Iron deficiency anemia in celiac disease

Iron is an important micronutrient that may be depleted in celiac disease. Iron deficiency and anemia may complicate well-established celiac disease, but may also be the presenting clinical feature in the absence of diarrhea or weight loss. If iron deficiency anemia occurs, it should be thoroughly evaluated, even if celiac disease has been defined since other superimposed causes of iron deficiency anemia may be present. Most often, impaired duodenal mucosal uptake of iron is evident since surface absorptive area in the duodenum is reduced, in large part, because celiac disease is an immune-mediated disorder largely focused in the proximal small intestinal mucosa. Some studies have also suggested that blood loss may occur in celiac disease, sometimes from superimposed small intestinal disorders, including ulceration or neoplastic diseases, particularly lymphoma. In addition, other associated gastric or colonic disorders may be responsible for blood loss. Rarely, an immune-mediated hemolytic disorder with increased urine iron loss may occur that may respond to a gluten-free diet. Reduced expression of different regulatory proteins critical in iron uptake has also been defined in the presence and absence of anemia. Finally, other rare causes of microcytic anemia may occur in celiac disease, including a sideroblastic form of anemia reported to have responded to a gluten-free diet.     

Small intestine glutaminase deficiency in celiac disease

Summary Human small intestine contains glutaminase I, an enzyme responsible for the deamination of glutamine. Glutaminase activity was assayed in the jejunal mucosa of patients with celiac disease and of control subjects. Enzymatic activity was markedly diminished in the jejunal biopsy specimens from these patients at the time the diagnosis of celiac disease was made, compared with glutaminase I levels from control subjects. With successful treatment on a gluten-free diet, small-intestinal glutaminase I values returned toward normal as the biopsy specimens improved histologically. Patients with celiac disease who continued to have some symptoms had biopsy evidence of moderately severe mucosal damage, and they maintained low enzyme levels. The patients with abnormal biopsies due to other small-bowel diseases also had diminished glutaminase I activity. This study suggests that patients with untreated celiac disease have a secondary deficency of this enzyme.Supported by Grants AM-5156 and AM-08870 from the National Institutes of Health, U. S. Public Health Service. The patients studied in this work were hospitalized on the Yale University Clinical Research Center, supported by USPHS Grant FR-00125.     

Vitamin B12 deficiency in untreated celiac disease

OBJECTIVES: Iron and folate malabsorption are common in untreated celiac disease as the proximal small intestine is predominantly affected. Vitamin B12 deficiency is thought to be uncommon, as the terminal ileum is relatively spared. This study aims to investigate the prevalence of vitamin B12, deficiency in patients with untreated celiac disease. METHODS: Prospective study of 39 consecutive biopsy-proven celiac disease patients (32 women, seven men; median age 48 yr, range 22-77 yr) between September 1997 and February 1999. The full blood count, serum vitamin B12, red blood cell folate, and celiac autoantibodies (IgA antigliadin and IgA antiendomysium antibodies) were measured before and after a median of 4 months (range 2-13 months) of treatment with a gluten-free diet. In vitamin B12-deficient patients, intrinsic factor antibodies and a Schilling test, part 1, were performed. RESULTS: A total of 16 (41%) patients were vitamin B12 deficient (<220 ng/L) and 16 (41%) patients (11 women and live men) were anemic. Concomitant folate deficiency was present in only 5/16 (31%) of the vitamin B12 patients. The Schilling test, performed in 10 of the vitamin B12-deficient patients, showed five low and five normal results. Although only five patients received parenteral vitamin B12, at follow-up the vitamin B12 results had normalized in all patients. Acral paraesthesia at presentation in three vitamin B12-deficient patients resolved after vitamin B12 replacement. CONCLUSIONS: Vitamin B12 deficiency is common in untreated celiac disease, and concentrations should be measured routinely before hematinic replacement. Vitamin B12 concentrations normalize on a gluten-free diet alone, but symptomatic patients may require supplementation.     

Dilated cardiomyopathy in celiac disease: role of carnitine deficiency

Celiac disease (CD) is an immune-mediated enteropathy in genetically susceptible persons and the disease can present with manifestations in the intestine and in organs outside the gut. An increased prevalence of CD in patients with idiopathic dilated cardiomyopathy or secondary cardiomyopathy and some other cardiac disorders has been reported. Here is described a case of dilated cardiomyopathy in a patient with CD and secondary carnitine deficiency. Dilated cardiomyopathy due to carnitine deficiency may occur in CD patients and carnitine deficiency may present not only at the time of diagnosis of CD but it may also develop during gluten-free diet, particularly in patients with fast weight gain and without carnitine supplementation.     

Reversal of IgM deficiency following a gluten-free diet in seronegative celiac disease

Selective IgM deficiency (sIGMD) is very rare; it may be associated with celiac disease (CD). We present the case of an 18-year-old man with sIGMD masking seronegative CD. Symptoms included abdominal pain, diarrhea and weight loss. Laboratory tests showed reduced IgM, DQ2-HLA and negative anti-transglutaminase. Villous atrophy and diffuse immature lymphocytes were observed at histology. Tissue transglutaminase mRNA mucosal levels showed a 6-fold increase. The patient was treated with a gluten-free diet (GFD) and six months later the symptoms had disappeared, the villous architecture was restored and mucosal tissue transglutaminase mRNA was comparable to that of healthy subjects. After 1 year of GFD, a complete restoration of normal IgM values was observed and duodenal biopsy showed a reduction of immature lymphocytes and normal appearance of mature immune cells.     

Intestinal disaccharidase deficiency without villous atrophy may represent early celiac disease

BACKGROUND: Intestinal disaccharidase activities are decreased in untreated celiac disease and also in other conditions without villous atrophy. Of 908 patients examined for suspected malabsorption, 37 (4.1%) had generalized disaccharidase deficiency without villous atrophy. The aim was to determine if generalized disaccharidase deficiency without villous atrophy represented latent celiac disease. METHODS: Case notes and histology of the 37 patients were reviewed. History and blood investigations including antigliadin and endomysial antibodies were checked. Where celiac disease was suspected, endoscopic duodenal biopsies for histology and disaccharidase estimation were repeated. RESULTS: Of the initial 37 patients, 6 patients had had repeat endoscopic biopsies; one having celiac disease. A further 18 patients were reviewed. The remainder declined further investigation. Eight had repeat endoscopic duodenal biopsies; one had celiac disease. Two with positive celiac serology also had enteroscopy with jejunal biopsies; both had celiac disease. CONCLUSIONS: At least 11% of patients with generalized disaccharidase deficiency without villous atrophy develop celiac disease. Enteroscopic biopsies from distal duodenum and proximal jejunum should be considered as the next investigation if endomysial or antigliadin antibodies are positive.     

Pathomechanisms in celiac disease

Celiac disease is an inflammatory disorder of the small intestine caused by an immune response to ingested wheat gluten and similar proteins of rye and barley. It affects at least 1 in 200 individuals, corresponding to roughly three million patients in Western Europe and Northern America alone. Data accumulated since the discovery of gluten specific T cells in the intestine of celiac disease patients the early 1990s have allowed the deciphering of the interplay between the triggering environmental factor, gluten, the main genetic risk factor, the HLA-DQ2/8 haplotypes and the autoantigen; the enzyme tissue transglutaminase (tTG). This established a key role of adaptive immunity orchestrated by lamina propria T cells responding to a set of gluten derived peptides. More recent work points to an important contribution of innate immunity triggered by a distinct gluten peptide and driven by the proinflammatory cytokine Interleukine-5 (IL-15). Together, these observations provide a unique explanation for the disease inducing capacity of gluten.     

Advances in celiac disease

In recent years, it has become evident that CD is much more common than previously appreciated, with a prevalence of 0.5% to 1% in Western, Arabian, and Indian populations. The disease may be present without symptoms (silent CD) or may present with extraintestinal manifestations only. Increasing awareness of the many faces of CD will increase diagnosis rate. CD patients have a cure for their disease, named the gluten-free diet, but this curative measure is very hard to adhere to. With the new insights into the pathogenesis of CD, clinicians enter an era where new treatment modalities for CD may turn into reality.     

Mortality in celiac disease

The mortality experienced by a cohort of 653 patients with celiac disease in Edinburgh and the Lothian region has been analyzed. Mortality overall was 1.9-fold (95% confidence limits, 1.5-2.2) that of the general population (115 deaths observed, 61.8 expected; p less than 0.0001). The increased mortality was greatest within 1 yr of diagnosis of celiac disease and steadily declined over time with the excess mortality being concentrated at ages 45-54 yr in men and 55-64 yr in women. Celiac disease was mentioned on the death certificate in 33 cases but in only 10 was it given as the underlying cause of death. Of 17 deaths from lymphoproliferative diseases (0.55 expected, p less than 0.001), 8 occurred within 2 yr of diagnosis of celiac disease compared with 8 (0.37 expected, p less than 0.001) occurring greater than 5 yr after diagnosis. Esophageal cancer was certified as the cause of four deaths (0.47 expected, p less than 0.01). In men mortality from all other malignant disease was also increased (15 deaths observed; 6.4 expected, p less than 0.01), but most of these deaths occurred within 5 yr of the diagnosis of celiac disease. In contrast, there was no deficit in deaths from ischemic heart disease or stroke and the mortality rate in those diagnosed in childhood as having celiac disease was similar to the general population.     

Copper deficiency in humans

Copper is an essential trace element that is required for a number of enzymes which are necessary for normal metabolic function. Metabolic balance studies have demonstrated that daily copper losses are approximately 1.3 mg/day. In order to remain in copper balance, the average adult male must consume a diet which contains at least 2 mg copper/day. It has been assumed that most diets satisfy this requirement because of the ubiquitous presence of copper in most foodstuffs. Recent studies, however, have shown that dietary copper may often fall below the estimated daily needs. Nevertheless, clinically evident copper deficiency has been documented in only a few situations. Of these disorders. Menkes' syndrome has been most intensively studied. This x-linked abnormality is associated with copper deficiency due to impaired gastrointestinal copper absorption. However, the clinical disorder cannot be corrected readily with copper replacement, thus suggesting that Menkes' syndrome may reflect more than simple copper deficiency. Nutritional copper deficiency appears to be well documented in two situations: (1) the newborn, usually premature, undergoing rapid growth on a diet poor in copper, and (2) the patient maintained on total parenteral nutrition for long periods of time without copper supplementation. In both of these situations, anemia and neutropenia are the most striking hematologic abnormalities associated with copper deficiency. Sideroblastic changes as well as nuclear maturation defects observed in erythroid precursors. However, suggest that there is an effect of copper deficiency on the hematopoietic system which cannot be explained solely by defective plasma iron transport.     

The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease

BACKGROUND & AIMS: Celiac disease and hereditary hemochromatosis are common HLA-defined conditions in northwestern Europe. We sought to determine whether there is a genetic relationship between the 2 diseases and if hemochromatosis susceptibility gene (HFE) mutations are protective against iron deficiency in celiac disease. METHODS: Polymerase chain reaction amplification using sequence-specific primers capable of identifying the 2 HFE gene mutations (H63D and C282Y) and the HLA class I and II alleles was used to type 145 white patients with celiac disease and 187 matched controls. Hemoglobin and fasting serum iron levels in celiac patients were measured at diagnosis. RESULTS: HFE gene mutations, H63D or C282Y, were identified in 70 celiac patients (48.3%) and 61 controls (32.6%) (P = 0.004). The C282Y mutation was associated with HLA-A*03 and B*07 alleles in controls and with A*01, A*03, B*08, and DRB1*0301 alleles in celiac patients; the H63D mutation was associated with HLA-A*25 and DRB1*03 alleles in controls and A*29 and DRB1*03 alleles in celiac patients. At diagnosis, celiac patients with the C282Y mutation had higher mean hemoglobin and fasting serum iron levels compared with the HFE wild type (P = 0.0002 and 0.006, respectively). This was not observed with the H63D mutation. CONCLUSIONS: In celiac disease, HFE gene mutations are common and are in linkage disequilibrium with different HLA alleles compared with controls. A disease-specific haplotype that carries C282Y and DQB1*02 is suggested. We propose that HFE gene mutations provide a survival advantage by ameliorating the iron deficiency seen in celiac patients.