• Clinical science

Celiac disease (Celiac sprue…)

Abstract

Celiac disease, also referred to as celiac sprue or non-tropical sprue, is a common condition characterized by a maladaptive immune response to gluten, a protein found in many grains (e.g., wheat). The disease often occurs in patients with other autoimmune illnesses, as both are associated with HLA variants (human leukocyte antigens, which encode immunoregulatory proteins) that cause pathologically increased immune responses. The underlying pathophysiology is believed to be a combination of gluten intolerance, which triggers an autoimmune reaction, and production of autoantibodies that target tissue transglutaminase, specifically within the proximal small intestine. Typical findings include changes in bowel habits and symptoms associated with malabsorption (e.g., fatigue, weight loss, vitamin deficiencies). Diagnostic tests include the detection of various antibodies. To confirm the diagnosis, an endoscopic biopsy from the small intestine is needed. Histopathological findings often include villous atrophy and crypt hyperplasia. A firm diagnosis is necessary, as therapy involves a lifelong commitment to a gluten-free diet. If patients comply with this diet, the prognosis is generally very good and the increased risk of celiac-associated malignancies (e.g., intestinal lymphoma) is mitigated.

Definition

  • Definition: an autoimmune disorder characterized by an intestinal hypersensitivity to gluten, a grain protein
  • Synonyms for celiac disease include celiac sprue and gluten-sensitive enteropathy
  • Historically, different conditions were thought to affect adults and children with celiac disease, and the term celiac disease was only used when referring to children. In adults, the disease was known as non-tropical sprue. Since research confirmed that both children and adults suffer from the same condition, celiac disease or its synonyms have become the common terms for both.

References:[1][2]

Epidemiology

  • Sex: >
  • Age of onset
    • Bimodal distribution:
      • At 8–12 months (or 2–3 months following the first exposure to gluten through diet containing wheat)
      • Third to fourth decade of life
    • But can occur at any age; other common age groups:
      • School-aged children and adolescents
      • > 60 years
  • Prevalence: in the US ∼ 1:3000
  • More common in individuals of northern European descent

References:[1][3][4]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

  • Genetic predisposition with association to HLA antigens
    • Common: HLA-DQ2 (90–95%)
    • Alternatively: HLA-DQ8 (5–10%)
  • Consuming gliadin from grains such as wheat, rye, and barley leads to an autoimmune reaction within the small intestinal wall.
  • Commonly associated with autoimmune diseases (see “Clinical features” below)

References:[5][6]

Pathophysiology

Symptoms occur when an individual who is genetically predisposed develops an immunological response to gliadin, an alcohol-soluble fraction of gluten.

  • Consumption of food containing glutentissue transglutaminase is released; → modifies gliadin from gluten proteins → pathogenic T cells react to and are activated by modified gliadin → mediate chronic intestinal inflammationepithelial damage resulting in villous atrophy, crypt hyperplasia, and loss of brush border → impaired resorption of nutrients in the small intestine → malabsorption symptoms

References:[5][3][7]

Clinical features

Gastrointestinal symptoms

Extraintestinal symptoms and associations

In both children and adults, mild or asymptomatic cases are more common than the classic presentation of the disease.

References:[1][8][5][9]

Subtypes and variants

  • Classic (typical) celiac disease
    • Characterized primarily by intestinal symptoms
    • Typical findings in serology and small intestine biopsy (see "Diagnostics" below)
    • Improvement on gluten-free diet
  • Atypical celiac disease
  • Asymptomatic (silent) celiac disease
    • No physical symptoms
    • Positive biopsy of the small intestine
    • Positive antibody test
  • Potential celiac disease
    • No physical symptoms
    • Negative biopsy of the small intestine
    • Positive celiac-specific antibodies
    • Patients may develop full disease at a later stage
  • Latent celiac disease
    • Rarely occurs
    • Patients with one or several known episodes of celiac disease in the past
    • Negative biopsy of the small intestine

Diagnostics

If celiac disease is suspected (based on the medical history and clinical features), serum antibodies may be tested. Ultimately, the diagnosis should be confirmed via biopsy.

Laboratory tests

  • Gold standard: IgA (anti‑)tissue transglutaminase antibody (tTG)
    • The single recommended test to diagnose celiac disease.
    • In addition to the initial diagnosis, also useful for follow-up.
  • Quantitative IgA test: In the case of an IgA deficiency, patients are tested for IgG-based antibodies.
  • IgG deamidated gliadin peptide (DGP) indications:
    • IgA deficiency
    • Also the test of choice in children under the age of two
  • Anti-endomysial antibody (EMA)
  • Low urine d-xylose levels following D-xylose absorption test
  • Fat malabsorption can be detected by quantitative stool fat assays or qualitatively by fat stains (e.g., Sudan III stain)

Endoscopy with small intestine biopsy

References:[10][11][12][1][8][6][13]

Differential diagnoses

Tropical sprue

  • Definition: : A disease characterized by chronic diarrhea with subsequent malabsorption in association with a stay in the tropics or subtropics.
  • Epidemiology: occurs in residents of the tropics and subtropics or in travelers returning from these areas (after trips lasting several weeks)
  • Etiology: most likely caused by a bacterial infection that leads to structural damage of the intestinal mucosa
  • Clinical findings
    • Chronic diarrhea with steatorrhea
    • Abdominal cramps
    • Progressive weight loss
    • Fatigue
    • See clinical features of malabsorption
  • Diagnostics
  • Treatment: :oral administration of 4 x 250 g/d tetracycline in combination with folic acid for 3–6 months

Whipple disease

  • Definition: infection with the bacteria Tropheryma whipplei
  • Epidemiology: very rare, mainly males 30–60 years of age
  • Clinical features
    • Intestinal manifestations: malabsorption syndrome, abdominal pain
    • Extraintestinal manifestations: enteropathic arthritis (60% of cases) , sacroiliitis (40% of cases), fever, polyserositis, lymphadenopathy, cardiac symptoms (e.g., valve insufficiencies), and neurological conditions (myoclonia, ataxia, impairment of oculomotor function)
  • Diagnostics
    • Small intestine biopsies: detection of PAS-positive macrophages
      • If gastrointestinal symptoms are absent, biopsies may also be taken from other sites with disease activity
    • PCR testing and immunohistochemistry staining
    • If neurological complaints occur → liquor diagnostics, potentially MRI
  • Treatment

Other wheat-related diseases

References:[14][15][16]

The differential diagnoses listed here are not exhaustive.

Treatment

  • Lifelong gluten-free diet
    • Abstain from products containing: wheat, rye, barley, spelt
    • Recommended foods: rice, maize, potatoes, soy beans, millet, potentially oats
    • In ∼ 70% of cases, clinical improvement occurs within two weeks after initiating the diet.
    • Histological improvement occurs within weeks to months after beginning the diet.
  • In case of secondary lactase deficiency: avoid milk products
  • Iron and vitamin substitution
  • Supplementation of calcium and vitamin D to prevent bone loss

Managing celiac disease mainly consists of maintaining a lifelong gluten-free diet!
References:[11][1][17]

Complications

  • See clinical features of malabsorption
  • Secondary lactase deficiency
  • Refractory celiac disease (RCD): persistence and worsening of celiac symptoms despite strict adherence to gluten-free diet for 12 months
    • The condition manifests with one of three possible courses
      • Only partial improvement despite gluten-free diet
      • Initial improvement followed by relapse despite maintaining gluten-free diet
      • Nonresponsive celiac disease (no response to gluten-free diet)
    • May lead to ulcerative jejunitis
    • In severe cases, total parenteral nutrition and treatment with steroids or immunosuppressants may be necessary.
  • Ulcerative jejunitis (UJ)
    • Multiple ulcerations of the small intestine due to underlying celiac disease
    • Precursor of EATL
  • Enteropathy-associated T-cell lymphoma (EATL)
    • Epidemiology: very rare; average age at diagnosis 60–65 years
    • Etiology: associated with celiac disease in about 80% of cases
    • Origin: intraepithelial T cells
    • Localization: often proximal jejunum
    • Clinical presentation: initially often asymptomatic, but B symptoms and gastrointestinal symptoms may be present
  • Adenocarcinoma of the small bowel
  • Celiac crisis in children
    • Occurs rarely in severely affected children; may be life-threatening
    • Clinical findings:
      • Explosive, watery diarrhea
      • Dehydration
      • Pronounced abdominal distension
      • Severe electrolyte imbalances, particularly hypokalemia

References:[11][1]

We list the most important complications. The selection is not exhaustive.

Prevention

With infants, maintaining a gluten-free diet that only introduces small amounts of wheat (into the supplementary diet) between 17–26 weeks of age appears to have a protective effect against developing celiac disease.

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last updated 12/13/2018
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