Summary![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Celiac disease, also referred to as celiac sprue or nontropical 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 definitive 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![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Epidemiology![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
- Sex: ♀ > ♂
- Age of onset
- Prevalence: in the US ∼ 1:150 [2]
- Race: more common in individuals of northern European descent
Epidemiological data refers to the US, unless otherwise specified.
Etiology![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
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Genetic predisposition with association to HLA antigens [3]
- HLA-DQ2 in 90–95% of patients
- HLA-DQ8 in 5–10% of patients
- 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)
Pathophysiology![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Symptoms manifest when a genetically predisposed individual develops an immunological response to gliadin, an alcohol-soluble fraction of gluten.
- Consumption of food containing gluten → tissue transglutaminase is released ; → modifies gliadin from gluten proteins → pathogenic T cells react to and are activated by modified gliadin → mediate chronic intestinal inflammation → epithelial damage resulting in villous atrophy, crypt hyperplasia, and loss of brush border → impaired resorption of nutrients in the small intestine (especially in the distal duodenum and proximal jejunum) → malabsorption symptoms
Clinical features![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Gastrointestinal symptoms
- Chronic or recurring diarrhea: steatorrhea
- Flatulence, abdominal bloating, and pain
- Nausea/vomiting
- Lack of appetite
- Constipation (rarely)
Extraintestinal symptoms and associations
- Malabsorption symptoms: fatigue, weight loss, vitamin deficiency, iron deficiency anemia, osteoporosis, hypocalcemia
- In children: failure to thrive, growth failure, delayed puberty, secondary hyperparathyroidism
- Dermatologic associations: dermatitis herpetiformis
- Neuropsychiatric symptoms: peripheral neuropathies (numbness, burning and tingling of the hands and feet) , headache, ataxia, depression, irritability [4]
- Gynecological associations: reduced fertility or infertility
- Endocrine associations: autoimmune thyroid disease, type 1 diabetes mellitus
- Associated chromosomal syndromes: Turner syndrome, Down syndrome
- Other associated conditions
In both children and adults, mild or asymptomatic cases are more common than the classic presentation of the disease.
Diagnostics![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
General principles [5][6][7]
- Celiac disease is an underdiagnosed condition that requires a high index of suspicion.
-
Diagnosis is based on serology (initial testing) and EGD with duodenal biopsy (confirmation).
- A gluten-free diet can cause negative test results.
- HLA-based testing and/or a gluten challenge are options for patients not consuming gluten.
- Common indications for testing include:
- Symptoms of malabsorption (e.g., steatorrhea)
- First-degree relatives with celiac disease [6]
- Iron deficiency anemia unresponsive to treatment [6]
- Elevated liver enzymes with no discernable cause
- Type 1 diabetes mellitus
- Signs of osteoporosis (e.g., repeated, unexplained fractures)
- Workup of other autoimmune disorders (e.g., thyroiditis, hepatitis)
Laboratory studies [5][7]
Routine studies
-
IgA tissue transglutaminase antibody (tTG IgA): initial test, crucial part of celiac disease serology
- Widely available test with high specificity (≥ 96%) [5]
- Risk of false negatives (e.g., in IgA deficiency, gluten-free diet)
-
Total IgA
- Indicated for all patients because of the high prevalence of IgA deficiency in patients with celiac disease (approx. 2–3%) [3]
- If patients have low IgA, perform further IgG-based testing.
Additional studies
-
Deamidated gliadin peptide
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IgG-based testing: indicated in IgA deficiency or discordant biopsy and serology
- IgG-tissue transglutaminase (tTG IgG)
- IgG deamidated gliadin peptide (DGP IgG)
- IgA-based testing: IgA deamidated gliadin peptide (DGP IgA)
-
IgG-based testing: indicated in IgA deficiency or discordant biopsy and serology
-
HLA testing: second-line testing after unclear initial evaluation
- Assesses for haplotypes HLA-DQ2 and HLA-DQ8
- Indications include:
- Uncertain diagnosis (e.g., disparity between serology and histopathology)
- Gluten-free diet prior to diagnosis
- Patients with Down syndrome [3]
- Anti-endomysial antibody (EMA): Potential second-line confirmatory test (high-specificity) [7]
Endoscopy [5][7]
-
EGD with small intestine biopsy (confirmatory test) [8]
- Indications: positive serology or high clinical suspicion despite negative serology
- At least five duodenal biopsies should be taken (with ≥ 1 from the duodenal bulb). [5][9]
-
Histological findings: typically ranked by severity according to the Marsh classification ; [10]
- Intraepithelial lymphocytic infiltration
- Crypt hyperplasia
- Villous atrophy
- Video capsule endoscopy: if EGD is declined or as follow-up if symptoms persist despite treatment [11]
False-negative serology and histopathology results are possible if patients are already adhering to a gluten-free diet.
Diagnosis without endoscopy [5][7]
- Adults: diagnosis without biopsy not recommended.
- Children: consider diagnosis without biopsy in case of high titers of tTG-IgA and positive EMA (controversial) [12][13]
Further evaluation
- Gluten challenge: may be indicated if patients are already adhering to a gluten-free diet [5]
-
Nutrient deficiency screening (individualize): indicated in confirmed celiac disease [14][15]
- Ferritin, iron (see “Diagnosis of iron deficiency anemia”)
- Zinc, calcium
- Vitamin B12 and B6, folate
- Fat-soluble vitamins, especially vitamin D
- Associated autoimmune disorders: Consider further testing if there are symptoms for thyroiditis, autoimmune hepatitis, and/or diabetes.
-
Tests for malabsorption: not routinely indicated (low sensitivity and specificity)
- D-xylose absorption test: low urine d-xylose levels (The passive absorption of d-xylose in the proximal small intestine is impaired by the mucosal defect and bacterial overgrowth.)
- Fat malabsorption: quantitative stool fat assays or qualitatively via fat stains (e.g., Sudan III stain)
- See “Diagnostics” in “Malabsorption” for further information.
Follow-up
- Repeat laboratory studies after 3–6 months and 12 months, then annually [5][7]
- tTG-IgA or DGP antibodies
- Nutrient levels if the patient had a deficiency at the time of diagnosis [8]
- Endoscopy: only if symptoms persist or return in patients adhering to a gluten-free diet [5][6][8]
Differential diagnoses![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
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: exact cause not known; most likely due to bacterial infection that leads to structural damage of the intestinal mucosa
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Clinical features
- Chronic diarrhea with steatorrhea
- Abdominal cramps
- Progressive weight loss
- Fatigue
- See clinical features of malabsorption
-
Diagnostics
- Blood tests: megaloblastic anemia (due to deficiency of folate and vitamin B12), hypoalbuminemia, hypocalcemia, vitamin D deficiency
- Serology for antibodies to rule out celiac disease (see “Diagnostics” above)
-
Stool analysis
- Fecal fat 10–40 g/d
- Rule out infection with pathogens (e.g., Giardia lamblia, Entamoeba histolytica)
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Endoscopy of the small bowel and biopsy
- Villous atrophy, elongated crypts, presence of inflammatory cells (plasma cells, lymphocytes, eosinophils)
- Mainly affects duodenum and jejunum but may progress to ileum
- Treatment: tetracycline in combination with folic acid for 3–6 months [16]
Celiac disease and tropical sprue have similar features (e.g., steatorrhea, abdominal pain, weight loss), but only tropical sprue responds to antibiotics.
Whipple disease
- Definition: : an infectious disease caused by Tropheryma whipplei, an intracellular gram-positive bacteria
-
Epidemiology
- Very rare
- Most commonly occurs in males older than 40 years [17][18]
-
Clinical features
-
Intestinal manifestations
- Abdominal pain
- Malabsorption syndrome (including diarrhea and/or steatorrhea): commonly occurs later in the disease progression
-
Extraintestinal manifestations
- Enteropathic arthritis(60% of cases)
- Migrating arthralgias and arthritis, especially sacroiliitis (40% of cases) [19]
- Fever
- Hyperpigmentation affecting sun-exposed areas
- Polyserositis
- Lymphadenopathy
- Cardiac symptoms (e.g., valve insufficiencies)
- Neurological symptoms (e.g., myoclonia, ataxia, impairment of oculomotor function)
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Intestinal manifestations
-
Diagnostics
- Small intestine biopsies: detection of PAS-positive foamy macrophages in the lamina propria
- PCR testing and immunohistochemistry staining
- Imaging may show enlarged mesenteric nodes.
- If neurological complaints occur: Perform a lumbar puncture and CSF analysis and neuroimaging (MRI).
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Treatment
- IV ceftriaxone for 2 weeks
- Maintenance treatment with oral trimethoprim-sulfamethoxazole for 1 year
Anyone who CANT appreciate the foamy, PAStoral rivers of England gets Whipped: the most important features of Whipple disease are Cardiac symptoms, Arthralgias, Neurologic symptoms, Trots (diarrhea), and foamy, PAS-positive macrophages on biopsy.
Whipple disease is lethal if left untreated.
The differential diagnoses listed here are not exhaustive.
Treatment![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Diet [5][20]
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Strict, lifelong gluten-free diet
- Abstain from products containing wheat, rye, barley, or spelt.
- Symptoms usually improve quickly [20]
- Recommended foods: rice, corn, potatoes, soybeans, millet
- Patients with secondary lactase deficiency: Avoid milk products.
Other
- Iron and vitamin supplementation, if there are deficiencies (e.g., iron deficiency anemia) [15]
- Consider osteoporosis screening in adult patients [8]
- Refer patients to a dietitian and advise joining support groups. [5][8]
Managing celiac disease mainly consists of maintaining a lifelong gluten-free diet.
Complications![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
- See “Clinical features” in “malabsorption.”
- Secondary lactase deficiency
- Moderately increased risk of malignancies
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Enteropathy-associated T-cell lymphoma (EATL)
- 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
- Esophageal cancer [21]
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Enteropathy-associated T-cell lymphoma (EATL)
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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
- May lead to ulcerative jejunitis
- In severe cases, total parenteral nutrition and treatment with steroids or immunosuppressants may be necessary.
We list the most important complications. The selection is not exhaustive.
Prevention![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
- There is no proven measure to prevent celiac disease.
- With infants, introducing small amounts of wheat (into the supplementary diet) between 4–6 months of age does not increase the risk of developing celiac disease