A team of doctors based in the Netherlands recently set out to assess the effectiveness of computed tomography (CT) in diagnosing refractory celiac disease, and enteropathy-associated T-cell lymphoma (EATL). EATL is a generally rare, but particularly aggressive form of bowel cancer that is the leading cause of death in adults with celiac disease.

The study team was made up of doctors Maarten Mallant, Muhammed Hadithi, Abdul-Baqi Al-Toma, Matthijs Kater, Maarten Jacobs, Radu Manoliu, Chris Mulder, and Jan Hein van Waesberghe.

The team looked at 46 patients with clinically proven celiac disease, refractory celiac disease I, refractory celiac disease II, or EATL including 18 males and twenty-eight females. The first group contained 14 patients with uncomplicated celiac disease and 10 with type I refractory celiac disease. The second group contained 15 patients with type II refractory celiac disease and 7 patients with EATL. 5 patients from group II showed lymphandenopathy, compared to none in the first group. 20 patients from group I showed a higher number of small mesenteric vessels compared to just 11 from group II.

This is significant because increased numbers of small mesenteric vessels are associated with an absence of refractory celiac disease II and EATL, while reduced numbers of small mesenteric vessels are associated with a higher rate of refractory celiac disease II and EATL.

The team evaluated the two groups within eleven categories: abnormal intestinal fold patterns; bowel wall thickness, excess fluid; intestinal insussuction; ascites; lymphadenopathy; increases in lymph node numbers; mesenteric vascular changes; and spleen size. One other area the doctors found important was in differences in the average thickness of the bowel wall. Group I showed thinner bowel walls compared to group II. In group I, average bowel thickness ranged from 4mm to 11mm, with an average thickness of 7.0mm. In group II, average bowel thickness ranged from 5mm to 15mm, with an average thickness of 10.0mm. So, group II showed about 30% thicker bowel walls than group I.

The doctors’ conclusions reaffirmed the need for a biopsy before confirming a diagnosis of celiac disease. Regarding the use of CT, the team found CT unnecessary for cases of uncomplicated celiac disease, but found CT very useful in cases of complicated and pre-cancerous celiac disease.

The study team also found that pattern reversal and/or loss of jejunal folds is specific to celiac disease, though they had an admittedly small sample of just 24 of their 46 patients, so their measures are far from definitive.

All of this drives home the importance of encouraging early and accurate screening for celiac disease. Ideally, we will get to the point where, like many European countries, we will begin to catch celiac disease before it ever becomes refractory, and before it ever develops into EATL.

Until then, stay informed and take an active role in maintaining your own health.

World J Gastroenterol 2007; 13(11): 1696-1700

One problem with studying EATLs is that the best statistical information regarding its prevalence is still based on estimates. Until recently, there had been no study made to determine the rate at which EATLs occur in the general population. A team of doctors based in the Netherlands recently set out to conduct such an assessment using the Dutch national network and patient registry of cyto- and histopathology reports (PALGA). The research team included Wieke H. M. Verbeek, Jolanda M. W. Van de Water, Abdulbaqi al-Toma, Joost J. Oudejans, Chris J. J. Mulder & Veerle M. H. Coupé.

The team looked at all T-cell lymphomas found from January 2000 to December 2006 that originated in the small bowel, and they computed some basic average rates of EATL occurrence for the Netherlands and worldwide, along with occurrence rates by gender and age. The team also factored in the location of the lymphoma, Marsh categorization for celiac disease, and the means by which the patients’ lymphomas were detected.

In people with celiac disease, eating wheat causes the wheat protein to trigger an adverse immune reaction that leads to inflammation of the intestinal lining, which can eventually cause the cells in the inflamed region to become cancerous. Even though celiac disease occurs twice as often in women as in men, men are far more likely to develop EATLs. Out of every 10 people who develop EATLs, only 2 to 5 of them have any obvious symptoms. Also, these statistics apply to untreated celiacs, and those diagnosed as adults, while people diagnosed as children and following a gluten-free diet have about the same rates of EATL as the general population.

Adults with untreated celiac disease are nearly 70 times more likely to die from lymphoma than people without celiac disease. Again, since more and more people are being diagnosed with celiac disease as adults, it’s important to get the clearest possible picture of the associated risks, especially when they are as serious as EATLs. The team also noted that most EATLs seemed to be centered in theproximal small intestine, and that diagnosis was generally madesurgically.

The team looked at 116 incidents of EATL and found a rate in the general Dutch population of .10/100,000. This is about double the estimated western rate of about .05/100,000. For those over 50 years of age, the Dutch rate of EATL increased by a factor of 10 to 2.08/100,000, while over 60, the Dutch rate was 2.92/100,000. Still, in addition to afflicting almost only those with celiac disease, EATL seems to afflict mostly men. For those over 50, EATL rates were .09/100,000 for women, but nearly 3 times that, 2.95/100,000 for men.

One interesting part of the study was the acknowledgment by the doctors that increased cancer rates in celiacs have not been judged “sufficiently large” to warrant screening the general population that way some countries do. Instead, the doctors have adopted a strategy of checking patients with EATL for celiac disease. By their own admission, most patients with EATL have already been diagnosed with celiac disease. In any case, if you have a particularly deadly type of cancer it would seem a little late to test you for celiac disease. We at Celiac.com propose that a better strategy would be to test those with celiac disease for EATLs (and screen the general population for gluten intolerance).

This study drives home the importance of diagnosing and treating celiac disease as early as possible, and also reinforces the importance of faithfully following a gluten-free diet and getting regular follow-up biopsies and screening that would reveal an EATL.

Article citation:
Scandinavian Journal of Gastroenterology
Published on July 11, 2008
DOI: 10.1080/00365520802240222

In another publication from the database at PubMed.gov (Open Original Shared Link), a study that showed that when a patient with MGUS and Celiac Disease was put on a gluten-free diet the monoclonal proteins entirely disappeared by the end of 3 years! Hence you can imagine what big news this is to all the MGUS patients, on the various online MGUS forums. Here is the suggestion that Celiacs might avoid becoming MGUS patients, that MGUS patients might perhaps avoid progression to multiple myeloma, and that multiple myeloma patients might have halted or slower progression of their disease, simply by being on a gluten-free diet! This is indeed big news!

The ramifications of this are that everyone with Celiac Disease really should undergo testing for MGUS/Myeloma which can be associated with various autoimmune diseases, increased rate of osteoporosis,  and neuropathy, or no symptoms at all! Likewise all MGUS patients should be tested for celiac disease, which again can be associated with various autoimmune diseases, increased rate of osteoporosis,  and neuropathy, or no symptoms at all! Do you see the similarities?

I am currently working on a letter to Blue Cross Blue Shield,  informing them of the results of these studies and suggesting that their policy of reimbursing for celiac DNA testing of first degree relatives of known celiacs should be expanded to also include all persons having serum monoclonal proteins. This would include not just MGUS and multiple myeloma, but also Waldenstrom's macroglobulinemia.

I would also like to call for intensified research on the link between celiac disease and paraproteinemia.
Open Original Shared Link

Homozygosity is the condition of having two identical genes, of many possible combinations, on a single chromosome site.  

HLA-DQ2 homozygosity means that a person has inherited the HLA-DQ2 gene from both parents.

In addition to having a much higher risk of developing celiac disease in general, people with HLA-DQ2 homozygosity have a much higher risk of developing refractory celiac disease type II, and enteropathy-associated T-cell lymphoma. Refractory celiac disease is a rare type of celiac disease in which a gluten-free diet fails to eliminate symptoms and to reverse celiac-associated damage. Eneteropathy-associated T-cell lymphoma is a type of cancer that often develops in people with advanced intestinal damage such as commonly found in celiac patients.

A team of Dutch doctors recently set out to determine if the presence of the MY09B gene carries an elevated risk of refractory celiac disease type II, and enteropathy-associated T-cell lymphoma.

The research team evaluated 62 people who were confirmed to have both refractory celiac disease type II and enteropathy-associated T-cell lymphoma. They also evaluated 421 people with simple celiac disease, along with a control group of 1624 people without celiac disease.

The team conducted genotyping of MY09B along with molecular HLA-DQ2 typing on all of the patients.

The tests showed that one nucleotide variation in MY09B was substantially different in the refractory celiac group than in either the simple celiac or the control group.

The allele in question is known as the rs7259292 T allele, and the results of the tests showed that it occurs far more frequently in patients with refractory celiac and enteropathy-associated T-cell lymphoma than in either the control group or the group with simple celiac disease. In fact, the halpotype that carries the rs7253292 T allele occurs in 11% of the patients with refractory celiac disease type II, and enteropathy-associated T-cell lymphoma compared with just 2% of the control group and 3% or patients with regular celiac disease.

Additionally, the results showed that patients who carry the MY09B rs7259292 allele or who showed HLA-DQ2 homozygosity faced similarly high risk levels for refractory celiac disease type II, and enteropathy-associated T-cell lymphoma compared to patients with simple celiac disease.

The results did not show any connection or interaction between the MY09B rs7259292 allele and HLA-DQ homozygosity.

Clinical Gastroenterology and Hepatology; 2007: 5(12): 1399-1405

Celiac.com 08/14/2007 - It has long been documented that there is a connection between celiac disease and neoplasm. In fact, in the 1960s, a population-based study reported a 100-fold increase in risk of non-Hodgkins lymphoma in patients with celiac disease.

It has also been shown that people with celiac disease are at greater risk for developing small bowel adenocarcinoma. Also, studies have shown an increased mortality rate from cancer among celiac patients, and there is mounting, but not conclusive evidence that a gluten-free diet provides a measure of protection against the development of malignancies. Strangely, several studies have documented a lower risk of breast cancer among celiac patients.

However, to date, very little is known about the associated factors, particularly with regard to the development of gastrointestinal malignancies and their corresponding risk levels. A study recently published in BMC Gastroenterology documents the efforts of a team of Italian doctors to evaluate the risks of developing various types of gastrointestinal neoplasms associated with delayed diagnosis of celiac disease and the resulting consumption of gluten over time.

The team was made up of doctors Marco Silano; Umberto Volta; Anna Maria Mecchia; Mariarita Dessì; Rita Di Benedetto; and Massimo De Vincenzi. The team studied a group of 1,968 celiac patients from 20 GE referral centers between 01 January 1982 & 31 March 2005.

Study Shows Higher Rates of Gastrointestinal Malignancy that Increase with Age in Patients with Delayed Diagnosis of Celiac Disease

According to the results of the study celiac patients have an increased risk of developing cancer which corresponds directly with the age of diagnosis of celiac disease. This increased risk applies to gastro-intestinal malignancies. An accurate screening for tumors should be performed in patients diagnosed with celiac disease in adulthood. On average, the mean age of celiac patients who developed a neoplasm, either sooner or later, was 47.6 +/- 10.2 years, compared with 28.6 =/- 18.2 years in those did not develop neoplasm.

BMC Gastroenterology 2007, 7:8 (9 March 2007)

The researchers conclude that celiac disease patients have a significantly increased risk of developing non-Hodgkin lymphoma, but the association is lower than previously thought. Celiac disease is mainly associated with T-cell small bowel lymphoma which is, in general, a rare condition.

Celiac.com 01/20/2005 - A link between untreated celiac disease and a rare enteropathy-type T-cell lymphoma (ETTL) has been well established by Open Original Shared Link. According to Dr. Karin Ekstrom Smedby of the Karolinska Institute in Stockholm and colleagues, there is also an increase in the prevalence of other types of lymphomas in those with celiac disease, such as B cell and non-intestinal lymphomas. In their study the researchers reviewed and reclassified 56 cases of malignant lymphomas that occurred in 11,650 hospitalized celiac disease patients in Sweden. The observed numbers of lymphoma subtypes were compared with those expected in the Swedish population. The researchers discovered that a majority of the lymphomas were not intestinal T-cell lymphomas, but were B-cell non-Hodgkin lymphoma (NHL). In addition, 44% of the patients with B cell NHL had a history of other autoimmune/inflammatory diseases. As expected, the relative risks for T-cell NHL and primary gastrointestinal lymphomas were markedly increased. According to the researchers: "Most lymphomas complicating coeliac disease are indeed related to the disease and are not of the ETTL-type. There was a remarkable aggregation of autoimmune/inflammatory disorders, female sex, coeliac disease, and B cell lymphoma."

Scand J Gastroenterol. 2003 Aug;38(8):831-3.

Celiac.com 09/29/2003 - In the following abstract the authors point out that in endoscopic screenings, adenocarcinoma is found less often than statistics from studies suggest it should be, implying that routine endoscopic examinations are not adequate to detect it. If this interpretation of the study is correct, other methods of screening for it need to be utilized or developed. Another possible way to look at this is that celiac patients do not have an elevated risk of adenocarcinoma when compared to the normal population, but given the numerous studies that have shown otherwise this possibility seems unlikely. I would also like to point out that the 60- to 80-fold increased risk of small bowel adenocarcinoma in patients with celiac disease that the author mentions is true for untreated celiacs. -Scott Adams

Here is the abstract:

Am J Med. 2003 Aug 15;115(3):191-5

Celiac.com 09/03/2003 - The results of a study conducted by Dr. Peter Green and colleagues at the College of Physicians and Surgeons in New York City indicate that, despite a gluten-free diet, people with celiac disease still have an elevated risk of getting non-Hodgkins lymphoma. The good news is that the risk of getting other types of cancers like small intestinal adenocarcinoma, esophageal cancer and melanoma were reduced in patients who adhered to a gluten-free diet, as was the overall risk of getting non-Hodgkins lymphoma. The study looked at 381 celiac disease patients, out of which 43 were diagnosed with cancer (11%). The vast majority—34—were diagnosed at or before their celiac disease diagnoses, so it is safe to say that they were not following a gluten-free diet.

The results of this study emphasize the importance of adhering to a strict gluten-free diet, and of getting regular checkups by your doctor. Cancer screenings may also be advised, especially in cases where unexplained symptoms continue after going gluten-free. There is currently, however, no specific test for non-Hodgkins lymphoma, so one must learn about its warning signs and be on the lookout for any symptoms. - Scott Adams

Here is the abstract of the study:

QJM, May 1, 2003; 96(5): 345 - 353

Celiac.com 05/29/2003 – A survey was recently conducted by Professor P.D. Howdle, St. Jamess University Hospital (UK), et al, to estimate the frequency in the UK of small bowel malignancy, and its relationship to celiac disease. Data were collected from 1,327 clinicians on a monthly basis between June 1998 and May 2000. The clinicians were asked to report all cases of newly diagnosed primary small bowel malignancy, and whether or not the patients reported also had celiac disease. Normally malignancies of the small intestine are rare, and they only account for less than 2% of all gastrointestinal cancers.

Results: "Clinico-pathological data were ascertained for 395 cases, including 175 adenocarcinomas, 107 lymphomas and 79 carcinoid tumors. In 13% of adenocarcinoma cases and in 39% of lymphomas, there was a diagnosis of celiac disease. Survival rates at 30 months for adenocarcinomas, lymphomas and carcinoid tumors were 58%, 45% and 78%, respectively. Prognosis of all tumors was inversely related to stage at presentation, and lymphomas associated with celiac disease were associated with a poorer prognosis."

This study provides more evidence that those with celiac disease run a greater risk of getting adenocarcinoma of the small bowel, as well as lymphoma. Because of the high rate of metastatic disease in the patients studied, there appears to be a long time from the onset of symptoms to diagnosis, which is a concern.

Unfortunately this study does not address when celiac disease was diagnosed in these patients, and whether or not they were treating it with a gluten-free diet. Other studies have shown that cancer risk decreases to that of the normal population in patients who are on a gluten-free diet for at least five years.

Gastroenterology 2002 Nov;123(5):1428-1435 Links

Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, Ekbom A.

Clinical Epidemiology Unit, Department of Medicine, Karolinska Institute/Hospital, Stockholm, Sweden; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Institute of Oral Biology, University of Oslo, Oslo, Norway; and the Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden.

BACKGROUND & AIMS: Studies of cancer risk in celiac disease (celiac disease) or dermatitis herpetiformis (DH) indicate increased risks for malignant lymphoma and occasionally other neoplasms, but are characterized by small numbers, lack of systematic cancer assessment, and subjects identified from referral institutions.

METHODS: By using Swedish population-based inpatient and cancer registry data, we followed-up 12,000 subjects with celiac disease or DH, and evaluated cancer incidence by using standardized incidence ratios (SIR).

RESULTS: Adults (but not children and adolescents) with celiac disease had an elevated overall risk for cancer (SIR = 1.3) that declined with time and eventually reached unity. Elevated risks were found for malignant lymphomas, small-intestinal, oropharyngeal, esophageal, large intestinal, hepatobiliary, and pancreatic carcinomas. The excess occurrence of malignant lymphomas was confined to adults, decreased with time of follow-up evaluation, and decreased over successive calendar periods. Decreased risks were found for breast cancer. Subjects with DH had a slightly increased overall cancer risk (SIR = 1.2) owing to excesses of malignant lymphoma and leukemia, but no increases of gastrointestinal carcinomas.

CONCLUSIONS: Albeit increased, the relative risks for lymphomas and gastrointestinal cancers in this study are lower (and declining) than in most previous reports. The overall cancer risk is only moderately increased, and non-elevated during childhood and adolescence.

PMID: 12404215 [PubMed - as supplied by publisher]