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Letner D, Peloquin J, Durand J, Rutherford A, Yajnik V, Khalili H, Garber J. Elevated Total Iron-Binding Capacity Is Associated with an Increased Risk of Celiac Disease. Dig Dis Sci 2015; 60:3735-42. [PMID: 26173503 DOI: 10.1007/s10620-015-3791-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 06/29/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND Several lines of evidence suggest that abnormal iron homeostasis may itself play an important role in the development of celiac disease. AIM We sought to determine whether abnormalities in iron status could be detected prior to the diagnosis of celiac disease, and to understand the relationship between altered iron indices and the natural history of celiac disease. METHODS We conducted a case-control study at two major tertiary referral hospitals. Cases were comprised of patients with celiac disease in whom iron status was assessed prior to the diagnosis. Each case was matched to five controls without known gastrointestinal disease according to age and sex. Information on potential covariates and laboratory values within 1, 1-3, and 3-5 years prior to diagnosis was collected. We used conditional logistic regression to evaluate the effect of iron indices on risk of celiac disease. RESULTS We identified 157 celiac cases and 695 matched controls. Compared to participants with normal TIBC, the age-adjusted risk of celiac disease was significantly elevated among patients with elevated TIBC. For each 10 μg/dL increase in TIBC, the risk of celiac disease increased by 4.6, 3.8, and 7.9% within 1, 1-3, and 3-5 years prior to diagnosis, respectively. Patients with elevated pre-diagnosis TIBC were more likely to have abnormal liver enzymes and osteoporosis. CONCLUSIONS Elevated TIBC is associated with an increased risk of celiac disease. Further investigation into the potential role of altered iron homeostasis may uncover important environmental factors that contribute to the development of celiac disease.
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Affiliation(s)
- Dorothea Letner
- Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit Street, Jackson 7, Boston, MA, 02114, USA.
| | - Joanna Peloquin
- Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit Street, Jackson 7, Boston, MA, 02114, USA. .,Department of Medicine, Harvard Medical School, Boston, MA, USA.
| | - Jacquelyn Durand
- Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit Street, Jackson 7, Boston, MA, 02114, USA.
| | - Anna Rutherford
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham & Women's Hospital, 1620 Tremont Street, BC-3-002EE, Boston, MA, 02120, USA. .,Department of Medicine, Harvard Medical School, Boston, MA, USA.
| | - Vijay Yajnik
- Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit Street, Jackson 7, Boston, MA, 02114, USA. .,Department of Medicine, Harvard Medical School, Boston, MA, USA.
| | - Hamed Khalili
- Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit Street, Jackson 7, Boston, MA, 02114, USA. .,Department of Medicine, Harvard Medical School, Boston, MA, USA.
| | - John Garber
- Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit Street, Jackson 7, Boston, MA, 02114, USA. .,Department of Medicine, Harvard Medical School, Boston, MA, USA.
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Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives. J Immunol Res 2015; 2015:453046. [PMID: 26504855 PMCID: PMC4609477 DOI: 10.1155/2015/453046] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 08/02/2015] [Indexed: 12/17/2022] Open
Abstract
We performed a retrospective study of autoimmune conditions (ACs) in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH), diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe), and positivity for human leukocyte antigen (HLA) haplotypes A∗01, B∗08; A∗02, B∗44; A∗03, B∗07; A∗03, B∗14; and A∗29, B∗44. There were 138 men (58.7%). Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%). Prevalences of Hashimoto's thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5]), 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7%) had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR) 0.3 [0.1, 0.6]) and more likely in probands with a FH (OR 4.1 [1.4, 11.8]). Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH.
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Rostami-Nejad M, Haldane T, AlDulaimi D, Alavian SM, Zali MR, Rostami K. The role of celiac disease in severity of liver disorders and effect of a gluten free diet on diseases improvement. HEPATITIS MONTHLY 2013; 13:e11893. [PMID: 24348636 PMCID: PMC3842525 DOI: 10.5812/hepatmon.11893] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Revised: 09/21/2013] [Accepted: 09/25/2013] [Indexed: 02/07/2023]
Abstract
CONTEXT Celiac disease (CD) is defined as a permanent intolerance to ingested gluten. The intolerance to gluten results in immune-mediated damage of small intestine mucosa manifested by villous atrophy and crypt hyperplasia. These abnormalities resolve with initiationa gluten-free diet. EVIDENCE ACQUISITION PubMed, Ovid, and Google were searched for full text articles published between 1963 and 2012. The associated keywords were used, and papers described particularly the impact of celiac disease on severity of liver disorder were identified. RESULTS Recently evidence has emerged revealingthat celiac disease not only is associated with small intestine abnormalities and malabsorption, but is also a multisystem disorder affecting other systems outside gastrointestinal tract, including musculo-skeletal, cardiovascular and nervous systems. Some correlations have been assumed between celiac and liver diseases. In particular, celiac disease is associated with changes in liver biochemistry and linked to alter the prognosis of other disorders. This review will concentrate on the effect of celiac disease and gluten-free diets on the severity of liver disorders. CONCLUSIONS Although GFD effect on the progression of CD associated liver diseases is not well defined, it seems that GFD improves liver function tests in patients with a hypertransaminasemia.
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Affiliation(s)
- Mohammad Rostami-Nejad
- Department of Celiac Disease, Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Thea Haldane
- Department of Gastroenterology, Alexandra Hospital, Worcestershire, UK
| | - David AlDulaimi
- Department of Gastroenterology, Alexandra Hospital, Worcestershire, UK
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Disease Center, Tehran, IR Iran
| | - Mohammad Reza Zali
- Department of Celiac Disease, Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Kamran Rostami
- Department of Gastroenterology, Darent Valley Hospital, Darenth Wood Road, Dartford, UK
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Ludvigsson JF, Murray JA, Adams PC, Elmberg M. Does hemochromatosis predispose to celiac disease? A study of 29,096 celiac disease patients. Scand J Gastroenterol 2013; 48:176-182. [PMID: 23256862 PMCID: PMC3576703 DOI: 10.3109/00365521.2012.749511] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM Case reports suggest an association between hereditary hemochromatosis (HH) and celiac disease (CD), but estimates of association are lacking. We estimated the association between HH and CD in a population-based study. MATERIAL AND METHODS Case-control study. We identified 29,096 individuals with biopsy-verified CD (equal to villous atrophy, Marsh stage III) through biopsy reports from all 28 pathology departments in Sweden. We then investigated the risk of a clinical diagnosis of HH in CD and in 144,522 controls matched for age, sex, county and calendar year. Conditional logistic regression was used to calculate odds ratios (ORs) for CD in patients with HH. RESULTS HH was seen in 30 patients with CD and in 60 matched controls. HH was hence associated with an increased risk of CD (OR = 2.30; 95% CI = 1.53-3.45). Restricting HH to individuals with at least two records of HH, the OR for CD was 2.54 (95% CI = 1.57-4.11), with a similar risk estimate when we only looked at HH diagnosed before CD (and matched date in controls) (OR = 2.64; 95% CI = 1.24-5.60). CONCLUSION HH seems to be associated with an increased risk of CD.
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Abstract
Different hepatic and biliary tract disorders may occur with celiac disease. Some have been hypothesized to share genetic or immunopathogenetic factors, such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. Other hepatic changes in celiac disease may occur with malnutrition resulting from impaired nutrient absorption, including hepatic steatosis. In addition, celiac disease may be associated with rare hepatic complications, such as hepatic T-cell lymphoma.
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Affiliation(s)
- Hugh James Freeman
- Department of Medicine (Gastroenterology), University of British Columbia, Vancouver, British Columbia, Canada
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Abstract
Celiac disease is a common (1% prevalence) chronic immune-mediated disorder of the small intestine induced by dietary wheat, barley, and rye. Several hepatic disorders have been described in association with celiac disease. Isolated hypertransaminasemia with nonspecific histologic changes in a liver biopsy is the commonest hepatic presentation of celiac disease. A gluten-free diet normalizes liver enzymes and histologic changes in most patients. Moreover, celiac disease can coexist with autoimmune liver disorders such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. Celiac disease has increasingly been reported with a variety of other liver diseases. Thus, the hepatologist needs to consider celiac disease in the differential of abnormal liver blood tests and to be aware of the clinical implications of this frequent disease in patients with liver disorders. The possible mechanisms of liver injury and those common factors that explain the association of celiac disease with liver disorders are discussed. The aims of this article are (1) to review the spectrum and pathogenesis of liver injury related to celiac disease and (2) to provide direction to those caring for patients with chronic liver diseases regarding the detection and effective treatment of celiac disease.
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Affiliation(s)
- Alberto Rubio-Tapia
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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Abstract
A variety of hepatic and biliary tract disorders may complicate the clinical course of celiac disease. Some of these have been hypothesized to share common genetic factors or have a common immunopathogenesis, such as primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune forms of hepatitis or cholangitis. Other hepatic changes in celiac disease may be associated with malnutrition resulting from impaired nutrient absorption, including hepatic steatosis. In addition, celiac disease may be associated with rare hepatic complications, such as hepatic T-cell lymphoma. Finally, pancreatic exocrine function may be impaired in celiac disease and represent a cause of treatment failure.
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MESH Headings
- Celiac Disease/complications
- Celiac Disease/metabolism
- Celiac Disease/pathology
- Cholangitis, Sclerosing/complications
- Cholangitis, Sclerosing/metabolism
- Cholangitis, Sclerosing/pathology
- Fatty Liver/complications
- Fatty Liver/metabolism
- Fatty Liver/pathology
- Gallbladder Diseases/complications
- Gallbladder Diseases/metabolism
- Gallbladder Diseases/pathology
- Hemochromatosis/complications
- Hemochromatosis/metabolism
- Hemochromatosis/pathology
- Hepatitis, Autoimmune/complications
- Hepatitis, Autoimmune/metabolism
- Hepatitis, Autoimmune/pathology
- Humans
- Liver Cirrhosis, Biliary/complications
- Liver Cirrhosis, Biliary/metabolism
- Liver Cirrhosis, Biliary/pathology
- Liver Diseases/complications
- Liver Diseases/metabolism
- Liver Diseases/pathology
- Liver Failure/complications
- Liver Failure/metabolism
- Liver Failure/pathology
- Liver Neoplasms/complications
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Lymphoma, T-Cell/complications
- Lymphoma, T-Cell/metabolism
- Lymphoma, T-Cell/pathology
- Pancreatic Diseases/complications
- Pancreatic Diseases/metabolism
- Pancreatic Diseases/pathology
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Geier A, Gartung C, Theurl I, Weiss G, Lammert F, Dietrich CG, Weiskirchen R, Zoller H, Hermanns B, Matern S. Occult celiac disease prevents penetrance of hemochromatosis. World J Gastroenterol 2005; 11:3323-6. [PMID: 15929194 PMCID: PMC4316075 DOI: 10.3748/wjg.v11.i21.3323] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To report a patient with C282Y homozygocity, depleted body iron and intestinal atrophy caused by celiac disease (CD) who experienced resolution of the enteropathy with subsequent normalization of iron metabolism upon gluten-free diet.
METHODS: To obtain information on the tissue distribution and quantitative expression of proteins involved in duodenal iron trafficking, we determined the expression of divalent-metal transporter 1 (DMT1), ferroportin 1 (FP1) and transferrin receptor (TfR1) by means of immunohist-ochemistry and real-time PCR in duodenal biopsies of this patient.
RESULTS: Whereas in hereditary hemochromatosis patients without CD, DMT1 expression was up-regulated leading to excessive uptake of iron, we identified a significant reduction in protein and mRNA expression of DMT1 as a compensatory mechanism in this patient with HH and CD.
CONCLUSION: Occult CD may compensate for increased DMT1 expression in a specific subset of individuals with homozygous C282Y mutations in the hemochromatosis (HFE) gene, thus contributing to the low penetrance of HH.
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Affiliation(s)
- Andreas Geier
- Department of Internal Medicine III, Aachen University, Pauwelsstrasse 30, D-52074 Aachen, Germany.
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Singhal A, Moreea S, Reynolds PD, Bzeizi KI. Coeliac disease and hereditary haemochromatosis: association and implications. Eur J Gastroenterol Hepatol 2004; 16:235-7. [PMID: 15076002 DOI: 10.1097/00042737-200402000-00020] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Coeliac disease and hereditary haemochromatosis are genetic disorders paradoxically associated with altered intestinal absorption of iron. Hereditary haemochromatosis is the most common autosomal recessive disease in the Caucasian population and is characterised by an iron overload state. Coeliac disease, or gluten sensitive enteropathy, on the other hand is frequently associated with iron deficiency anaemia. We report the cases of two patients who developed both coeliac disease and hereditary haemochromatosis. We review the literature of this rare association and examine how the clinical presentation is modified by their co-existence and the potential genetic linkage of these two disorders.
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Affiliation(s)
- Amit Singhal
- Integrated Department of Gastroenterology, Bradford Teaching Hospitals NHS Trust, West Yorkshire, UK.
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Bowlus CL, Lie BA. Discussion of the role of hemochromatosis susceptibility gene mutation in protecting against iron deficiency in celiac disease. Gastroenterology 2003; 124:1562-3; author reply 1564. [PMID: 12744238 DOI: 10.1016/s0016-5085(03)00354-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Butterworth JR, Cooper BT, Rosenberg WMC, Purkiss M, Jobson S, Hathaway M, Briggs D, Howell WM, Wood GM, Adams DH, Iqbal TH. The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease. Gastroenterology 2002; 123:444-9. [PMID: 12145797 DOI: 10.1053/gast.2002.34778] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
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.
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