Celiac Disease: more than you ever wanted to know

Internal Medicine

Academic Half Day

Royal Victoria Hospital

Tuesday, March 9, 2010

Clare Bastedo R5, GI

Case 1:

24F with non-bloody diarrhea (6x/d) x 6 weeks. No PMHx. 5 lbs. wt. loss. Normal exam.

What else would you like to know on history and physical exam so you can come to a diagnosis and treat this patient?

(Remember: Time is limited! )

Acute vs. Chronic Diarrhea

Acute Diarrhea < 2 weeks Persistent > 2 wks

Chronic Diarrhea > 4 weeks Decrease in fecal consistency

Chronic Diarrhea

“Gather my thoughts” – really do this! “Wash my hands, introduce myself to the

patient” ABCs Vital signs including temperature

The Basics – don’t forget them!

PMHx Meds, Allergies, Alcohol, Smoking, Drugs Social History/Employment Family History

Esp. IBD, celiac dz, CRC, lactose intolerance

Hx. specific to chronic diarrhea

Details of the diarrhea Complications of the diarrhea Causes of the diarrhea

Details

OPQRST Onset, duration, frequency, volume Bloody, consistency, tenesmus, urgency,

steatorrhea Changes with meals/foods Nocturnal symptoms Associated sx: N/V, pain, jaundice,

constipation, fever, wt. loss

Complications

Hypovolumia/electrolyte disturbance Edema (protein-losing enteropathy) Arthritis - reactive Screen for nutritional deficiencies

Anemia, osteoporosis, Vit K and other FSV

Causes – 6 main categories

Infectious – exposures, travel, HIV, sex, daycare, Abx, recent hosp adm

Inflammatory – radiation, ischemia RFs, IBD (systemic), CRC (constitutional)

Osmotic – relation to lactose, antacids, laxatives, gum Stops while NPO, lower volume, high stool osm gap >125

Secretory – drugs, previous surgery, previous bowel disease, hx. tumors (carcinoid, VIPoma, ZE syndrome) Continues when NPO, high vol > 1L/d, low stool osm gap <50

Malabsorptive – wheat, ethnicity, other AI d/o, DH, liver dz screen, bile tract dz, bowel rsxn, pancreatitis

Motility – DM, hyperthyroidism, scleroderma, IBS, hyperthyroidism, Addison’s

Focused Physical Exam

Gen: Height, weight, signs of malnutrition VS: Orthostatic vital signs H&N: Uveitis, episcleritis, oral ulcers, LNs,

thyroid, pallor CVS/Resp: volume status, flow murmur Abdo: pain, distension, HSM, stigmata CLD,

masses, DRE, frank/occult blood MSSK/Derm: active joints, rash (EN, PG, DH),

bruising, clubbing

Investigations

CBC, lytes, Cr, glucose, calcium, albumin, liver profile, INR, Bilirubin, TSH, ESR/CRP

Stool C&S, C. diff, O&P, occult blood, ?fecal leukocytes

Antiendomysial Ab/Tissue transglutaminase Ab, EGD + Bx for ?celiac dz (NB IgA-based tests so can have false negative in IgA

deficiency … if high suspicion measure IgA level)

Celiac Disease

• An autoimmune disorder that occurs in genetically-predisposed individuals result of an immune response to gluten

• One of the most common chronic inflammatory conditions of the digestive system

• Present in approx. 1% of the population (U.S.)• Presentation

• Diarrhea has become less common (<50% of cases)• Typically presents age 10-40• Also iron-deficiency anemia, osteoporosis, dermatitis herpetiformis,

and neurologic disorders, (peripheral neuropathy and ataxia)• Non-invasive screening (based on serology) shows that

CD is often undiagnosed

Celiac disease

Characterized by: (1) Small intestinal malabsorption (2) Villous atrophy of the small intestinal

mucosa (3) Clinical and histologic improvement

following a gluten-free diet (4) Clinical and histologic relapse when gluten

is reintroduced Schleisenger

Dickey W (2006) Endoscopic markers for celiac diseaseNat Clin Pract Gastroenterol Hepatol 3: 546–551 doi:10.1038/ncpgasthep0601

Figure 1 Endoscopic markers of villous atrophy visible in the duodenum at esophagogastroduodenoscopy

Figure 1.  Endoscopic markers of villous atrophy visible in the duodenum at EGD. (A) Mosaic-patterned mucosa. (B) Deep mucosal grooves. (C) Scalloping of a duodenal fold. (D) Nodular mucosa. (E) Loss of duodenal folds. (F) Visible submucosal vessel on a background of fold loss. (G) Multiple duodenal erosions.

                                                            

Points to ponder

How should diagnosis of celiac disease be made?

Significance of “undiagnosed” celiac disease?

Known associations and observed M&M

Diagnosis of Celiac Disease

Small bowel disorder characterized by mucosal inflammation, villous atrophy, and crypt hyperplasia occurs on exposure to dietary gluten and

demonstrates improvement after withdrawal of dietary gluten

Wide use of serologic testing for celiac disease and upper endoscopy complicates the diagnosis these tests identify patients who appear to have the

disease but have variable degrees of histopathologic changes and/or symptoms

Disease spectrum – phenotypes

Atypical celiac sprue - gluten-sensitive enteropathy found in atypical manifestations including short stature, anemia, and infertility

Silent celiac sprue – villous atrophy and no symptoms Classic or typical celiac sprue - gluten-sensitive

enteropathy found in association with the classic features of malabsorption

Latent celiac sprue - Abnormal serology + normal histology + no symptoms; previously abnormal histology but now normal on GFD

Potential celiac sprue - abnormal serology + normal histology + no symptoms

Celiac Disease - variation

Natural history of variant forms of celiac disease is incompletely understood

Long-term risk of complications in asymptomatic patients is unclear

Asymptomatic patients may also be least likely to comply with a gluten free diet, even if diagnosis of celiac disease is made

Who should be tested?

NIH guidelines (2004) GI symptoms – diarrhea, weight loss, bloating, even if

c/w IBS or lactose intol Without other explanation for:

iron deficiency anemia, folate or vitamin B12 deficiency, persistent elevation in LFTs, short stature, delayed puberty, recurrent fetal loss, low birthweight infants, reduced fertility, persistent apthous stomatitis, dental enamel hypoplasia, idiopathic peripheral neuropathy, nonhereditary cerebellar ataxia, or recurrent migraines

Symptomatic patients at high-risk type 1 DM or other AI disorders, 1st- and 2nd-degree

relatives of individuals with celiac disease, patients with Turner, Down, or Williams syndromes

Screening of asymptomatic pts?

General population – not recommended Osteoporosis? – not officially

recommended, but study group with osteoporosis had significantly higher incidence of abn biopsies than controls (3.2 vs. 0.2%) Arch Intern Med 2005 Feb 28;165(4):393-9.

Most had other symptoms/signs Check if other clinical symptom/lab abn.

CD - diagnosis

No single test can confidently establish the diagnosis of celiac disease in every individual

Most important initial step recognition of the many clinical features that can be associated

Test on a gluten-rich diet (bx/serology) 2-12 weeks Gold-standard = small bowel biopsy abnormal on

gluten challenge

SB biopsy

At least four biopsies in 2nd/3rd stage of duodenum All who have anti-TTG or EMA positive unless

DH and positive biopsy Atrophic with loss of folds, visible fissures,

nodular appearance or scalloped folds Diagnosis presumed with serology and

biopsy, but confirmed with resolution on gluten-free diet

Dermatitis Herpetiformis:

Serology IgA anti-TTG and IgA endomysial Ab have

equivalent diagnostic accuracy – based on target Ag tTG

Antigliadin Ab tests - no longer used routinely because of lower sens and spec

IgA EMA – + or - ; sens 90%, spec 99%, reproducibility 93% gold standard

IgA anti-tTG is slightly less reliable; sens 93%, spec 95%, reproducibility 83%) 98% of ppl with celiac dz vs. 5% ppl without

Sens and spec depend on the prevalence of the disease in the tested population

EMA, anti-TTG

Negative result for either test has a high negative predictive value may eliminate need for small bowel biopsy

Positive predictive values are high even in low-risk populations

UTD: recommends performing both IgA endomysial (or TTG) and small bowel biopsy prior to dietary treatment

Screening – general population?

Screening studies suggest incidence of celiac disease in whites of N. European ancestry may be as high as 1:100 to 1:250

Benefit of screening (EMA or anti-TTG) not yet demonstrated

Theoretical benefits: reduction in risk for enteropathy-associated T-cell lymphoma reversal of unrecognized nutritional deficiency states resolution of mild or ignored intestinal symptoms avoidance of other auto-immune disorders improvement in general well-being

Screening?

Screening study of 4615 adults from N. Italy IgA EMA had PPV of 100% Acta Paediatr Suppl 1996 May;412:42-5.

17,201 children (6 - 15) from Italy were screened with a prevalence of CD of 1:184 The ratio of undiagnosed to diagnosed celiac disease was

a 7:1 Most children had minor but significant nonspecific

symptoms Acta Paediatr Suppl 1996 May;412:25-8

In the U.S. prevalence of CD was 1:22 in 1st-degree relatives, 1:39 in 2nd-degree relatives, 1:56 in symptomatic pts, and 1:133 in low-risk group Arch Intern Med 2003 Feb 10;163(3):286-92.

Risk of malignancy

Several studies have suggested increased overall mortality (mostly from GI malignancies) in patients with celiac disease compared to the general population Lancet 2001 Aug 4;358(9279):356-61., Gastroenterology 2002 Nov;123(5):1428-35.

Malignant lymphomas, small-intestinal, oropharyngeal, esophageal, large intestinal, hepatobiliary, and pancreatic carcinomas (1.3 –2.0 x risk)

Prospective cohort study with up to 24-years of follow-up (5684 person years) identified 31 malignancies compared with 30 that would have been expected in the general population (more NHL in CD population). Aliment Pharmacol Ther 2004 Oct 1;20(7):769-75.

Logistics

Patients who have a positive screen would have to comply with strict (expensive?) diet though they feel well

Psychological harm? Widely accepted to test for celiac disease

if subtle manifestation

Increase in Prevalence?

Number of cases detected may be increased due to improvements in serological markers and increased clinical suspicion British Medical Bulletin 2008 88(1):157-170

Recent Finnish report has observed an increasing prevalence (x2) in celiac

disease over a 20-year period Lohi S, Mustalahti K,

Kaukinen K, et al. Increasing prevalence of coeliac disease over time. Aliment Pharmacol Ther (2007) 26:1217–1225.