Current approach to hemochromatosis

Iron overload diseases of genetic origin are an ever changing world, due to major advances in genetics and molecular biology. Five major categories are now established: HFE-related or type1 hemochromatosis, frequently found in Caucasians, and four rarer diseases which are type 2 (A and B) hemochromatosis (juvenile hemochromatosis), type 3 hemochromatosis (transferrin receptor 2 hemochromatosis), type 4 (A and B) hemochromatosis (ferroportin disease), and a(hypo)ceruloplasminemia. Increased duodenal iron absorption and enhanced macrophagic iron recycling, both due to an impairment of hepcidin synthesis, account for the development of cellular excess in types 1, 2, 3, and 4B hemochromatosis whereas decreased cellular iron egress is involved in the main form of type 4A) hemochromatosis and in aceruloplasminemia. Non-transferrin bound iron plays an important role in cellular iron excess and damage. The combination of magnetic resonance imaging (for diagnosing visceral iron overload) and of genetic testing has drastically reduced the need for liver biopsy. Phlebotomies remain an essential therapeutic tool but the improved understanding of the intimate mechanisms underlying these diseases paves the road for innovative therapeutic approaches.     

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.     

Capsule endoscopy in celiac disease

Video capsule endoscopy is an attractive and patient- friendly tool that provides high quality images of the small bowel. Obscure gastrointestinal bleeding is the primary and most evaluated indication to capsule endoscopy; however, indications are expanding and a small number of preliminary reports have been presented concerning the role of video capsule endoscopy in the diagnosis of celiac disease. The purpose of this review is to update the current knowledge and to hypothesize on future perspectives of the use of video capsule endoscopy in patients with celiac disease.     

The global village of celiac disease

In the last years our knowledge on epidemiology of celiac disease has increased: there is a wide spectrum of its clinical presentation (classical, atypical, silent and latent forms of celiac disease), and of its pathological mucosal intestinal features, which range from early and mild pictures to severe villous atrophy (Marsh stages). In addition, a strong genetic component, associated with the susceptibility to the disease (HLA and non HLA genes), has been found. This knowledge, together with the availability of new high sensitive and specific serological tests (antigliadin, antiendomysium and antitransglutaminase antibodies), has led us to the realization that celiac disease is the most common food intolerance in the world, involving genetically predisposed individuals consuming gluten-containing cereals in their diet. So, today it is well known that celiac disease is a common disorder not only in Europe but also in populations of European ancestry (North and South Americas, Australia), in North Africa, in the Middle East and in South Asia, where until a few years ago it was historically considered extremely rare. Therefore, celiac disease is spread worldwide as in a common "Global Village", and greater levels of awareness and attention on gluten intolerance are needed, both in the Old and in the New World.     

HFE and non-HFE hemochromatosis

Hereditary hemochromatosis (HH) is a disorder of iron metabolism in which enhanced absorption of dietary iron causes increased iron accumulation in the liver, heart, and pancreas. Most individuals with HH are homozygous for a point mutation in the HFE gene, leading to a C282Y substitution in the HFE protein. The function of HFE protein is unknown, but the available evidence suggests that it acts in association with beta2-microglobulin and transferrin receptor 1 to regulate iron uptake from plasma transferrin by the duodenum, the proposed mechanism by which body iron levels are sensed. The identification of HFE has established the foundation for a better understanding of the molecular and cellular biology of iron homeostasis and its altered regulation in HH. Additionally, the ability to accurately diagnose iron overload disorders has been strengthened, family screening has been improved, and evaluation of patients with other forms of liver disease complicated by moderate-to-severe iron overload is now possible. However, the role of HFE testing in generalized population screening for HH is still controversial. Recently, other forms of HH have been described that are not related to HFE but are due to mutations in genes coding iron transport proteins.     

The myths and realities of hemochromatosis.

Hemochromatosis is a common genetic condition and yet there are still a number of misperceptions surrounding the diagnosis and management of this condition. Hemochromatosis affects both men and women. Typical patients do not have alcoholism or viral hepatitis, and often have normal liver enzymes. Clinical expression is highly variable. Genetic testing is widely available and particularly useful in family studies. Hemochromatosis can be readily diagnosed and treated. The purpose of the present review is to address the medical myths and misconceptions of hemochromatosis.     

Liver complications in celiac disease

Celiac disease (CD) is characterized by sensitivity to gluten, which is found in dietary wheat, barley, and rye. Many extra-intestinal manifestations have been described in association with CD. Liver disease and CD share widespread risk factors. Liver disorders such as autoimmune hepatitis, elevation of liver enzyme levels, primary biliary cirrhosis, nonspecific hepatitis, primary sclerosing cholangitis, and nonalcoholic fatty liver disease have been reported in patients with CD. In this review, we provide information regarding liver disorders that may be found in association with celiac disease and the effect of the treatment of CD on these disorders.     

Pre-endoscopic screening for Helicobacter pylori and celiac disease in young anemic women

AIM： To evaluate the usefulness of pre-endoscopic serological screening for He//cobacter py/or/ （H py/or/} infection and celiac disease in women aged 〈 50 years affected by iron-deficiency anemia （IDA）. METHODS： One hundred and fifteen women aged 〈 50 years with IDA were tested by human recombinant tissue transglutaminase IgA antibodies （tTG） and anti-H pylori IgG antibodies, tTG and H pylori IgG antibody were assessed using an enzyme-linked immunosorbent assay （ELISA）. All women were invited to undergo upper GI endoscopy. During gastroscopy, biopsies were collected from antrum （n = 3）, gastric body （n = 3） and duodenum （n = 4） in all patients, irrespective of test results. The assessment of gastritis was performed according to the Sydney system and celiac disease was classified by Marsh＇s System. RESULTS： 45.2% women were test-positive： 41 patients positive for H pylori antibodies, 9 patients for tTG and 2 patients for both. The gastroscopy compliance rate of test-positive women was significantly increased with respect to those test- negative （65.4% vs 42.8%; Fisher test P = 0.0239）. The serological results were confirmed by gastroscopy in 100% of those with positive H pylori antibodies, in 50% of those with positive tTG and in 81.5% of test- negative patient. Sensitivity and specificity were 84.8% and 100%, respectively for Hpylori infection and, 80% and 92.8% for tTG. Twenty-eight patients had positive H pylori antibodies and in all the patients, an active Hpylori infection was found. In particular, in 23 out of 28 （82%） patients with positive H pylori antibodies, a likely cause of IDA was found because of the active inflammation involving the gastric body. CONCLUSION： Anti-H pylori IgG antibody and tTG IgA antibody testing is able to select women with IDA to submit for gastroscopy to identify H pylori pangastritis and/or celiac disease, likely causes of IDA.     

The role of ultrasonography in patients with celiac disease

The aim of the present review was to summarize thecurrent evidence on the role of ultrasonography(US)anddoppler-US in the diagnosis of celiac disease.Several ultrasonographic signs have been reported inthe association with celiac disease in studies using real-time US.Firstly,case control studies identified some ofthese US signs and then in a prospective series someof these parameters,due to their high specificity,havebeen shown to be of value in confirming CD diagnosis,whereas others,due to their high sensitivity,have beendemonstrated to be useful in excluding the presence ofthe disease.The pattern of splanchnic circulation in CD haveextensively been investigated by several studies allof which reported similar results and identified a hy-perdynamic mesenteric circulation that reverts to no-rmal values after successful a gluten-free regimen.The last part of this review will deal with the possiblerole of US in identyfing the most severe and commonintestinal complication of CD,i.e.the enteropathy-associated T cell non-Hodgkin lymphoma.     

Refractory celiac disease

Refractory celiac disease (RCD) affects patients who have failed to heal after 6–12 months of a strict gluten-free diet (GFD) and when other causes of symptoms (including malignancy) have been ruled out. It may also occur in patients who previously had responded to a long-term GFD. RCD may be categorized as RCD1 (normal immunophenotype) and RCD2 (aberrant immunophenotype). RCD1 usually responds to a continued GFD, nutritional support, and therapeutic agents such as corticosteroids. In contrast, clinical response in RCD2 is incomplete and prognosis is often poor. RCD (particularly RCD2) is associated with serious complications, such as ulcerative jejunitis and enteropathy-associated T-cell lymphoma (EATL). Strict clinical and laboratory criteria should be used to diagnose RCD and specialized tests for aberrancy and clonality should be interpreted in the context of their sensitivity and specificity. Adequate nutritional support and anti-inflammatory treatment may even allow patients with RCD2 to attain a clinical remission.     

Role of oats in celiac disease

A gluten-free diet is currently the only effective means of treating individuals with celiac disease. Such a diet enables celiac patients to control their symptoms and avoid various complications associated with thiscondition. However, while the quality of gluten-free foods has significantly improved during recent decades, maintenance of a gluten-free diet does not necessarily ensure adequate nutritional intake. Because oats are an important source of proteins, lipids, vitamins, minerals, and fibre, their inclusion in a gluten-free diet might improve the nutritional status of a celiac patient. Although oats are included in the list of glutenfree ingredients specified in European regulations, their safety when consumed by celiac patients remains debatable. Some studies claim that pure oats are safe for most celiac people, and contamination with other cereal sources is the main problem facing people with this disease. However, it is necessary to consider that oats include many varieties, containing various amino acid sequences and showing different immunoreactivities associated with toxic prolamins. As a result, several studies have shown that the immunogenicity of oats varies depending on the cultivar consumed. Thus, it is essential to thoroughly study the variety of oats used in a food ingredient before including it in a gluten-free diet.     

Adult celiac disease with acetylcholine receptor antibody positive myasthenia gravis

Celiac disease has been associated with some autoimmune disorders. A 40-year-old competitive strongman with celiac disease responded to a glutenfree diet, but developed profound and generalized motor weakness with acetylcholine receptor antibody positive myasthenia gravis, a disorder reported to occur in about 1 in 5000. This possible relationship between myasthenia gravis and celiac disease was further explored in serological studies. Frozen stored serum samples from 23 acetylcholine receptor antibody positive myasthenia gravis patients with no intestinal symptoms were used to screen for celiac disease. Both endomysial and tissue transglutaminase antibodies were examined. One of 23 （or, about 4.3%） was positive for both IgA-endomysial and IgA tissue transglutaminase antibodies. Endoscopic studies subsequently showed duodenal mucosal scalloping and biopsies confirmed the histopathological changes of celiac disease. Celiac disease and myasthenia gravis may occur together more often than is currently appreciated. The presence of motor weakness in celiac disease may be a clue to occult myasthenia gravis, even in the absence of intestinal symptoms.     

Function of the hemochromatosis protein HFE： Lessons from animal models

Hereditary hemochromatosis （HH） is caused by chronic hyperabsorption of dietary iron. Progressive accumulation of excess iron within tissue parenchymal cells may lead to severe organ damage. The most prevalent type of HH is linked to mutations in the HFE gene, encoding an atypical major histocompatibility complex class I molecule. Shortly after its discovery in 1996, the hemochromatosis protein HFE was shown to physically interact with transferrin receptor 1 （TfR1） and impair the uptake of transferrin-bound iron in cells. However, these findings provided no clue why HFE mutations associate with systemic iron overload. It was later established that all forms of HH result from misregulation of hepcidin expression. This liverderived circulating peptide hormone controls iron efflux from duodenal enterocytes and reticuloendothelial macrophages by promoting the degradation of the iron exporter ferroportin. Recent studies with animal models of HH uncover a crucial role of HFE as a hepatocyte iron sensor and upstream regulator of hepcidin. Thus, hepatocyte HFE is indispensable for signaling to hepcidin, presumably as a constituent of a larger ironsensing complex. A working model postulates that the signaling activity of HFE is silenced when the protein is bound to TfR1. An increase in the iron saturation of plasma transferrin leads to displacement of TfR1 from HFE and assembly of the putative iron-sensing complex. In this way, iron uptake by the hepatocyte is translated into upregulation of hepcidin, reinforcing the concept that the liver is the major regulatory site for systemic iron homeostasis, and not merely an iron storage depot.     

Cutaneous manifestations in celiac disease

Celiac disease(CD)is an autoimmune gluten-dependententeropathy characterized by atrophy of intestinalvilli that improves after gluten-free diet(GFD).CD isoften associated with extra-intestinal manifestations;among them,several skin diseases are described in CDpatients.The present review reports all CD-associatedskin manifestations described in the literature and triesto analyze the possible mechanisms involved in thisassociation.The opportunity to evaluate the possiblepresence of CD in patients affected by skin disorders isdiscussed.     

Trends in the presentation of celiac disease

Purpose

Screening studies have revealed that celiac disease is common in the United States; however, there are scant data on the mode of presentation. We analyzed the trends in clinical presentation over the last 52 years in a large cohort of biopsy-proven patients seen in 1 center.

Subjects and methods

Patients (n = 590) were divided into 6 groups based on the year of diagnosis (1952-2004). Groups were compared for trends in age at diagnosis, childhood diagnosis, duration of symptoms, mode of presentation (diarrhea, bone disease, anemia, incidental at esophagogastroduodenoscopy, screening), and presence of malignancy.

Results

Diagnosis was at an older age since 1980 (P = .007), and there was a significant negative linear trend in patients presenting with diarrhea (P<.001) over time and a positive linear trend in asymptomatic patients detected on screening (P<.001). There was a significant negative linear trend in patients with a malignancy (P = .02) and duration of symptoms before diagnosis of celiac disease (P = .001), although only the subgroup without diarrhea had improvement in delay of diagnosis of celiac disease (assessed by a shorter duration of symptoms) (P = .05). Comparison of patients with and without diarrhea showed no significant difference in age (42.9 years vs 43.7 years, P = .59), gender (29.3% M vs 34.6%, P = .59), and presence of childhood disease (8.0% vs 9.8%, P = .43) or malignancies (9.8% vs 8.9%, P = .71).

Conclusion

There is a trend toward fewer patients presenting with symptomatic celiac disease characterized by diarrhea and a significant shift toward more patients presenting as asymptomatic adults detected at screening.     

Adult celiac disease in the elderly

There is an increased awareness that celiac disease may occur in the elderly although presentations with either diarrhea, weight loss or both may be less common causing delays in diagnosis for prolonged periods. Higher detection rates also seem evident owing to active case screening, largely through serodiagnostic measures. In some elderly patients who are genetically predisposed, it has been hypothesized that celiac disease might be precipitated late in life by an antigen, possibly from an infectious agent. As a result, peptide mimicry or other poorly-defined mechanisms may precipitate an autoimmune gluten-dependent clinical state. Although diarrhea and weight loss occur, only isolated iron deficiency anemia may be present at the time of initial diagnosis. In addition, the risk of other autoimmune disorders, particularly autoimmune thyroiditis, and bone disease, are increased. Osteopenia may also be associated with an increased risk of fractures. Finally, elderly celiacs have an increased risk of malignant intestinal disease, especially lymphoma.     

Examining the clinical use of hemochromatosis genetic testing

BACKGROUND:Hereditary hemochromatosis leads to an increased lifetime risk for end-organ damage due to excess iron deposition. Guidelines recommend that genetic testing be performed in patients with clinical suspicion of iron overload accompanied by elevated serum ferritin and transferrin saturation levels.OBJECTIVE:To evaluate guideline adherence and the clinical and economic impact of HFE genetic testing.METHODS:The electronic charts of patients submitted for HFE testing in 2012 were reviewed for genetic testing results, biochemical markers of iron overload and clinical history of phlebotomy.RESULTS:A total of 664 samples were sent for testing, with clinical, biochemical and phlebotomy data available for 160 patients. A positive C282Y homozygote or C282Y/H63D compound heterozygote test result was observed in 18% of patients. Patients with an at-risk HFE genotype had significantly higher iron saturation, serum iron and hemoglobin (P<0.001), without higher ferritin or liver enzyme levels. Fifty percent of patients referred for testing did not have biochemical evidence of iron overload (transferrin saturation >45% and ferritin level >300 μg/L). Patients were four times more likely to undergo phlebotomy if they were gene test positive (RR 4.29 [95% CI 2.35 to 7.83]; P<0.00001).DISCUSSION:One-half of patients referred for testing did not exhibit biochemical evidence of iron overload. Many patients with biochemical evidence of iron overload, but with negative genetic test results, did not undergo phlebotomy. A requisition to determine clinical indication for testing may reduce the use of the HFE genetic test. Finally, improvement of current genetic test characteristics would improve rationale for the test.CONCLUSION:A significant proportion of hemochromatosis genetic testing does not adhere to current guidelines and would not alter patient management.     

Potential celiac disease in type 1 diabetes: a multicenter study

Aims

To describe the prevalence of potential celiac disease (pot-CD) in young patients with type 1 diabetes mellitus (T1DM) and characterize their clinical features.

Methods

This cross-sectional multicenter study involved 8717 T1DM patients from 31 Italian centers. Information was collected on the total number of T1DM patients, CD patients and pot-CD patients. The following data were collected on pot-CD patients: gender, age at T1DM diagnosis, age at the first CD serological positivity, presence of CD-related symptoms, presence of other autoimmune disorders and treatment with gluten free diet (GFD). One thousand-three-hundred-sixty-one patients who were positive for CD serology were the control group.

Results

CD serological positivity was found in 7.2% T1DM patients. Prevalence of pot-CD was 12.2% (n = 77) among CD positive patients: symptoms were present in 12/77; a third autoimmune disorder was found in 15 patients. Prevalence of pot-CD in the control population was 8.4% (n = 114; p = 0.005). No difference was found with regard to clinical features. Only few symptomatic patients were on GFD both in T1DM and control patients.

Conclusions

A higher prevalence of pot-CD was found in T1DM patients, that may be ascribed to the routine screening, although the influence of genetic factors cannot be excluded.