Celiac disease

Jason Wasserman MD PhD FRCPC
August 1, 2024

Background:

Celiac disease is a medical condition where the body develops an abnormal reaction to gluten found in food. The abnormal reaction leads to inflammation which damages the tissue on the inner surface of the small bowel. The damage is caused by specialized immune cells called lymphocytes which are found in increased numbers in the small bowel of people with celiac disease. Another name for celiac disease is gluten-sensitive enteropathy.

What are the symptoms of celiac disease?

Celiac disease can present with a wide range of symptoms that vary from person to person. Some individuals may have severe symptoms, while others may have mild or no symptoms. The symptoms can affect different parts of the body and may include:

Gastrointestinal symptoms

• Diarrhea: Frequent, loose, and watery stools.
• Constipation: Difficulty passing stools or infrequent bowel movements.
• Abdominal pain: Cramping, bloating, and discomfort in the abdomen.
• Gas: Excessive flatulence.
• Nausea and vomiting: Feeling sick to the stomach or vomiting.
• Weight loss: Unintentional loss of weight despite a normal or increased appetite.

Non-gastrointestinal symptoms

• Fatigue: Persistent tiredness and lack of energy.
• Anemia: Often due to iron deficiency, leading to fatigue and weakness.
• Bone or joint pain: Due to nutrient deficiencies.
• Skin rash: Dermatitis herpetiformis, an itchy, blistering skin rash.
• Mouth ulcers: Sores inside the mouth.
• Headaches: Frequent migraines or headaches.
• Neurological symptoms: Numbness or tingling in the hands and feet, balance problems, and cognitive impairment.
• Menstrual irregularities: Missed periods or infertility in women.
• Mood changes: Depression, anxiety, or irritability.

What causes celiac disease?

Celiac disease is caused by an abnormal immune response to gluten, a protein found in wheat, barley, and rye. The exact cause of this immune response is not fully understood, but it involves a combination of genetic, environmental, and immunological factors.

Genetic Factors

• HLA-DQ2 and HLA-DQ8 genes: Most people with celiac disease have specific variants of these genes, which play a role in the immune system’s recognition of gluten. However, having these genes alone is not enough to cause the disease; other factors are also involved.

Environmental Factors

• Gluten Exposure: Consuming foods containing gluten triggers the immune response that leads to damage in the small intestine.
• Infections: Certain infections, particularly in childhood, may increase the risk of developing celiac disease in genetically predisposed individuals.
• Diet: The timing and amount of gluten introduced into an infant’s diet may influence the risk of developing celiac disease.

Immunological Factors

• Autoimmune response: In celiac disease, the immune system mistakenly attacks the lining of the small intestine when gluten is present. This leads to inflammation and damage to the villi, which are essential for nutrient absorption.

How is the diagnosis of celiac disease made?

A biopsy is usually performed because the patient has symptoms suggestive of celiac disease (gluten-sensitive enteropathy), which may include weakness and diarrhea. These symptoms occur when the patient eats food that contains gluten.  Biopsies are usually taken from the 2nd part of the duodenum, where the changes associated with celiac disease are easiest to recognize.

A diagnosis of celiac disease (gluten-sensitive enteropathy) requires both clinical and pathological confirmation. Clinical confirmation is usually made by performing blood tests for antibodies that target tissue transglutaminase (anti-TTG), which is found in most patients with celiac disease.

Pathology of celiac disease

When a pathologist examines a duodenum biopsy to assess for celiac disease, they look for specific microscopic features, including villous atrophy, villous blunting, crypt hyperplasia, and increased intraepithelial lymphocytes. These features help establish a diagnosis and assess the severity of the disease.

Normal histology of the duodenum

The duodenum is the first part of the small intestine and plays a crucial role in digestion and nutrient absorption. Under the microscope, a healthy duodenum shows:

• Villi: These finger-like projections increase the surface area for nutrient absorption.
• Crypts: These are gland-like structures at the base of the villi that produce new cells to replace those on the villi.
• Enterocytes: These are the main type of cells on the surface of the villi, responsible for absorbing nutrients.
• Goblet cells: These cells are scattered among the enterocytes and produce mucus to protect the intestinal lining.
• Intraepithelial lymphocytes (IELs): These are immune cells present between the enterocytes, playing a role in immune surveillance.

A healthy duodenum has tall, finger-like villi, shallow crypts, and few IELs.

Microscopic features of celiac disease

Villous Atrophy

Villous atrophy is the flattening and loss of the normal finger-like projections (villi) lining the small intestine. Villous atrophy is seen in active celiac disease when the immune response to gluten causes significant damage to the intestinal lining. In partially treated celiac disease, villous atrophy may be less pronounced, with some regeneration of the villi occurring. Villi are crucial for nutrient absorption. Their atrophy reduces the surface area available for absorption, leading to malabsorption and nutrient deficiencies.

Villous Blunting

Villous blunting is a milder form of villous atrophy in which the villi are shortened but not completely flattened. It can be an early sign of celiac disease before full villous atrophy develops. In partially treated disease, villous blunting may improve, with villi becoming longer but not yet fully normal. This indicates an early or less severe form of mucosal damage compared to complete villous atrophy.

Crypt hyperplasia

Crypt hyperplasia refers to the elongation and increased number of crypts, which are glands located at the base of the villi. Crypts normally produce new cells to replace the villi. In celiac disease, the crypts become larger and more numerous as the body attempts to regenerate the damaged mucosa, but this regeneration is ineffective due to ongoing inflammation.

Intraepithelial lymphocytes (IELs)

Intraepithelial lymphocytes (IELs) are immune cells (a type of white blood cell) that infiltrate the epithelial layer of the intestine. A normal duodenum typically has fewer than 25 IELs per 100 enterocytes. In celiac disease, the number of IELs increases, often exceeding 25 per 100 enterocytes. Pathologists often describe this as intraepithelial lymphocytosis. Increased numbers of IELs are a hallmark of celiac disease and indicate an immune response to gluten in the diet.

Modified Marsh classification

The modified Marsh classification is a grading system used to describe the extent of mucosal damage in celiac disease. This classification system is useful for setting an initial baseline of disease activity and for assessing response to therapy and a gluten-free diet. It ranges from Marsh 0 to Marsh 3:

Marsh 0

• Microscopic features: Normal mucosa without any changes.
• What it means: Indicates no signs of celiac disease.

Marsh 1

• Microscopic features: Increased number of IELs (>25 per 100 enterocytes).
• What it means: Suggests early changes or mild celiac disease, often seen in patients with potential or partially treated celiac disease.

Marsh 2

• Microscopic features: Increased IELs and crypt hyperplasia.
• What it means: Indicates more pronounced mucosal changes, but villi are still present. May be seen in mild or partially treated celiac disease.

Marsh 3

• Microscopic features: Subdivided into three stages based on the degree of villous atrophy:
  • Marsh 3a: Partial villous atrophy with mild blunting.
  • Marsh 3b: Subtotal villous atrophy with more severe blunting.
  • Marsh 3c: Total villous atrophy with complete flattening of the villi.
• What it means: Indicates severe mucosal damage and is diagnostic of active or untreated celiac disease.

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