FDA info on celiac disease

[xchocoholic]

This looks like a newer version of what celiac disease actually is. Just from what I've seen since 2005, they're taking into account some important new findings ... tc ... x

I copied this in because trying to read the pdf was driving me nuts ... I've edited this to make it easier to read but if in doubt, go to the pdf.


http://www.fda.gov/downloads/Food/S.../RiskAssessmentSafetyAssessment/UCM264152.pdf

Health Hazard Assessment for Gluten Exposure
in Individuals with Celiac Disease:
Determination of Tolerable Daily Intake Levels
and Levels of Concern for Gluten
Office of Food Safety
Center of Food Safety and Applied Nutrition
Food and Drug Administration

May 2011

The following document is a health hazard assessment for gluten exposure in a sensitive
subpopulation group, specifically individuals with celiac disease (CD). It consists of
several components

1. The introductory hazard identification section examines and
provides an overview of the nature and characteristics of the adverse effects associated
with CD found in susceptible individuals and also that of gluten proteins involved in
inducing these effects. The hazard assessment section first describes the nature of the
evaluation performed on the available health effects data associated with CD.

This
evaluation includes both a dose-response assessment and a safety assessment derived
from data from individuals in this sensitive subpopulation. The former assessment
describes and characterizes the dose-effect data examined for morphological and clinical
adverse effects that are reflective of CD, and the latter determines the tolerable daily
intake (TDI) levels of exposure for each of these types of adverse effects in sensitive
individuals.

The hazard assessment section also includes an exposure assessment in
which a number of estimates of gluten consumption from food products are determined
and presented. The final risk characterization section addresses the uncertainty issues
associated with the data available and the estimates derived, and identifies the TDI of
primary focus for adverse morphological and clinical effects in this assessment.

In
addition, these TDIs, along with the exposure estimates, were employed to derive various
levels of concern (LOC) for gluten in food for individuals with CD.


Hazard Identification
Health Effects
Celiac Disease

Exposure to certain grains or certain protein components of them can result in adverse
health consequences, particularly the development of celiac disease (CD), in genetically
predisposed individuals (Maki and Collin, 1997; AGA, 2001; Farrell and Kelly, 2002;
Green and Jabri, 2003; Dickson et al., 2006).

A significant part of the genetic
predisposition to CD is associated with specific human leukocyte antigen (HLA) class II
genes in the major histocompatibility complex (MHC) of chromosome 6 (Godkin and
Jewell, 1998; Fasano and Catassi, 2001; Green and Jabri, 2003). For the most part,
individuals with CD express either the HLA-DQ2 or the HLA-DQ8 haplotypes (Green
and Jabri, 2003; Konig, 2005; Kagnoff, 2005).

The majority (90 95%) of those who
develop CD encode the HLA-DQ2 molecules, while the rest of those who suffer from CD
typically express the HLA-DQ8 molecules (Dewar et al., 2004; Konig, 2005; Kagnoff,
2005).

The presence and expression of these HLA-DQ alleles are recognized as necessary
for the development of CD but not alone sufficient for the disease to occur (Green and
Jabri, 2003; Dewar et al., 2004; Kagnoff, 2005).

The contribution of other non-HLA
genes, some not yet defined, also has emerged as pivotal in the genetic susceptibility
associated with the development of CD (Godkin and Jewell, 1998; Fasano and Catassi,
2001; Green and Jabri, 2003; Dewar et al., 2004; Hunt, 2008).

Finally, other factors may
also have a determining influence on disease susceptibility (Murray, 1999; Green and
Jabri, 2003). They include environmental factors (e.g., breast-feeding, infections),
abnormalities in the immune system (e.g., selective IgA deficiency), and certain geneticbased
syndromes (e.g., Down syndrome, Turners syndrome) (Murray, 1999; Fasano and
Catassi, 2001; Green and Jabri, 2003; AGA, 2006).

CD is a permanent hypersensitivity reaction triggered by ingestion of wheat, barley, or
rye2, or the plant storage proteins of these grains (Farrell and Kelly, 2002; Green and
Jabri, 2003; Dickson et al., 2006) that can occur at any age (Marsh, 1992; AGA, 2001;
Fasano and Catassi, 2001).

It results in an immune-mediated enteropathy which is
associated with damage to the lining of the small intestine (AGA, 2001; Fasano and
Catassi, 2001; Dickson et al., 2006).

The mucosal lesion in the small intestine that is
characteristic of CD typically involves abnormal morphology such as inflammatory cell
infiltrate in the lamina propria, influx of lymphocytes in the epithelium, flattened or
irregular epithelial cells, hyperplasia of crypts, stunted and disorganized microvilli and
ultimately, a significant degree of villous atrophy (Marsh, 1992; AGA, 2001; Fasano and
Catassi, 2001; Farrell and Kelly, 2002; Green and Jabri, 2003; Dickson et al., 2006).

The
most significant histological abnormalities are usually found in the proximal small
intestine (e.g., duodenum) with the abnormalities less severe distally along the small
intestine, but the disorder can progress distally (e.g., jejunum), and even involve the
entire small intestine in some individuals (MacDonald et al., 1964; Dickson et al., 2006;
Murray et al., 2008).

A diverse array of clinical signs and symptoms are often associated with untreated CD
(Fasano and Catassi, 2001). Many are tied, at least in part, to the enteropathy associated
with CD. However, the manifestation of the clinical responses in CD, along with their
severity, are not associated with the extent of this enteropathy in the small intestine or the
degree of mucosal damage seen (Rostom et al., 2006; Brar et al., 2007; Murray et al.,
2008; Murray and Rubio-Tapia, 2008).

The extent and emergence of clinical responses
seen is thought to be related to the length of the small intestine affected by enteropathic
changes with more symptomatology present as mucosal histopathology progresses
distally starting from the duodenum (Fasano and Catassi, 2001; Farrell and Kelly, 2002;
Green and Jabri, 2003; Dickson et al., 2006).

The so-called classic signs and symptoms
of CD include chronic diarrhea or constipation, steatorrhea, recurrent abdominal
distension or abdominal pain, nausea and/or vomiting (Maki and Collin, 1997; AGA,

2001; Fasano and Catassi, 2001; Green et al., 2001; Farrell and Kelly, 2002; Green and
Jabri, 2003; Dickson et al., 2006). Often seen with the enteropathy of CD are aspects of
malabsorption and related sequelae associated with substantial morbidity such as anemia,
nutritional deficiencies, growth disturbances, weight loss and osteopenia or osteoporosis
(Maki and Collin, 1997; AGA, 2001; Fasano and Catassi, 2001; Green et al., 2001;
Meyer et al., 2001; Farrell and Kelly, 2002; Green and Jabri, 2003; Dickson et al., 2006).


Other signs and symptoms that have been reported in those afflicted by CD are, among
many others, fatigue, irritability, malaise, anorexia, mouth ulcers, headaches, mood
changes, depression, pain and various neurological responses (Maki and Collin, 1997;
AGA, 2001; Fasano and Catassi, 2001; Green et al., 2001; Farrell and Kelly, 2002; Green
and Jabri, 2003).

However, these clinical reactions are not always exhibited in CD. Many
individuals can have underlying histological abnormalities in the small intestine mucosa
that characterizes them as having CD but they remain asymptomatic or subclinical
(Maki and Collin, 1997; AGA, 2001; Fasano and Catassi, 2001; Green and Jabri, 2003;
Dickson et al., 2006).

This disease status is sometimes referred to as silent CD (Maki
and Collin, 1997; Green and Jabri, 2003). Further, in some cases of CD, individuals
appear to be asymptomatic or they do not report the classic CD-related gastrointestinal
symptoms (Fasano and Catassi, 2001), but closer evaluation of their clinical state reveals
they often experience some degree of atypical CD-related condition(s) (e.g., anemia,
fatigue, neurological problems, short stature) not always readily recognized, at least
initially, by the patients or their physicians as CD (Ventura et al., 1999; Fasano and
Catassi, 2001; Green and Jabri, 2003).

This often leads to a delayed diagnosis of many
years (often >10 years) for CD sufferers with contributing factors to this delay being
adherence first to one or more alternate diagnoses and/or consultation with more than one
physician prior to receiving a correct diagnoses of their illness (Green and Jabri, 2003;
Green et al., 2001) .

Finally, some investigators (Maki and Collin, 1997; Fasano and
Catassi, 2001; Murray et al., 2003) have noted a change in the nature and/or pattern of the
presentation of the signs and symptoms in those afflicted with CD in recent decades.

A
greater proportion of newly diagnosed cases exhibit atypical clinical features of the
disease than seen in the past where the typical, classic CD-associated gastrointestinal
symptoms were more likely identified.

 

[xchocoholic]

Dermatitis Herpetiformis


Dermatitis herpetiformis (DH) is another chronic condition associated with exposure to
wheat gluten and related protein derivatives in rye and barley (Fasano and Catassi, 2001;
Farrell and Kelly, 2002).

It is an autoimmune skin disease in genetically susceptible
individuals that results in clusters of an intensely pruritic skin rash characterized by
papules and vesicles (Farrell and Kelly, 2002; Green and Jabri, 2003) . These lesions are
typically located in a symmetrical fashion on the extensor surface of the elbows and
knees in addition to the lower back or buttocks, scalp of the back of the head and
posterior neck (Fasano and Catassi, 2001; Farrell and Kelly, 2002; Green and Jabri,
2003). DH usually has a gradual onset and usually emerges in adulthood (Merck Manual,
2006).

Those with a family history of DH have an increased risk of developing DH.
Almost all patients with DH have some degree of gluten-sensitive enteropathy (Fasano
and Catassi, 2001; Farrell and Kelly, 2002; Green and Jabri, 2003), but it is typically not
accompanied by intestinal symptoms (Maki and Collin, 1997; Fasano and Catassi, 2001).



Thus, it is considered a subclinical and/or asymptomatic enteropathy. Finally, DH is
thought of by some clinicians as a variant of or a type of manifestation of CD rather than
an associated disease (Maki and Collin, 1997; Fasano and Catassi, 2001).
Other Health Effects
Other medical conditions or states have also emerged as a part of the spectrum of clinical
presentations associated with CD (and also with DH) (Fasano and Catassi, 2001).


A brief
overview of some of the significant secondary adverse health effects associated with CD
is presented below.


Autoimmune Diseases
A number of autoimmune diseases are more likely to occur in patients with CD than in
the general population (Collins et al., 1994; Fasano and Catassi, 2001; Farrell and Kelly,
2002; Green and Jabri, 2003).

Some examples of these autoimmune diseases are Type 1
diabetes mellitus, autoimmune thyroiditis, autoimmune hepatitis, Sjogrens syndrome,
Addisons disease, and rheumatoid arthritis, among a number of others (Collin et al.,
1994; Maki and Collin, 1997; Ventura et al., 1999; Fasano and Catassi, 2001; Green et
al., 2001; Farrell and Kelly, 2002; Green and Jabri, 2003).

Factors suggested as important
in this relationship between CD and the development of autoimmune diseases are the
duration of exposure to diets containing the relevant cereal proteins or the age at
diagnosis of CD (Ventura et al., 1999; Green and Jabri, 2003; Peters et al., 2003).



Some
have put forth the notion that the increased risk of individuals with CD developing these
types of diseases is proportional to the time of exposure to gluten (Fasano and Catassi,
2001; Farrell and Kelly, 2002; Green and Jabri, 2003). Children with CD diagnosed and
treated at a young age show no increased frequency of autoimmune disorders (Ventura et
al., 1999; Green and Jabri, 2003); whereas, those diagnosed with and treated for CD as
older children or adults do (Ventura et al., 1999; Collin et al., 1994; Guidetti et al., 2001).


However, others have not found an association between the prevalence of autoimmune
diseases in adults and an index of duration of gluten exposure (Guidetti et al., 2001) or in
adults when their age of diagnosis was assessed across different decades of life grouped
together (Biagi et al., 2002).

Possibly the relationship between gluten exposure and the
development of autoimmune disease is a factor in the first few decades of life but not in
older adults.


However, because only indirect indices of actual total gluten exposure
before and after CD occurrence have been examined to date, a clear delineation of the
relationship between gluten exposure and the development of autoimmune disease in
those individuals with CD is difficult at this time until more precise dietary exposure
analyses over time (and maybe age), including on GFDs, are performed.
Next, when the presence of CD is silent, the autoimmune disorder is often diagnosed
first (Ventura et al., 1999; Green and Jabri, 2003), and thus the detrimental effects of
continued intake of significant grain proteins are unrecognized until if or when CD is
ultimately diagnosed.

Finally, the emergence of CD sometimes follows the development
of an autoimmune disease. At least one example of this is found with Type I diabetes
mellitus, where in some cases CD is not present at the time of diagnosis of diabetes but
emerges later (Glastras et al., 2005; Barton and Murray, 2008).
5
Bone Diseases
CD is often accompanied by secondary diseases that reflect the existence of abnormalities
in bone metabolism (Green and Jabri, 2003; Bianchi and Bardella, 2002; Capriles et al.,
2009). A high risk of developing the bone diseases of osteopenia, osteoporosis and/or the
less common osteomalacia is associated with individuals with CD (Valdimarsson et al.,
1996; Meyer et al., 2001; Bianchi and Bardella, 2002; Bernstein et al., 2003; Bianchi,
2010).


Osteopathic complications of CD are thought to be the most frequently occurring
of the secondary health effects associated with CD (McGough and Cummings, 2005;
Cranney et al., 2007). The bone pathogenesis that can emerge as an outcome of CD is
multifactorial in nature (Meyer et al., 2001; Green and Jabri, 2003; Stazi et al., 2008;
Capriles et al., 2009) and attributed to a complex cascade of aberrant effects linked to the
compromised state of the gastrointestinal mucosa in CD (Corazza et al., 1995; Bernstein
et al., 2003; Capriles et al., 2009; Bianchi, 2010).

Chronic malabsorption of dietary
calcium and vitamin D, along with the activation of intestine mucosal inflammatory
responses (e.g., cytokine release), contributes to the reduced bone mineral density (BMD)
and/or bone mineral content (BMC) that is often found in individuals with CD (Corazza
et al., 1995; Bianchi and Bardella, 2002; Bernstein et al., 2003; Stazi et al., 2008;
Capriles et al., 2009; Bianchi, 2010).


The abnormalities in the regulation of calcium
homeostasis associated with CD-related bone loss and/or weakness also includes elevated
levels of the hypercalcemic parathyroid hormone and altered levels of plasma vitamin D
metabolites (e.g., 1,25(OH)2 vitamin D) which are two humeral factors that typically play
a significant and coordinated role in maintaining normal serum calcium levels, and
equilibrium in, and thus normal, bone turnover and bone remodeling levels (Corazza et
al., 1995; Bianchi and Bardella, 2002; McGough and Cummings, 2005; Stazi et al., 2008;
Capriles et al., 2009; Bianchi, 2010).


Reduced BMD levels are commonly found in individuals at the time of diagnosis with
CD (Valdimarsson et al., 1996; Meyer et al., 2001; Green and Jabri, 2003; Goddard and
Gillett, 2006).

It is seen in those diagnosed as adults as well as those diagnosed as
children or in adolescence (Meyer et al., 2001; Green and Jabri, 2003; Goddard and
Gillett, 2006; Capriles et al., 2009). Although the findings are limited in nature, some
evidence also suggests that a reduced bone mineral content (BMC) can also be observed
at the time of diagnosis of CD (Bianchi and Bardella, 2002; Bianchi, 2010). This
increased risk of CD-associated low BMD, and possibly of low BMC, serves to also
increase the likelihood of individuals with CD not reaching the typical optimal peak
bone mass (Corazza et al., 1995; Meyer et al., 2001; Bianchi, 2010), a state that is
normally achieved by bone mass gains made by ages 20 to 30 years old and that is critical
as a basis for maintaining bone health throughout life and during aging (Corazza et al.,
1995; Bernstein et al., 2003; Stazi et al., 2008; Capriles et al., 2009).


In addition,
attaining a lower (i.e., less than optimal) peak bone mass during growth and maturation
potentially leads to a higher risk of developing osteopenia and/or osteoporosis (and/or
probably osteomalacia) as well as fractures in later years (Stazi et al., 2008; Capriles et
al., 2009; Bianchi, 2010).


The bone disorder of osteopenia has been observed in children and adults at the time of
diagnosis with CD with a large proportion of diagnosed adults presenting with osteopenia
(Bianchi and Bardella, 2002; Bernstein et al., 2003; Capriles et al., 2009; Bianchi, 2010).


Osteopenia is found in individuals with CD who are symptomatic as well as those with
CD who are asymptomatic (Corazza et al., 1995; Valdimarsson et al., 1996; Cellier et al.,
2000; Bianchi and Bardella, 2002; Bianchi, 2010).

Individuals who have silent CD are
also susceptible to developing osteopenia (Maki and Collin, 1997; Bianchi, 2010).
Osteoporosis, a state that reflects a progression to a more severe reduction in BMD along
with alteration in bone microarchitecture (Capriles et al., 2009; Bianchi, 2010), is also
observed in young and adult celiac patients (McFarlane et al., 1995; Bernstein et al.,
2003; Goddard and Gillett, 2006; Capriles et al., 2009) and includes both symptomatic
and asymptomatic patients (Bernstein et al., 2003; Bianchi and Bardella, 2002; Bianchi,
2010).

The likelihood of its presence at the time of diagnosis of CD is greater than is seen
for the occurrence of this disease in the general population (Bernstein et al., 2003) where
it is typically an affliction associated with middle to elder age.

Next, osteomalacia is
another bone-related clinical manifestation of CD (Ciclitira et al., 2001; Bianchi and
Bardella, 2002; Bernstein et al., 2003; Murray, 2005; Bianchi, 2010). It reflects a reduced
mineralization of the collagen matrix component of bone and leads to softening of bone
(Stazi et al., 2008; Bianchi, 2010). This less common condition was more often
recognized as a complication of CD in earlier studies (Corazza et al., 1995; Bianchi and
Bardella, 2002; Bianchi, 2010) but direct assessment (by biopsy) of its presence has not
been routinely performed in recent years (Ciclitira et al., 2001; Meyer et al., 2001;
Bianchi, 2010).

The low bone mass seen in CD may be due at times at least in part to
osteomalacia (Corazza et al., 1995; Murray, 2005).

The consequence of osteoporosis
and/or osteomalacia for celiac sufferers is an increased susceptibility to bone fragility
fractures, an affect seen in both children and adults (Bernstein et al., 2003, Cranney et al,
2007; Ludvigsson et al., 2007; Stazi et al., 2008; Capriles et al., 2009; Bianchi, 2010).
The association between CD and bone fractures is supported by findings of increases in
bone fractures experienced by those with CD in comparison to individuals without CD
when considerations such as fractures of all bone types total or of certain specific bones
(e.g., wrist, hip), or history of previous fractures were assessed (Bianchi and Bardella,
2002; Bernstein et al., 2003; Goddard and Gillett, 2006; Ludvigsson et al., 2007; Olmos
et al., 2008; Capriles et al., 2009; Bianchi, 2010).

Finally, the metabolic bone
derangement found in CD is often accompanied by elevated levels of the hypercalcemic
parathyroid hormone which leads to a persistent state of hyperparathyroidism (Corazza et
al., 1995; Bianchi and Bardella, 2002; Capriles et al., 2009; Bianchi, 2010).

This can in
some instances become a chronic, irreversible condition which is referred to as
secondary hyperparathyroidism that remains even after CD treatment is employed and
that negatively influences skeletal improvements observed with a gluten-free diet
(Bernstein et al., 2003; Bianchi, 2010).


Last, exposure to gluten plays a significant role in the development of metabolic bone
disease in CD. Treatment of CD with a gluten-free diet over an extended time (1 - 5
years) can lead to improvement in a proportion of individuals with CD that are afflicted
by the range of gluten-induced bone abnormalities (e.g., less than optimal peak bone
mass, reduced BMD, osteopenia, osteoporosis) (McFarlane et al., 1995; Valdimarsson et
al., 1996; Fasano and Catassi, 2001; Ciclitira et al., 2001; Bianchi and Bardella, 2002;
Bernstein et al., 2003; McGough and Cummings, 2005; Capriles et al., 2009), but a large individual variability is seen in the nature and degree of responsiveness to an avoidance
diet with respect to bone health effects (Corazza et al., 1995; Meyer et al., 2001; Goddard
and Gillett, 2006; Capriles et al., 2009).

Instances of complete reversal to attain optimal
peak bone mass and to accrual normal BMD are typically only seen in young children
diagnosed with CD who chronically adhere to a strict gluten-free diet (Corazza et al.,
1995; Bernstein et al., 2003; Capriles et al., 2009; Bianchi, 2010). No information on the
lowest levels of exposure to gluten associated with induction of abnormalities in bone
metabolism is available.

However, the gluten avoidance diet typically employed to date
has not been found to counter in a significant number of cases, particularly in adults and
at times in adolescents, all adverse effects on bone and long-term skeletal health
associated with CD (Corazza et al., 1995; Meyer et al., 2001; Ciclitira et al., 2001 and
2003; Capriles et al., 2009; Bianchi, 2010).
Malignancies
Next, a number of malignancies also occur more often in celiac patients than in others
without the disease (Maki and Collin, 1997; Green et al., 2001; Green and Jabri, 2003).



Many of the cancers associated with CD are gastrointestinal malignancies such as
enteropathy-associated T-cell lymphoma, small bowel adenocarcinoma, and esophageal
and oropharyngeal squamous carcinoma (Logan et al, 1989; Maki and Collin, 1997;
Fasano and Catassi, 2001; Green et al., 2001; Farrell and Kelly, 2002; Green and Jabri,
2003; Peters et al., 2003; Catassi et al., 2005).


An increase incidence of primary liver
cancer and an increase occurrence of extra-intestinal lymphomas and B-cell lymphomas
have also been reported in patients with CD (Green and Jabri, 2003; Peters et al., 2003;
Catassi et al., 2005).

As with many autoimmune diseases, an increased risk of developing
cancer, especially gastrointestinal malignancies, is proportional to the time of exposure to
grains linked to CD (Logan et al, 1989; Fasano and Catassi, 2001; Peters et al., 2003;
Catassi et al., 2005) or degree of compliance with GFD (Fasano and Catassi, 2001;
Catassi et al., 2005).

Correspondingly, children diagnosed at a young age and maintained
on a strict celiac prevention diet to control CD show no increased risk of cancer versus
the general population.


Mortality Rate


Third, a higher mortality rate is reported for individuals with CD than for the general
population (Logan et al, 1989; Corrao et al., 2001; Peters et al., 2003), which has been
attributed to both the associations between CD and autoimmune disease(s) and/or
malignancies (Logan et al, 1989; AGA, 2001; Corrao et al., 2001; Fasano and Catassi,
2001; Green and Jabri, 2003; Peters et al., 2003; Catassi et al., 2005).

There is also some
suggestion that the association between CD and osteoporosis and bone fractures is a
potential contributing factor (Ciclitira et al., 2001; Bianchi and Bardella, 2002).
Supporting these findings with respect to autoimmune disease(s) and malignancies is that
an increased mortality rate is not seen in individuals that are diagnosed in childhood
(Logan et al, 1989; Fasano and Catassi, 2001; Green and Jabri, 2003; Catassi et al., 2005)
and particularly not in those children that chronically maintain a strict celiac protective
diet (Fasano and Catassi, 2001; Catassi et al., 2005). Furthermore, mortality is seen to
increase in CD patients that experienced a delay in diagnosis after onset of symptoms
(Corrao et al., 2001) or that exhibited poor compliance with the dietary regimen treatment
(Corrao et al., 2001). Lastly, the association between long-term or chronic ingestion of a
8
very low level or trace amount of cereal protein in an avoidance diet and the subsequent
development of cancer, autoimmune diseases or bone diseases has not been
systematically investigated in any comprehensive fashion (Chartrand et al., 1997; Catassi
et al., 2005).

 

[xchocoholic]

hi all,

I wanted to bump this so everyone could see how the info on gluten intolerance has improved
in the last few years. Imho, The doctors referenced in this paper are on the cutting edge here.
Theglutenfile covers anything missed here tho.

I get concerned when I see some posting that celiacs can eat gluten again
when imho, the fact that gluten can cause damage in anyone who's sensitive to gluten has been proven repeatedly.

Fwiw, I'm a celiac who's been on the gf diet for 6 years now. Actually, I've been on a paleo, no grain, diet
fir the last 3 -4 years. This significantly cuts my risk of gluten cross contamination. Like a dummy,
I've been eating a couple of "gf" goodies prior to every stool test to see if I could handle gluten yet. I
just wanted to be "normal" ..

And if these test are accurate, then the answer is no .. I get gluten antibodies still. My serum test from 2006,
for gluten was negative when I was stil eating those "gf" foods everyday, so I don't trust that test.

Tc .. X