Case scenario:A 36 years old woman with chronic intermittent diarrhea from childhood and weight loss,Abdominal distention and bloating,

idiopathic peripheral neuropathy,weakness,fatigue,bone pain and with unexplained iron-deficiency anemia,Folat deficiency,

Vitamin D deficiency, abnormal liver function tests that by serologic evaluation and small bowel biopsy and clinical-histologic response to gluten-free diet, established the diognosis of coeliac disease.

The patient is worried about risk of malignancy and mortality.

Is she in risk of overal mortality compared with the general population?

PICO:

P:A 36 years old woman known case of coeliac disease.

.I:Coeliac patient

.C:Non- coeliac patient

.O:Mortality and malignancy

Meta-analysis:

coeliac disease and the risk of all-cause mortality

any malignancy and

lymphoid malignancy

M. Tio, M. R. Cox & G. D. Eslick

Celiac Disease

Celiac disease is common autoimmune disorder

and common cause of malabsorption of one or more nutrients.

This picture shows the damage that is caused by gluten to the microvilli in someone who suffers from Celiac Disease. As you can see, the image on the left, a healthy intestine, has much greater surface area than the one on the right, damaged by gluten

consumption .

Celiac disease is considered an "iceberg" disease with a small

number of individuals with classical symptoms and

manifestations related to nutrient malabsorption

The Celiac IcebergSymptomaticCeliac Disease

Silent Celiac Disease

Latent Celiac Disease

Genetic susceptibility: - DQ2, DQ8 Positive serology

Manifest mucosal lesion

Normal Mucosa

Classical Celiac Disease (1:4500)

Atypical

Silent

Latent

Detected by screening (1:250)

:Etiology

The etiology of celiac disease is not known, but environmental, immunologic, and genetic factors all appear to contribute to the disease.

Environmental factor is the clear association of the disease with gliadin,a component of gluten that is present in wheat, barley, and rye.

In addition to the role of gluten restriction in treatment, the instillation of gluten into both normal-appearing rectum and distal ileum of patients with celiac disease results in morphologic changes within hours.

Sources of Gluten

•OBVIOUS SOURCES–Bread–Bagels–Cakes–Cereal–Cookies–Pasta / noodles–Pastries / pies–Rolls

Sources of Gluten

•POTENTIAL SOURCES–Candy–Communion wafers–Cured Pork Products–Drink mixes–Gravy–Imitation meat / seafood–Sauce–Self-basting turkeys–Soy sauce

An immunologic component in the pathogenesis of celiac disease is critical Serum antibodiesIgA antigliadin,IgA antiendomysial, IgA anti-tTG antibodies—are present. The antiendomysial antibody has 90–95% sensitivity and 90–95% specificity. patients with these antibodies should undergo with .deudenal biopsy

Genetic factor(s) are also involved in celiac disease. The incidence of symptomatic celiac disease is 10% in first-degree relatives of celiac disease patients. all patients with celiac disease express the HLA-DQ2 or HLA-DQ8 allele, though only a minority of people expressing DQ2/DQ8 have celiac disease. Absence of DQ2/DQ8 excludes the diagnosis of celiac disease.

DQA1*0501

DQB1*0201DQ

2 {DQA1*0201{

DR3

CIS

DR5/DR7

Trans

DR3/DR3

CIS

DQB1*03

DQA: Any

APC Gluten

DQ2 DQ8

Be aware DR3 should now be referred to as DR17

Several genes are involved

The most consistent genetic component depends on the .presence of HLA-DQ (DQ2 and / or DQ8) genes

Other genes (not yet identified) account for 60 % of the .inherited component of the disease

HLA-DQ2 and / or DQ8 genes are necessary (No DQ2/8, no Celiac Disease!) but not sufficient for the .development of the disease

HLA

?? ?

?

Gluten

Celiac Disease

+

Genes

Genetics

:DiagnosisA biopsy should be performed in

patients with symptoms and laboratory findings suggestive of nutrient malabsorption and/or deficiency and with a positive

endomysial antibody test.

The diagnosis of celiac disease requires the presence of characteristic histologic changes on small-intestinal biopsy together with a prompt clinical and histologic response following the institution of a gluten-free diet. If serologic studies have detected the presence of IgA antiendomysial or tTG antibodies, they too should disappear after a gluten-free diet is started.

The hallmark of celiac disease is the presence of an abnormal small-intestinal biopsy (Fig. 294-4) and the response of the condition—symptoms and the histologic changes on the small-intestinal biopsy—to the elimination of gluten from the diet.

The histologic changes have a proximal-to-distal intestinal distribution of severity, which probably reflects the exposure of the intestinal mucosa to varied amounts of dietary gluten.

Diagnosis

1st: Physical exam and blood testing2nd: Duodenal biopsy

3rd: Implement gluten-free diet

http://www.csaceliacs.org/celiac_diagnosis.php

The classical changes seen on duodenal/jejunal biopsy :are restricted to the mucosa and include 1:an increase in the number of intraepithelial .lymphocytes2: absence or reduced height of villi, resulting in a flat appearance with increased crypt cell proliferation, resulting in crypt hyperplasia and loss of villous structure, with consequent villous, but not mucosal, .atrophy3:cuboidal appearance and nuclei that are no longer oriented basally in surface epithelial cells.4:increased lymphocytes and plasma cells in the lamina propria.

Histology of intestinal biopsy in CD Modified Marsh score

Normal small

intestine

Normal villi

Small intestine

with scalloping

Small intestine

with villous atrophy

It Takes A Villi

•Damaged •Healthy

Duodenum

Normal Scalloped Gluten-free diet

CELIAC DISEASE

Increased IEL Villous atrophy Recovering

END

OSC

OPY

HIS

TOLO

GY

This is what the small intestine looks like under the microscope when the mucosa is injured like the left photo shows. The villi are essentially flat and numerous lymhocytes are near the surface lining.

This endoscopic photo of the small bowel (duodenum) shows the classic fissuring or cobblestoning of the surface as well as "scalloping" of the folds in Celiac disease.

This endoscopic photo was taken with special light technique called Narrow Band Imaging (NBI). It brings out some of features of atrophy, fissuring or cobblestone appearance of the mucosa (surface lining) and the "scalloping" of the folds seen in Celiac disease.

The folds are flattened and the mucosa in this patient with Celiac.

GI symptoms

• diarrhea • weight loss• weakness• pedal edema - protein malabsorption • easy bruising - vitamin K malabsorption• classic steatorrhea• increase in stool mass in most patients

Extraintestinal features

Hematopoietic

• anemia - iron or folate deficiency, but also increased blood loss

• B12 deficiency in severe cases• hyposplenism - may resolve with dietary

therapy• thrombocytosis with Howell-Jolly bodies• bleeding diathesis

Osteopenic bone disease

• decrease Ca absorption• decrease in absorption fat-soluble vitamin D• binding of Ca and Mg in lumen by unabsorbed

dietary fatty acids

Osteopenic bone disease

• Osteoporosis with bone pain and pathologic fractures

• paresthesia, muscle cramps and tetany if severe hypocalcemia

• chronic can result in secondary and even tertiary hyperparthyroidism

• problems with premenopausal bone mass

Neurologic symptoms

• peripheral neuropathy• myopathy• cerebellar ataxia• myoclonus• cerebral atrophy and dementia• cerebral vasculitis• brain-stem encephalitis• epilepsy and cerebral calcifications

Renal and liver disease

• Glomerulonephritis• IgA nephropathy may respond to gluten-free

diet • PBC, PSC and chronic active hepatitis• elevated transaminases

Autoimmune and Connective tissue disease

• Vasculitis• cryoglobulinemia• Sjogren’s syndrome• SLE• selective IgA deficiency• thyroid disease • IDDM- and celiac both have HLA-DR3 and

DQB1*0201 alleles

OB-GYN

• Impaired fertility in women• high incidence of spontaneous abortion• low birth-weight babies• reduced breast milk production• paripartum exacerbation or first presentation• correctable with gluten-free diet

Treatment OptionsOption #1:

Remove the genesOption #2:

Remove the grains

Treatment

Only treatment for celiac disease is a gluten-free diet (GFD)

.Strict, lifelong diet

Avoid:WheatRye

Barley

:Associated DiseasesCeliac disease is associated with dermatitis herpetiformis (DH), Almost all patients with DH have histologic changes in the small intestine consistent with celiac disease, although usually much milder and less diffuse in distribution. Most patients with DH have mild or no gastrointestinal symptoms.Celiac disease is also associated with:

Diabetes mellitus type 1IgA deficiencyDown syndromeTurner's syndrome.

Dermatits herpetiformis

Erythematous macule > urticarial papule > tense

vesicles

Severe pruritus

Symmetric distribution

90% no GI symptoms

75% villous atrophy

Gluten sensitive

Dermatitis Herpetiformis

Skin manifestation of coeliac disease.Raised, red patches, often blistered.Commonly on elbows/knees/buttocks.

SymmetricalSkin biopsy, treated with dapsone.

The most important complication of celiac disease is the development of cancer .

An increased incidence of both gastrointestinal and nongastrointestinal neoplasms as well as intestinal lymphoma exists in patients with celiac disease.

The possibility of lymphoma must be considered whenever a patient with celiac disease previously doing well on a gluten-free diet is no longer responsive to gluten restriction or a patient who presents with clinical and histologic features consistent with celiac disease does not respond to a gluten-free diet.

Other complications of celiac disease include the development of intestinal ulceration independent of lymphoma and so-called refractory sprue and collagenous sprue.

In the past, patients with celiac disease or DH had been reported to have a 10-fold increased risk for certain gastrointestinal tract malignancies and 40- to 70-fold increased risk for non-Hodgkin's lymphoma (NHL).

Recent studies, however, indicate that the increase in risk of malignancy, particularly lymphoma, is much .less than initially believed

Small intestinal lymphoma, often multifocal and diffuse, accounts for one half to two thirds of the malignancies complicating celiac disease and typically occurs after 20 to 40 years of disease.

Whereas in the general population, most small intestinal lymphomas are of B-cell origin, intestinal lymphoma in celiac disease is typically of T-cell origin.

the term EATL (enteropathy-associated T-cell lymphoma) was coined to describe both the intestinal and extraintestinal lymphomas that complicate celiac disease.

EATL commonly is accompanied by mucosal ulceration, as seen in ulcerative jejunoileitis, and these ulcers sometimes are the only endoscopic manifestation of lymphoma.

Although some patients with EATL have a partial or temporary response to a strict gluten-free diet, most are eventually unresponsive to gluten withdrawal.

In patients whose disease was previously controlled on a gluten-free diet, recurrence of gastrointestinal symptoms (e.g., abdominal pain, weight loss, diarrhea) should raise the clinical suspicion of lymphoma.

Other features suggesting lymphoma include :

Intestinal obstruction

Intestinal bleeding

Fever

Hypoalbuminemia

Lymphadenopathy

Erythrophagocytosis evident in bone marrow or the peripheral blood .

:Diagnose

Small intestinal radiologyenteroscopy with biopsy of the mucosa at multiple levelscapsule endoscopyCT or MR scanning.

If the index of suspicion is high and studies are not diagnostic, full-thickness biopsy specimens of the small intestine should be obtained at laparoscopy or laparotomy with careful examination of the entire length of the small intestine and examination of mesenteric lymph nodes. Even with such an aggressive approach, EATL can be extremely

difficult to diagnose .

EATL commonly is fatal:

Overall one-year and five-year survival rates of 31% and 11% ,respectively, were reported in one small series ,

with long-term survival almost exclusively confined to those treated with chemotherapy.

one third of the remaining malignancies complicating celiac disease. The average patient so affected is older than 50 years .

The Swedish study reported elevated risks for small intestinal cancer (standardized incidence ratio,SIR, 10), oropharyngeal cancer (SIR, 2.3), esophageal cancer (SIR, 4.2), and primary liver cancer (SIR, 2.7).

Patients with DH also had a slightly increased overall cancer risk (SIR, 1.2) owing to excesses of lymphoma and leukemia, .but they had no increases in gastrointestinal carcinomas

The mechanisms responsible for the increased prevalence of malignancy in celiac disease are unknown.

potential factors:

Increased crypt mitotic activity

increased turnover of lymphoid cells within the mucosa

penetration of the damaged intestinal mucosa by carcinogens

infection with oncogenic viruses

epithelium underlying abnormalities in the mucosal immune system and surface

.

the excess risk of malignancies, which was confined to adults, disappeared after a 10-year follow-up.

This declining risk of malignancies with increased duration of follow-up, and thus with the length of gluten-free diet, supports the results of a previous study, which indicated that a strict gluten-free diet for five years reduced the risk of all malignancies, not just EATL, to that of the general .population

Meta-analysis:

coeliac disease and the risk of all-cause mortality

any malignancy and

lymphoid malignancy

M. Tio, M. R. Cox & G. D. Eslick

:INTRODUCTIONCoeliac disease is a common autoimmune disorder, witha prevalence approaching 1% in the United States.

Although it is classically associated with malabsorptionand the attendant complications that can arise from themalabsorptive state, it has also been associated with anincreased risk of lymphoid malignancies.

This association is particularly clear in the case of a specific non-Hodgkin lymphoma (NHL) subtype, enteropathy-associated Tcell lymphoma (EATL), which has been long established as a complication of coeliac .disease

The magnitude of the risk of other forms of lymphoid malignancies is much less clear. Data on lymphoid malignancy risk other than NHL are scant, and the risk estimates for the more commonly reported NHL vary significantly.

Similarly, whether coeliac disease increases the overall risk of malignancy or not remains unknown, with large discrepancies in reported estimates.

Coeliac disease has also been associated with an increased risk of all-cause mortality, although again, the estimates vary widely, ranging from no association to a 3.9-fold increased risk.

:METHODS

: Search strategy

Relevant articles were identified by one reviewer (M.T.) by systematically searching through MEDLINE (from 1950), PubMed (from1946),EMBASE (from 1949) and Current Contents Connect (from 1998) through to 4 January 2012 .

No language restrictions were used in either the search or study selection. A search for unpublished literature was not performed.

:Study selection

To be included, eligible studies needed to:1-have a study design of either a cohort or case control ;

2-report the risk of all-cause mortality, any specific mortality any malignancy or any lymphoid malignancy .in coeliac patients

3-report the risk point estimate as an odds ratio (OR), hazard rate or relative risk.

4-report the 95% confidence interval (CI) for the point estimate.

5-use an internal comparison when calculating the risk estimate .

:RESULTSFrom 8698 citations screened by our search, we identified a total of 17 observational studies that met our inclusion criteria (Figure 1). Table 1 shows selected characteristics of the identified studies.2, 8, 15–29. In terms of study design, nine were case control studies and eight were cohort studies.

There was heterogeneity in the method of coeliac disease diagnosis, with six studies using medical records, one study using patient interview, three studies using patient interview or positive serology plus positive histopathology and two studies using positive histopathology. Latent or undiagnosed coeliac disease was used as a coeliac disease subtype diagnosis in seven studies, with two studies using positive eurospital tissue-transglutaminase antibodies (Eu-tTG) plus positive endomysial antibodies (EMA) or positive celikey tissue-transglutaminase antibodies (celikey-tTG), two studies using positive tTG plus positive EMA, two studies using positive tTG or positive EMA or positive antigliadin antibody and two studies using positive EMA

alone .

All-cause mortality:

the all-cause mortality meta-analysis of five prospective studies[8, 22, 24, 26, 29] comprising of 38 039 coeliac cases with a total of 304 694 individuals, indicating that coeliac patients are at an increased risk of all-cause mortality with a pooled OR of 1.24 (95% CI 1.19–1.30). There was .no significant heterogeneity

:Non-Hodgkin lymphoma

Eight studies[15, 16, 18, 21, 23, 25, 27, 28] (six case control studies and two cohort studies) comprising of 110 245 cancer or coeliac cases with a total of 538 493 individuals were identified for the non-Hodgkin lymphoma (NHL) meta-analysis. Coeliac patients were at significantly increased risk of NHL.This resulted in a pooled OR of 2.61 (95% CI 2.04–3.33), .with no significant heterogeneity

:T-cell non-Hodgkin lymphoma

Five studies[15, 16, 18, 25, 28] (four case–control studies, one cohort study) comprising of 35 358 cancer cases with a total of 311 888 individuals were identified for the TNHL meta-analysis. The risk of TNHL was significantly elevated, with a pooled OR of 15.84 (95% CI 7.85–31.94) (Figure 4). There was no significant heterogeneity (I2 = 55.6%, P =

0.06) .

:Any malignancy

Three prospective studies[8, 23, 26] (two cohort studies, one nested case–control study) comprising of 5134 cancer or coeliac cases with a total of 35 582 individuals were identified for the any malignancy meta-analysis. There was no association between coeliac disease and the risk of any malignancy, with a pooled OR of 1.07 (CI 0.89–1.29) (Figure 5). There was no significant

heterogeneity (I2 = 0%, P = 0.58) .

Cause specific mortality and other :lymphoid malignancies

As shown in Table 2, we found that coeliac patients had an increased risk of cardiovascular mortality 1.19 (95% CI 1.12–1.27), lymphoproliferative disease/malignancy 2.53 (95% CI 1.59–4.04), Hodgkin lymphoma 2.01 (95% CI 1.01–4.01) and diffuse large cell B-lymphoma 2.25 (95% CI 1.32–

3.85) .There was no increased risk of any malignancy mortality 1.24 (95% CI 0.96–1.60), lymphoma 1.99 (95% CI 0.29–13.58), chronic lymphocytic leukaemia 0.80 (95% CI 0.46–1.38) or multiple myeloma 1.26 (95% CI 0.83–1.90). However, all of these results are based on pooling .together only two or three studies

:Discussion

Our systematic review and meta-analysis shows that coeliac patients are at an increased risk of mortality, and are at a substantially increased risk of NHL and

TNHL .Serologically defined coeliac patients are at a similarly increased risk of both NHL and mortality.

However, coeliac patients do not have an increased .risk of any malignancy overall

The all-cause mortality results:

This raises the possibility that as the current pooled mortality risk estimate is based on an average of 13.4 years of follow up, this may in fact be an underestimate of the true risk.

Further prospective studies with a longer follow-up are needed to determine if the mortality risk is higher than the current estimate .

However, our estimate still needs to be interpreted with caution, as it is limited by the availability of only six studies to analyse, combined with the heterogeneity in coeliac disease diagnosis method between studies.

Nonetheless, it is likely that our pooled result is the most .reliable estimate currently available

This increased risk of all-cause mortality in coeliac patients may be partly explained by our findings that coeliac patients have an increased risk of cardiovascular

mortality .

our cardiovascular mortality result is based on only three studies, more studies using internal comparisons are required to determine this association.

Further studies examining specific mortality risks among coeliac patients may help guide future studies on whether any preventative measures beyond the gluten free diet

.could be taken to minimise mortality

:Any malignancy and coeliac diseaseNo association between the risk of any malignancy and

.coeliac disease was found in our pooled risk estimate

It is not clear how an increased risk of any malignancy overall is not found when there is a clear increased risk of NHL, although one study[36] found a decreased risk of breast cancer in

coeliac disease .If coeliac disease decreases the risk of certain non-lymphoid malignancies, it may explain why there is no increased risk of

any malignancy overall .Further study into the possibility of decreased cancer risks other than NHL may be warranted. However, it is possible that the lack of increased risk is due to a lack of statistical power, given .low absolute risk of NHL

The serology subgroup analysis found that serologically diagnosed coeliac patients had an increased risk of mortality and NHL compared with non-coeliac patients.

These results suggest that serologically defined coeliac patients may be subject to a similar level of risk as coeliac

patients diagnosed by other means .

However, given that these results are only marginally significant, further research into clarifying any association

between positive coeliac serology and NHL .is warranted and mortality

We were not able to determine from our systematic review and meta-analysis if compliance with a gluten-free diet had any effect on the risk of mortality and NHL in coeliac patients.

There is evidence suggesting that the gluten-free diet decreases the risk of mortality and malignancy; however, some studies have not found this association.

Future studies should include measurement of .compliance with the gluten-free diet

:Conclusion

Our systematic review and meta-analysis shows that coeliac patients are at an increased risk of mortality and non-Hodgkin lymphoma, but do not have an

increased risk of any malignancy overall .

Serologically defined coeliac patients also have an elevated risk of mortality and non-Hodgkin lymphoma .

Our results are limited by the small number of studies available for analysis, and by heterogeneity in diagnostic methods. More studies using internal comparators are needed, particularly to more accurately determine the risk of NHL and mortality in both serologically defined .and histologically defined coeliac patients

THANKS FOR YOUR ATTENTION