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_ Coeliac disease _
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Introduction
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Coeliac disease (Commonwealth English) or celiac disease (American
English) is a chronic autoimmune disease, mainly affecting the
small intestine. It is caused by an abnormal immune system response
to gluten, a protein found in wheat and other grains such as barley
and rye. Coeliac disease causes a wide range of symptoms and
complications that can affect multiple organs outside the
gastrointestinal tract.
The classic form of the disease can affect any age group, but is
usually diagnosed in early childhood and causes symptoms of
malabsorption such as weight loss, diarrhoea, and stunted growth.
Non-classic coeliac disease is more commonly seen in adults,
characterised by vague abdominal symptoms and complications in
organs outside the gastrointestinal tract, such as bone disease,
anaemia, and other consequences of nutritional deficiencies. In
people with a genetic predisposition to the condition, eating
gluten causes inflammation in the small intestine, damaging its
lining and leading to malabsorption. The development of coeliac
disease is believed to be influenced by other environmental
factors, such as infections.
Diagnosis is based on symptoms, blood tests, and biopsies of the
small intestine. For people who have already cut gluten from their
diet, gluten may need to be reintroduced before testing to ensure
an accurate diagnosis. A lack of awareness and the diverse
symptoms, which overlap with other disorders, often complicate the
diagnosis by leading to a delay in diagnosis. Current research
indicates that there is not enough evidence to advocate for mass
screening for coeliac disease in those without symptoms.
The only treatment for coeliac disease is a lifelong gluten-free
diet (GFD). A GFD involves removing all food and drink containing
wheat, rye, barley, and gluten derivatives. Symptoms can improve
within days of adopting a GFD, and the diet can improve quality of
life, prevent further complications, and normalise some effects of
the disease such as stunted growth.
Approximately 1 in 200 to 1 in 50 people have coeliac disease.
Diagnoses of coeliac disease have increased recently due to
increased awareness and availability of blood testing. The disease
is still thought to be underdiagnosed, with a significant number of
people with the condition remaining undiagnosed and untreated. The
disease usually develops before age 10; it is slightly more common
in women than in men.
Terminology and classification
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"Coeliac disease" is the preferred spelling in Commonwealth
English, whereas "celiac disease" is typically used in North
American English. The terms 'sprue', 'coeliac sprue',
'gluten-sensitive enteropathy', 'non-tropical sprue' and
'idiopathic steatorrhoea' have been used as synonyms for coeliac
disease in the past. Both 'gluten intolerance' and 'gluten
sensitivity' have been used as synonyms of coeliac disease or to
describe other symptoms triggered by gluten. The terms are
nonspecific and lack a consistent definition. Gluten-related
disorders are conditions related to gluten such as coeliac disease,
gluten ataxia, wheat allergy, dermatitis herpetiformis, and
non-coeliac gluten sensitivity.
Many individuals with coeliac disease are asymptomatic, meaning
they do not have any symptoms associated with coeliac disease.
Those with asymptomatic coeliac disease are commonly diagnosed
through screening programs. The term "silent coeliac disease" is
equivalent to asymptomatic, but usage is discouraged. Coeliac
disease can be symptomatic (previously called 'overt coeliac
disease') or subclinical. Subclinical coeliac disease has
historically had many different definitions, such as those with
symptoms mainly outside the gastrointestinal tract, or those with
clinical signs of the disease (anaemia, laboratory abnormalities,
and endoscopic features) but no symptoms. Subclinical coeliac
disease is now used when individuals who do not have symptoms that
commonly warrant testing for coeliac disease have positive serology
for coeliac disease. Symptomatic coeliac disease (characterised by
symptoms related to gluten) can be further categorised into
classical and non-classical. Classical coeliac disease, which in
the past has also been called typical coeliac disease, is coeliac
disease presenting with malnutrition, malabsorption, and diarrhoea.
Non-classical coeliac disease, historically referred to as atypical
coeliac disease, is when individuals primarily present with
symptoms unrelated to malabsorption.
Potential coeliac disease refers to those who have positive
serology for coeliac disease but no changes in the small intestine.
The term 'latent coeliac disease' has been used interchangeably
with potential coeliac disease, but has no consistent definition,
and its use is therefore discouraged.
Sometimes, those with coeliac disease will continue to experience
symptoms or signs of the disease despite being on a gluten-free
diet. "Slow responders" or "non responsive coeliac disease" (NRCD)
is the persistence of symptoms despite exclusion of gluten for 6 to
12 months. Refractory coeliac disease (RCD) is the persistence of
malabsorption and damage to the small intestine after at least 12
months of a gluten-free diet. Most people with NRCD do not have
RCD; instead, their symptoms are caused by some other factor. There
are two types of RCD: type one has histopathological changes
similar to those seen in untreated coeliac disease, whereas type
two has abnormal histopathological changes not consistent with
untreated coeliac disease.
Signs and symptoms
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Coeliac disease causes a wide range of symptoms and complications
that can involve several different organs. The presentation of
coeliac disease can be classified as classic, non-classic, and
subclinical. Classic coeliac disease is commonly seen in young
children, but can affect any age group, and is characterised by
malabsorption manifesting as diarrhoea, weight loss, and failure to
thrive. Non-classic coeliac disease is seen more often in adults,
and symptoms primarily manifest outside the intestine
(extraintestinal). Many undiagnosed individuals who consider
themselves asymptomatic are, in fact, not, but rather have become
accustomed to living in a state of chronically compromised health.
After starting a gluten-free diet and a subsequent improvement
becomes evident, such individuals are often able to retrospectively
recall and recognise prior symptoms of their untreated disease that
they had mistakenly ignored.
Gastrointestinal
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Diarrhoea that is characteristic of coeliac disease is chronic,
sometimes pale, of large volume, and abnormally foul in odour.
Other symptoms of coeliac disease include abdominal pain, cramping,
bloating with abdominal distension, and mouth ulcers. As the bowels
become more damaged, lactose intolerance can develop.
Extraintestinal manifestations
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Coeliac disease is a systemic disorder, meaning it affects the
entire body. Although many common symptoms of the disease are
related to the gastrointestinal tract, those with coeliac disease
may also experience symptoms and complications in other organs,
known as extraintestinal manifestations. These manifestations may
be related to malabsorption or systemic inflammation. Common
extraintestinal manifestations of coeliac disease include
headaches, fatigue, brain fog, muscle pain, and joint pain.
Nutritional status in coeliac disease may be compromised due to
lower intake, maldigestion, and malabsorption, leading to
nutritional deficiencies. Common deficiencies in coeliac disease
include iron, folate, zinc, vitamin D, and vitamin B12. Vitamin D
deficiency can cause secondary hyperparathyroidism. Hyperoxaluria
and kidney stones can be caused by malabsorption of fats, and
peptides. Iron deficiency may lead to anaemia, which is one of the
most common extraintestinal presentations of coeliac disease.
Coeliac disease also often affects the bones, causing low bone mass
density (osteopenia) and osteoporosis. Causes of bone changes in
coeliac disease are believed to be caused by malabsorption,
inflammation, and autoimmunity.
If left untreated, coeliac disease can affect hormones, causing
delayed periods or puberty and reproductive disorders. Coeliac
disease is associated with infertility and complications during
pregnancy such as intra-uterine growth restriction and spontaneous
abortion. Reproductive disorders are thought to be caused by
nutritional deficiencies, particularly zinc, iron, folate, and
selenium deficiencies in coeliac disease.
Coeliac disease often affects the liver, causing increased
transaminase levels. This elevation of transaminases seen in
coeliac disease is known as coeliac hepatitis. Mildly increased
transaminases without symptoms and without other possible factors
such as autoimmune or viruses that could cause liver abnormalities,
characterise coeliac hepatitis.
In patients with persistent symptoms despite treatments for coeliac
disease, IgE-mediated allergic diseases, including food allergy,
allergic rhinitis, and asthma, should be considered in the
differential diagnosis, as they may coexist with celiac disease.
Due to the systemic nature of coeliac disease and its potential to
affect any organ, there are many rarer presentations of coeliac
disease, some of which have an unclear relationship to the disease.
Some of these more uncommon manifestations include peripheral
neuropathy, epilepsy, psoriasis, recurrent aphthous stomatitis,
pericardial effusion, and Lane-Hamilton syndrome.
Causes
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Coeliac disease is caused by an inflammatory reaction to gliadins
and glutenins (gluten proteins) found in wheat and to similar
proteins found in the crops of the tribe Triticeae (which includes
other common grains such as barley and rye) and to the tribe
Aveneae (oats). Wheat subspecies (such as spelt, durum, and
khorasan wheat) and wheat hybrids (such as triticale) also cause
symptoms of coeliac disease.
A small number of people with coeliac disease react to oats.
Sensitivity to oats in coeliac disease may be due to
cross-contamination of oats and other foods with gluten,
differences between gluten content, immunoreactivity, and genetic
variability seen between oat cultivars or dietary intolerance to
oats. Most people with coeliac disease do not have adverse
reactions to uncontaminated or 'pure' oats, however clinical
guidelines differ on whether those with coeliac disease should
consume oats.
Other cereals such as maize, millet, sorghum, teff, rice, and wild
rice are safe for people with coeliac disease to consume, as well
as non-cereals such as amaranth, quinoa, and buckwheat. Noncereal
carbohydrate-rich foods such as potatoes and bananas do not contain
gluten and do not trigger symptoms.
Risk modifiers
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Environmental factors such as infections, geographic latitude,
birth weight, antibiotic use, intestinal microbiota, socioeconomic
status, hygiene, breastfeeding, and the timing of introduction of
gluten into an infant's diet are theorised to contribute to the
development of coeliac disease in genetically predisposed
individuals. The consumption of gluten and timing of introduction,
in a baby's life does not appear to increase the risk of coeliac
disease, however in those who are genetically predisposed to
coeliac disease, large amounts of gluten early in life may increase
the risk of developing coeliac disease.
Mechanism
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Coeliac disease appears to be multifactorial, both in that more
than one genetic factor can cause the disease, and in that more
than one factor is necessary for the disease to manifest in a
person.
Almost all people with coeliac disease have either the HLA-DQ2
variant (allele) or, less commonly, the HLA-DQ8 allele. However,
about 40% of people without coeliac disease have also inherited
either of these alleles. This suggests that additional factors are
needed for coeliac disease to develop; that is, the predisposing
HLA risk allele is necessary but not sufficient to develop coeliac
disease. Furthermore, a small percentage of those who do develop
coeliac disease do not have typical HLA-DQ2 or HLA-DQ8 alleles.
Genetics
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The vast majority of people with coeliac disease have one of two
types (out of seven) of the HLA-DQ protein. HLA-DQ is part of the
MHC class II antigen-presenting receptor (also called the human
leukocyte antigen) system and is used by the immune system to
distinguish between the body's own cells and others. The two
subunits of the HLA-DQ protein are encoded by the HLA-DQA1 and
HLA-DQB1 genes, located on the short arm of chromosome 6.
There are seven HLA-DQ variants (DQ2 and DQ4-DQ9). Over 95% of
people with coeliac disease have the isoform of DQ2 or DQ8, which
is inherited in families. The reason these genes increase the 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 people with coeliac bear a two-gene HLA-DQ2 haplotype called
DQ2.5. 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 (DQ2.5cis). Most coeliacs
inherit only one copy of this DQ2.5 haplotype, while some inherit
it from 'both' parents; the latter are especially at risk of
coeliac disease as well as being more susceptible to severe
complications. The frequency of coeliac disease haplotypes can vary
by geography.
Some individuals inherit DQ2.5 from one parent and an additional
portion of the haplotype (either 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 (DQ2.5trans), and these individuals are at similar risk of
coeliac disease as those with a single DQ2.5-bearing chromosome 6.
Among those with coeliac disease who do not have DQ2.5 (cis or
trans) or DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), 2-5%
have the DQ2.2 isoform, and the remaining 2% lack DQ2 or DQ8.
Other genetic factors have been reported in coeliac disease, but
involvement in the disease has variable geographic recognition.
Only the HLA-DQ loci show a consistent involvement across the
global population. Many of the detected loci are associated with
other autoimmune diseases. The prevalence of the HLA-DQ2 genotype
and gluten consumption has increased over time. Since untreated
coeliac disease can cause serious health problems and affect
fertility, it would be expected that HLA-DQ2 and HLA-DQ8 would
become less common. The opposite is true--they are most common in
areas where gluten-rich foods have been eaten for thousands of
years. The HLA-DQ2 gene may have been genetically favoured in the
past because it helps protect against tooth decay.
Prolamins
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Most of the proteins in food responsible for the immune reaction in
coeliac disease are prolamins. These are storage proteins rich in
proline ('prol-') and glutamine ('-amin') that dissolve in alcohols
and are resistant to proteases and peptidases of the gut. Prolamins
are found in cereal grains with different grains having different
but related prolamins: wheat (gliadin), barley (hordein), rye
(secalin) and oats (avenin).
Tissue transglutaminase
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Tissue transglutaminase modifies gluten peptides into a form that
may stimulate the immune system more effectively. These peptides
are modified by tTG in two ways, deamidation or transamidation.
Deamidation is the reaction by which a glutamate residue is formed
by cleavage of the epsilon-amino group of a glutamine side chain.
Transamidation is the cross-linking of a glutamine residue from the
gliadin peptide to a lysine residue of tTg in a reaction that is
catalysed by the transglutaminase. Cross-linking may occur either
within or outside the active site of the enzyme. The latter case
yields a permanently covalently linked complex between the gliadin
and the tTg. This results in the formation of new epitopes believed
to trigger the primary immune response of the autoantibodies
against tTg.
Stored biopsies from people with suspected coeliac disease have
revealed that autoantibody deposits in the subclinical coeliacs are
detected before clinical disease.
Villous atrophy and malabsorption
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The inflammatory process, mediated by T cells, leads to disruption
of the structure and function of the small bowel's mucosal lining
and causes malabsorption as it impairs the body's ability to absorb
nutrients from food.
Alternative causes of this tissue damage have been proposed. They
involve the release of interleukin 15 and activation of the innate
immune system by a shorter gluten peptide (p31-43/49).
Diagnosis
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The variety in symptoms, overlap with other disorders, and lack of
awareness in medical professionals often complicate the diagnosis
of coeliac disease by leading to a delay in the diagnosis. A
diagnosis may take more than a decade after symptoms develop, and
most people with coeliac disease remain undiagnosed. Delays in
diagnosis can reduce quality of life, use more medical resources
and increase risk of complications associated with the disease.
Coeliac disease is diagnosed based on symptoms, blood tests, and
biopsies of the small intestine. To make an accurate diagnosis, an
individual must be consuming gluten, as the reliability of biopsies
and blood tests reduces if a person is on a gluten-free diet. In
those who have already reduced their gluten intake, reintroducing
gluten (gluten challenge) may be required to reach an accurate
diagnosis. Within months of eliminating gluten from one's diet,
antibodies associated with coeliac disease decrease, meaning that
gluten has to be reintroduced several weeks before diagnostic
testing.
Blood tests
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Current medical guidelines recommend testing tissue
transglutaminase 2 immunoglobulin A (TTG IgA) in those with
suspected coeliac disease. Because IgA deficiency is more common in
those with coeliac disease, guidelines recommend testing for IgA
deficiency as a part of the diagnostic workup for coeliac disease.
If an individual with IgA deficiency is getting tested for coeliac
disease, immunoglobulin G (IgG) based tests such as deamidated
gliadin peptide IgG (DGP IgG) or endomysial antibody (EMA) can be
used instead of IgA-based tests. Antigliadin antibodies (AGA) and
antireticulin antibodies (ARA) were historically used to test for
coeliac disease; however, due to the development of more accurate
tests, they are no longer recommended. Due to the risk of false
positive or negative serological tests and the consequences of
leaving coeliac disease untreated or introducing unnecessary
dietary restrictions. In the case of a false positive, biopsies are
used to confirm the diagnosis regardless of blood test results.
TG2 IgA has a high sensitivity (92.8%) and specificity (97.9%), and
is cost-efficient and widely available, making it the first choice
for serological tests in the diagnosis of coeliac disease.
Performance of the TG2 IgA test differs between labs and no formal
standardisation between assays exists. The severity of small
intestine damage generally correlates with the levels of TG2 IgA
found in the blood, meaning that the sensitivity is lower in people
who have less damage to their intestines. EMA has a lower
sensitivity, but its specificity is near 100%; it can be used to
confirm coeliac disease in those who have borderline TG2 IgA
levels. EMA testing is costly, hard to interpret, and vulnerable to
inter-observer and inter-site variability. DGP IgG is used to
evaluate coeliac disease in those with IgA deficiency. Coeliac
disease is more common in those with IgA deficiency, so medical
guidelines recommend that people being tested for coeliac disease
are also tested for IgA deficiency. Because IgA-based tests are
unreliable in those with IgA deficiency, IgG-based tests are used
instead. These include EMA IgG, DGP IgG, and TTG IgA, which are
less accurate than IgA testing. Multiparametric serological assays
allowing simultaneous detection of TG2 IgA and total IgA have been
proposed to improve screening efficiency for coeliac disease. A
study evaluating the Polycheck ® Celiac IgA + total IgA test
reported high sensitivity and specificity for TG2 IgA and total IgA
measurements in coeliac disease diagnostics.
A 2020 guideline by the European Society of Paediatric
Gastroenterology, Hepatology, and Nutrition (ESPGHAN) suggests
biopsy can be avoided in children who have symptoms of coeliac
disease, TTG IgA levels ten times higher than normal, and a
positive EMA antibody. There is insufficient evidence to suggest
that a nonbiopsy approach can be used in adults. Genetic testing is
not needed to diagnose coeliac disease, but is sometimes used to
clarify discrepancies between blood tests and histology. In those
who have already started a gluten-free diet, HLA testing can help
to determine whether a gluten challenge should be performed.
Endoscopy
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An upper endoscopy with biopsy of the duodenum (beyond the duodenal
bulb) or jejunum is performed to obtain multiple samples from the
duodenum. Not all areas may be equally affected; if biopsies are
taken from healthy bowel tissue, the result would be a false
negative. Even in the same bioptic fragment, different degrees of
damage may be present.
Most people with coeliac disease have a small intestine that
appears to be normal on endoscopy before the biopsies are examined.
Endoscopic features of coeliac disease include scalloping of the
small bowel folds ('pictured'), fissures, a mosaic pattern to the
mucosa, prominence of the submucosa blood vessels, and a nodular
pattern to the mucosa.
Capsule endoscopy (CE) allows identification of typical mucosal
changes observed in coeliac disease and may be used as an
alternative to endoscopy in those who cannot or do not want one.
Pathology
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The Marsh-Oberhuber classification is commonly used to assess the
pathological changes seen in coeliac disease. Marsh originally
described three different stages of coeliac disease lesions in
1992. These three stages were updated in 1999 by Oberhuber to
classify stage three further. The Marsh classification is based on
three histological features: intraepithelial lymphocytes count
above 25/100 enterocytes (intraepithelial lymphocytosis), elongated
crypts of Lieberkuhn (crypt hyperplasia), and shortening or absence
of villi (villous atrophy). As these features can be seen in other
disorders, they are not diagnostic for coeliac disease without
serological or clinical indications. Current guidelines do not
recommend a repeat biopsy unless there is no improvement in the
symptoms on a gluten-free diet
Marsh classification
Type !! Increased intraepithelial lymphocytes !! Crypt hyperplasia
!! Villi
|0 (normal) |<40 lymphocytes/100 enterocytes rowspan="2"
|Normal rowspan="3" |Normal
1 (infiltrative) rowspan="5" | >40 lymphocytes/100
enterocytes
2 (hyperplastic) rowspan="4" | Increased
3a (destructive) Mild atrophy
3b (destructive) Moderate atrophy
3c (destructive) Complete atrophy
Gluten challenge
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A gluten challenge is no longer required to confirm the diagnosis
in patients with intestinal lesions compatible with coeliac disease
and a positive response to a gluten-free diet. A gluten challenge
involves consuming over 10 grams of gluten a day for three months
or until an individual tests positive for TG2 IgA. Nevertheless, in
some cases, a gluten challenge with a subsequent biopsy may be
useful to support the diagnosis, for example, in people with
positive HLA genetic testing who have negative blood antibodies and
are already on a gluten-free diet. Gluten challenge is discouraged
before the age of 6 years and during pubertal growth.
Differential diagnosis
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The histopathological features associated with coeliac disease can
arise from other conditions as well. Differential diagnosis of
negative coeliac blood tests and villous atrophy or increased
inter-epithelial lymphocytes includes tropical sprue, eosinophilic
gastroenteritis, lactose intolerance, lymphoma, Crohn's disease,
Helicobacter pylori, drug-induced enteropathy (azathioprine,
methotrexate, mycophenolate, olmesartan, colchicinenon,
non-steroidal anti-inflammatory drugs, and proton pump inhibitors),
Whipple's disease, giardiasis, radiation enteritis, tuberculosis,
Zollinger-Ellison syndrome, collagenous sprue, common variable
immunodeficiency, autoimmune enteropathy, HIV enteropathy, small
intestinal bacterial overgrowth, and gastrinoma with acid
hypersecretion. If the histological changes improve with a
gluten-free diet despite negative coeliac disease blood tests, a
diagnosis of seronegative coeliac disease may be made.
Positive blood tests for coeliac disease with a lack of changes in
the bowels can be caused by errors in collecting blood for the
test, recent infections, congestive heart failure, chronic liver
disease, and hypergammaglobulinemia. Potential coeliac disease,
formerly known as "latent coeliac disease", is diagnosed when there
are positive coeliac blood tests, positive HLA genetic testing, and
a lack of villous atrophy.
Non-celiac gluten sensitivity (NCGS) is a functional disorder that
causes intestinal and extraintestinal symptoms in response to
gluten. The symptoms of NCGS are often similar to those seen in
coeliac disease; they tend to have a more rapid onset and offset
when compared to coeliac disease. The diagnosis of NCGS is made by
excluding coeliac disease and wheat allergy, and a resolution of
symptoms after adhering to a gluten-free diet.
Screening
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There is debate as to the benefits of widespread screening measures
for coeliac disease. In 2017, the United States Preventive Services
Task Force published a report which found insufficient evidence to
make a recommendation regarding screening for coeliac disease in
those without symptoms. Due to the lack of evidence that screening
for coeliac disease in those without symptoms, clinical guidelines
advise testing people based on symptoms and selective screening for
certain populations at a higher risk of developing coeliac disease.
National Institute for Health and Clinical Excellence (NICE)
indications of testing for coeliac disease
Testing recommended !! Testing considered
* Persistent unexplained gastrointestinal symptoms * Faltering
growth * Chronic fatigue * Severe or persistent mouth ulcers
* Unexplained iron, vitamin B12, or folate deficiency * At the
diagnosis of type 1 diabetes * At the diagnosis of an autoimmune
thyroid disease * Irritable bowel syndrome in adults *
First-degree relative of those with coeliac disease * Metabolic
bone disease (reduced bone mineral density or osteomalacia) *
Unexplained neurological symptoms (such as peripheral neuropathy
and ataxia) * Fertility problems or recurrent miscarriage *
Persistently raised liver enzymes with unknown cause * Dental
enamel defects * Down syndrome * Turner syndrome
Management
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Currently, the only treatment for coeliac disease is a lifelong
gluten-free diet (GFD). Current guidelines recommend regular
follow-up doctor's appointments, monitoring the disease activity,
preventative care, and consultation with a dietitian.
Diet
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A GFD involves removing all food and drink that contains wheat,
rye, barley, and gluten derivatives. Coeliac disease symptoms can
improve within days of adopting a GFD, and the diet improves
quality of life, prevents further complications, and can normalise
some effects of the disease such as stunted growth.
The GFD can be difficult, requiring significant education and
motivation. Additionally, the GFD diet may lead to nutritional
deficiencies due to difficulties accessing nutritionally balanced
gluten-free food. As such, a referral to a dietitian is recommended
by treatment guidelines. A dietitian can help those with coeliac
disease identify gluten-containing food and maintain a
nutritionally balanced diet.
The exact amount of gluten that may be tolerable for those with
coeliac disease varies, with some people able to consume around 35
mg per day without damage to the intestines, while others can not
tolerate more than 10 mg a day. Currently, international regulatory
agencies require a product to contain less than 20 ppm (about 6 mg
per day) of gluten to be labelled as gluten-free.
Monitoring
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Long-term monitoring of those with coeliac disease is an important
aspect of managing the disease. Usually, someone newly diagnosed
with coeliac disease is advised to visit their doctor multiple
times a year, with follow-ups becoming less frequent (once or twice
a year) after initial diagnosis. After the diagnosis, follow-up
doctor's appointments focus on controlling symptoms, improving
compliance with the GFD, preventative care, monitoring for comorbid
diseases, and detection of complications. The exact testing done
depends on an individual's needs but may include a complete blood
count, iron panel, thyroid testing, liver enzymes, and vitamin D
levels. Due to osteoporosis being a common complication of coeliac
disease, bone mineral density may be tested with a DEXA scan.
Although negative anti-TG2 IgA tests do not always correlate with
adherence to a GFD, guidelines recommend routine testing for
anti-TG2 IgA, as positive values may indicate gluten intake. The
role of repeat biopsies is controversial, with studies finding
little evidence that it is beneficial outside of investigating
persistent symptoms
Alongside routine vaccinations, current guidelines recommend
pneumococcal vaccination due to increased risk of pneumonia in
coeliac disease.
Non-responsive coeliac disease
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Around 20-40% of those with coeliac disease experience
non-responsive coeliac disease (NRCD), which is the continuation of
symptoms despite elimination of gluten from their diets for at
least 6 to 12 months.
The most common cause of NRCD is unintentional gluten ingestion;
however other conditions such as small intestinal bacterial
overgrowth, giardiasis, disaccharide or FODMAP intolerance, Crohn's
disease, fructose intolerance, microscopic colitis, pancreatic
insufficiency, irritable bowel syndrome, and lactose intolerance
can cause persistent symptoms or villous atrophy despite adhering
to the GFD.
Refractory coeliac disease
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About 1.5% of those with coeliac disease develop refractory coeliac
disease (RCD), which is the persistence of symptoms of
malabsorption and villous atrophy despite at least one year of the
GFD. RCD has a high mortality and morbidity rate, is associated
with more severe symptoms and is more common in older individuals
(50<). Those with RCD are often referred to specialists and the
diagnostic process usually includes monitoring compliance with the
GFD, confirming the initial diagnoses of coeliac disease, and
excluding alternative explanations for small intestine damage such
as Crohn's disease, peptic duodenitis, small intestinal bacterial
overgrowth, hypogammaglobulinemia, common variable
immunodeficiency, autoimmune enteropathy, tropical sprue,
collagenous sprue, and eosinophilic enteritis.
There are two subtypes of RCD, type 1 and type 2. Biopsies of the
duodenum and analysis of the intraepithelial lymphocytes in the
duodenum are required to distinguish between the two types. Type 2
RCD is characterised by abnormal T cells in the small intestine;
these findings are absent in type 1 RCD. In type 2 RCD, healthy
lymphocytes are replaced by abnormal lymphocytes, increasing the
risk of complications such as enteropathy-associated T-cell
lymphoma (EATL), severe malabsorption, and ulcerative
jejunoileitis, and results in poorer outcomes.
Type 1 RCD is treated with steroids, azathioprine, and budesonide.
The treatment of type 2 RCD is more complicated as it often does
not improve with steroids, and azathioprine may increase the risk
of EATL. Proposed treatment of type 2 RCD includes cladribine,
cyclosporine, and stem cell transplants.
Outlook
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Individuals with coeliac disease have a higher risk of developing
cancer in certain parts of the gastrointestinal tract (oropharynx,
oesophagus, and small intestine) compared to those without the
disease. Small intestinal lymphoma is the most common cancer caused
by complications of coeliac disease; however, it is still
considered a rare complication. The prognosis for
enteropathy‐associated T‐cell lymphoma (EATL) is poor with low
survival rates. Risk factors for developing cancer among those with
coeliac disease include older age and refractory coeliac disease.
Coeliac disease also increases mortality risk; however, the extent
of the increase is inconsistent across research.
Epidemiology
______________________________
In most countries, between 1 in 50 and 1 in 200 people have coeliac
disease. Rates vary in different regions of the world; coeliac
disease is less common in places where gluten-containing crops are
rarely eaten, and in parts of east Asia and sub-Saharan Africa
where populations rarely carry the HLA-DQ genes that predispose to
the disease. The risk of developing coeliac disease is higher in
those who have a first-degree relative with the disease; a less
dramatic increase in risk is also seen in second-degree relatives.
Diagnoses of coeliac disease have increased dramatically in recent
decades due to increased awareness of the disease and the
availability of blood testing. However, the disease is still
thought to be underdiagnosed, with an estimated 70% of people with
coeliac disease undiagnosed and untreated. Undiagnosed cases are
more common in poorer areas and in countries that do not regularly
test at-risk people.
While coeliac disease can arise at any age, most people develop the
disease before age 10. Roughly 20 percent of individuals with
coeliac disease are diagnosed after 60 years of age. Coeliac
disease is slightly more common in women than in men, though some
of that may be due to differences in diagnostic practice, as men
with gastrointestinal symptoms are less likely to receive a biopsy
than women. Other populations at increased risk for coeliac
disease, include individuals with Down and Turner syndromes, type 1
diabetes, and autoimmune thyroid disease, including both
hyperthyroidism (overactive thyroid) and hypothyroidism
(underactive thyroid).
Etymology and early history
_____________________________
The term 'coeliac' comes from Greek () 'abdominal' and was
introduced in the 19th century in a translation of what is
generally regarded as an Ancient Greek description of the disease
by Aretaeus of Cappadocia.
Humans first cultivated grains in the Neolithic period (beginning
about 9500 BCE) in the Fertile Crescent in Western Asia; coeliac
disease likely did not occur before this time. Aretaeus of
Cappadocia, living in the 2nd century in the same area, recorded a
malabsorptive syndrome with chronic diarrhoea, causing a
debilitation of the whole body. A 15th-century medical prescription
from Mamluk Cairo, attributed to Shams al-Din ibn al-'Afif, the
personal physician to Sultan Barsbay and director of the Qalawun
complex hospital, describes a treatment for symptoms consistent
with coeliac disease. The remedy combines herbs and plant waters
for patients intolerant to wheat.
Post-1800s
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Aretaeus of Cappadocia's "Cœliac Affection" gained the attention of
Western medicine when Francis Adams presented a translation of
Aretaeus's work at the Sydenham Society in 1856. The patient
described in Aretaeus's work had stomach pain and was atrophied,
pale, feeble, and incapable of work. The diarrhoea manifested as
loose stools that were white, malodorous, and flatulent, and the
disease was intractable and liable to periodic return. Aretaeus
believed a lack of heat in the stomach, necessary for digestion,
and a reduced ability to distribute the digestive products
throughout the body, caused this incomplete digestion, resulting in
diarrhoea. He regarded this as an affliction of the old and more
commonly affecting women, explicitly excluding children. The cause,
according to Aretaeus, was sometimes either another chronic disease
or even consuming "a copious draught of cold water."
The paediatrician Samuel Gee gave the first modern-day description
of the condition in children in a lecture at the Hospital for Sick
Children, Great Ormond Street, London, in 1887. Gee acknowledged
earlier descriptions and terms for the disease and adopted the same
term as Aretaeus (coeliac disease). He perceptively stated: "If the
patient can be cured at all, it must be by means of diet." Gee
recognised that milk intolerance is a problem with coeliac children
and that highly starched foods should be avoided. However, he
forbade rice, sago, fruit, and vegetables, which all would have
been safe to eat, and he recommended raw meat as well as thin
slices of toasted bread. Gee highlighted particular success with a
child fed "a quart of the best Dutch mussels daily"; the child
could not bear this diet for more than one season.
Christian Archibald Herter, an American physician, wrote a book in
1908 on children with coeliac disease, which he called "intestinal
infantilism". He noted their growth was retarded and that fat was
better tolerated than carbohydrate. The eponym 'Gee-Herter disease'
was sometimes used to acknowledge both contributions. Sidney V.
Haas, an American paediatrician, reported positive effects of a
diet of bananas in 1924. This diet remained in vogue until the
actual cause of coeliac disease was determined.
While a role for carbohydrates had been suspected, the link with
wheat was not made until the 1940s by the Dutch paediatrician
Willem Karel Dicke. Clinical improvement of his patients during the
Dutch famine of 1944-1945 (during which flour was scarce) likely
contributed to his discovery. Dicke noticed that the shortage of
bread led to a significant drop in the death rate among children
affected by coeliac disease from greater than 35% to essentially
zero. He also reported that once wheat was again available after
the conflict, the mortality rate soared to previous levels. The
link with the gluten component of wheat was made in 1952 by a team
from Birmingham, England. Villous atrophy was described by British
physician John W. Paulley in 1954 on samples taken at surgery. This
encouraged biopsy samples taken by endoscopy. Throughout the 1960s,
other features of coeliac disease were elucidated. Its hereditary
character was recognised in 1965. In 1966, dermatitis herpetiformis
was linked to gluten sensitivity.
Society and culture
______________________________
May has been designated as "Coeliac Awareness Month" by several
coeliac organisations.
Dietary challenges
____________________
Adhering to the GFD can negatively impact those with coeliac
disease, requiring major changes for an individual and their
family. The restrictive nature of the GFD can lead to no longer
enjoying food and pressure to be constantly vigilant about diet.
The social life of those with coeliac disease is also negatively
affected by the GFD. Cross-contamination--gluten-free food coming
into contact with gluten--is a common worry for those eating away
from home. Eating out may cause anxiety as it requires disclosing
dietary restrictions and risking potential cross-contamination.
Receiving a diagnosis of coeliac disease and the dietary changes
required to manage the disorder can affect a person's relationship
with food and lead to disordered eating as well as anxiety and
depression. A diagnosis of coeliac disease can carry stigma, which
may affect individuals' ability to seek help or disclose their
condition when needed.
Accessing gluten-free food can be a burden due to limited
availability and variety, as well as higher costs compared to
gluten-containing foods. Over the past ten years, the costs of
gluten-free food have decreased; however, it remains significantly
more expensive than gluten-containing food. There has been an
increase in the popularity of the GFD among those without coeliac
disease, which has improved the availability of gluten-free foods.
However, the increase in those without coeliac disease eating
gluten-free may lead to decreased vigilance of food manufacturers
and misunderstandings around the importance of avoiding
cross-contamination.
Many gluten-free substitutions are lower in nutritional quality and
may lack vitamins and nutrients that their gluten-containing
counterparts have. Ingredients commonly used in gluten-free
substitutes, such as rice, potato, corn, and tapioca starches, have
lower levels of fibre, carbohydrates, and vitamins but are higher
in sugars and fats than gluten-containing diets.
Currently, there are no federal regulations for gluten in non-food
products such as medications, cosmetics, and hygiene products.
Although the amount of gluten in non-food products is usually
minimal, mislabelling of gluten products can confuse people and
potentially adversely impact health.
Christian churches and the Eucharist
______________________________________
Speaking generally, the various denominations of Christians
celebrate a Eucharist in which a wafer or small piece of
sacramental bread from wheat bread is blessed and then eaten. Small
communion wafers typically contain 2-5 mg of gliadin if they are
not a gluten-free variety, and many people with coeliac disease
report altering their religious practices because of coeliac
symptoms caused by these wafers.
Some Christian churches such as the United Methodist, Christian
Reformed, Episcopal, Anglican and Lutheran churches offer their
communicants gluten-free alternatives, usually in the form of a
rice-based cracker or gluten-free bread. Catholics may receive from
the chalice alone, or ask for gluten-reduced hosts; gluten-free
ones however are not considered still to be wheat bread, and hence
are invalid matter.
Roman Catholic doctrine states that for a valid Eucharist, the
bread to be used at Mass must be made from wheat. Low-gluten hosts
meet all of the Catholic Church's requirements, but they are not
entirely gluten-free. As of 2017, the Vatican still disapproves of
the use of gluten-free bread for Holy Communion.
Passover
__________
The Jewish festival of Pesach (Passover) may present problems with
its obligation to eat matzah, which is unleavened bread made in a
strictly controlled manner from wheat, barley, spelt, oats, or rye.
In addition, many other grains that are normally used as
substitutes for people with gluten sensitivity, including rice, are
avoided altogether on Passover by Ashkenazi Jews. Many
kosher-for-Passover products avoid grains altogether and are
therefore gluten-free. Potato starch is the primary starch used to
replace grains.
Research directions
______________________________
Research into diagnosis has aimed to develop new blood tests,
including tests that could be used for those who are not currently
eating gluten. These tests measure certain immune cells that react
to gluten, such as CD4+ T cells and HLA-DQ-gluten tetramers.
New technologies have been developed to help people follow a GFD in
recent years. Food sensors, such as the Nima sensor, could help
people measure the amount of gluten in food to prevent accidental
gluten consumption. Testing kits that measure gluten levels in
urine and waste may help measure adherence the GFD.
Many strategies have been proposed to develop new treatments for
coeliac disease. Altering wheat to be safer for those with coeliac
disease has been explored using methods such as genetic wheat
manipulation and using a chemical process (transamidation) that
changes gluten proteins so they no longer trigger an immune
reaction. Medications and techniques such as chitosan and AGY
gluten sequestering aim to prevent gluten from interacting with the
immune system. Glutenases are enzymes taken with food designed to
help break down and neutralise gluten in the intestines. Glutenases
being studied include latiglutenase-ALV003, Aspergillus niger
prolyl endoprotease, Kuma030-TAK-062, and endoproptease-40.
Larazotide acetate is a peptide that helps tighten the junctions
between intestinal cells, reducing intestinal permeability. It
helps decrease reactions to gluten by preventing gluten fragments
from passing through the gut lining and triggering the immune
system. Treatments focused on immunomodulation aim to target the T
cells that react to gluten and reduce intolerance to gluten.
License
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Original Article: http://en.wikipedia.org/wiki/Coeliac_disease
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