Celiac Disease

Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Patients typically present with diarrhea and symptoms related to malabsorption (steatorrhea, weight loss, and nutritional deficiencies). Patients are screened with serological antibody testing, and diagnosis is confirmed by small intestine biopsy. Treatment requires a lifelong gluten-free diet.

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Epidemiology and Etiology

Epidemiology

  • Occurs primarily in Whites of northern European descent: prevalence between 1:70 and 1:300
  • More common in women
  • Bimodal age distribution, but more common in childhood:
    • 8‒12 months of age
    • 3rd to 4th decades of life
  • Family history is positive in 10%‒15% of patients.
  • Celiac disease is associated with:
    • Down’s syndrome
    • Moderately increased risk of small bowel lymphoma

Etiology

Environmental, immunologic, and genetic factors contribute to the disease process:

  • Environmental 
    • Triggered by gliadin, which is a component of gluten (found in wheat, barley, and rye)
    • The only autoimmune disease in which the antigen is known
  • Immunologic
    • Involves both innate and adaptive immune response (type 4 hypersensitivity reaction)
    • Autoantibodies: 
      • Immunoglobulin A (IgA) anti-tissue transglutaminase 
      • Anti-endomysial
      • Anti-deamidated gliadin peptide
  • Genetics: associated with HLA-DQ2 and HLA-DQ8

Pathophysiology

Gluten peptides trigger the innate immune response in intestinal epithelial cells, leading to T cell–mediated mucosal damage of the proximal small intestine (distal duodenum and proximal jejunum).

  1. Presence of gliadin → release of tissue transglutaminase (tTG) (intracellular enzyme) → deaminated gliadin
  2. Antigen-presenting cells process and present this to T cells → T helper cell and plasma cell activation
  3. Plasma cells release anti-tTG, anti-endomysial, and anti-deamidated gliadin antibodies.
  4. T helper cells → cytokine release → intraepithelial lymphocytosis and activation of fibroblasts → matrix proteases → intestinal destruction, including loss of the brush border, crypt hyperplasia, and villous atrophy 
  5. This process causes impaired absorption of fat, fat-soluble vitamins, and minerals → malabsorption

Pathophysiology of celiac disease

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Clinical Presentation

Clinical manifestations

Celiac disease may present in infancy or in the 3rd to 4th decades of life.

  • Gastrointestinal (GI) symptoms:
    • Diarrhea (most common symptom)
    • Steatorrhea (bulky, foul-smelling, floating stool)
    • Bloating and flatulence
    • Abdominal cramping
  • Extraintestinal manifestations:
    • Weight loss and muscle wasting
    • Fatigue and weakness
    • Failure to thrive in infants and children
    • Anemia → impaired iron and folate absorption
    • Bleeding diathesis → impaired fat-soluble vitamins → prothrombin deficiency
    • Osteopenia → defective calcium transport and vitamin D deficiency
    • Motor weakness, paresthesias, sensory loss → hypocalcemia and vitamin deficiencies
    • Dermatitis herpetiformis (pruritic papules, vesicles, and bullae on the extensor surface of extremities)
    • Peripheral edema → impaired amino acid absorption
    • Amenorrhea, delayed menarche, and infertility
Table: Manifestations and laboratory findings of malabsorption syndrome
ManifestationsLaboratory finding
Steatorrhea (bulky, foul-smelling, light-colored stool)Increased fecal fat due to fat malabsorption
Diarrhea (increased fecal content)Increased stool osmolality gap due to unabsorbed fats and carbohydrates
Weight loss/failure to thrive/muscle wastingDecreased D-xylose absorption due to inability to absorb any food content
Bleeding/repeated ecchymosisProlonged PT/INR (prothrombin time/international normalized ratio) due to inability to absorb vitamin K
Microcytic anemiaLow ferritin due to inability to absorb iron
Macrocytic anemiaLow serum B12 or folic acid due to inability to absorb vitamin B12 and B
Bone pain/fractures on minimal traumaOsteopenia on plain film and osteoporosis on DEXA (dual-energy X-ray absorptiometry) due to inability to absorb calcium and vitamin D
Milk intoleranceAbnormal lactose tolerance test due to inability to absorb lactose
EdemaDecreased serum protein and albumin due to inability to absorb amino acids from the diet

Dermatitis herpetiformis rash involving the extensor surface of the forearms, hands, and lower limbs in a patient with celiac disease

Image: “Skin lesions on dorsum of hand and legs” by Department of Surgery, The Aga Khan University Hospital (Stadium Road), Karachi (74800), Pakistan. License: CC BY 3.0

Associated conditions

Celiac disease is also associated with:

  • Diabetes mellitus
  • Selective immunoglobulin A (IgA) deficiency
  • Autoimmune thyroid diseases
  • Gastroesophageal reflux disease
  • Inflammatory bowel disease and microscopic colitis
  • Autoimmune myocarditis
  • Idiopathic dilated cardiomyopathy

Diagnosis

Diagnostic evaluation

  • 1st, screen for suspected celiac disease with serological testing: 
    • Autoantibodies
      • IgA tissue transglutaminase antibody (98% sensitivity and specificity) 
      • IgA anti-endomysial antibody
    • Antibodies targeting gliadin
      • Antigliadin antibody 
      • IgA deamidated gliadin peptide
    • Total IgA levels  
      • Rules out IgA deficiency, as that will affect the veracity of the above tests
      • If IgA deficiency is detected, IgG-based testing should be pursued.
    • IgG-based testing
      • IgG tissue transglutaminase
      • IgG deamidated gliadin peptide
  • If serologic testing is positive: upper endoscopy with small bowel biopsy
    • Endoscopic features: atrophic mucosa, fissures, scalloping, submucosal vascularity
    • Histology: increased intraepithelial lymphocytes, crypt hyperplasia, and villous atrophy
    • A normal biopsy excludes the diagnosis of celiac disease.
  • If there is discrepancy between serology and histology findings: HLA-DQ2/DQ8 typing
    • If negative, celiac is excluded, and an alternative diagnosis should be explored.
    • If positive, a high-gluten diet is used with follow-up endoscopy and biopsy.

Evaluation of malabsorption

  • Electrolytes
    • Hypokalemia
    • Hypocalcemia
    • Hypomagnesemia
  • ↓ albumin
  • ↓ cholesterol
  • ↓ hemoglobin
  • ↑ INR, partial thromboplastin time (PTT)
  • ↓ iron, ferritin
  • ↓ vitamin B12
  • ↓ folate
  • ↑ fecal fat

Management and Prognosis

Management

  • Education about the disease
  • Life-long gluten-free diet
    • Consultation with a dietitian
    • Avoid barley, rye, and wheat.
    • Many will have a secondary lactose intolerance.
    • Approximately 70% of patients will have clinical improvement within 2 weeks.
  • Monitoring:
    • Repeat IgA anti-tissue transglutaminase antibody at 6 and 12 months after diagnosis.
    • Small bowel biopsy after 3–6 months on a gluten-free diet
  • Identify and treat any nutritional deficiencies (vitamin and mineral supplements, as needed).
  • Most common reason for treatment failure is incomplete removal of gluten from the diet.
  • Refractory disease:
    • 5% of patients may not respond to a gluten-free diet.
    • Consider an alternative or concurrent disease:
      • Irritable bowel syndrome
      • Small bowel bacterial overgrowth
      • Pancreatic insufficiency
      • Microscopic colitis
    • Glucocorticoids and immunosuppressants may be considered.

Prognosis

  • Excellent prognosis for those who respond to treatment
  • Complications associated with increased mortality:
    • Increased risk of lymphoma and GI cancer 
      • 6%–8% of patients
      • Manifests after 20–40 years with the disease
    • Collagenous sprue
      • Refractory disease with subepithelial collagen deposition
      • Leads to severe malabsorption
    • Ulcerative jejunitis
      • Aberrant T cell monoclonality causing multiple, chronic ulcers in the jejunum
      • Can lead to intestinal obstruction due to strictures

Differential Diagnosis

  • Irritable bowel syndrome (IBS): a functional bowel disease presenting with recurrent abdominal pain and altered bowel habits. Irritable bowel syndrome is a diagnosis of exclusion, and celiac disease should be ruled out with a negative IgA tissue transglutaminase. Treatment includes reassurance, dietary modifications, and symptom-control measures.
  • Inflammatory bowel disease (IBD): includes Crohn’s disease and ulcerative colitis, and is characterized by chronic inflammation of the GI tract due to a cell-mediated immune response to the GI mucosa. Symptoms include diarrhea, abdominal pain, weight loss, and extraintestinal manifestations. Diagnosis includes imaging, endoscopy, and biopsy. Celiac antibody serology will be negative. Treatment involves steroids, aminosalicylates, immunomodulators, and biologic agents.
  • Chronic pancreatitis: persistent inflammation, fibrosis, and irreversible cell damage to the pancreas. Alcohol and biliary obstruction are common causes. Patients may have steatorrhea, abdominal pain, and other malabsorption symptoms. Imaging will show an atrophic pancreas, dilated ducts, and calcifications. Celiac disease antibody testing will be negative. Therapy includes alcohol cessation, diet changes, pain control, and treatment of pancreatic insufficiency.
  • Lactose intolerance: an intolerance to lactose-containing foods due to lactase deficiency. Symptoms include crampy abdominal pain, bloating, nausea, and diarrhea. Diagnosis is based on the association with lactose-containing foods and a lactose hydrogen breath test. Management includes restriction of dietary lactose and enzyme replacement. It is common for patients with celiac disease to also have concurrent lactose intolerance.
  • Small intestinal bacterial overgrowth: defined as excessive bacteria growing in the small intestine, and can result due to alteration in the intestinal anatomy or motility. Symptoms can range from mildly symptomatic to chronic diarrhea, weight loss, and malabsorption. Bacterial cultures and breath tests can distinguish this condition from celiac disease. Treatment includes antibiotics and correction of nutritional deficiencies.
  • Microscopic colitis: a chronic inflammatory disease of the colon; can be categorized as collagenous or lymphocytic colitis. Patients tend to be middle-aged with chronic, watery diarrhea; abdominal pain; and bloating. A colonoscopy will appear normal, but inflammatory cells, cryptitis, or a subepithelial collagen band will be seen on biopsy, differentiating the condition from celiac disease. Treatment includes trigger avoidance, glucocorticoids, and symptom management.

References

  1. Schuppan, D., and Dieterich, W. (2020). Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults. In Grover, S. (Ed.). Uptodate. Retrieved November 17, 2020, from https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-adults
  2. Kelly, C.P. (2020). Diagnosis of celiac disease in adults. In Grover, S. (Ed.). Uptodate. Retrieved November 17, 2020, from https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults
  3. Ciclitira, P.J. (2020). Management of celiac disease in adults. In Grover, S. (Ed.). Uptodate. Retrieved November 17, 2020, from https://www.uptodate.com/contents/management-of-celiac-disease-in-adults
  4. Goebel, S.U. (2019). Celiac disease (sprue). In Anand, B.S. (Ed.). Medscape. Retrieved November 17, 2020, from https://emedicine.medscape.com/article/171805-overview
  5. Ruiz, Jr., A.R. (2019). Celiac disease (gluten enteropathy). [online] MSD Manual Professional Version. Retrieved November 17, 2020, from https://www.msdmanuals.com/professional/gastrointestinal-disorders/malabsorption-syndromes/celiac-disease

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