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Celiac Disease

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Celiac Centers:

BIDMC Celiac Center, Harvard Medical School

 

Celiac Disease Center at Columbia University

 

Celiac Disease Center, the University of Chicago Mecial Center

 

Celiac Disease: A hidden epidemic by Peter H.R. Green, Rory Jones

 

Gluten-Free Diet: A Comprehensive Resource Guide
by Shelley Case

 

Celiac Disease: A guide to living with gluten intolerance by Sylvia Bower, et al.

 

Let's Eat Out!: Your Passport to Living Gluten And Allergy Free by Kim Koeller, et al.

 

Frontiers in Celiac Disease by A. Fasano

 

HLA Genetic Typing

* Questions and answers on HLA typing and Celiac Disease by Michael Jones, et al.

* Celiac Disease Tests by Lab Tests Online

* Celiac Disease DNA Test by Kimball Genetics

 

• Celiac Disease
• Bamboo Spine
• Silk Road Disease
• Lactose Intolerance
• Stevens-Johnson Syndrome
• Nasopharyngeal Carcinoma
• Esophageal Cancer

Organizations:

 

Celiac Disease Awareness Campaign

 

Celiac Disease Foundation

 

Celiac.com

 

Celiac Sprue Association

 

Canadian Celiac Association

 

Coeliac UK

 

Association of European Celiac Societies

 

Spanish Celiac Associations

 

German Celiac Associaiton

 

Keliakialiito

 

Associazione Italiana Celiachia

 

Celiac Society of Australia

 

Turkish Celiac Association

 

Israeli Celiac Association

 

 

Excerpts from Wikipedia.org

Coeliac disease (乳糜瀉), also spelled celiac disease, is an autoimmune disorder of the small bowel that occurs in genetically predisposed people of all ages from middle infancy. Symptoms include chronic diarrhoea, failure to thrive (in children) and fatigue, but these may be absent and symptoms in all other organ systems have been described. It is estimated to affect about 1% of Indo-European populations, although significantly underdiagnosed. A growing portion of diagnoses are being made in asymptomatic persons as a result of increasing screening.

Coeliac disease is caused by a reaction to gliadin, a gluten protein found in wheat (and similar proteins of the tribe Triticeae which includes other cultivars such as barley and rye). Upon exposure to gliadin, the enzyme tissue transglutaminase modifies the protein, and the immune system cross-reacts with the bowel tissue, causing an inflammatory reaction. That leads to flattening of the lining of the small intestine, which interferes with the absorption of nutrients. The only effective treatment is a lifelong gluten-free diet.

 

Role of Other Grains: Wheat varieties or subspecies containing gluten such as spelt and Kamut®, and the rye/wheat hybrid triticale, also trigger symptoms.

Barley and rye also induce symptoms of coeliac disease.  A small minority of coeliac patients also react to oats.  It is most probable that oats produce symptoms due to cross contamination with other grains in the fields or in the distribution channels.  Other cereals, such as maize (corn), quinoa, millet, sorghum, rice are safe for a patient to consume. Other carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms.

 

Signs and Symptoms: Classic symptoms of coeliac disease include diarrhoea, weight loss (or stunted growth in children), and fatigue, but while coeliac disease is primarily a bowel disease, bowel symptoms may also be limited or even absent. Some patients are diagnosed with symptoms related to the decreased absorption of nutrients or with various symptoms which, although statistically linked, have no clear relationship with the malfunctioning bowel. Given this wide range of possible symptoms, the classic triad is no longer a requirement for diagnosis.

Children between 9 and 24 months tend to present with bowel symptoms and growth problems shortly after first exposure to gluten-containing products. Older children may have more malabsorption-related problems and psychosocial problems, while adults generally have malabsorptive problems.  Many adults with subtle disease only have fatigue or anaemia.

Coeliac disease has been linked with a number of conditions. In many cases it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition.

• IgA deficiency is present in 2% of patients with coeliac disease, and in turn this condition features a tenfold increased risk of coeliac disease. Other features of this condition are an increased risk of infections and autoimmune disease.
• Dermatitis herpetiformis; this itchy cutaneous condition has been linked to a transglutaminase enzyme in the skin, features small bowel changes identical to those in coeliac disease and occurs more often (in 2%) in patients with coeliac disease.
• Neurological associations: epilepsy, ataxia (coordination problems), myelopathy, peripheral neuropathy and schizophrenia have all been linked with coeliac disease, but the strength of these associations and the causality are still subject to debate.
• Growth failure and/or pubertal delay in later childhood can occur even without obvious bowel symptoms or severe malnutrition. Evaluation of growth failure often includes coeliac screening.
• Miscarriage and infertility.
• Hyposplenism (a small and underactive spleen) - it is unclear whether this actually increases infection risk in the same way as in other people without a functioning spleen.
• Other auto-immune disorders: diabetes mellitus type 1, autoimmune thyroiditis, primary biliary cirrhosis and microscopic colitis.

 

Antibody Testing: Four serological blood tests exist for coeliac disease. The most widely used ones detect an antibody of the IgA type against particular antigens in the small bowel. Older tests detected antibodies against reticulin (ARA) or gliadin (AGA), but recent evidence supports the use of the more modern tests, namely those detecting IgA antibodies against endomysium (EMA) or tissue transglutaminase (TTG). Generally, serology may be unreliable in young children, with anti-gliadin performing somewhat better than other tests in children under five.

Guidelines recommend that a total serum IgA level is checked in parallel, as coeliac patients with IgA deficiency may be unable to produce the antibodies on which these tests depend ("false negative"). In those patients, IgG antibodies against transglutaminase (IgG-TTG) may be diagnostic.

 

HLA Genetic Typing: Antibody testing and HLA testing have similar accuracies.

 

Endoscopy: An upper endoscopy with biopsy of the duodenum (beyond the duodenal bulb) or jejunum is performed. It is important for the physician to obtain multiple samples (four to eight) from the duodenum. Not all areas may be equally affected; if biopsies are taken from healthy bowel, it would result in false negative results.

Most patients with coeliac disease have a small bowel that appears normal on endoscopy; however, five endoscopic findings have been associated with a high specificity for coeliac disease when all are found: scalloping of the small bowel folds (pictured), paucity in the folds, a mosaic pattern to the mucosa (described as a cracked-mud appearance), prominence of the submucosal blood vessels and a nodular pattern to the mucosa.

Until the 1970s, biopsies were obtained using metal capsules attached to a suction device. The capsule was swallowed and allowed to pass into the small intestine. After X-ray verification of its position, suction was applied to collect part of the intestinal wall inside the capsule. One much utilized capsule system is the Watson capsule. This method has now been largely replaced by fiberoptic endoscopy, which carries a higher sensitivity rate and a lower error frequency.

 

 

 

Epidemiology

The disease is thought to affect between 1 in 1,750 (with CD defined as clinical cases including dermatitis herpetiformis) to 1 in 105 (CD defined by presence of IgA TG in blood donors) people in the United States. The prevalence of clinically diagnosed disease (symptoms prompting diagnostic testing) is 0.05–0.27% in various studies. However, population studies from parts of Europe, India, South America, Australasia and the USA (using serology and biopsy) indicate that the prevalence may be between 0.33 and 1.06% in children (5.66% in one study of Sahrawi children) and 0.18–1.2% in adults. People of African, Japanese and Chinese descent are rarely diagnosed; this reflects a much lower prevalence of the genetic risk factors. Population studies also indicate that a large proportion of coeliacs remain undiagnosed; this is due, in part, to many clinicians being unfamiliar with the condition.

Coeliac disease is more prevalent in women than in men.

A large multicentre study in the U.S. found a prevalence of 0.75% in not-at-risk groups, rising to 1.8% in symptomatic patients, 2.6% in second-degree relatives of a patient with coeliac disease and 4.5% in first-degree relatives. This profile is similar to the prevalence in Europe. Other populations at increased risk for coeliac disease, with prevalence rates ranging from 5% to 10%, include individuals with Down and Turner syndromes, type 1 diabetes, and autoimmune thyroid disease, including both hyperthyroidism (overactive thyroid) and hypothyroidism (underactive thyroid).

Historically, coeliac disease was thought to be rare, with a prevalence of about 0.02%. Recent increases in the number of reported cases may be due to changes in diagnostic practice, but there is evidence that coeliac disease may be becoming more common in the United States.

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Genetics

The vast majority of coeliac patients have one of two types of HLA-DQ. This gene is part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguishes cells between self and non-self for the purposes of the immune system. The gene is located on the short arm of the sixth chromosome and has been labelled CELIAC1.

There are seven HLA-DQ variants (DQ2 and DQ4–DQ9). Over 95% of coeliac patients have the isoform of DQ2 or DQ8, which is inherited in families. The reason these genes produce an increase in risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process.

Most coeliac patients bear a two-gene HLA-DQ2 haplotype referred to as DQ2.5 haplotype. This haplotype is composed of two adjacent gene alleles, DQA1*0501 and DQB1*0201, which encode the two subunits, DQ α5 and DQ β2. In most individuals, this DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents. Most coeliacs inherit only one copy of this DQ2.5 haplotype, while some inherit it from both parents; the latter are especially at risk for coeliac disease, as well as being more susceptible to severe complications. Some individuals inherit DQ2.5 from one parent and portions of the haplotype (DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent, called a trans-haplotype association, and these individuals are at similar risk for coeliac disease as those with a single DQ2.5-bearing chromosome 6, but in this instance, disease tends not to be familial. Among the 6% of European coeliacs that do not have DQ2.5 (cis or trans) or DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), 4% have the DQ2.2 isoform, and the remaining 2% lack DQ2 or DQ8.

The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe (Basque Country and Ireland with highest frequencies) and portions of Africa and is associated with disease in India, but is not found along portions of the West Pacific rim. DQ8 has a wider global distribution than DQ2.5, and is particularly common in South and Central America; up to 90% of individuals in certain Amerindian populations carry DQ8 and thus may display the coeliac phenotype.

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HLA-DQ2

	DQA1	DQB1
DQ2.2	*0201	*0202
DQ2.3	*0303	*0202
DQ2.5	*0501	*0201

 

HLA-DQ2 (DQ2) is a serotype group within HLA-DQ (DQ) serotyping system. The serotype is determined by the antibody recognition of β2 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ2 are encoded by the HLA-DQB1*02 allele group. This group currently contains 2 common alleles, DQB1*0201 and DQB1*0202. HLA-DQ2 and HLA-DQB1*02 are almost synonymous in meaning. DQ2 β-chains combine with α-chains, encoded by genetically linked HLA-DQA1 alleles, to form the cis-haplotype isoforms. These isoforms, nicknamed DQ2.2 and DQ2.5, are also encoded by the DQA1*0201 and DQA1*0501 genes, respectively.

DQ2 is most common in Western Europe, North and West Africa. Highest frequencies are observed in parts of Spain and Ireland, this distribution correlates with the frequency of two of the most prevalent autoimmune diseases. There is also a increase in DQB1*0201 in Central Asia, peaking in Kazakhstan and declining slowly east to west into China and finally Southeast Asia. DQA1*0501 : DQB1*0201. DQ2.5 is one of the most predisposing factors for autoimmune disease. DQ2.5 is encoded, often, by a haplotype associated with a large number of diseases. This haplotype, HLA A1-B8-DR3-DQ2 is associated with diseases in which HLA-DQ2 has suspect involvement. Direct involvement of DQ2 is certain in coeliac disease.

DQ2.5: DQ2.5 haplotype is created by close genetic linkage of two alleles, written as a haplotype, DQA1*0501:DQB1*0201. The haplotype encodes DQ2.5cis isoform, referring to the cis arrangement of the DQA1*0501 and DQB1*0201 on the same variant of chromosome 6. The isoform can also be encoded trans-haplotype (between two sister chromosomes) forming the DQ2.5trans isoform. This isoform occurs when a person has the DQ7.5/DQ2.2 phenotype.

DQ2.5 and the linked DR3 are associated with probably the greatest frequency of autoimmune occurrence relative to any other haplotypes. The haplotype is positively associated with coeliac disease, dermatitis herpetiformis, juvenile diabetes, Lambert-Eaton myasthenic syndrome (LEMS), Sjögren's syndrome, and autoimmune hepatitis (although significant proportion of the risk is secondary to coeliac disease). DR3 and/or DQ2.5 are linked to the following diseases: Moreen's ulceration, "bout onset" multiple sclerosis, Grave's disease and systemic lupus erythematosus.

DQ2.2: DQ2.2 is shorthand for the DQ α2β2 heterodimeric isoform. The isoform is encoded almost exclusively by the DQA1*0201:DQB1*0202 haplotype. The haplotype is linked to DR7. A small percentage of coeliac disease are associated with this haplotype, and some disease causing gliadins are presented by DQ2.2. The haplotype is found at high frequencies in the Mediterranean and West Africa. The Eurasian geographic distribution of DQ2.2 is slightly greater than DQ2.5. Compared to DQ2.5, the freqeuncy in Sardinia is low, but in Iberia it is high reaching a maximum frequency of ~30% in Northern Iberia, and half that in the British Ilses. It extends along the Mediterranean and Africa at relatively high frequency and is found in high frequencies in some Central Asian, Mongolians, and Han Chinese. It does not appear to have an indigenous presence in the West Pacific Rim or the New World and DQ2.2 presence in Southeast Asia and Indonesia is likely the result of gene flow from India and China in post-neolithic times. The haplotype shows considerable diversity in Africa and this has translated to Iberia with 2 addition haplotypes, DQA1*0303:DQB1*0202 and DR7:DQA1*0201:DQB1*0303. The expansion of DQ2.2 into Europe appears to have been slightly later or biased by some constriction between Iberia and the rest of the continent.

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HLA-DQ8

	DQA1	DQB1
DQ8.1	*0301	*0302
DQ8.1v	*0302	*0302
DQ8.4	*0401	*0302
DQ8.5	*0503	*0302

 

HLA-DQ8 (DQ8) is a human leukocyte antigen serotype within the HLA-DQ (DQ) serotype group. DQ8 is a split antigen of the DQ3 broad antigen. DQ8 is determined by the antibody recognition of β8 and this generally detects the gene product of DQB1*0302.

DQ8 is commonly linked to autoimmune disease in the human population. DQ8 is the second most predominant isoform linked to coeliac disease and the DQ most linked to juvenile diabetes. DQ8 increases the risk for rheumatoid arthritis and is linked to the primary risk locus for RA, HLA-DR4. DR4 also plays an important role in juvenile diabetes. While the DQ8.1 haplotype is associated with disease, there is no known association with the DQB1*0305, DQ8.4 or DQ8.5 haplotypes (see infobox) with autoimmune disease; however, this may be the result of lack of study in populations that carry these and the very low frequency.

DQ8.1 also differs from other HLA in population frequencies. Typically for MHC Class II antigens in humans, haplotype frequencies do not exceed 40%. For example, in the US the highest haplotype frequency, the haplotype that encoded DQ6.2, is around 15%, this translates into phenotype frequencies of less than 30%. Atypically haplotype frequencies exceed 40%. For DQ8 the highest haplotype frequencies approach 80% in parts of Central and South America and the phenotype frequencies approach 90%. This is the highest phenotype frequency observed for any DR or DQ phenotype in the human population by a wide margin.

DQ8.1 is found almost ubiquitously in every human regional population, but because of its unique distribution it becomes an object of molecular anthropology. There are 3 places where haplotype frequency is elevated, Central and South America, NE Pacific Rim, and Northern Europe.

Global Spread of DQ8: DQ8 along with a few other Haplotypes appears to be split NW/SE in Eurasia and with the evidence for DQ2.5 and other haplotypes suggest an ancient Central Asian population was displaced by a more recent African migration. There are many common markers found in French, Germans, Danes, Swedes, Tibetans, Amur River, Japanese and Koreans that are potential indicators of this bilateral spread. The DQ8 haplotypes is found at high frequencies in the !kung, albeit one expects more DQ8 in Austronesia it is ubiquitously spread if at some times low frequencies, other times higher frequencies (Thai). The path of DQ8 spread to the New World is enigmatic, certainly Japan and Amur River are potent sources, but other displaced populations cannot be ruled out. If the mode of travel was through the Beringia corridor as proposed by archaeologist, the very low frequency of DQ8 at present is a very unusual find with regard to evidence for complete displacement elsewhere in the World. Markers that are shared between Japanese, TW-aboriginals tend to decline in frequency as one approaches Siberia, mtDNA markers decline in the Kuril chain. During the Jōmon period of Japan it appears there would have been displacement by Ninhvet/Ainu ancestors and depression of DQ8 throughout northern Japan, but the decline throughout the region is somewhat inexplicable outside of a catastrophic climate event between the settling of the New World and the current time. An alternative model is that there were multiple sources of DQ8 in the peopling of NE Asia, some sources were from Central Asia and some from the Indochinese region, some of the DQ8 found in NW Eurasia could be from an admixture of West Pacific Rim and Central Asian sources, and were displaced from the more central regions but not from the more Eastern regions.

High Frequencies in the Americas: The global node for DQ8 is in Central America and northern South America where it reaches the highest frequency for any single DQ serotype, close to 90% phenotype frequency (77% haplotype frequency), and is at relatively high frequency in the indigenous North American population, and the coastal regions of the Gulf of Mexico and up the Mississippi Valley. The high freqeuncy of DQ8 in South America's northeastern regions and low frequency in Indigenous Americans of more recent Asian ancestry or Siberian origin suggest that DQ8 was at high frequency in the earliest Amerinds. The pattern of distribution is consistent with recent mtDNA results suggesting the first migrants to the New World settled in the lowland coastal regions, river valleys and moved slowly inland, subsequent settlers moved into the highland regions. DQ8 and DQ2.5 have many analogous functional similarities, and this first settler bias may be a reason for the similarity. Studies on Epstein Barr Virus and other proteins suggest both proteins are acidic (meaning peptides with increased negative charge) peptide presenters and may have been adaptive for certain hunting and gathering lifestyles, possibly coastal foragers.

High Levels of DQ8 in Northern Europe: DQ8 is also abundant in Northern Europe and is found at high frequencies in the German-Scandinavian-Uralic population north of Switzerland. HLA A-B haplotypes suggest that a migration from people east of the Urals is responsible for DQ8, possibly from as far east as the West Pacific Rim. The high level of DQ8 and DQ2.5 is something of great interest for DQ mediated diseases of Scandinavia and Northern Europe. DQ8 is also found in Iberia and places where east to west gene flow by other genetic markers cannot be substantiated, and the levels within the African or Middle Eastern population are possible sources, Iberia has considerable A1/B1 equilbration suggesting independent sources from Africa.

Abundance in Asia: Hiatus of DQ8 in the NE Siberian Arctic, Elevated Levels in Amur Region and Eastern Turks The levels of DQ8 in SW to West Pacific Rim are at variable haplotype frequencies, from 2 to 30%, and level off around 10% for Ryūkyūan, Japanese, Koreans, Amur Regions and in the NW Pacific Rim drop to less than 1% in the Nivkh. There is a modern hiatus of DQ8 in the Alaska-Eastern Siberian region and it is unclear whether this is due to replacement, selection, or the mode in which first Americans arrived (i.e strictly maritime route). The DR types associated with DQ8 are DRB1*0403, *0404, *0406, *0407, *0408, and *0401 is split between many DQA1:B1 haplotypes. DQB1*0405 is commonly associated with DQA1*0303:DQB1*04 and so it is not included in DRB1*0401 in high resolution assessments. The Cook Island DQ8 had only one associated DR haplotype suggesting diversity limiting introduction into the region, either via the Taiwan-(Japan/Korea/China) route or through the west, for example the Bunun have high DRB1*0403. The majority of DRB1*04 appear to have redistributed from Eastern Asia from an unknown source, possibly in Central Asia or India. The distribution can be compared with native groups such as South Americans. Three groups with high levels, the Kogui, Sikuni, and Yucpa, have about 75% DQ8, the dominant DRB1* allele in 2 of 3 is the *0411 (N. China = 0), but *0407 (Ryūkyū, Japanese, Mansi-Eastern Ural, Naxi Chinese) and *0403 (Nganasan, Buryat, Negidal, Tunisians, Ryūkyū, Korea, Ainu) are also found. In North America DRB1*0404 and *0407 are more common than *0403 and, in the Lakota Souix, B1*0411 is rare. The DRB1*0404-DQ8 haplotype is more common in North Western Asia, and Northern Europe.

 

DQA1*03:DQB1*0302 levels in the Asia
(given as frequency in %)

Reference	DQA1	DQB1	Estimated
Population	*03	*0302	DQ8.1
Nivkhi (NNE. Sakalin I.)		0.0	0
Zorastra, Yadz (Iran)	20.8	0.8	0.8
Khoton (Mongolia)	24.4	1.2	1.2
Madang (Papua New Guinea)	1.5	1.5	1.5
Yao (China)		2.6	2.6
Naxi (Lijiang, China)		2.7	2.7
Ainu (Japan)		3.0	3.0
Shandong Han (China)		3.1	3.1
Khalkha (Mongolia)	22.3	6.1	6.1
Thais	21.5	7.4	7.4
Ket, Yenisey (Siberia)	14.7	8.4	8.4
South Korea		10.3	10.3
Japanese		10.8	10.8
Nganasan (Siberia)	39.6	11.4	11.4
Uygars, Urumqi (China)	21.9	11.4	11.4
Kazahk		11.4	11.4
Negidal (Siberia)	50.0	18.6	18.6
Cook Isl. (Pacific)		25.0	25.0

 

DQ8 and Selection: Like DQ2.5, DQ8 might have been under selection for maritime, coastal foraging peoples and in particular for peoples adapted to the climate/habitat situation on the northern end of the habitable West Pacific Rim at the Last Glacial Maximum. Triticeae cultivation may apply negative selection on DQ8. While there were numerous members of Triticeae species similar to Mid Eastern wild Triticeae in the Americas, and a great number of domesticated plants in the new world, no single species of Triticeae appears to have been domesticated in the New World, and no clear examples in closely related tribes of grasses. Among new world grass species in post Columbian times, one species of Elymus has been domesticated for human consumption and another as a pastoral cultivar. This could be interpreted in 2 ways. First, that levels of DQ8, negatively, inhibited the domestication of Triticeae strains. Second, that the absence of such cultivars more suitable than already developed cultivars allowed DQ8 to rise or remain high, while DQ2.5 levels in NW under much longer term selection have fallen, or a little of both. Most of American cultivars were domesticated south of the Rio Grande river (exceptions are Caddo rice and Texas varigated squash, etc.). Wheat, particularly Barley and Rye are preferential cultivars in cooler climate, whereas Zea (maize) is more adaptive in tropical climates and some cultivars are relatively drought tolerant, Zea however lacks certain amino acids that must be supplimented by other foods to prevent malnutrition. The proximity of neolithization to the Equator in the New World may have much to do with the unapparent negative selection of DQ8 relative to the neolithization of Western Eurasia.

DQ8 and Disease: In Europe, DQ8 is associated with Type 1 diabetes and to a lessor degree Coeliac disease. The highest risk factor for type 1 diabetes is the HLA DQ8/DQ2.5 phenotype. In parts of eastern Scandinavia both DQ2.5 and DQ8 are high increases frequencies of late onset Type I and ambiguous Type I/II diabetes. DQ8 is also found in many indigeonous peoples of Asia, it was detected early on in the Bedoin population of Arabia where DQ2.5 is frequently absent, and in these instances DQ8 is solely associated HLA in Coeliac Disease.

In the United States, however there appears to be shift in autoimmune disease risk for immigrants from Mexico. Increased immunoreactivity of Hispanics in Houston appear to be associated with DR4-DQ8. The haplotype may incur the highest risk for rheumatoid arthritis.

In Japan DQ3 (DQ7, DQ8, DQ9) is associated with Myasthenia gravis in the early onset female population, though it does not appear DQ8 has the greater role, there are similarities between myastenia gravis in Japan and that detected in the Houston hispanic population, with DQ8 associated with younger females relative to the associations of all other HLA DQ types. Coeliac Disease is on the rise in Japan, and it is clear that dietary shifts are the reason, but, also there is no DQ2.5 in Japan and therefore it is not a risk factor. Diabetes, which was once considered a problem of the wealthy in Japan, but is also on the rise in the general population. The similarities with the Indigeonous Americans cannot be dismissed, because both wheat consumption, beef consumption and milk consumption are on the rise in Japan, but since there is no DQ2.5 the increased risk of late onset and Type I/II is almost eliminated from consideration.

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DQ8/DQ2.5 Heterozygotes

The distribution of this phenotype is largely the result of admixtures between peoples of eastern or central Asian origin and peoples of western or central Asian origin. The highest frequencies, by random mating, are expected in Sweden, but pockets of high levels also occur in Mexico, and a larger range risk exists in Central Asia.

Diseases that appear to be increased in Heterozygotes are Type 1 Diabetes. New evidence is showing an increased risk for late onset Type 1 diabetes in Heterozygotes (which includes ambiguous Type I/Type II diabetes. Celiac Disease may have a slightly increased risk with a more severe course of disease.

 

	DQ2.5	DQ8	DQ2.5/DQ8
Sweden	15.9	18.7	5.9
Jalisco	11.4	22.8	5.2
England	12.4	16.8	4.2
Kazakh	13.1	11	2.9
Uygur	12.6	11.4	2.9
Finland	9	15.7	2.8
Poland	10.7	9.9	2.1

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Taiwan

 

* The Origin of Minnan and Hakka, the So-Called "Taiwanese", Inferred by HLA Study by M. Lin, et al.

Abstract: The Minnan and Hakka people groups, the so-called "Taiwanese", are the descendants of early settlers from the southeast coast of China during the last few centuries. Genetically they showed affinities to southern Asian populations as determined by phylogenetic trees and correspondence analysis calculated from HLA allele frequencies. This corresponds historically with the fact that they are the descendants of the southeast coastal indigenous population (Yueh) of China and should therefore not be considered as descendants of "pure" northern Han Chinese. A33-B58-DRB1*03 (A33-Cw10-B58-DRB1*03-DQB1*02), the most common HLA haplotype among "Taiwanese", with a haplotype frequency of 6.3%, has also been found to be the most common haplotype among Thai-Chinese and Singapore Chinese, two other populations also originating from the southeast coast of China. These observations suggest that this haplotype is the most well conserved ancient haplotype of the Yueh.

HLA Gene Frenquencies (DQ8)

Population	DRB1*04	DQB1*0302c	DQB1*0302d
Minnan	14.7	19.4	7.4
Hakka	14.6	16.2	7.6

*0301c:0311-012/04/09/10, *0302d:0302/05/07-08

HLA Gene Frenquencies (DQ2)

Population	DRB1*03	DQB1*02
Minnan	7.4	8.8
Hakka	8.6	10.6

 

 

* Towards Understanding the Origin and Dispersal of Austronesians in the Solomon Sea: HLA class II polymorphism in eight distinct populations of Asia-Oceania by H. Zimdahl, et al.

Most Frequent Haplotypes With Linkage Disequilibrium in Studied Populations of Asia-Oceania

Taiwan Aborigines (Ami, Atayal, Bunun and Paiwan): DRB1*0404-DQB1*0302 = 8.3%

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Insulin-dependent Diabetes Mellitu

Insulin-dependent diabetes mellitus (IDDM; 胰島素依賴性糖尿病) is a medical term that describes diabetes mellitus that requires insulin therapy to avoid ketoacidosis. IDDM is often considered a synonym for juvenile diabetes mellitus and type 1 diabetes mellitus, though the three terms are not entirely congruent:

• Juvenile diabetes is considered an unsatisfactory and somewhat obsolete term because type 1 diabetes (1型糖尿病) can develop in adults, and type 2 can occur in children.
• IDDM includes type 1 diabetes, but as type 2 diabetes (2型糖尿病) progresses, in some people it may reach a degree of insulin deficiency that requires insulin treatment.

 

* Association of Insulin-dependent Diabetes Mellitus in Taiwan with HLA Class II DQB1 and DRB1 Alleles by

Abstract: The allelic constitution at HLA class II DRB1, DQB1, DQA1, and DPB1 loci of IDDM patients from Taiwan was compared with that of ethnically matched nondiabetic individuals by PCR-based DNA typing. Of the three haplotypes found to be positively associated with IDDM in Taiwan, two (DRB1*0301-DQA1*0501-DQB1*0201 and DR4-DQA1*0301-DQB1*0302) appear to be identical to the susceptible haplotypes in Caucasian and black populations, whereas the third haplotype (DR4-DQA1*0301-DQB1*04) has been reported to be positively associated with IDDM only in the Japanese population. The three haplotypes, DRB1*1502-DQA1*0102-DQB1*0601 and DRB1*1201 (or 1202)-DQA1*0501-DQB1*0301 and DRB1*0803-DQA1*0103-DQB1*0601, were negatively associated with IDDM in Taiwan; a protective effect of the last haplotype has not been reported previously. Neither DQ beta non-Asp-57 nor DQA1*0301 alone appears sufficient to account for the HLA-associated susceptibility to IDDM in Taiwan. Also, the DQ alpha beta heterodimer encoded by the alleles DQA1*0301/DQB1*0201, DQA1*0301/DQB1*0302, or DQA1*0501/DQB1*0201 does not explain the susceptibility of a larger fraction of the IDDM patients than the residue at position 57 of the DQ beta chain or DQA1*0301. Finally, the DRB1 alleles appear to affect IDDM susceptibility, although for most haplotypes the effect of individual loci cannot be assessed due to the linkage disequilibrium between the DQ and the DR region.

 

* HLA-encoded Susceptibility to Insulin-dependent Diabetes Mellitus Is Determined by DR and DQ Genes as Well as Their Linkage Disequilibria in a Chinese Population by HS Huang, et al.

Abstract: HLA-DRB1 and -DQB1 genes were analyzed in 98 Chinese IDDM patients and 205 control subjects from Taiwan. The DRB1*0301-DQB1*0201 haplotype conferred strong susceptibility (RR = 7.7, pc < 10(-5)). DRB1*0405 also conferred susceptibility (RR = 3.1, Pc < 0.0005) whereas DRB1*0403 (RR = 0.7) and DRB1*0406 (RR = 0.2) conferred protection. Indeed, the relative risk for the DRB1*0405-DQB1*0302 haplotype (RR = 33.7, Pc < 0.002) was 48 and 168 times higher than those conferred by the DRB1*0403-DQB1*0302 and DRB1*0406-DQB1*0302 haplotypes, respectively, suggesting that the protection conferred by DRB1*0403 and 0406 is dominant over DQB1*0302. The strong linkage disequilibrium observed between DQB1*0302 and DRB1*0403(0406) can thus explain the surprising finding that the frequency of DQB1*0302 was not significantly increased in the Chinese IDDM patients (RR = 0.9). Because the DRB1*0405-DQB1*0302 haplotype (RR = 33.7) conferred higher susceptibility than the DRB1*0405-DQB1*0401 (RR = 2.5) or DRB1*0405-DQB1*0301 (RR = 2.1) haplotypes, DQB1*0302 is indeed a susceptibility factor, while both DQB1*0301 and DQB1*0401 may confer protection against IDDM. The increased frequency of the protective DQB1*0401 allele in patients compared to controls is due to linkage disequilibrium between DRB1*0405 and DQB1*0401. Interestingly, the previously demonstrated protective effect of DQB1*0602 was not very strong in the Chinese (RR = 0.4). Our results suggested that HLA-encoded susceptibility to IDDM is determined by the combined effects of all DR and DQ molecules present in an individual. Therefore, the genotypic combinations of DR and DQ genes as well as their linkage disequilibria can influence IDDM susceptibility. At least four DR and DQ molecules conferring high susceptibility (DRB1*0301, DRB1*0405, and DQ alpha/beta 0301/0201 and 0301/0302) occur at high frequency in the Chinese population. However, linkage disequilibria between highly susceptible DR and protective DQ or vice versa (e.g., DRB1*0405-DQB1*0301[0401] and DRB1*0403[0406]-DQB1*0302) are probably responsible for the lower incidence of IDDM in the Chinese.

 

* The Influence of Age at Onset and Gender on the HLA-DQA1, DQB1 Association in Chinese Children With Insulin Dependent Diabetes Mellitus by BH Chen, et al.

Abstract: Certain alleles of human leukocyte antigen (HLA)-DR and -DQ genes have been strongly associated with susceptibility and resistance to insulin- dependent diabetes mellitus (IDDM). To further clarify the association of HLA DQ alleles with IDDM and the influence of age at onset and gender on the association with IDDM, we investigated the association of HLA-DQA1, -DQB1 in 54 childhood onset Chinese (21 male) IDDM patients and 65 normal controls by using polymerase chain reaction-sequence specific primer (PCR-SSP). The mean age plus or minus SD at onset of IDDM patients was 8.37+/-3.54 year old. Our results revealed that the frequencies of DQA1 *0301, *0302, DQB1 *0201, and *0302 in IDDM patients were significantly higher than that in the control group (p < 0.025, < 0.005, < 0.001, and < 0.001, respectively). The frequency of DQA1 *0301, *0302, DQB1 *0201, and *0302 were susceptible alleles to IDDM with relative risks of 2.0, 3.5, 5.0 and 4.3, respectively. The protective alleles to IDDM were DQA1 *0101, *0103, DQB1 *0301, *0503, and *0602. We divided IDDM patients into three groups according to age at onset (1-5, 6-10, and 11-15 years old). The frequency of DQA1 *0302 decreased as age increased, and the frequency of DQA1 *0501 increased as age increased. Our results also showed that male IDDM patients had higher frequencies of DQA *0501, DQB1 *0201 than female IDDM patients (p < 0.025 and < 0.025, respectively), while female IDDM patients had higher frequencies of DQB1 *0502 than male IDDM patients (p < 0.05). In our study significant susceptibility haplotypes to IDDM were DQA1 *0301-DQB1 *0302, DQA1 *0501-DQB1 *0201, DQA1 *0301-DQB1 *0201, and DQA *0302-DQB1 *0201.

 

* Transcomplementation of HLA DQA1-DQB1 in DR3/DR4 and DR3/DR9 Heterozygotes and IDDM in Taiwanese Families by L M Chuang, et al.

Abstract

Objective: To study the human leukocyte antigen (HLA)-DQ heterodimers in the susceptible DR haplotypes for patients with insulin-dependent diabetes mellitus (IDDM) in Taiwan.

Research Design and Methods: Extended class II HLA haplotypes were studied in 57 unrelated IDDM patients, 31 simplex IDDM families, and 105 unrelated control subjects recruited from the same area in Taiwan. Class II HLA genotyping was based on PCR-SSO DNA typing techniques. Extended class II HLA haplotypes were deduced unequivocally by the Taiwanese pedigree studies.

Results: DR3/DR3, DR3/DR4, and DR3/DR9 genotypes were strongly associated with IDDM susceptibility in this population. In addition to the reported DR3/DR4 in Caucasians, the heterozygotic effect of DR3/DR9 for IDDM was remarkable in the Taiwanese population. Extended HLA haplotypes studies revealed that DRB1*0301/DQA1*0501/DQB1*0201, DRB1*0405/DQA1*0301/DQB1*0302, and DRB1*0405/DQA1*0301/DQB1*0401 were the susceptible haplotypes in this population. There were several hypothetical ways to produce susceptible HLA-DQ heterodimers to explain the susceptibility carried by DR3/DR4 and DR3/DR9 genotypes. Among all DR4 subtypes, only DRB1*0405 was associated with the increased risk of IDDM.

Conclusions: These data strongly suggest that the HLA-DR-associated IDDM susceptibility is most likely explained by the formation of the susceptible DQ heterodimers encoded by the DQA1/DQB1 either in cis or in trans.

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Graves' Disease

Graves' disease (葛瑞夫茲氏症) is an autoimmune disease where the thyroid is overactive, producing an excessive amount of thyroid hormones (a serious metabolic imbalance known as hyperthyroidism (甲狀腺機能亢進症) and thyrotoxicosis). This is caused by autoantibodies (TSHR-Ab) that activate the TSH-receptor (TSHR), thereby stimulating thyroid hormone synthesis and secretion, and thyroid growth (causing a diffusely enlarged goiter). The resulting state of hyperthyroidism can cause a dramatic constellation of neuropsychological and physical signs and symptoms.

Graves' disease is the most common cause of hyperthyroidism in children and adolescents, and usually presents itself during early adolescence. It has a powerful hereditary component, affects up to 2% of the female population, and is between five and ten times as common in females as in males. Graves’ disease is also the most common cause of severe hyperthyroidism, which is accompanied by more clinical signs and symptoms and laboratory abnormalities as compared with milder forms of hyperthyroidism. About 25-30% of people with Graves' disease will also suffer from Graves' ophthalmopathy (a protrusion of one or both eyes), caused by inflammation of the eye muscles by attacking autoantibodies.

Diagnosis is usually made on the basis of symptoms, although thyroid hormone tests may be useful. However, Graves’ thyrotoxicosis often gradually affects the life of the patients, usually for many months, but sometimes years, prior to the diagnosis. This is partially because symptoms can develop so insidiously that they go unnoticed; when they do get reported, they are often confused with other health problems. Thus, diagnosing thyroid disease clinically can be challenging. Nevertheless, patients can experience a wide range of symptoms and suffer major impairment in most areas of health-related quality of life.

There is no cure for Graves’ disease. There are, however, treatments for its consequences: hyperthyroidism, ophthalmopathy and mental symptoms.The Graves’ disease itself - as defined, for example, by high serum TSHR-Ab concentrations or ophthalmopathy - often persists after its hyperthyroidism has been successfully treated.

 

* Comprehensive Genotyping in Two Homogeneous Graves' Disease Samples Reveals Major and nNvel HLA Association Alleles by PL Chen, et al.

Abstract

Background: Graves' disease (GD) is the leading cause of hyperthyroidism and thyroid eye disease inherited as a complex trait. Although geoepidemiology studies showed relatively higher prevalence of GD in Asians than in Caucasians, previous genetic studies were contradictory concerning whether and/or which human leukocyte antigen (HLA) alleles are associated with GD in Asians.

Methodology/Princial Findings: We conducted a case-control association study (499 unrelated GD cases and 504 controls) and a replication in an independent family sample (419 GD individuals and their 282 relatives in 165 families). To minimize genetic and phenotypic heterogeneity, we included only ethnic Chinese Han population in Taiwan and excluded subjects with hypothyroidism. We performed direct and comprehensive genotyping of six classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1) to 4-digit resolution. Combining the data of two sample populations, we found that B*46:01, DPB1*05:01, DQB1*03:02, DRB1*15:01 and DRB1*16:02 were associated with GD. HLA-DPB1*05:01 is the major gene of GD in our population and singly accounts for 48.4% of population-attributable risk.

Conclusions/Significance: These GD-associated alleles we identified in ethnic Chinese Hans, and those identified in other Asian studies, are totally distinct from the known associated alleles in Caucasians. Identification of population-specific association alleles is the critical first step for individualized medicine. Furthermore, comparison between different susceptibility/protective alleles across populations could facilitate generation of novel hypothesis about GD pathophysiology and indicate a new direction for future investigation.

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Oral Cancer

Oral cancer (口腔癌) is a subtype of head and neck cancer, is any cancerous tissue growth located in the oral cavity.

In many Asian cultures chewing betel, paan and Areca is known to be a strong risk factor for developing oral cancer. In India where such practices are common, oral cancer represents up to 40% of all cancers, compared to just 4% in the UK.

 

* Association Between HLA DQA1, DQB1 and Oral Cancer in Taiwan by Sheng-Chien Tsai

Abstract: In Taiwan, the incidence of oral cancer increase every year. In recent decade, the number of chewing betel nut increase also. It was estimated that the number of chewing betel was about 2.0 to 2.8 million. Betel chewing is the main cause of submucosa fibrosis, leukoplakia and oral cancer. Not everyone chewing betel nut suffered from oral cancer. There was someone with long term betel nut chewing did not have oral cancer. There still remains controversy of betel nut chewing causing oral cancer and the difference may come from genetic origin. In the past time, there were only few papers concerning about the relationship between oral cancer and HLA class I A, B, C. and very few papers concerning about the relationship between oral cancer and HLA class II DQA1, DQB1. For further characterize the association between HLA DQA1, DQB1 and oral cancer in Taiwan, we investigated 134 Chinese oral cancer patients and 268 normal Chinese adults from Division of Surgical Oncology, Department of Surgery, Kaohsiung Medical University Hospital by using PCR-SSP (polymerase chain reaction-sequence specific primer). For 134 oral cancer patients, the male to female ratio is 34:1. 95.5% of all patients had history of betel nut chewing and all of the participants were Chinese living in Taiwan. We divided oral cancer patients into three mouth, tongue and cheek groups according to location. We found that there was no significant difference of HLA DQA1, DQB1 allele frequencies between oral cancer patients and normal adults for mouth, tongue and cheek, respectively and total oral cancer group. We observed a significantly decreased frequency of haplotype HLA DQA1*0103-DQB1*0601 and DQA1*0501-DQB1*0201 in our patients. From our data we suggests that HLA haplotype DQA1*0103-DQB1*0601 and DQA1*0501-DQB1*0201 may play some role in the pathogenesis of oral cancer.

 

Human Papillomavirus

Human papillomavirus (HPV; 人類乳突病毒) is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in the stratified epithelium of the skin or mucous membranes. While the majority of the nearly 200 known types of HPV cause no symptoms in most people, some types can cause warts (verrucae), while others can – in a minority of cases – lead to cancers of the cervix, vulva, vagina, and anus in women or cancers of the anus and penis in men.

More than 30 to 40 types of HPV are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPV types may cause genital warts. Persistent infection with "high-risk" HPV types—different from the ones that cause skin warts—may progress to precancerous lesions and invasive cancer. HPV infection is a cause of nearly all cases of cervical cancer. However, most infections with these types do not cause disease.

Most HPV infections in young females are temporary and have little long-term significance. 70% of infections are gone in 1 year and 90% in 2 years. However, when the infection persists—in 5% to 10% of infected women—there is high risk of developing precancerous lesions of the cervix, which can progress to invasive cervical cancer. This process usually takes 15–20 years, providing many opportunities for detection and treatment of the pre-cancerous lesion. Progression to invasive cancer can be almost always prevented when standard prevention strategies are applied, but the lesions still cause considerable burden necessitating preventive surgeries which do in many cases involve loss of fertility.

In more developed countries, cervical screening using a Papanicolaou (Pap) test or liquid-based cytology is used to detect abnormal cells which may develop into cancer. If abnormal cells are found, women are invited to have a colposcopy. During a colposcopic inspection biopsies can be taken and abnormal areas can be removed with a simple procedure, typically with a cauterizing loop or—more common in the developing world—by freezing (cryotherapy). Treating abnormal cells in this way can prevent them from developing into cervical cancer.

Pap smears have reduced the incidence and fatalities of cervical cancer in the developed world, but even so there were 11,000 cases and 3,900 deaths in the U.S. in 2008. Cervical cancer has substantial mortality in resource-poor areas; worldwide, there are an estimated 490,000 cases and 270,000 deaths.

HPV vaccines (Cervarix and Gardasil), which prevent infection with the HPV types (16 and 18) that cause 70% of cervical cancer, may lead to further decreases.

 

* Molecular Epidemiology of Human Papillomavirus Infection: Detection Methods and Associations with Human Leukocyte Antigens and Rectal Cancer Risk by Li-Chung Chuang

Abstract: Infection of certain high-risk type of human papillomavirus (HPV) is considered as carcinogen of many kinds of cancer, such as carcinoma of the cervix, oral cavity and anus. This thesis consists of three parts to investigate molecular epidemiology of HPV infection that include Part 1: Comparison of HPV detection by two methods in vaginal samples; Part 2: A cohort study of HPV infection in cervix and adenocarcinoma of rectum and recto-sigmoid junction and Part 3: Molecular epidemiology of human leukocyte antigen (HLA) class II with the natural history of high risk HPV infection and the cervical intraepithelial neoplasia. The participants living in seven Taiwan townships were enrolled during the period from 1991 to 1992 in Part 2 and 3, and from 2008 to 2009 in Part 1. ...

In Part 3, there was a significant association between DRB1*0403 allele and high HPV18 viral load over 1,000 copies in 50 ng of total DNA prepared from cervical cells at study entry, showing odds ratio(OR) (95% CI) was 7.2 (2.0-25.2). After adjustment for age and viral load at study entry, haplotype HLA-DRB1*0405-DQA1*0301-DQB1*0302 was significantly associated with persistent HPV18 infection, showing OR (95% CI) was 13.3 (1.7-105.9). ....

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Myasthenia Gravis

Ptosis of the left eyelid

Myasthenia gravis (from Greek μύς "muscle", ἀσθένεια "weakness", and Latin: gravis "serious"; abbreviated MG; 重肌無力症) is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability. It is an autoimmune disorder, in which weakness is caused by circulating antibodies that block acetylcholine receptors at the postsynaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine. Myasthenia is treated medically with cholinesterase inhibitors or immunosuppressants, and, in selected cases, thymectomy. The disease incidence is 3–30 cases per million and rising as a result of increased awareness.

The hallmark of myasthenia gravis is fatigability. Muscles become progressively weaker during periods of activity and improve after periods of rest. Muscles that control eye and eyelid movement, facial expressions, chewing, talking, and swallowing are especially susceptible. The muscles that control breathing and neck and limb movements can also be affected. The onset of the disorder can be sudden. Often symptoms are intermittent.

In myasthenic crisis a paralysis of the respiratory muscles occurs, necessitating assisted ventilation to sustain life. In patients whose respiratory muscles are already weak, crises may be triggered by infection, fever, an adverse reaction to medication, or emotional stress.

Thymoma (胸腺瘤) is a tumor originating from the epithelial cells of the thymus. Thymoma is an uncommon tumor, best known for its association with the neuromuscular disorder myasthenia gravis. Thymoma is found in 15% of patients with myasthenia gravis. Once diagnosed, thymomas may be removed surgically. In the rare case of a malignant tumor, chemotherapy may be used.

A third of all people with a thymoma have symptoms caused by compression of the surrounding organs by an expansive mass. These problems may take the form of superior vena cava syndrome, dysphagia (difficulty swallowing), cough, or chest pain.

One-third of patients have their tumors discovered because they have an associated autoimmune disorder.

One-third to one-half of all persons with thymoma have no symptoms at all, and the mass is identified on a chest X-ray or CT/CAT scan performed for an unrelated problem.

 

* HLA Genotyping and Building a Database for the Genetic study of Myasthenia Gravis by Jeng-Yi Chen

Abstract: Myasthenia gravis (MG) is a autoimmune disease, which characteristic feature is fatigue of ocular or skeletal muscle. According to the investigation of NTU hospital, the prevalence of MG (in Taiwan) is 8 cases per hundred thousand. It has been discovered that pathogenesis of MG results from the autoantibody produced by most patients themselves, which would block the signal transmitted by moto neuron, and stop it from passing through synapse in neuromuscular junction (NMJ). The autoantibody affects the motion of muscles. Some immunological, genetic, biochemical research indicates that multiple factors, including mutation, affection of immune system or even virus infection, would cause MG synergistically. With the studies of family cases, it is suggested that the transmission of MG is related to some genetic factors, but further research is required to understand the genetic component of MG. Myasthenia gravis was first described in 17th century, but the genetic factors are not referred to in literatures until much lately. Recent studies of the genetic factors are aimed to understand the gene mutation or the genes that affect immune system. It is proposed in a number of studies that the HLA gene complex located on the chromosome 6p is a candidate regions, which is one of the highly polymorphic gene clusters ever known. Differences with regard to race and gender have been shown in clinical symptoms of myasthenia gravis. The percentage of the male and female Caucasian patients of MG is 2 : 3, however, the number of the female patients (in Taiwan) is twice the number of the male patients. By onset-age analysis, we found that almost seventy percent MG 15% of MG patients, while it rises up to 50% in Taiwan. Male MG patients with thymoma have more percentage than female patients. Almost thirty percent MG patients are SNMG. We found that the percentage of generalized MG patients with late onset-age are increased in onset-age vs. clinical stage analysis. By onset-age vs. thymus status analysis, we found that MG patients with late onset-age and thymoma are increased. MG patients with early onset-age are more SNMG. MG patients with more severe clinical stage and thymoma are increased percentage. MG patients with more severe clinical stage and not SNMG are increased percentage. In this study, the HLA genotypes of MG patients in Taiwan are analyzed with the sequence-based typing method. The HLA alleles with significant frequency differences were revealed in the results to be associated with the sex of female, sero-positive, generalized MG and hyperplasia. DQB1*0201 was also found to be closely related to late onset age and thymoma, and the allele frequency of it is decreased among the patients; DQB1*05031 was connected with early onset age and thymus hyperplasia, and the allele frequency of it is much higher than that among ordinary Chinese people. In HLA-DRB vs. clinical information analysis, the allele frequency of DRB5*01011 is increased in female MG patients with late onset-age. And we also found that HLA-A and -B of HLA class I genes have no significant association. In this research, a database was built to record the clinical information and HLA genotypes of MG patients in Taiwan, and embedded programming language was utilized to develop a program for the analysis of HLA genotypes and clinical information as well as a helpful system for the studies of MG. It is hoped that it can be used as a faster and more convenient way for a larger scale of HLA genotyping analysis and further understanding of its causes.

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Rheumatoid Arthritis

Rheumatoid arthritis (RA; 風濕性關節炎) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium (synovitis) secondary to hyperplasia of synovial cells, excess synovial fluid, and the development of pannus in the synovium. The pathology of the disease process often leads to the destruction of articular cartilage and ankylosis of the joints. Rheumatoid arthritis can also produce diffuse inflammation in the lungs, pericardium, pleura, and sclera, and also nodular lesions, most common in subcutaneous tissue. Although the cause of rheumatoid arthritis is unknown, autoimmunity plays a pivotal role in both its chronicity and progression, and RA is considered a systemic autoimmune disease.

About 1% of the world's population is afflicted by rheumatoid arthritis, women three times more often than men. Onset is most frequent between the ages of 40 and 50, but people of any age can be affected. It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility if not adequately treated.

 

* Influence of HLA-DRB1 Genes and the Shared Epitope on Genetic Susceptibility to Rheumatoid Arthritis in Taiwanese by Shih-Chia Liu, et al.

Abstract

Objective: To investigate the association of predisposing and protective HLA-DRB1 alleles with rheumatoid arthritis (RA) and its clinical markers in a Taiwanese population.

Methods: A total of 273 patients with RA and 480 healthy controls, all of Taiwanese origin, were genotyped for HLA-DRB1 alleles by polymerase chain reaction and sequence-based typing assays. The associations between RA and HLA-DRB1 alleles and genotypes were investigated by chi-squared test.

Results: The DRB1*0405 and *1001 phenotypes showed the most significant associations with RA (OR 4.04, 95% CI 2.84-5.77, pc = 3.2 10-14; OR 5.25, 95% CI 2.10-13.06, pc = 3.0 10-3, respectively). Individuals carrying single or double doses of the shared epitope (SE/non-SE or SE/SE) had higher risks of RA. The compound heterozygote of DRB1*0405/*1001 showed the largest increase in RA risk (OR 15.8, 95% CI 2.48-100.7, pc = 0.004). Single or double doses of SE alleles were significantly associated with a higher bone erosion rate. Rheumatoid factor positivity and bone erosion were more frequent in patients with at least one copy of DRB1*0405.

Conclusion: Our results show that SE-encoding HLA-DRB1*0405 and *1001 are associated with RA in a Taiwanese population; this is the first time DRB1*1001 has been described in persons of Asian ethnicity. Heterozygotes of DRB1*0405 and *1001 predicted the strongest susceptibility to RA, suggesting that this genotype enhances susceptibility to RA in Taiwanese.

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Breast Cancer

Breast cancer (malignant breast neoplasm; 乳癌) is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas.

Prognosis and survival rate varies greatly depending on cancer type and staging. With best treatment and dependent on staging, 5-year relative survival varies from 98% to 23, with an overall survival rate of 85%.

In 2008, breast cancer caused 458,503 deaths worldwide (13.7% of cancer deaths in women). Breast cancer is more than 100 times more common in women than breast cancer in men, although males tend to have poorer outcomes due to delays in diagnosis.

 

 

* HLA-DQA1 and -DQB1 Alleles Typing in Southern Taiwanese Women With Breast Cancer by Bai-Hsiun Chen

Abstract

Background and Aim: The pathogenesis of breast cancer is multifactorial. Genetic predisposition, environmental factors, hormones and even infections agent are thought to interact in the manifestation of breast cancer. Particular human leukocyte antigen (HLA) alleles play a pivotal role in cellular immunity and may be an important genetically determined host trait. Regardless of the importance and functions of HLA genes in the evolution of cancer, the allele specific association of HLA molecules in cancer patients has not been well established. Recently, there are a few studies concentrating on the association between HLA and breast cancer. Besides, the results of those studies were controversial.

Materials and Methods:  We designed a study to evaluate the association between the genotype of HLA class II genes and the breast cancer, polymorphism of HLA-DQA1 and -DQB1 were determined by polymerase chain reaction with sequence specific primers (PCR-SSP) in 101 Taiwanese women patients with breast cancer and 115 matched control subjects. We also investigated the effect of breast cancer site estrogen receptor, progesterone receptor, HER-2/neu on the association between HLA-DQA1, DQB1 and female breast cancer.

Result: By PCR SSP typing, the HLA-DQA1 and -DQB1 locus comparison of allele frequencies between breast cancer patients and healthy controls showed no significant difference at the HLA-DQA1 and-DQB1 locus. In female breast cancer patients with HER-2/neu positivity, the frequencies of DQA1*0501 24% were significant higher then that of HER-2/neu negativity 7.7% (Pc=0.04)

Conclusion: We have established the importance to a lack of HLA-DQA1 and -DQB1 association with breast cancer in southern Taiwanese women, and we found that the HLA-DQA1*0501 allele frequencies of breast cancer patients with HER-2/neu positivity were significantly higher then that of HER-2/neu negativity (Pc=0.04). The results of this study may provide information for further clarification of the etiology of breast cancer in this region.

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Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC, also called malignant hepatoma) is the most common type of liver cancer (肝癌). Most cases of HCC are secondary to either a viral hepatitide infection (hepatitis B or C) or cirrhosis (alcoholism being the most common cause of hepatic cirrhosis).

The main risk factors for hepatocellular carcinoma are

• Alcoholism
• Hepatitis B
• Hepatitis C
• Aflatoxin
• Cirrhosis of the liver
• Hemachromatosis
• Wilsons disease (while some theorize the risk increases, case studies are rare and suggest the opposite where Wilson's disease actually may confer protection)
• Type 2 Diabetes (probably aided by obesity)

 

* Specific HLA-DQB1 Alleles Associated With Risk for Development of Hepatocellular Carcinoma: A meta-analysis by Yong-Ning Xin, et al.

Abstract

Aim: To evaluate the association of human leukocyte antigen (HLA)-DQB1 alleles with hepatocellular carcinoma (HCC) through meta-analysis of published data.

Methods: Case-control studies on HLA-DQB1 allele association with HCC published up to January 2010 were included in the analyses. The odds ratios (ORs) of HLADQB1 allele distributions in HCC patients were analyzed and compared with healthy controls. The meta-analysis software REVMAN 5.0 was applied for investigating heterogeneity among individual studies and for summarizing all the studies. A meta-analysis was performed using fixed-effect or random-effect methods, depending on the absence or presence of significant heterogeneity. Seven case-control studies containing 398 cases and 594 controls were included in the final analysis.

Results: Among the five family alleles, two (DQB1*02 and DQB1*03) were found to be significantly associated with the risk of HCC. The combined OR for the association of DQB1*02 and DQB1*03 allele with the risk for HCC was 1.78 (95% CI: 1.05-3.03, P = 0.03) and 0.65 (95% CI: 0.48-0.89, P = 0.007), respectively. Among the 13 specific alleles, two (DQB1*0502 and DQB1*0602) were significantly associated with risk of HCC. The combined OR for the association of DQB1*0502 and DQB1*0602 allele with the risk for HCC was 1.82 (95% CI: 1.14-2.92, P = 0.01) and 0.58 (95% CI: 0.36-0.95, P = 0.03), respectively. No significant association was established for other HLA-DQB1 family alleles and specific alleles.

Conclusion: Our results support the hypothesis that specific HLA-DQB1 allele families and alleles might influence the susceptibility or resistance to HCC, although it needs further investigations.

 

* Analysis of Human Leukocyte Antigen Polymorphism with Outcomes of Hepatitis B Virus Infection and the Immunologic Responses to Hepatitis B Vaccination by Zong-Ying Wu

Abstract: Following an acute hepatitis B virus (HBV) infection, spontaneously clearance or chronic carrier is determined by the host immune response. Vaccination is important in preventing hepatitis B infection. However, approximately 5-10% of vaccines were poor or no response to hepatitis B (HB) vaccine. Since the human leukocyte antigen system (HLA) is an integral component of the immune response, we hypothesized that the highly polymorphic HLA genes are key determinants of viral clearance and immune response to HB vaccine.

Subjects in this study were participants into two studies: (i) the HBV infected study, we enrolled a total of 434 persons who had visited Medical Center for renal or heat transplantation, as either recipients or donors, between January 2001 and September 2007. Subjects were confirmed who have ever infected Hepatitis B virus history, and categorized into 2 different groups: the ‘‘Chronic Carrier Group’’ (CC), and ‘‘Spontaneously Cleared Group’’ (SC) according to the course of HBV infection. The “CC” group who had been hepatitis B surface antigen (HBsAg)-positive for at least 6 months. The “SC” group who was HBsAg-negative with antibodies to HBsAg (anti-HBs) and hepatitis B core antigen (anti-HBc). We excluded subjects who were HBsAg-negative and had anti-HBs, but not anti-HBc. (ii) the vaccination study were obtained from 121 persons (48 health care workers and 73 university students) who and before and after three dose of 20 ug/ml hepatitis B vaccine (Engerix B Hepatitis B Recombinant Vaccine). Each sample was assayed for HBs Ag, Anti-HBs and Anti-HBc using commercial available kits (VITROS ECi Immunodiagnostic System). DNA was extracted from 200 ul sample of blood by Viogene Blood and Tissue Genomic DNA Extraction Miniprep System. HLA-A, -B and -DR typing was performed using commercial PCR-reverse SSOP kits. (Dynal Bioteck Ltd. U.K). Chi-square and Fisher exact test was used to compare categorical variables as appropriate. A p less than 0.05 was considered statistically significant.

In HBV infected subject, a total of 16 individuals fulfilled our criteria for a “CC” HBV infection and were matched to 70 individuals with “SC”. In vaccination subject, 121 persons who were HBV-naïve were enrolled After 3 doses of HB vaccination, 15 were nonresponders (Anti-HBs <10 mIU/ml) _with and the remaining 106 were responders (Anti-HBs ≥ 10 mIU/ml). HLA typing to HLA A, B and DR locus were undertaken using sequence-specific oligonucleotide probe hybridization. Compared to “SC”, the “CC” had significant increased frequency of HLA-DRB1*09 (28.13% versus 4.86%, OR=4.58, 95% CI: 1.53-13.68, p=0.003). Compared to responders, the non-responders had significant and marginally-significant increased frequency of HLA-B*55 (16.67% versus 4.72%, OR=4.04, 95% CI: 1.10-14.32, p=0.033), HLA DRB1*04 (36.37% versus 17.45%, OR=2.74, 95% CI 1.11-6.92, p=0.026).

HLA-DRB1*09 allele be associated with the chronic HBV infection. The other hand, the HLA-B*55 and HLA DRB1*04 alleles be associated with the no responsiveness to hepatitis B vaccination. The possibility of association to other alleles could not be ruled out due to the limited sample size in this study.

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Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC; 鼻咽癌) is the most common cancer originating in the nasopharynx, the uppermost region of the pharynx or "throat", where the nasal passages and auditory tubes join the remainder of the upper respiratory tract. NPC differs significantly from other cancers of the head and neck in its occurrence, causes, clinical behavior, and treatment. It is vastly more common in certain regions of East Asia and Africa than elsewhere, with viral, dietary and genetic factors implicated in its causation. It is most common in males.

NPC is uncommon in the United States and most other nations, but is extremely common in southern regions of China, particularly in Guangdong accounting for 18% of all cancers in China. It is sometimes referred to as Cantonese cancer because it occurs in about 25 cases per 100,000 people in this region, 25 times higher than the rest of the world. It is also quite common in Taiwan. This could be due to the South East Asian diet which typically includes consumption of salted vegetables, fish and meat. While NPC is seen primarily in middle-aged persons in Asia, a high proportion of African cases appear in children. The cause of increased risk for NPC in these endemic regions is not entirely clear.

EBV (Epstein-Barr virus) NPC is the most common epithelial cancer in adults. The detection of nuclear antigen associated with Epstein-Barr virus (EBNA) and viral DNA in NPC type 2 and 3, has revealed that EBV can infect epithelial cells and is associated with their transformation . The etiology of NPC (particularly the endemic form) seems to follow a multi-step process, in which EBV, ethnic background, and environmental carcinogens all seem to play an important role. Lo et al. showed that EBV DNA was detectable in the plasma samples of 96% of patients with non-keratinizing NPC, compared with only 7% in controls. More importantly, EBV DNA levels appear to correlate with treatment response and they may predict disease recurrence, suggesting that they may be an independent indicator of prognosis. In adults, other likely etiological factors include genetic susceptibility, consumption of food (in particular salted fish) containing carcinogenic volatile nitrosamines, and as in children, EBV .

 

* Association of HLA Class I and II Alleles and Extended Haplotypes With Nasopharyngeal Carcinoma in Taiwan by Hildesheim A, et al.

Abstract

Background: Nasopharyngeal carcinoma (NPC), which occurs at a disproportionately high rate among Chinese individuals, is associated with Epstein-Barr virus (EBV). Human leukocyte antigen (HLA) polymorphisms appear to play a role in NPC, because they are essential in the immune response to viruses. We used high-resolution HLA genotyping in a case-control study in Taiwan to systematically evaluate the association between various HLA alleles and NPC.

Methods: We matched 366 NPC case patients to 318 control subjects by age, sex, and geographic residence. Participants were interviewed and provided blood samples for genotyping. High-resolution (polymerase chain reaction-based) genotyping of HLA class I (A and B) and II (DRB1, DQA1, DQB1, and DPB1) genes was performed in two phases. In phase I, 210 case patients and 183 control subjects were completely genotyped. In phase II, alleles associated with NPC in the phase I analysis were evaluated in another 156 case patients and 135 control subjects. Extended haplotypes were inferred.

Results: We found a consistent association between HLA-A*0207 (common among Chinese but not among Caucasians) and NPC (odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.5 to 3.5) but not between HLA-A*0201 (most common HLA-A2 allele in Caucasians) and NPC (OR = 0.79, 95% CI = 0.55 to 1.2). Individuals with HLA-B*4601, which is in linkage disequilibrium with HLA-A*0207, had an increased risk for NPC (OR = 1.8, 95% CI = 1.2 to 2.5) as did individuals with HLA-A*0207 and HLA-B*4601 (OR = 2.8, 95% CI = 1.7 to 4.4). Individuals homozygous for HLA-A*1101 had decreased risks for NPC (OR = 0.24, 95% CI = 0.13 to 0.46). The extended haplotype HLA-A*3303-B*5801/2-DRB1*0301-DQB1*0201/2-DPB1*0401, specific to this ethnic group, was associated with a statistically significantly increased risk for NPC (OR = 2.6, 95% CI = 1.1 to 6.4).

Conclusions: The restriction of the association of HLA-A2 with NPC to HLA-A*0207 probably explains previously observed associations of HLA-A2 with NPC among Chinese but not Caucasians. The extended haplotypes associated with NPC might, in part, explain the higher rates of NPC in this ethnic group.

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China

 

* Is Adult Celiac Disease Really Uncommon in Chinese? by Ling-ling Jiang, et al.

Abstract: Celiac disease (CD) is a type of intestinal malabsorption syndrome, in which the patients are intolerant to the gliadin in dietary gluten, resulting in chronic diarrhea and secondary malnutrition. The disease is common in Europe and the United States, but only sporadic reports are found in East Asia including China. Is CD really rare in China? We examined 62 patients by capsule endoscopy for chronic diarrhea from June 2003 to March 2008. Four patients with chronic diarrhea and weight loss were diagnosed to have CD. Under the capsule endoscopy, we observed that the villi of the proximal small bowel became short, and that the mucous membrane became atrophied in these four patients. Duodenal biopsies were performed during gastroscopy and the pathological changes of mucosa were confirmed to be Marsh 3 stage of CD. A gluten free diet significantly improved the conditions of the four patients. We suspect that in China, especially in the northern area where wheat is the main food, CD might not be uncommon, and its under-diagnosis could be caused by its clinical manifestations that could be easily covered by the symptoms from other clinical situations, particularly when it came to subclinical patients without obvious symptom or to patients with extraintestinal symptoms as the initial manifestations.

 

* Coeliac Disease: Emerging in China? by J. Wu, et al.

Excerpts: Here we report on a serological screening for CD (Celiac Disease) in China. CD has been historically considered to be absent in the Far East (China, Japan, Korea, Malaysia, etc.). However, since the major known risk factors for CD are common in China, we used serological tests for immunoglobulin G (IgG) antigliadin antibodies (AGAs) and IgA antitissue transglutaminase antibodies (tTGs) to screen for CD in high risk patients, comprising 73 cases of diarrhoea-predominant irritable bowel syndrome (IBS-D) and five cases of insulin-dependent diabetes mellitus (IDDM), 30 women and 48 men, ...

Our serological screening demonstrated that CD might exist in Jiangsu province. This province is one of the main wheat producing areas in China.5 The CD predisposing human leucocyte antigen (HLA)-DQ alleles, accounting for 30% of heritability in Caucasians, are not rare in Han inhabitants of this area. Their frequency of haplotype DQA1*0501-DQB1*02 is 7.2% and of DQA1*03-DQB1*0302 is 4.7%, and the frequencies of haplotypes DQA1*02-DQB1*02 and DQA1*05-DQB1*03 together capable of encoding DQ2 in trans are 9.4% and 7.8%, respectively. Even though there were no serological test results, Jiang et al had reported four cases of CD by duodenal biopsy this year in Zhejiang province which is neighbour of Jiangsu. The results of our research are encouraging. Considering the increasing gluten intake, frequency of common HLA-DQ2/DQ8 alleles and the large population size of Jiangsu province, we speculate that CD might not be rare....

 

* Coeliac Disease in China, a Field Waiting for Exploration by Wu J, et al.

This Map Displays the Cultivation Intensity of Wheat in China

Conclusions: this study previously published as a letter in GUT (Wu J, Xia B, von Blomberg BME, Zhao C, Yang XW, Crusius JBA, Peña AS. Coeliac disease: emerging in China? Gut 2010; 59(3): 418-9) demonstrated that CD may exist in the Jiangsu province of P.R. China. The present article draws attention to the difficulties of following a standard protocol in China such as established in western countries and highlights important factors less well known in the west in relation to the development of CD in China. Wheat production became significant in China between 1600 and 1300 B.C. After the Han dynasty (500-200 B.C.), wheat was one of the main cereals in China. One the major wheat fields in China is located in the Jiangsu province where the research for this article was performed. A review of Chinese literature shows that the predominant HLA-DQ CD risk alleles and haplotypes are present in the Jiangsu province. Genetic background, food consumption, and the results of our study suggest that CD should actively be investigated in P.R. China.

 

* 中国四个民族HLA-DRB1、DQA1、DQB1基因多态性研究(HLA-DRB1,H)

Abstract: The human leucocyte antigen (HLA) genes exhibit highest degrees ofpolymorphism and remarkable ethnic differences in their allele andhaplotype frequencies. Study on polymorphism of HLA in different populations could supply the basic data for disease-correlation, tissue transplantation matching and anthropology analysis. HLA-DRB1,DQA1 and DQB1 genotypes were investigated in four Chinese minor nationalities including Lahu, Li, Sala and Tu using PCR-SSP genotyping method.... At DQA1 locus, in Lahus,the most prevalent were DQA1*0501 (0.1909)、*0101 (0.1682)、 *0301 (0.1546)、*0102 (0.1364)、*0104 (0.1273), the rarest were DQA1*0302 (0.0182)、 *0401 (0.0091) ; in Lis, the most prevalent were DQA1*0101 (0.2070)、*0102 (0.1543)、 *0301 (0.1223), the rarest were DQA1*0103 (0.0426); in Salas, the most prevalent were DQA1*0301 (0.2313)、*0101(0.1866)、*0501 (0.1269)、the rarest were DQA1*0104 (0.0224)。 in Tus, the most prevalent were DQA1*0301 (0.2536)、*0501 (0.1667)、 *0101 (0.1304)、*0102 (0.1304), the rarest were DQA1*0103 (0.0362)、 *0104

 

* Influences of the Iodine Nutrition Status and the HLA-DQA1*0501 and-DQA1*0201 Alleles on the Pathogenesis of AITDs in Coastal Area of Shandong Province by Zhao Wen-juan, et al.

Objective To investigate the association of HLA-DQA1*0501 and-DQA1*0201 alleles with autoimmune thyroid disea-(AITDs) patients in Shandong seashore areas,and evaluate the effects of iodine nutrition status on AITDs.Methods AITDs were divided into graves disease(GD) group and hashimoto thyroiditis(HT) group.The HLADQA1*0501 and DQA1*0201 alleles were detected by polymerase chain reaction with sequence-specific primers(PCR-SSP).The urine iodine concentration was determined by China national standard method.Results The frequency of the HLA-DQA1*0501 allele was significantly higher in GD and HT female groups than in control(GD: P 0.05,OR = 0.33;HT: P 0.01,OR = 0.27).The frequency of the HLA-DQA1*0201 allele was significantly lower in GD and HT groups than in control(GD P 0.01,OR = 0.4;HT P 0.05,OR = 0.42).The median values of urinary iodine of GD and HT patients were significantly higher than that of control group in Shandong seashore areas(P 0.05).In the subjects of DQA1*0501 allele(-),the median values of urinary iodine in GD and HT patients with hyperthyroidism were significantly higher than that in control group(P 0.05).In the subjects of DQA1*0201(+),the median values of urinary iodine in GD and HT patients was significantly higher than that in control group(P 0.05).The logarithm of urinary iodine and the DQA1*0501 were positive correlated with GD and HT by multiple logistic regression analysis;DQA1*0201 was negative correlated with GD and HT.Conclusion The HLA-DQA1*0501 allele is positively associated with morbidity of GD and HT in Shandong coastal districts,whereas HLA-DQA1*0201 allele is associated with protection of GD and HT,especially for female patients.Iodine,HLA-DQA1*0501,and HLA-DQA1*0201 alleles have cooperative effect on the pathogenesis of GD and HT.

 

* The Association Between the Genetic Polymorphism of HLA-DQA1, DQB1, and DRB1 and Serum Alanine Aminotransferase Levels in Chronic Hepatitis C in the Chinese Population by Rong-Bin Yu, et al.

Abstract

Background and Aim:  To investigate a possible association between HLA genes with serum alanine aminotransferase (ALT) levels and evaluate whether the HLA-DQA1, DQB1, and DRB1 genes could influence the development of liver damage in chronic hepatitis C.

Conclusions:  These results suggest that particular HLA alleles may have an influence on the serum ALT level of chronic HCV infection as a host genetic factor in the Chinese population. The DQA1*0501, DQB1*0301, and DRB1*0401 alleles, and the DQA1*0301-DQB1*0301, DQA1*0501-DQB1*0301, and DRB1*1101-DQB1*0301 haplotypes seem to be associated with low hepatitis activity; whereas DQB1*0201 allele is closely correlated with the progression of liver injury in chronic HCV infection.

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Dilated Cardiomyopathy

Dilated cardiomyopathy or DCM (擴張性心肌病變) is a condition in which the heart becomes weakened and enlarged and cannot pump blood efficiently. The decreased heart function can affect the lungs, liver, and other body systems.

DCM is one of the cardiomyopathies (心臟病), a group of diseases that primarily affect the myocardium (the muscle of the heart). Different cardiomyopathies have different causes and affect the heart in different ways. In DCM a portion of the myocardium is dilated, often without any obvious cause. Left or right ventricular systolic pump function of the heart is impaired, leading to progressive cardiac enlargement and hypertrophy, a process called remodeling.

Dilated cardiomyopathy is the most common form of non-ischemic cardiomyopathy. It occurs more frequently in men than in women, and is most common between the ages of 20 and 60 years. About one in three cases of congestive heart failure (CHF; 鬱血性心衰竭) is due to dilated cardiomyopathy. Dilated cardiomyopathy also occurs in children.

 

* HLA-DQA1, -DQB1 Polymorphism and Genetic Susceptibility to Idiopathic Dilated Cardiomyopathy in Hans of Northern China by Liu W, et al.

Abstract: Autoimmune mechanisms are likely to participate in the pathogenesis of at least a subgroup of idiopathic dilated cardiomyopathy (IDC), and components of the major histocompatibility complex (MHC) may serve as markers for the propensity to develop immune-mediated myocardial damage. Human leukocyte antigen (HLA) class II genes, especially HLA-DQ genes, which are highly polymorphic, play an important role in the activation of immune responses and thus control the predisposition to, or protection from, IDC. This study was conducted to investigate the association of HLA-DQA1, -DQB1 allele polymorphisms with an autoantibody against the myocardial mitochondria ADP/ATP carrier, and to explore susceptibility to idiopathic dilated cardiomyopathy (IDC) among the Han ethnic group in northern China and the immunological mechanisms and hereditary susceptibility to IDC....The frequencies of HLA-DQA1*0501 and HLA-DQB1*0303 were 0.3889 and 0.1806 in the IDC group, significantly higher than those of the healthy controls (0.0900 and 0.0364 respectively, both P < 0.05)....

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Lung Cancer

Lung cancer (肺癌) is a disease that consists of uncontrolled cell growth in tissues of the lung. This growth may lead to metastasis, which is the invasion of adjacent tissue and infiltration beyond the lungs. The vast majority of primary lung cancers are carcinomas, derived from epithelial cells. Lung cancer, the most common cause of cancer-related death in men and women, is responsible for 1.3 million deaths worldwide annually, as of 2004. The most common symptoms are shortness of breath, coughing (including coughing up blood), and weight loss.

The most common cause of lung cancer is long-term exposure to tobacco smoke. Nonsmokers account for 15% of lung cancer cases, and these cases are often attributed to a combination of genetic factors, radon gas, asbestos, and air pollution including secondhand smoke.

 

* Analysis of HLA-A, HLA-B and HLA-DRB1 Alleles in Chinese Patients with Lung Cancer by L. Yang, et al.

Abstract: The primary function of the human leukocyte antigen (HLA) system is to regulate the immune response. Because of its important role in the immune response and its high degree of polymorphism, the HLA system is associated with many diseases. We examined the polymorphisms of HLA-A, B and DRB1 alleles in 100 unrelated patients with lung carcinoma and in 438 unrelated normal controls of Han nationality from North China, using sequence-based typing and PCR with sequence-specific primers. We found that the frequencies of HLA-A*0201, A*2601, B*1518, B*3802, DRB1*0401, DRB1*0402, and DRB1*1201 were higher in the lung carcinoma group than in the normal control group. The P values were 0.035, 0.040, 0.001, 0.017, 0.014, 0.004, and 0.019, respectively, and the odds ratio values were 1.052, 3.513, 4.047, 3.054, 4.237, 19.397, and 2.128, respectively. The frequency of HLA-DRB1*1302 was lower in the lung carcinoma group than in the normal control group (P = 0.046, odds ratio = 0.168). We concluded that patients with lung cancer and healthy controls of Han nationality from North China differ in the frequencies of various HLA alleles.

 

* Fumes from Meat Cooking and Lung Cancer Risk in Chinese Women by Adeline Seow, et al.

Abstract: Chinese women are recognized to have a high incidence of lung cancer despite a low smoking prevalence. Several studies have implicated domestic exposure to cooking fumes as a possible risk factor, although the exact carcinogens have yet to be identified. Heterocyclic amines are known carcinogens, which have been identified in cooked meat, and also in fumes generated during frying or grilling of meats. We conducted a case-control study of 303 Chinese women with pathologically confirmed, primary carcinomas of the lung and 765 controls to examine the association between exposure to meat cooking and lung cancer risk. Data on demographic background, smoking status, and domestic cooking exposure, including stir-frying of meat, were obtained by in-person interview while in hospital. The response rates among eligible cases and controls were 95.0 and 96.9%, respectively. The proportion of smokers (current or ex-smokers) among cases and controls was 41.7 and 13.1%, respectively. Adenocarcinomas comprised 31.5% of cancers among smokers and 71.6% among nonsmokers. When cases were compared with controls, the odds ratio (OR) for lung cancer (all subtypes) among ex-smokers was 4.3 [95% confidence interval (CI) 2.7–6.8] and that among current smokers was 5.0 (95% CI, 3.4–7.3). Among smokers, women who reported that they stir-fried daily in the past had a significantly increased risk of lung cancer (adjusted OR, 2.0; 95% CI, 1.0–3.8) and among these women, risk was enhanced for those who stir-fried meat daily (OR, 2.7; 95% CI, 1.3–5.5). Women who stir-fried daily but cooked meat less often than daily did not show an elevated risk (OR, 1.0. 95% CI, 0.5–2.4). Risk was further increased among women stir-frying meat daily who reported that their kitchen was filled with oily fumes during cooking (OR, 3.7; 95% CI, 1.8–7.5). These cooking practices on their own did not increase risk among nonsmokers in our study population. Our results suggest that inhalation of carcinogens, such as heterocyclic amines generated during frying of meat, may increase the risk of lung cancer among smokers. Further studies in different settings are warranted to examine this possibility, which may also help to explain the higher risk observed among women smokers compared with men.

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Conditions Associated with Celiac Disease

 

Severe coeliac disease leads to the characteristic symptoms of pale, loose and greasy stool (steatorrhoea), and weight loss or failure to gain weight (in young children). People with milder coeliac disease may have symptoms that are much more subtle and occur in other organs rather than the bowel itself. Finally, it is possible to have coeliac disease without any symptoms whatsoever. Many adults with subtle disease only have fatigue or anaemia.

Gastrointestinal: The diarrhoea that is characteristic of coeliac disease is (chronic) pale, voluminous and malodorous. Abdominal pain and cramping, bloatedness with abdominal distension (thought to be due to fermentative production of bowel gas) and mouth ulcers may be present. As the bowel becomes more damaged, a degree of lactose intolerance may develop. Frequently, the symptoms are ascribed to irritable bowel syndrome (IBS), only later to be recognised as coeliac disease; a small proportion of patients with symptoms of IBS have underlying coeliac disease, and screening for coeliac disease is recommended for those with IBS symptoms.

Coeliac disease leads to an increased risk of both adenocarcinoma (small intestine cancer) and lymphoma of the small bowel (enteropathy-associated T-cell lymphoma or EATL). This risk returns to baseline with diet. Longstanding and untreated disease may lead to other complications, such as ulcerative jejunitis (ulcer formation of the small bowel) and stricturing (narrowing as a result of scarring with obstruction of the bowel).

Malabsorption-related

The changes in the bowel make it less able to absorb nutrients, minerals and the fat-soluble vitamins A, D, E, and K.

• The inability to absorb carbohydrates and fats may cause weight loss (or failure to thrive/stunted growth in children) and fatigue or lack of energy.
• Anaemia may develop in several ways: iron malabsorption may cause iron deficiency anaemia, and folic acid and vitamin B12 malabsorption may give rise to megaloblastic anaemia.
• Calcium and vitamin D malabsorption (and compensatory secondary hyperparathyroidism) may cause osteopenia (decreased mineral content of the bone) or osteoporosis (bone weakening and risk of fragility fractures).
• A small proportion have abnormal coagulation due to vitamin K deficiency and are slightly at risk for abnormal bleeding.
• Coeliac disease is also associated with bacterial overgrowth of the small intestine, which can worsen malabsorption or cause malabsorption despite adherence to treatment.

Miscellaneous

Coeliac disease has been linked with a number of conditions. In many cases, it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition.

• IgA deficiency is present in 2.3% of patients with coeliac disease, and in turn, this condition features a tenfold increased risk of coeliac disease. Other features of this condition are an increased risk of infections and autoimmune disease.
• Dermatitis herpetiformis; this itchy cutaneous condition has been linked to a transglutaminase enzyme in the skin, features small-bowel changes identical to those in coeliac disease, and may respond to gluten withdrawal even if there are no gastrointestinal symptoms.
• Growth failure and/or pubertal delay in later childhood can occur even without obvious bowel symptoms or severe malnutrition. Evaluation of growth failure often includes coeliac screening.
• Recurrent miscarriage and unexplained infertility.
• Hyposplenism (a small and underactive spleen); this occurs in about a third of cases and may predispose to infection given the role of the spleen in protecting against bacteria.
• Abnormal liver function tests (randomly detected on blood tests).

Coeliac disease is associated with a number of other medical conditions, many of which are autoimmune disorders: diabetes mellitus type 1, autoimmune thyroiditis, primary biliary cirrhosis, and microscopic colitis.

A more controversial area is a group of diseases in which anti-gliadin antibodies (an older and non-specific test for coeliac disease) are sometimes detected, but no small bowel disease can be demonstrated. Sometimes, these conditions improve by removing gluten from the diet. This includes cerebellar ataxia, peripheral neuropathy, schizophrenia and autism.

 

* Risk of Malignancy in Patients with Celiac Disease by Green PH, et al.

Abstract

Purpose: Studies from Europe have demonstrated an increased risk of malignancy, especially non-Hodgkin's lymphoma, in patients with celiac disease. However, there are no data on the risk for similar patients in the United States. Our aim was to estimate the risk of malignancy in a cohort of patients with celiac disease compared with the general U.S. population and to determine if a gluten-free diet is protective.

Methods: Patients with celiac disease seen between July 1981 and January 2000 at a referral center were included. Standardized morbidity ratios (SMRs) (ratio of observed to expected) and corresponding 95% confidence intervals (CI) were calculated, using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program.

Results: Forty-three (11%) of 381 celiac disease patients had a diagnosis of cancer; 9 were after the diagnosis of celiac disease, 7 were simultaneous (during same month or admission), and 27 were before the diagnosis. The standardized morbidity ratio for all cancers combined was 1.5 (95% CI: 0.3 to 7.5), with significantly increased values for small bowel cancer (SMR = 34; 95% CI: 24 to 42), esophageal cancer (SMR = 12; 95% CI: 6.5 to 21), non-Hodgkin's lymphoma (SMR = 9.1; 95% CI: 4.7 to 13), and melanoma (SMR = 5.0; 95% CI: 2.1 to 12). Following the diagnosis of celiac disease, patients were at increased risk of non-Hodgkin's lymphoma only (SMR = 6.2; 95% CI: 2.9 to 14), despite adherence to a gluten-free diet. The non-Hodgkin's lymphoma included both T-cell and B-cell types and occurred in both gastrointestinal (n = 5) and extraintestinal sites (n = 4).

Conclusion: In this cohort of patients with celiac disease, we observed increased risks of small intestinal adenocarcinoma, esophageal cancer, melanoma, and non-Hodgkin's lymphoma. The risk of non-Hodgkin's lymphoma persisted despite a gluten-free diet.

 

* Causes of Death in Patients with Celiac Disease in a Population-based Swedish Cohort by Peters U, et al.

Abstract

Background: Patients with celiac disease have an increased risk of death from gastrointestinal malignancies and lymphomas, but little is known about mortality from other causes and few studies have assessed long-term outcomes.

Methods: Nationwide data on 10 032 Swedish patients hospitalized from January 1, 1964, through December 31, 1993, with celiac disease and surviving at least 12 months were linked with the national mortality register. Mortality risks were computed as standardized mortality ratios (SMRs), comparing mortality rates of patients with celiac disease with rates in the general Swedish population.

Results: A total of 828 patients with celiac disease died during the follow-up period (1965-1994). For all causes of death combined, mortality risks were significantly elevated: 2.0-fold (95% confidence interval [CI], 1.8-2.1) among all patients with celiac disease and 1.4-fold (95% CI, 1.2-1.6) among patients with celiac disease with no other discharge diagnoses at initial hospitalization. The overall SMR did not differ by sex or calendar year of initial hospitalization, whereas mortality risk in patients hospitalized with celiac disease before the age of 2 years was significantly lower by 60% (95% CI, 0.2-0.8) compared with the same age group of the general population. Mortality risks were elevated for a wide array of diseases, including non-Hodgkin lymphoma (SMR, 11.4), cancer of the small intestine (SMR, 17.3), autoimmune diseases (including rheumatoid arthritis [SMR, 7.3] and diffuse diseases of connective tissue [SMR, 17.0]), allergic disorders (such as asthma [SMR, 2.8]), inflammatory bowel diseases (including ulcerative colitis and Crohn disease [SMR, 70.9]), diabetes mellitus (SMR, 3.0), disorders of immune deficiency (SMR, 20.9), tuberculosis (SMR, 5.9), pneumonia (SMR, 2.9), and nephritis (SMR, 5.4).

 

* Delayed Diagnosis of Coeliac Disease Increases Cancer Risk by Marco Silano, et al.

Abstract

Background: The association between coeliac disease (CD) and neoplasms has been long established, but few data are available about the risk factors. The aim of this paper is to estimate the risk of developing a neoplasm among non diagnosed coeliac patients and to evaluate if this risk correlates with the age of patients at diagnosis of coeliac disease.

Methods: The study population consists of patients (n = 1968) diagnosed with CD at 20 Italian gastroenterology referral Centers between 1st January 1982 and 31st March 2005.

Results: The SIR for all cancers resulted to be 1.3; 95% CI = 1.0-1.7 p < 0.001. The specific SIRs for non Hodgkin lymphoma was 4.7; 95% CI = 2.9-7.3 p < 0.001, for the small bowel carcinoma 25; 95% CI = 8.5-51.4 p < 0.001, for non Hodgkin lymphoma 10; 95% CI = 2.7-25 p = 0.01, finally for the stomach carcinoma 3; 95% CI = 1.3-4.9 p < 0.08. The mean age at diagnosis of CD of patients that developed sooner or later a neoplasm was 47,6 ± 10.2 years versus 28.6 ± 18.2 years of patients who did not.

Conclusion: Coeliac patients have an increased risk of developing cancer in relation to the age of diagnosis of CD. This risk results higher for malignancies of the gastro-intestinal sites. An accurate screening for tumors should be performed in patients diagnosed with CD in adulthood and in advancing age.

 

* Malignancy and Mortality in People with Coeliac Disease: Population based cohort study by West J, et al.

Abstract

Objective: To quantify the risks of malignancy and mortality in people with coeliac disease compared with the general population.

Results: Of the 4732 people with coeliac disease, 134 (2.8%) had at least one malignancy and 237 (5.0%) died. The overall hazard ratios were: for any malignancy 1.29 (95% confidence interval 1.06 to 1.55), for mortality 1.31 (1.13 to 1.51), for gastrointestinal cancer 1.85 (1.22 to 2.81), for breast cancer 0.35 (0.17 to 0.72), for lung cancer 0.34 (0.13 to 0.95), and for lymphoproliferative disease 4.80 (2.71 to 8.50). The increased risk was primarily in the first year after diagnosis, with the risk for only lymphoproliferative disease remaining significantly raised thereafter. After excluding events in the year after diagnosis, the hazard ratio for malignancy was 1.10 (0.87 to 1.39) and for mortality was 1.17 (0.98 to 1.38), giving absolute excess rates of 6 and 17 per 10,000 person years, respectively.

Conclusions: People with coeliac disease have modest increases in overall risks of malignancy and mortality. Most of this excess risk occurs in the year of follow up after diagnosis. People with coeliac disease also have a noticeably reduced risk of breast cancer. The mechanism of this merits further attention as it may provide insights into the cause of this common malignancy.

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Gastrointestinal Cancer

Gastrointestinal cancer refers to malignant conditions of the gastrointestinal tract, including the esophagus, stomach, liver, biliary system, pancreas, bowels, and anus. Prognosis is variable,and depends almost entirely on the specific type of cancer. Esophageal cancer has a dismal prognosis, largely because it is often detected late, while colon cancer has an excellent prognosis,when detected early. Pancreatic cancer also has a very poor prognosis, with only 5% of patients surviving more than 5 years after diagnosis.

See:

• Gastrointestinal stromal tumors (GIST)
• Esophageal cancer
• Stomach cancer (also called gastric cancer)
• liver cancer (also called hepatocellular carcinoma, HCC, and hepatoma)
• Gallbladder cancer
• Pancreatic cancer
• Colorectal cancer (also called colon cancer, bowel cancer, and rectal cancer)
• Anal cancer

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Small Intestine Cancer

Small intestine cancer (小腸癌), also small bowel cancer and cancer of the small bowel, is a cancer of the small intestine. It is relatively rare compared to other gastrointestinal malignancies such as gastric cancer (stomach cancer) and colorectal cancer.

Small intestine cancer can be subdivided into duodenal cancer (the first part of the small intestine) and cancer of the jejunum and ileum (the later two parts of the small intestine). Duodenal cancer has more in common with stomach cancer, while cancer of the jejunum and ileum have more in common with colorectal cancer.

Several different subtypes of small intestine cancer exist. These include:

• adenocarcinoma
• gastrointestinal stromal tumor
• lymphoma
• ileal carcinoid tumor

 

Risk factors for small intestine cancer include:

• Crohn's disease
• Celiac disease
• Radiation exposure
• Hereditary GI cancer syndromes: familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome
• Males are 25% more likely to develop the disease

 

* 小腸癌 腸胃罕見腫瘤 by 洪素卿

小腸癌是相當少見的腫瘤，在所有腸胃道腫瘤中，所佔比例不到五%。

發生在小腸的惡性腫瘤包括腺癌、類癌、肉瘤以及淋巴癌等。依其種類不同、治療對策及存活情況也不完全一樣。

以腺癌為例，如果發現時，已有轉移、則存活期可能只剩幾個月，但若是發現時，淋巴結陽性、但仍侷限於小腸，那麼開刀切除腫瘤後，五年存活率約有十二%到三十五%。

但若是淋巴癌，對化學治療反應良好，五年存活率還可以超過五成；如果是腸胃道基質瘤，甚至可以長期存活。

馬偕醫院肝膽腸胃科主治醫師章振旺指出，小腸腫瘤初期沒有特殊症狀，有些患者是持續不明原因腹痛、噁心、嘔吐、貧血等症狀，在大腸、十二指腸及胃都找不到問題，最後發現腫瘤在小腸。臨床上，也有不少人直到腫瘤塞住腸道，甚至破裂出血才就醫。

過去主要診斷小腸腫瘤的工具包括：小腸鋇劑攝影、斷層掃描，近年則發展出大小如魚肝油膠囊般的膠囊內視鏡，以及氣囊輔助式小腸鏡。但包括膠囊內視鏡以及氣囊輔助式小腸鏡都要自費。

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Dermatitis Herpetiformis

Dermatitis herpetiformis (DH; 皰疹樣皮炎), or Duhring's Disease, is a chronic blistering skin condition, characterised by blisters filled with a watery fluid. Despite its name, DH is not related to or caused by herpes virus: the name means that it is a skin inflammation having an appearance similar to herpes.

DH was first described by Dr. Louis Duhring in 1884. A connection between DH and gluten intolerance (celiac disease) was recognised in 1967, although the exact causal mechanism is not known.

The age of onset is usually about 15-40, but DH can also affect children and the elderly. Men and women are equally affected. Estimates of DH prevalence vary from 1 in 400 to 1 in 10000.

Symptoms: Dermatitis herpetiformis is characterized by intensely itchy, chronic papulovesicular eruptions, usually distributed symmetrically on extensor surfaces (buttocks, back of neck, scalp, elbows, knees, back). The blisters vary in size from very small up to 1 cm across.

The condition is extremely itchy, and the desire to scratch can be overwhelming. This sometimes causes the sufferer to scratch the blisters off before they are examined by a doctor. Intense itching or burning sensations are sometimes felt before the blisters appear in a particular area.

Untreated, the severity of DH can vary significantly over time, it is presumed, in response to the amount of gluten ingested.

Dermatitis herpetiformis symptoms typically first appear in the early years of adulthood between 20 and 30 years of age.

Although the first signs and symptoms of dermatitis herpetiformis are intensive itching and burning, the first visible signs are the small papules or vesicles that usually look like red bumps or blisters. Sometimes they appear on the face and along the hairline, and, on occasion, on the shoulders, the lower end of the spinal column, and within the mouth. The rash rarely occurs on other mucous membranes, excepting the mouth or lips. The symptoms range in severity from mild to serious, but they are likely to disappear if gluten ingestion is avoided and appropriate treatment is administered. However, the consumption of aliments that contain gluten as well as oral contraceptives may exacerbate the symptoms.

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Schizophrenia

Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social or occupational dysfunction. The onset of symptoms typically occurs in young adulthood, with a global lifetime prevalence of about 0.3–0.7%. Diagnosis is based on observed behavior and the patient's reported experiences.

Genetics, early environment, neurobiology, and psychological and social processes appear to be important contributory factors; some recreational and prescription drugs appear to cause or worsen symptoms. Current research is focused on the role of neurobiology, although no single isolated organic cause has been found. The many possible combinations of symptoms have triggered debate about whether the diagnosis represents a single disorder or a number of discrete syndromes. Despite the etymology of the term from the Greek roots skhizein (σχίζειν, "to split") and phrēn, phren- (φρήν, φρεν-; "mind"), schizophrenia does not imply a "split mind" and it is not the same as dissociative identity disorder—also known as "multiple personality disorder" or "split personality"—a condition with which it is often confused in public perception.

The mainstay of treatment is antipsychotic medication, which primarily suppresses dopamine, and sometimes serotonin, receptor activity. Psychotherapy and vocational and social rehabilitation are also important in treatment. In more serious cases—where there is risk to self and others—involuntary hospitalization may be necessary, although hospital stays are now shorter and less frequent than they were.

The disorder is thought mainly to affect cognition, but it also usually contributes to chronic problems with behavior and emotion. People with schizophrenia are likely to have additional (comorbid) conditions, including major depression and anxiety disorders; the lifetime occurrence of substance abuse is almost 50%. Social problems, such as long-term unemployment, poverty and homelessness, are common. The average life expectancy of people with the disorder is 12 to 15 years less than those without, the result of increased physical health problems and a higher suicide rate (about 5%).

 

* Schizophrenia Three Times as Likely in Celiac Disease Patients by Sally Koch Kubetin

Individuals with celiac disease are more than three times as likely to develop schizophrenia than the general population and more than twice as likely as people with Crohn's disease or ulcerative colitis to do so, Dr. William W. Eaton and his associates reported.

Removal of dietary gluten is neither dangerous nor expensive and effectively treats celiac disease. Dr. Eaton, of Johns Hopkins University, Baltimore, and his associates did not assess whether a gluten-free diet decreased the symptoms of schizophrenia in their study population; however, work by other investigators has shown such an effect (BMJ 328 [7437]:438-39, 2004).

The relationship between schizophrenia and celiac disease was studied in a case sample of 7,997 people who entered a Danish psychiatric facility for the first time between 1981 and 1998 with a diagnosis of schizophrenia. Patients were older than 15 years at the time of their hospitalization, and the identities of their mothers were known.

Each case was matched with 25 controls who did not have schizophrenia, and shared the case patient's year of birth and sex. Danish national patients' registries were searched for cases of celiac disease and dermatitis herpetiformis, which is closely related to celiac disease. Registries were also searched for cases of Crohn's disease and ulcerative colitis, which have not been linked to schizophrenia, among cases, controls, and their parents. The diagnosis of celiac disease had been made in four patients, five mothers of patients, and three fathers of patients before the psychiatric hospitalization for schizophrenia.

The relative risk for schizophrenia in someone with a history of celiac disease was 3.2 after adjustment for socioeconomic status, urban residence, and a family history of schizophrenia. When the four cases of dermatitis herpetiformis among the patients were added to the cases of celiac disease, the relative incidence of either disorder was 3.1, compared with neither disorder.

The adjusted relative risk for schizophrenia in patients with either Crohn's disease or ulcerative colitis was 1.4.

 

* The Gluten Connection: The association between schizophrenia and celiac disease by Kalaydjian AE, et al.

Abstract

Objective: Schizophrenia affects roughly 1% of the population and is considered one of the top 10 causes of disability worldwide. Given the immense cost to society, successful treatment options are imperative. Based on initial findings, gluten withdrawal may serve as a safe and economical alternative for the reduction of symptoms in a subset of patients.

Method: A review of the literature relevant to the association between schizophrenia and celiac disease (gluten intolerance) was conducted.

Results: A drastic reduction, if not full remission, of schizophrenic symptoms after initiation of gluten withdrawal has been noted in a variety of studies. However, this occurs only in a subset of schizophrenic patients.

Conclusion: Large-scale epidemiological studies and clinical trials are needed to confirm the association between gluten and schizophrenia, and address the underlying mechanisms by which this association occurs.

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Gluten-freen Diet

At present, the only effective treatment is a life-long gluten-free diet. No medication exists that will prevent damage or prevent the body from attacking the gut when gluten is present. Strict adherence to the diet allows the intestines to heal, leading to resolution of all symptoms in most cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer and in some cases sterility.

Even while on a diet, health-related quality of life (HRQOL) may be lower in people with coeliac disease. Studies in the United States have found that quality of life becomes comparable to the general population after staying on the diet, while studies in Europe have found that quality of life remains lower, although the surveys are not quite the same. Men tend to report more improvement than women. Some have persisting digestive symptoms or dermatitis herpetiformis, mouth ulcers, osteoporosis and resultant fractures. Symptoms suggestive of irritable bowel syndrome may be present, and there is an increased rate of anxiety, fatigue, dyspepsia and musculoskeletal pain.

Many people with coeliac disease also have one or more additional food allergies or food intolerances, which may include milk protein (casein), corn (maize), soy, amines, or salicylates.

Gluten-free Food: Several grains and starch sources are considered acceptable for a gluten-free diet. The most frequently used are corn, potatoes, rice, and tapioca (derived from cassava). Other grains and starch sources generally considered suitable for gluten-free diets include amaranth, arrowroot, millet, montina, lupin, quinoa, sorghum (jowar), taro, teff, chia seed, and yam. Various types of bean, soybean, and nut flours are sometimes used in gluten-free products to add protein and dietary fiber. In spite of its name, buckwheat is not related to wheat; pure buckwheat is considered acceptable for a gluten-free diet, although many commercial buckwheat products are actually mixtures of wheat and buckwheat flours, and thus not acceptable. Gram flour, derived from chickpeas, is also gluten-free (this is not the same as Graham flour made from wheat).

Gluten is also used in foods in some unexpected ways, for example as a stabilizing agent or thickener in products like ice-cream and ketchup.

People wishing to follow a completely gluten free diet must also take into consideration the ingredients of any over-the-counter or prescription medications and vitamins. Also, cosmetics such as lipstick, lip balms, and lip gloss may contain gluten and need to be investigated before use. Glues used on envelopes may also contain gluten.

Most products manufactured for Passover are gluten free. Exceptions are foods that list matzah as an ingredient, usually in the form of cake meal.

Gluten-free Bread: Bread, which is a staple in the Western diet, is typically made from grains such as wheat which contain gluten. Wheat gluten contributes to the elasticity of dough and is thus an important component of bread. Gluten-free bread is made with ground flours from a variety of materials such as rice, sorghum, corn, or legumes like beans , but since these flours lack gluten it can be difficult for them to retain their shape as they rise and they may be less "fluffy".

Alcoholic Beverages: Several celiac groups report that according to the American Dietetic Association's "Manual of Clinical Dietetics" many types of alcoholic beverages are considered gluten free, provided no colourings or other additives have been added as these ingredients may contain gluten. Although most forms of whiskey are distilled from a mash that includes grains that contain gluten, distillation removes any proteins present in the mash, including gluten. Although up to 49% of the mash for Bourbon and up to 20% of the mash for corn whiskey may be made up of wheat, or rye, all-corn Bourbons and corn whiskeys do exist, and are generally labeled as such. Spirits made without any grain such as brandy, wine, mead, cider, sherry, port, rum, tequila and vermouth generally do not contain gluten, although some vineyards use a flour paste to caulk the oak barrels in which wine is aged, and other vineyards use gluten as a clarifying agent (though it's unclear whether gluten remains at the end of the clarification process). Therefore, some coeliacs may wish to exercise caution. Liqueurs and pre-mixed drinks should be examined carefully for gluten-derived ingredients.

While many spirits were traditionally made without grain, such as tequila, rum and vodka, today they are more commonly made with barley, wheat or rye (instead of agave, sugar or potatoes, et cetera). Often, only high-end specialty alcoholic brands are made with what are considered the traditional ingredients.

Almost all beers are brewed with malted barley or wheat and will contain gluten.

 

 

* Malignancy and Survival in Dermatitis Herpetiformis: A comparison with coeliac disease by Collin P, et al.

Conclusions: The incidence of non-Hodgkin's lymphoma was significantly increased in patients with dermatitis herpetiformis. The results also confirm that the patients with dermatitis herpetiformis treated mainly with a gluten free diet have no increased general mortality.

 

* Malignancies and Mortality in Patients With Coeliac Disease and Dermatitis Herpetiformis: 30-year population-based study by Viljamaa M, et al.

Conclusions: The overall prognosis in our patients was good. Non-Hodgkin lymphoma emerged in patients with undiagnosed or poorly treated coeliac disease. The mortality rate in dermatitis herpetiformis was even lower than in the population. Our data support the early diagnosis and dietary treatment of these conditions.

 

* Systemic Autoimmune Disorders in Celiac Disease by Alessio Fasano

Abstract

Purpose of Review: Celiac disease is an immune-mediated disorder clinically characterized by a multitude of symptoms and complications. The comorbidity between celiac disease and other autoimmune disorders has been clearly established.

Recent Findings: Two main theories have been postulated to explain this comorbidity: (1) linkage disequilibrium between the genes responsible for celiac disease and those responsible for the coexpressed autoimmune diseases or (2) untreated celiac disease leading to the onset of other autoimmune diseases. This article reviews the current literature supporting either theory and places the current knowledge in the field within the context of the most recent data on the pathogenesis of celiac disease.

Summary: The current literature did not clearly establish which of the two theories explain the comorbidity between celiac disease and other autoimmune disorders. There is, however, growing evidence that the loss of the intestinal barrier function typical of celiac disease could be responsible of the onset of other autoimmune disease. This concept implies that the autoimmune response can be theoretically stopped and perhaps reversed if the interplay between autoimmune predisposing genes and trigger(s) is prevented or eliminated by a prompt diagnosis and treatment.

 

* Celiac Disease by Wolfgang Holtmeier, et al.

Abstract: Celiac disease is a chronic intestinal disease caused by intolerance to gluten. It is characterized by immune-mediated enteropathy, associated with maldigestion and malabsorption of most nutrients and vitamins. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes. The main symptoms are: stomach pain, gas, and bloating, diarrhea, weight loss, anemia, edema, bone or joint pain. Prevalence for clinically overt celiac disease varies from 1:270 in Finland to 1:5000 in North America. Since celiac disease can be asymptomatic, most subjects are not diagnosed or they can present with atypical symptoms. Furthermore, severe inflammation of the small bowel can be present without any gastrointestinal symptoms. The diagnosis should be made early since celiac disease causes growth retardation in untreated children and atypical symptoms like infertility or neurological symptoms. Diagnosis requires endoscopy with jejunal biopsy. In addition, tissue-transglutaminase antibodies are important to confirm the diagnosis since there are other diseases which can mimic celiac disease. The exact cause of celiac disease is unknown but is thought to be primarily immune mediated (tissue-transglutaminase autoantigen); often the disease is inherited. Management consists in life long withdrawal of dietary gluten, which leads to significant clinical and histological improvement. However, complete normalization of histology can take years.

 

* Complications of Coeliac Disease: Are all patients at risk? by C J R Goddard, et al.

Excerpt: Unfortunately, owing to the difficulties in studying the incidence of malignancy in patients with coeliac disease, few studies in the literature have considered this important issue. The design of these studies mostly involved analysis of cohorts identified retrospectively and the studies are therefore open to methodological criticism. Few have explored the differences between symptomatic and asymptomatic disease, and few data exist regarding the influence of compliance with a GFD.

The best known data regarding malignancy in coeliac disease come from a series of studies from Derby, UK. Holmes et al followed up a cohort of 210 patients with coeliac disease for a mean of 19 years between 1972 and 1985. A total of 39 cancers had developed in the group, with 33 malignancy-related deaths. The expected numbers of tumours were calculated from the local cancer registry. Overall, patients with coeliac disease had an increased risk of developing oropharyngeal cancer (relative risk (RR) 9.7, p<0.01, 95% CI 2.0 to 28.3), oesophageal cancer (RR 12.3, p<0.01, 95% CI 2.5 to 36.5) and non-Hodgkin’s lymphoma (RR 42.7, p<0.001, 95% CI 19.6 to 81.4). In patients who had been on a GFD for >5 years, the risk of malignancy was no higher than that in the general population. However, in those not adhering to the diet, the risks of developing malignancy were much increased (oropharangeal and oesophageal cancer, RR 22.7, p<0.001; and lymphoma, RR 77.8, p<0.001). Importantly, the method of assessing the dietary compliance is not stated, but seems to be an estimation from case note review. This cohort of patients was, of course, collected in the early 1970s, at a time when most patients would have had major symptoms leading to the diagnosis of coeliac disease. More recently, however, Card et al reported long-term follow-up data from a cohort of patients with treated coeliac disease, and found a lower risk of small-bowel lymphoma than previously thought (1 patient with 0.02 expected).

 

* Fertility and Pregnancy in Women with Celiac Disease by Michelle Melin-Rogovin by  Scott Adams

* Infertility and Celiac Disease by Celiac Central

* Infertility and Adverse Outcomes of Pregnancy by Coeceliac.uk

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乳糜瀉（coeliac disease），舊稱非熱帶脂肪瀉，又稱乳糜腹瀉、麥膠引起的腸病(簡稱麥膠腸病)。乳糜瀉是一種具有遺傳性的發生於小腸的自身免疫性疾病，從嬰兒到各年齡段的人都有。癥狀包括慢性腹瀉，生長遲滯（兒童），和疲勞，但有些人癥狀不明顯。

 

自體免疫性疾病（Autoimmune disease），亦作自體免疫問題，是一種人體內自己的免疫系統攻擊自己身體正常細胞的疾病，就是正常的免疫能力下降，而異常的免疫能力卻突顯的一種問題。

所謂異常的免疫能力，就是認友為敵，把自己身體裡本來不是病毒或細菌的東西，當成病毒或細菌來攻擊，希望將之驅出體外。人體內免疫系統的抗體原本是針對外來的抗原或體內不正常的細胞（如腫瘤細胞）進行攻擊與清除，是保護身體的一種生理機制。但在一些情形下，免疫系統可能會產生出對抗自己身體內正常細胞（甚至細胞內的各種正常組成部份）的抗體，造成不正常的過度發炎反應或是組織傷害，進而影響身體健康造成疾病。這些認友為敵、攻擊不該攻擊對象的抗體，便稱為自體免疫抗體（Autoantibody，亦作自體抗體）。

目前還不能完全確定這些自體免疫抗體的成因是什麼。自體抗體所攻擊的，大都是細胞核，或是細胞裡的其他目標。隨它們攻擊目標的不同，有攻擊「染色體」的，有攻擊「(雙鏈)DNA」的，有攻擊「RNA」的，還有攻擊「ENA」的,等等許多種。由於不論「染色體」還是「(雙鏈)DNA」還是「RNA」，還是「ENA」，都是構成細胞與我們身體必要的元素，所以免疫系統一旦將之視為仇敵，不斷地攻擊，就會造成我們的細胞與器官遭到破壞的嚴重後果。

事實上，由於自體抗體攻擊的對象極為細微、複雜，所以自體抗體的種類也極為繁多。以攻擊「ENA」的抗體，也就是所謂的「抗ENA抗體」(Anti-ENA Antibodies)而言，就可再細分為「抗Sm抗體」、「抗SS-A/Ro抗體」、「抗SS-B/ La抗體」、「抗Scl-70抗體」、「抗RNP抗體」等多種。

一種抗體，可能形成多種不同的病症。譬如說，「抗SS-A/Ro抗體」可能導致「乾燥性綜合症」，或者「紅斑性狼瘡」等等。

一種病症，也可能是由各種不同的抗體所導致。譬如說，「紅斑性狼瘡」可能是「抗SS-A/Ro抗體」所導致，但也可能是「抗Sm抗體」、「抗SS-B/ La抗體」等等所導致。

由於自體免疫的徵狀往往都有軟組織關節疼痛的問題，而軟組織關節疼痛又名風濕，所以許多醫院中的「自體免疫科」又名「風濕免疫科」，而這些與「風濕」無關，但病徵近似的免疫毛病則被歸類為「類風濕問題」。

常見疾病

• 乳糜瀉（Coeliac disease）
• 1型糖尿病（舊時稱Insulin-dependent diabetes mellitus，IDDM; Type 1 Diabetes mellitus，T1DM）
• 系統性紅斑性狼瘡（SLE，System Lupus Erythematosus）
• 修格連氏症候群或乾燥症候群（Sjögren's syndrome）
• 多發性硬化症（MS，Multiple sclerosis）
• 橋本氏甲狀腺炎（Hashimoto's thyroiditis）
• 葛瑞夫茲氏病（Graves' disease）
• 自發性血小板缺乏紫斑症（Idiopathic thrombocytopenic purpura）
• 類風濕性關節炎（RA，Rheumatoid arthritis）
• 再生不良性貧血