History and Metabolic Context

History and Definition of Celiac Disease:

By definition, Celiac disease is a systemic autoimmune response triggered by dietary gluten in people with the susceptible genetic composition (Fasano and Catassi, 2012). Artaeus, who described a patient with chronic diarrhea and degrading health, most likely gave the first description of Celiac disease in the 2nd century AD. In his frankly comical ignorance, he described the disease as an “atony of the heat which digest, and refrigeration of the stomach”. According to Artaeus, the heat dissolves the food but does not digest it, which causes the food to essentially change into diarrhea. He did, however, discern a reasonable treatment, in that he treated his patients with restricted diets (Paveley, 1988).

Visual depiction of Artaeus. Source: William F Paveley
Visual depiction of Artaeus. Source: Paveley, 1998

Celiac disease was not again relevant until the late 19th century, when Dr. Gibbons described four children afflicted with the disease as frail and weak. He eventually lectured in the early 20th century, in which he suggested that the disease was the result of a “digestive disturbance”, and that bread and starch were the main causes of aggravating of the condition (Paveley, 1988).

Believe it or not, the next important development in the disease came in 1924, when Sidney Haas successfully treated eight afflicted individuals with a “banana diet”. His diet was designed to specifically exclude bread, potatoes, crackers, and cereals. This dietary treatment continued to be implemented until the 1950’s, so much so that during the second world war, children with Celiac were allowed extra rations of bananas (Paveley, 1988).

An extremely important shortage of bread occurred in the Netherlands around the time of the second world war. During this shortage, incidences of Celiac disease supposedly decreased. This led Christopher Boothe Dicke and his coworkers to eventually make the association between wheat and Celiac disease (van Berge-Henegouwen, 1993). Eventually, in conjunction with van de Kamer and Meyers, Dicke was able to determine that that the alcohol soluble portion of wheat, gliadin, was the pathogenic aspect of the food. Eventually, the gluten free diet evolved to subsist of any foods that do not contain wheat, rye, or barely, and in the United States, due to processing, oats as well (van Berge-Henegouwen, 1993).

Recent years have seen the dramatic increase in the number of gluten free foods in circulation. In part, this is because the disease has been demonstrated to be incredibly prevalent (at least 1 in 100 people), and has therefore gained popularity. The increase in foods can also be attributed, however, to the development of the gluten free diet as a “fad diet”, which radically expanded the market for gluten free foods.

Symptoms Associated With Celiac Disease

Clinically, patients are defined to present with classical, atypical, or silent celiac disease. Classical presentation generally results in the first two years of an individual’s life, where after the introduction of gluten in the child’s diet, the child begins to show symptoms of malabsorption (Iwańczak, et. al, 2013). These symptoms include chronic diarrhea, failure to thrive, abdominal distension and pain, growth delay and iron deficiency anemia. Atypical presentation is characterized by presentation of less clinical symptoms, often later in life. These symptoms include a lack of body mass increase and growth retardation, anemia, dental enamel hypoplasia, osteoporosis, or pubertal delay. Silent diagnosis of the disease occurs in asymptomatic individuals who are characterized as high risk for the disease. High-risk markers include other immune associated diseases such as diabetes or IgA antibody deficiency (Iwańczak, et. al, 2013).

Diagnosis of Celiac Disease:

Although symptoms can be indicative of the disease, The most commonly used and effective diagnosis for Celiac disease is testing for the presence of IgA antitissue transglutaminase antibodies. This test is generally over 95% effective at diagnosing Celiac disease in individuals. Blood testing for the HLA-DQ2 haplotype have been shown to have similar diagnostic effectiveness. Upper endoscopic biopsies of the duodenum are also commonly used to confirm the Celiac diagnosis. This test falls short, however, in that not all areas of the small intestine and duodenum are equally effected, and biopsying an unaffected region could lead to false negatives (van der Windt et. al, 2010).

Symptomatic diagnoses, given the variety of symptom presentations, are not commonly used to diagnose the disease, although the symptoms can be powerful indicators of the disease. Anemia tests and other symptomatic assays are generally used to confirm complications of the disease after diagnosis has occurred (Barrartt et al., 2013).

Metabolic Context of Celiac Disease

The overall process of digesting proteins involves breaking down the proteins into amino acids, dipeptides, and tripeptides, which can subsequently be easily absorbed into enterocytes. After eating in general, protein stimulation of gastric mucosa results in the release of gastrin. Gastrin in turn stimulates the release of pepsinogen and HCl. The acidic environment acatalytically converts pepsinogen into pepsin, denatures globular proteins, and kills any bacteria that accompany the food into the stomach. However, in vitro studies have shown that gluten proteins are only partially degraded by pepsin and arrive at high concentration and high molecular weight in the small intestine. This is because gluten prolamins, in particular, are predominantly comprised of proline residues, making them difficult for the human body to digest as they are resistant to degradation by peptidases (Caminero, et. al, 2014).

Once in the small intestine research has demonstrated that the high concentration of proline in gluten proteins (10-15%) endows the proteins resistance to brush border membrane and pancreatic proteases as well. This is primarily because these enzymes lack prolyl-endopeptidasic activity, which is the ability to cleave at the C-terminal side of proline residues. In normal gluten metabolism, the partially digested gluten peptides are too large to be transported by PEPT-1, the canonical amino acid, dipeptide, and tripeptide transporter. These large peptides, therefore, remain in circulation in the lumen of the small intestine. There is some evidence that shoes the gram negative bacteria that reside in the small intestine might have catalytic activity capable of digesting large oligopeptides and therefore might aid in the digestion of partially digested gluten in the lumen. Canonically, large gluten peptides pass through the small intestine, into the large intestine, and are passed as waste. The high concentration of bacteria in the lower digestive tract, however, leads to the belief that some of these bacteria might participate in the digestion of gluten proteins (Caminero, et. al., 2014).


Protein digestion and absorption in the small intestine. Proteins are hydrolyzed to amino acids, dipeptides, or tripeptides, and eventually transported through enterocytes past the intestinal mucosa. Peptidase resistant peptides, such as gluten proteins, remain in the lumen as they cannot pass through the membrane. Source: Caminero et. Al,
Protein digestion and absorption in the small intestine. Proteins are hydrolyzed to amino acids, dipeptides, or tripeptides, and eventually transported through enterocytes past the intestinal mucosa. Peptidase resistant peptides, such as gluten proteins, remain in the lumen as they cannot pass through the membrane. Source: Caminero et. al, 2014


Jump to other pages of Celiac disease:

Title Page

Molecular Basis of the Disease State

Treatment and Disease Management

Conclusions and Proposals for Future Work

Annotated Bibliography


5 Replies to “History and Metabolic Context”

  1. Good job mentioning the fad of the gluten-free diet, although I’m sure individuals with Celiac Disease appreciate the increase gluten-free options 😉

    What is known about the history of Celiac Disease onset, and has the disease always shown such a wide range of development? Also, are we even able to separate possible environmental effects from better diagnoses?

    1. Hey Greg,

      Thanks for the comment! I myself am gluten free so I absolutely agree that the increase in options is appreciated.

      As far as onset is concerned, a recent study found that about 40% of children who are highly genetically susceptible (homozygous for the HLA-DQ2 haplotype) to the disease generally develop the disease within the first ten years of life. Overall, approximately 80% of children who have some genetic susceptibility to the disease will develop the the overt disease during childhood. This study also suggested that delaying the introduction of gluten into an infants diet may help to delay the onset of the disease.

      As far as adults, there is evidence that cigarettes and human intestinal adenovirus are environmental factors that can increase an individuals chance of developing the disease.

      For diagnoses, isolating individual environmental effects in humans that can lead to Celiac is incredibly difficult, especially given the small amount of information that is known about the specific nature of the environmental effects. There are clearly certain activities one can participate in that increase risk, but even if an individual contains the right genetics to be suscetible to the disease, there is still no gurantee that any event will spark the disease.

      Links to the paper i referenced:




  2. Hi Tommy,

    Good job on a really interesting disease. You noted that one of the main problems with Celiac is that gluten proteins, like prolamins, enter the small intestine in only a partially degraded form, so they are too large to be absorbed through the small intestine and into the rest of the body. Do you think it would be possible to increase digestion of these proteins in the stomach? This way, by the time the proteins reached the small intestine, they would be more fully digested and small enough to be transported as normal by PEPT-1, and thus less likely to cause inflammation and other symptoms of Celiac. I was thinking it might be possible to take a pill that contains an enzyme right before eating (similar to those with lactose intolerance), which would provide the necessary enzymes to break down the gluten in the stomach, so only digested pieces of the protein would enter the small intestine. Do you think this would be possible, or would this be too difficult because the stomach is so acidic, which might inactivate these newly added enzymes?

    You also mentioned several different treatment options that are currently in testing, including larazotide acetatehave and several endopeptidases. Have these medications been tested for effectiveness in animal studies, and have there been actual clinical trials proving that these drugs reduce symptoms of Celiac? How successful have they been? Would either of these two treatments be effective enough so that the patient could eat a totally normal diet, or would they still have to limit their gluten intake to prevent symptoms?

    Finally, when looking at the genetic causes of the disease, 95% of patients have HLA-DQ2 or HLA-DQ8 haplotypes of Celiac disease, while 39% of healthy patents have this same haplotype. Does this mean that healthy people with this haplotype are at increased risk for Celiac disease, and similarly able to pass such susceptibility on to their progeny? I know you said that HLA-DQ2 and 8 are the most closely linked haplotypes to Celiac, but it still seems like this is a somewhat poor prognosticator, as we know that 39% of society does not have Celiac. Is it perhaps that the 39% of society are simply more sensitive to gluten? Could, for example, the symptoms present on a spectrum, with most people experiencing mild/no symptoms, while others experiencing very severe symptoms (and are correspondingly diagnosed with Celiac)?

    1. Hey Mike,

      To answer your first question, there are actually a few treatments being worked on that focus on the aided digestion of prolamins. These treatments have traditionally focused on oratory enzymes (Khosla, 2011), but your suggestion of a stomach enzyme in the form of a pill is intriguing. I agree that the hardest part about the stomach might be finding an enzyme that was ideally suited for such a low pH. It also might lead to significant stomach problems, as it might be hard to regulate a peptidase at that low of a pH.

      As far as I know, these treatments are both in clinical trials, so they have clearly shown some effectiveness. I can only speculate as to the absolute effectiveness of each drug, but I would imagine it would vary. Even a gluten free diet has been shown to not be fully effective in some individuals.

      To answer your third question, having either of the two mentioned haplotypes is not a guarantee that you will have Celiac disease, but simply puts you at risk for developing the disease. Healthy people with the haplotype could potentially pass the disease down to their progeny. My parents, for example do not have Celiac disease while I do (although I do not know my genotype). Diagnosis generally boils down to the antibody test mentioned above, especially if symptoms are present. There is definitely a spectrum of symptoms already seen in Celiac patients. Gluten intolerance is also seen in many people who don’t actually have Celiac disease, so it is very possible that these people represent a large fraction of the 39% that have the HLA haplotypes but are not technically Celiacs.

      Links I referenced:



  3. your link at the bottom of the page to molecular basis of the disease takes you back to this page, history and metabolic context.

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