Managing Celiac Disease and Diagnosing Appendicitis

Educational Objectives

The goals of this program are to improve the management of celiac disease (CD) and the diagnosis of appendicitis. After hearing and assimilating this program, the clinician will be better able to:

1.   Recognize common presentations of CD.

2.   Explain risks associated with CD.

3.   Identify candidates for CD screening.

4.   Determine the cause of abdominal pain, and establish the diagnosis of appendicitis.

5.   Compare the efficacy of computed tomography and ultrasonography in the diagnosis of abdominal pain.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning com­mittee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Pope was recorded in San Diego, CA, at the 2008 Scientific Assembly, presented September 17-21, 2008, by the American Academy of Family Physicians (AAFP). Dr. Vissers was recorded at Clinical Decision Making in Emergency Medicine, sponsored by Mount Sinai Medical Center, University of Florida, Jacksonville, Mayo Clinic College of Medicine, the George Washington University, Brigham and Women’s Hospital, the Foundation for Education and Research in Neurologic Emergencies, Best Prac­tices, Inc, and Emergency Medicine Practice, and held June 26-28, 2008, in Ponte Vedra Beach, FL. The Audio-Digest Founda­tion thanks the speakers and the sponsors for their cooperation in the production of this program.

Celiac Disease

John B. Pope, MD, Professor of Clinical Family Medicine, Louisiana State University Health Science Center, Shreveport

Description: small bowel disorder characterized by mucosal inflammation (can involve epithelium and extend be­yond lamina propria); results in villous atrophy of small bowel structure and hyperplasia of Lieberkühn’s crypts; occurs after exposure to gluten; when gluten withdrawn from diet, changes reversed; difficult to diagnose

Epidemiology: classically seen in whites (eg, Northern European ancestry), but also reported in those of Middle Eastern, South American, Asian, and Saharan North African descent; recent studies show high prevalence (in at-risk populations, 1 in 100); incidence higher in people with positive family history of celiac disease (CD), IgA defi­ciency, autoimmune diseases, type 1 diabetes, hypothyroidism, connective tissue diseases (eg, Sjögren’s syn­drome), or Down syndrome; diagnosis 3 times more common in women than in men

Pathophysiology: gliadin component of gluten triggers complex inflammatory cascade; associated with HLA-DQ2 and HLA-DQ8 gene loci; adaptive immune response involves CD4 cells; innate immunity involves cytotoxic lym­phocytes and natural killer cells; changes predominantly in jejunum and duodenum

Forms of CD: atypical  —  villous atrophy with milder or atypical symptoms (eg, iron deficiency anemia, osteoporo­sis, short stature, infertility); more common; silent  —  villous atrophy with no symptoms; classical  —  villous atro­phy; malabsorption (eg, steatorrhea, weight loss, vitamin and mineral deficiency, anemia); resolution of symptoms and correction of mucosal lesions after gluten withdrawn from diet; severity of disease does not necessarily corre­late with symptoms; increased intraepithelial lymphocytes with presence of preinfiltrative lesions; hyperplastic le­sions lead to shrinkage and destruction of villi; alterations can lead to other symptoms, eg, blood loss; latent  —  1) CD previously diagnosed and improves after gluten-free diet; CD remains silent even after adoption of normal diet (»20% of patients remain asymptomatic and have normal villous architecture; atrophy recurs in some patients); can be transient; variable; 2) patients develop CD after normal mucosa diagnosed while on normal diet; potential  —  no evidence of CD on biopsy, but patient has immunologic abnormalities characteristic of CD (eg, positive serology); patients often show genetic predisposition (eg, DQ2 genetic marker); first-degree relatives with CD increase risk for active disease by 6% to 20%

Clinical manifestations: classic presentation (child with life-threatening malabsorption) rarely seen; presentation of adult with, eg, diarrhea or weight loss, more common; shift from traditional presentation may be due to longer breast-feeding or delayed (>4 mo) introduction of gluten into diet; classic signs  —diarrhea; fatty stools; steatorrhea; increased flatulence; explosive bowel movements; malabsorption; growth failure and weight loss in children; ane­mia; neurologic disorders; osteopenia; osteoporosis; young infants  —  bloating; diarrhea; malabsorption; failure to thrive; children  —  abdominal pain; mouth lesions; stomatitis; angular chelitis; aphthous ulcers; atopic dermatitis; seizure disorder; young adults  —  dermatitis herpetiformis (DH); diarrhea; increased flatulence; floaty stools; mouth ulcers; alopecia; adults  —  additional symptoms of osteopenia, osteoporosis, and anemia; patients with long-stand­ing problems develop more serious symptoms (eg, osteoporosis, lymphoma, chronic liver disease); older adults  —  diarrhea; bloating; belching; nonspecific complaints

Subclinical CD: mild; undetected for long time; symptoms (eg, fatigue, iron deficiency anemia) subtle; spectrum wide, with variable severity; be aware that CD can account for unexplained symptomatology; risks associated with undiagnosed CD  —nutritional deficiency; osteoporosis; autoimmune disorders; risk for malignancy less than in pa­tients with diagnosed CD and malabsorption; malignancy risk decreases once patients in remission on gluten-free diet; diabetes; collagen vascular disease; thyroiditis

Nutritional deficiencies: iron; may lead to recurrent abdominal pain, mood changes, stomatitis, poor appetite, and recurring diarrhea

Nongastrointestinal (non-GI) manifestations: neuropsychiatric diseases  —  polyneuropathies; memory distur­bances; depression; anxiety; pathogenesis unclear; data suggest headache and ataxia could be sole manifestations of CD; high prevalence of arthritis (untreated patients typically do worse); iron deficiency; osteopenia; osteoporosis (correcting diet does not completely reduce risk for fracture or bone abnormality); hyposplenism (uncommon); kid­ney disease (IgA deposition in »33% of cases of CD; typically, no clinical manifestations, but CD can cause renal failure); malignancy  —  overall mortality in GI malignancies increased; 40- to 100-fold increased risk for non-Hodgkin lymphoma; decreased risk for breast and lung cancers; effect of gluten-free diet uncertain; DH  —  papulovesicular rash; blisters rupture fairly rapidly; usually on extensor surfaces of extremities, and on trunk, el­bows, knees, and face; deposition of IgA in nonaffected tissue; antibodies against tissue transglutaminase (tTG) el­evated; 85% of patients with DH have CD; itching and burning resolve after lesions rupture (resembles herpes); type 1 diabetes  —  uncertain whether affected by gluten-free diet; selective IgA deficiency  —  look at IgG levels to di­agnose CD; Down syndrome  —  24-fold increase in biopsy-proven CD, compared to general population; liver disease  —  elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), or g-glutamyl transferase (GGT) levels; CD associated with congenital liver fibrosis, massive steatosis, hepatitis, primary biliary cirrhosis, and autoimmune hepatitis; may improve on gluten-free diet; early detection important; reproductive issues  —  infertility associated with untreated CD; menstrual abnormalities (eg, later menarche, earlier menopause); abnor­malities in sperm motility and morphology; myocarditis; cardiomyopathy; atrophic glossitis common in young adults and adults; pancreatitis

Candidates for screening: patients with chronic diarrhea, malabsorption, weight loss, abdominal distention, unex­plained elevated serum transferase levels, short stature, delayed puberty, iron deficiency anemia, miscarriages, or infertility; symptomatic patients at high risk for CD  —  those with, eg, type 1 diabetes, autoimmune endocrinopa­thies, first-degree relative with CD, Down syndrome, Turner’s syndrome, Williams syndrome; consider testing pa­tients with irritable bowel syndrome (IBS), aphthous stomatitis, autoimmune diseases, migraines, and dental enamel hyperplasia; screening not recommended for general population or patients with osteoporosis; before test­ing, patients must be on gluten-containing diet; look for clinical feature or complaint associated with CD

Serologic testing: antigliadin antibodies (AGA) less sensitive and specific than IgA-based anti-tTG antibodies and antiendomysial antibodies (AEMA); second-generation AGA testing with enhanced specificity “might make a comeback”; AEMA  —  high sensitivity and specificity; more expensive; harder to perform; immunoassay test; must be done with tTG test; normal results can be seen in patients on gluten-free diets (resume regular diet for several weeks before testing); consider referral for malabsorption testing (eg, d-xylose absorption testing, lactulose adher­ence testing); antibody levels remain elevated for variable time after beginning gluten-free diet

Small bowel biopsy: gold standard for diagnosis; identifies villous atrophy and crypt hyperplasia; perform in patients with positive AEMA or anti-tTG test result; not necessary in patients with biopsy-proven DH; multiple (4-8) sam­ples in multiple areas required; look for characteristic changes (eg, scalloping of edges of duodenum, loss of plicae circularis, mosaic pattern); diagnosis sometimes presumptively established based on concordance between sero­logic results and biopsy findings; diagnosis confirmed by improvement of symptoms with gluten-free diet

Diagnostic approach for low-risk patients: negative serologic test results  —  consider selective IgA deficiency (test for IgG antibodies); rate for false-negative test results, £15% (repeat test or perform small bowel biopsy); consider other conditions, eg, bacterial overgrowth, Crohn’s disease, cow milk intolerance, eosinophilic gastroenteritis, Giardia infection, Whipple’s disease, tuberculosis, radiation exposure, autoimmune enteropathies; negative predic­tive value of HLA-DQ2 and -DQ8 markers high; positive serologic test results and negative small bowel biopsy  —  consider sampling error; false-positive serologic test results rare, but possible; consider high-gluten diet and repeat biopsy; negative serologic test results and negative biopsy  —  unclear why some patients with IBS-type symptom­atology respond to gluten-free diet (“it’s not absolutely cut and dry”); in most low-risk patients, small bowel biopsy not necessary (in moderate or high-risk patients, diagnosis based on serology and small bowel biopsy before di­etary treatment)

Adherence and follow-up: antibody levels correlate with compliance with gluten-free diet; baseline usually reached in 3 to 12 mo; persistently elevated levels indicate intentional or inadvertent exposure to gluten; gluten-free diet ex­pensive and adherence difficult; if antibody levels not initially elevated, follow-up difficult; possible variation be­tween laboratory tests (use same manufacturers); minor dietary infractions can increase risk for associated diseases

More about screening: no demonstrated benefit to screening asymptomatic patients; screening may be appropriate in subclinical group with minor laboratory abnormalities and symptoms; other tests  —  small bowel radiography and capsule endoscopy do not provide specific diagnosis

Management: consult dietitian; educate patient about disease process; lifelong adherence to gluten-free diet re­quired; treat nutritional deficiencies; patients need support; continuous long-term follow-up by multidisciplinary team most beneficial; gluten-free diet  —  elimination of dietary wheat, rye, and barley; oats may be acceptable, but often contaminated in collection process; benefits of rigid gluten avoidance not proven; most authorities advocate strict adherence, due to associated risks; supplement nutritional deficiencies; prevent bone loss (perform dual-en­ergy x-ray absorptiometry [DEXA]); pneumococcal vaccine, polyvalent (Pneumovax 23); monitor response; gluten rechallenge not recommended unless diagnosis uncertain (gliadin shock phenomenon of intense inflammatory re­sponse can occur); persistent symptoms usually due to poor compliance or inadvertent gluten ingestion (also, con­sider, eg, IBS or lactose intolerance); refractory sprue  —  can be severe; progressive malabsorption can lead to death; typically treated with immunosuppression or corticosteroids; risk for ulcerative jejunitis or intestinal lym­phoma predicted by performing biopsy and looking for aberrant T-cell monoclonality

Pitfalls in Appendicitis

Robert Vissers, MD, Adjunct Associate Professor, Oregon Health Sciences University, and Director, Emergency Depart­ment, and Chief Medical Officer, Legacy Emanuel Hospital, Portland, OR

Pinpointing causes of abdominal pain: depending on patient’s age and sex; uncertain in »50% of cases (based on history and physical examination [PE]); take-home message  —  do not guess on diagnosis; make patient comfort­able; admit or arrange follow-up (£ 24 hr)

Patient management: try to have some justification for sending patient home; many patients undiagnosed at dis­charge; supplement history and PE with laboratory tests or observation; re-examine within short time

Diagnosing Appendicitis

Case example: man 25 yr of age; symptoms  —  pain for 1.5 days, nausea and anorexia, loose stools, vomiting, and ten­derness in right lower quadrant (relatively specific sign); normal bowel and rectal sounds; no peritoneal signs; nor­mal white blood cell (WBC) count and slight hematuria; laboratory tests  —  should not change actions; allow surgeon to participate in decision-making; options  —  evaluate for probable appendicitis, order renal protocol, order computed tomography (CT) for appendix, or admit to observe (rare, but appropriate if concerned); result  —  appendicitis revealed on CT; note — intravenous (IV) contrast alone or no contrast adequate and accurate for diag­nosis of appendicitis

Risk and diagnosis: 12% to 28% of patients with abdominal pain (33% if >50 yr of age); diagnosis  —  history and PE; no pathognomonic or historical finding to diagnose appendicitis; some factors more revealing than others; lab­oratory tests  —  not helpful; imaging  —  helpful when used rationally and correctly; likelihood ratio (LR)  —  eg, pre­dicting appendicitis based on response to right lower quadrant test; LR >10 or <0.1 should change action (if between 0.1 and 10, do not use in isolation); right lower quadrant pain best available (LR=7); anorexia (LR=1.27); nausea or vomiting too ubiquitous; features somewhat helpful but not definitive; palpation  —  nonspecific in ab­dominal pain (still worthwhile); unreliable in immunocompromised, elderly, and very young; rebound tenderness  —  false-positive rate »25%; specific findings  —  include rigidity, psoas sign, fever, rebound tenderness, guarding, and rectal tenderness; rectal examination  —  often unnecessary; need good reason (eg, perirectal pain, bleeding); WBC testing  —  nonspecific (normal WBC in some patients with appendicitis); waiting (6 hr) and repeat­ing WBC test  —  no change in outcome and no diagnostic value; C-reactive protein (CRP)  —  low sensitivity and specificity; pain for 3 days  —  pyuria or hematuria in »50%;  more common in elderly; make sure test results ex­plain symptoms; pyuria and hematuria often accompany ruptured appendix

CT vs Ultrasonography (US)

Overview: 1994 comparative prospective trial  —  CT more accurate, sensitive, and specific than US and better at de­tection of other pathologies; US techniques  —  operators and technology improving in adults and children; CT  —  increasing concerns about cost, time, and radiation exposure; look for distended appendix, fecalith, thickened wall, and periappendiceal inflammation; to reduce radiation exposure and cost, request focused noncontrast CT of ap­pendix

CT without oral contrast: 1999 study  —  300 patients without oral contrast; of 5 missed cases of appendicitis, 3 oc­curred early in study (learning curve for radiologists); remaining 2 cases  —  young slender women (easier to find appendicitis in obese patients); bottom line  —  educate patient on possibility of false negatives; analysis of noncon­trast CT (23-article review)  —  on all parameters, CT without contrast as good or better than with contrast; can pre­vent unnecessary laparoscopy, laparotomy (or negative laparotomy), and admissions; negative laparotomy rate remains high (8%-12% range, even using CT); lower cost; helps pick up another diagnosis (approximately two-thirds of time); broad differential (eg, 60-yr-old with right lower quadrant pain) or atypical features  —discuss use of contrast or less focused study with radiologist

Who needs CT? study (New England Journal of Medicine)  —  if classic signs using history and PE, call surgeon; if equivocal, consider CT and discuss with surgeon; who needs US  —  pregnant women and children; if positive, send to surgery; if negative, or equivocal CT results, consider observation and follow-up; limitations of US  —  false negatives; operator-dependent; US accuracy  —  sensitivity and specificity »90% in children (may improve with addition of color Doppler methods)

CT in pediatric patients: pain for extended periods; before laparotomy, check for ruptured appendicitis (much higher false-negative rate than with US); duration of symptoms suggests ruptured appendix (uncomfortable, worsens, then gets better)

CT in elderly patients: appendicitis comprises »10% of abdominal emergencies (>50 yr of age); population ac­counts for »50% of deaths from appendicitis; be aggressive about CT

Suggested Reading

Brennan GD: Pediatric appendicitis: pathophysiology and appropriate use of diagnostic imaging. CJEM 8:425, 2006; Bur­gin-Wolff A et al: Two-step approach for diagnosing celiac disease. Clin Gastroenterol Hepatol 6:1173; author reply 1173, 2008; Freeman HJ: Neurological disorders in adult celiac disease. Can J Gastroenterol 22:909, 2008; Kharbanda AB et al: A clinical decision rule to identify children at low risk for appendicitis. Pediatrics 116:709, 2005; Kurppa K et al: Chang­ing phenotype of celiac disease after long-term gluten exposure. J Pediatr Gastroenterol Nutr 47:500, 2008; Melnick ER et al: Pelvic ultrasound in acute appendicitis. J Emerg Med June 18, 2008 [Epub ahead of print]; O'Shea U et al: Investigation of molecular markers in the diagnosis of refractory coeliac disease in a large patient cohort. J Clin Pathol 61:1200, 2008; Poortman P et al: Improving diagnosis of acute appendicitis: results of a diagnostic pathway with standard use of ultraso­nography followed by selective use of CT. J Am