celiac sprue (gluten-sensitive enteropathy)

Etiology

• sensitivity to wheat gluten & related rye & barley proteins
• may coexist with autoimmune liver disorders including
  • autoimmune hepatitis
  • primary biliary cirrhosis
  • primary sclerosing cholangitis
• association with:
  • diabetes mellitus type 1
  • autoimmune thyroiditis
  • microscopic colitis
  • small intestinal lymphoma
• enterovirus may be associated with early development of celiac disease

* introduction of gluten < 4 month of age or > 6 months of age not associated with increased incidence of celiac disease

* higher gluten intake early in life is associated with increased risk for celiac disease in children genetically at risk

Epidemiology

• more frequent in patients with diabetes mellitus type-1
• more frequent in patients with autoimmune thyroid disease
• 19 cases in 22,000 children by 5 years of age
  • 2.6 years of age youngest patient with diagnosis
• prevalence of 1% at 7 years of age
• overall prevalence of positive celiac serology is 0.8%
• 2-fold higher rate of celiac disease in Sweden (vs. U.S.)
• prevalence of 1.4% of women vs 0.8% of men avoid gluten without evidence of celiac disease
• prevalence higher in northern U.S. lattitudes
  • globally, prevalence higher in northern lattitudes
• make present (as initial presentation) in elderly

Pathology

• villus blunting & atrophy of small bowel mucosa
• crypt elongation
• submucosa, muscular layers & serosa are spared
• histopathologic changes resolve when dietary gluten is withdrawn
• autoantibody to tissue transglutaminase
• intraepithelial lymphocytes, CD3+ T-cells
• duodenal villous atrophy, crypt hyperplasia, intraepithelial lymphocytosis

Genetics

• associated with HLA-DR3 & HLA-DQ2 or HLA-DQ8
  • alleles common in the general population
  • most useful for ruling out celiac disease
  • homozygosity for HLA haplotype DR3-DQ2 confers 5.7 fold risk
• susceptibility linked to CTLA4, myosin-9b

Clinical manifestations

• majority of cases are probably asymptomatic (7:1)
• variable presentation & age of onset
• typical features include: diarrhea, bloating, weight loss
  • children with irritable bowel syndrome 4-fold more likely to have celiac disease than general population
• growth retardation in children
• hematologic
  • iron deficiency anemia in adults unresponsive to oral iron
  • vitamin B12 deficiency, folate deficiency
  • splenic atrophy, functional asplenia
  • elevated PT/INR & bleeding may occur secondary to vitamin K deficiency
• GI symptoms in 1/2 of newly diagnosed cases
  • diarrhea
  • steatorrhea, malodorous stools
  • abdominal cramping: constant abdominal pain is unusual
  • bloating
• musculoskeletal
  • osteomalacia (may be present without steatorrhea with proximal small bowel involvement)
  • osteopenia, osteoporosis
  • arthropathy
• neurological manifestations
  • peripheral neuropathy (RR=2.5, AR=0.4%)
  • paresthesias
  • sensory abnormalities
  • muscle weakness, myopathy, & ataxia less common
  • seizures
• dermatitis herpetiformis
  • pruritic papulovesicular rash on extensor surfaces
• glomerular IgA deposition
• infertility, recurrent miscarriages
• tooth enamel defects

* see Differential diagnosis

Diagnostic criteria

• positive tissue transglutaminase IgA
• small intestine biopsy consistent with diagnosis of celiac disease (absence of mucosal villi)

Laboratory

• serology
  • tissue transglutaminase IgA in serum (most reliable)
    • titers >= 10X upper limit of normal diagnostic
    • repeat titers determine effectiveness of diet therapy/compliance
  • if patient is on a gluten-free diet, testing is less specific
    • if tissue transglutaminase IgA in serum is normal, repeat testing after resuming gluten-containing diet
    • consider genetic testing for HLA-DQ2 &/or HLA-DQ8
    • nearly all patients with celiac disease carry HLA-DQ2 or HLA-DQ8 haplotype
    • 40% of general population carries one of these haplotypes
    • only useful for exclusion
  • IgA in serum
    • patients with IgA deficiency may have false-negative serology
    • if IgA deficiency
      • tissue transglutaminase IgG in serum
      • anti-deamidated gliadin peptide IgG in serum - antigliadin antibodies (IgA &/or IgG) (poor sensitivity & specificity, not recommended)
  • reticulin antibody in serum
  • commercial assays not standardized; diagnoses may be missed
• complete blood count: iron deficiency anemia
• peripheral smear may show Howell-Jolly bodies (10-15%)
• serum chemistries
  • serum calcium & serum albumin; hypocalcemia may be present
  • serum magnesium: hypomagnesemia
  • serum albumin: hypoalbuminemia (correct serum calcium for low serum albumin, see Misc Tools)
  • serum vitamin B12 & serum folate: vitamin B12 deficiency & folate deficiency
  • serum 25-OH vitamin D may be diminished
  • serum iron, TIBC suggestive of iron deficiency
  • serum transaminases, serum AST & serum ALT, may be elevated
  • serum lipase may be elevated
  • serum PTH may be elevated if serum 25-OH vitamin D is low
• PT/INR may be prolonged due to vit K deficiency
• see ARUP consult

Diagnostic procedures

• upper GI endoscopy
  • biopsy of the proximal small intestine
  • gold standard for diagnosis
  • indicated if antiendomysial antibody IgA (tissue transglutaminase IgA in serum) is positive
  • histopathology shows absence of villi
• repeat upper GI endoscopy with biopsy indicated if initial upper GI endoscopy & colonoscopy are negative for source of GI bleed

Radiology

• barium enema
• abdominal CT
  • lymphadenopathy may be seen
• bone mineral density in newly diagnosed patients

Complications

• microscopic colitis is the most common cause of diarrhea in a patient adherent to a gluten-free diet
• increased risk of lymphoproliferative cancer (RR = 4.8)
  • small bowel lymphoma is a late complication
    • incidence peaks 50-60 years
    • usually develops in the jejunum
    • recurrent malabsorption in a compliant patient
      • relapse of celiac disease symptoms
  • T-cell lymphoma*, Hodgkins lymphoma
  • well-controlled disease lowers risk
• increased risk of other cancers:
  • oropharyngeal cancer
  • esophageal cancer
  • breast cancer
  • small bowel adenocarcinoma
• increased risk of gastrointestinal cancer (RR = 1.8)
• most cancers occur during 1st year after diagnosis of celiac sprue
• cerebellar ataxia
• neuropathic pain associated with gluten neuropathy
• fat soluble vitamin deficiencies: vitamin D deficiency, vitamin K deficiency
• osteoporosis due to vitamin D deficiency & secondary hyperparathyroidism

* if symptoms worsen in patient in their 50's, T-cell lymphoma most likely diagnosis (despite lack of corroborating evidence)

Differential diagnosis

• tropical sprue
• graft versus host disease
• irritable bowel syndrome
  • celiac disease needs to be ruled out prior to diagnosis of irritable bowel syndrome
• primary hyperparathyroidism
  • celiac disease is a cause of secondary hyperparathyroidism
  • elevated serum PTH with normal serum calcium
• small intestinal bacterial overgrowth
  • vitamin B12 deficiency; serum folate high
• lactose intolerance

Management

• gluten-free diet
  • response is diagnostic
  • of benefit for children with serologic evidence of celiac disease regardless of small bowel biopsy
  • only symptomatic patients benefit
  • strict gluten-free diet may protect from neuropathic pain associated with gluten neuropathy
  • lifelong avoidance of wheat, rye & barley
• gluten-free medications &/or supplements may be necessary for some patients
  • consult pharmacist for possible sources of gluten, such as dextrin, pregelatinized starch, or sodium starch glycolate
  • if a starch is listed, the manufacturer may need to be contacted to find out what the starch is derived from
• prednisone for refractory disease NOT responding to a gluten-free diet
• vitamins, iron, vitamin D, & calcium, vitamin K
  • untreated disease is unresponsive to oral iron
  • for vitamin D deficiency, 50,000 IU vitamin D orally weekly for 6-12 weeks
• dapsone may facilitate resolution of dermatitis herpetiformis
  • check G6PD in erythrocytes for G6PD deficiency prior to initiation of dapsone
• most common cause of recurrence is dietary indiscretion
  • assess recurrence for dietary indiscretion (1st step)
  • patients adherent to diet should be evaluated for microscopic colitis & small intestinal lymphoma
• screening unlikely to be of benefit
  • insufficient evidence to recommnend for or against screening asymptomatic individuals (USPSTF)
• prevention:
  • early introduction (4-6 months) of gluten into diets of high-risk infants does not appear to reduce risk of celiac disease
• experimental tranglutaminase-2 inhibitor ZED1227 attenuates gluten- induced duodenal mucosal damage

More general terms

• autoimmune disease
• intestinal disease
• food intolerance

Additional terms

• dermatitis herpetiformis; Duhring-Brocq disease
• food allergy
• gluten
• gluten-free diet
• tropical sprue

Patient information

celiac sprue patient information

Database

• OMIM: https://mirror.omim.org/entry/609753