome in lymphoma and allied disease involving the mesenteric lymph glands.
BMJ
1937
;
1
:
375
–380.