Celiac Disease

Slide 1 · Celiac Disease

Immune pathogenesis · mucosal morphology · diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain why dietary gluten triggers T-cell–mediated mucosal injury in susceptible hosts.

Identify the three major microscopic features and their functional consequences.

Integrate clinical features, serology, histology, and HLA testing.

Recognize refractory symptoms and important malignant complications.

Slide 3 · Celiac disease: Defining features

Immune-mediated enteropathy caused by dietary gluten in genetically predisposed individuals

Also called celiac sprue or gluten-sensitive enteropathy.

Gluten exposure induces a mucosal immune response rather than direct dietary toxicity.

Small-intestinal mucosal injury is central to malabsorption.

Slide 4 · How celiac disease fits into malabsorption

Intraluminal digestion

Conversion of food macromolecules into absorbable units

Terminal digestion

Brush-border hydrolysis of residual peptides and carbohydrates

Transepithelial transport

Absorption and epithelial processing of nutrients and fluid

Lymphatic transport

Movement of absorbed lipids from intestinal mucosa

Slide 5 · Celiac disease primarily disrupts the mucosa

Loss of villous surface

Reduced area available for absorption

Immature enterocytes

Impaired brush-border terminal digestion

Damaged mucosal epithelium

Inefficient transepithelial nutrient transport

Slide 6 · Normal villous architecture

Long absorptive villi with underlying crypts

Schematic—not a histological specimen

Slide 7 · The disease requires more than gluten alone

Dietary gluten

Susceptible HLA background

TG2-modified peptides

Mucosal immune response

Environment, antigen presentation and mucosal immunity converge.

Slide 8 · Dietary exposure: The initiating trigger

Wheat, rye and barley contain the relevant gluten-related proteins.

Luminal and brush-border enzymes generate smaller gluten-derived peptides.

Some peptides retain sequences rich in proline and glutamine.

Susceptible individuals develop immune recognition of these peptides.

Slide 9 · Why gluten-derived peptides are immunogenic

Proline- and glutamine-rich peptides

Products of partial digestion of gluten proteins

TG2 enzymatic modification

Glutamine residues can be deamidated

Modified peptide presentation

HLA-DQ2/DQ8 binding drives antigen-specific CD4 activation

Slide 10 · Tissue transglutaminase 2 is a central mediator

TG2 converts selected glutamine residues in gluten peptides to glutamic acid

The reaction is deamidation.

Negatively charged peptide residues facilitate HLA-DQ2/DQ8 presentation.

TG2 also becomes the target of disease-associated autoantibodies.

Slide 11 · Genetic predisposition: HLA-DQ2 and HLA-DQ8

HLA-DQ2

HLA-DQ8

Present in most patients.

Presents appropriately modified gluten peptides to CD4 T cells.

Accounts for much of the remaining HLA-associated disease.

Performs a related peptide-presentation function.

Slide 12 · HLA susceptibility does not establish disease

HLA-DQ2/DQ8 alleles are susceptibility factors, not a stand-alone diagnosis.

Environmental exposure and immune responses remain necessary.

Disease-concordance patterns in twins support additional genetic and nongenetic contributions.

Absence of both alleles can help exclude celiac disease.

Slide 13 · Additional genetic and autoimmune associations

Beyond the main HLA alleles

Associated immune disorders

Other HLA and non-HLA loci contribute to risk.

Polymorphisms affect inflammatory and immunoregulatory pathways.

Type 1 diabetes mellitus

Autoimmune thyroiditis

Sjögren syndrome and IgA nephropathy

Slide 14 · The initiating antigen-presentation cascade

Gluten peptides

TG2 deamidation

HLA-DQ2/DQ8 APC

Gluten-specific CD4 T cells

Cytokines

Epithelial IL-15

Cytotoxic CD8 IELs

Epithelial injury

Parallel epithelial IL-15 and CD4 T-cell help drive the IEL injury arm

Slide 15 · Antigen-presenting cells activate CD4 T cells

TG2-deamidated peptide

HLA-DQ2/DQ8 presentation

Gluten-specific CD4 T-cell activation

Recognition of the peptide–MHC complex initiates the adaptive mucosal response.

Slide 16 · Cytokines amplify the inflammatory response

Gluten-responsive CD4 T cells release inflammatory mediators.

The source highlights IFN-γ, IL-21 and IL-2.

Cytokine signaling supports mucosal inflammation and lymphocyte responses.

This immune activation links antigen presentation to tissue injury.

Slide 17 · Epithelial IL-15 promotes intraepithelial immunity

IL-15 from intestinal epithelial cells helps expand and activate cytotoxic intraepithelial lymphocytes

IL-15 operates alongside CD4 T-cell–driven responses.

The epithelium becomes an active participant in inflammation.

Expansion of cytotoxic lymphocytes increases epithelial injury.

Slide 18 · Intraepithelial CD8 T cells are effectors

Activated intraepithelial CD8 T cells accumulate among enterocytes.

These cells can produce IFN-γ and granzyme B.

They contribute directly to epithelial cell damage.

Their increase is a key microscopic clue to celiac disease.

Slide 19 · Cytotoxic recognition involves innate-like receptors

Effector receptors

NKG2D and NKG2C on activated cytotoxic cells

Epithelial ligands

MICA and HLA-E on intestinal epithelial cells

Functional outcome

Enhanced recognition and epithelial cytotoxicity

Slide 20 · B-cell responses generate anti-TG2 antibodies

Gluten peptide–TG2 complexes

Immune recognition

Anti-TG2 IgA plasma cells

Anti-TG2 antibodies are diagnostically useful markers of the mucosal immune response.

Slide 21 · Celiac pathogenesis: Integrated mechanism

Gluten peptides

TG2 deamidation

HLA-DQ2/DQ8 APC

Gluten-specific CD4 T cells

Cytokines

Epithelial IL-15

Cytotoxic CD8 IELs

Epithelial injury

Parallel epithelial IL-15 and CD4 T-cell help drive the IEL injury arm

Slide 22 · Epithelial injury changes intestinal architecture

Epithelial cytotoxicity

Accelerated epithelial turnover

Compensatory crypt proliferation

Villous shortening

Repeated injury and regeneration produce the characteristic mucosal pattern.

Slide 23 · Histologic evaluation targets proximal small bowel

Diagnostic tissue is generally obtained from the second part of the duodenum or proximal jejunum.

These segments receive high concentrations of dietary gluten.

Assess villi, crypts, epithelium and lamina propria together.

Morphologic findings are interpreted with clinical and serologic context.

Slide 24 · The classic histopathologic triad

Villous atrophy

Crypt hyperplasia

Intraepithelial lymphocytosis

Increased lamina propria inflammatory cells commonly accompany fully developed disease.

Slide 25 · Villous atrophy: Lost absorptive architecture

Shortened absorptive projections; Increased proliferative crypt compartment

Schematic—not a histological specimen

Slide 26 · Why villous loss produces malabsorption

Villous shortening

Less mucosal surface in contact with nutrients

Loss of brush border

Reduced terminal digestive capacity

Less mature epithelium

Lower capacity for epithelial transport

Slide 27 · Crypt hyperplasia is compensatory

Injury increases epithelial turnover.

Crypts become enlarged and proliferative.

Increased crypt mitotic activity accompanies mucosal regeneration.

Rapid cell production can limit terminal enterocyte maturation.

Slide 28 · Intraepithelial lymphocytosis marks immune injury

Small CD8 T lymphocytes increase within surface epithelium.

Lymphocytes lie among larger epithelial cells.

This finding may appear before marked villous atrophy.

It reflects activated mucosal immunity but is not specific on its own.

Slide 29 · Lamina propria inflammatory expansion

Plasma cells become prominent in established disease.

Mast cells and eosinophils may also increase.

Changes are particularly conspicuous in upper lamina propria.

These findings support inflammation but do not define celiac disease alone.

Slide 30 · Early disease may lack complete villous atrophy

Earlier or subtle injury

Fully developed injury

Increased intraepithelial lymphocytes

Preserved or less severely shortened villi

Marked villous flattening

Crypt hyperplasia and prominent IELs

Lamina propria cellular infiltrate

Slide 31 · The triad is not pathognomonic

Neither intraepithelial lymphocytosis nor villous atrophy is specific to celiac disease

Other enteritides, including viral enteritis, may overlap histologically.

A biopsy alone can be misleading without supporting information.

Correlate tissue findings with disease-specific serology.

Slide 32 · Compare normal and celiac mucosa

Normal mucosal architecture

Celiac mucosal injury

Tall villi + shorter crypts

Shortened villi + crypt hyperplasia + IELs

Schematic—not a histological specimen

Slide 33 · Morphology predicts physiologic impairment

Villi become shorter

Absorptive area decreases

Crypts turn over faster

Mature brush-border function decreases

Epithelial inflammation persists

Nutrient transport becomes inefficient

Slide 34 · Terminal digestion suffers from epithelial immaturity

Newly generated enterocytes may not develop full brush-border digestive function

Increased crypt mitoses reflect accelerated turnover.

Terminal carbohydrate and peptide digestion can be impaired.

Mucosal structural damage and functional deficits reinforce malabsorption.

Slide 35 · Transepithelial transport is compromised

Intestinal absorptive epithelium is the site of nutrient uptake.

Villous atrophy decreases functioning epithelial surface.

Inflammation and rapid turnover impair mature transport capacity.

Combined defects account for the varied nutritional consequences.

Slide 36 · Malabsorption explains gastrointestinal symptoms

Inadequate nutrient absorption

Chronic diarrhea and steatorrhea may occur

Retained intestinal contents

Bloating, distention and flatus

Persistent negative nutrient balance

Weight loss and muscle wasting

Slide 37 · Micronutrient deficiency has systemic effects

Deficiency / mechanism

Potential clinical expression

Impaired iron or vitamin absorption

Anemia; fatigue

Calcium and vitamin D deficits

Osteopenia / osteoporosis

Additional nutrient insufficiency

Growth failure; other systemic symptoms

Prolonged intestinal injury

Broader malnutrition phenotype

Slide 38 · Adult disease can remain unrecognized

The source describes common adult recognition between 30 and 60 years of age.

Presentation ranges from chronic gastrointestinal symptoms to subtle complaints.

Atypical or asymptomatic disease can escape attention for years.

Iron-deficiency anemia may be a presenting clue.

Slide 39 · The adult symptom spectrum is broad

Gastrointestinal presentation

Less obvious presentation

Chronic diarrhea

Bloating

Weight loss or abdominal discomfort

Fatigue

Anemia

Incidental positive disease serology

No overt symptoms

Slide 40 · Silent and latent disease are distinct

Term in Robbins

Serology

Villous atrophy

Symptoms

Silent disease

Positive

Present

Absent

Latent disease

Positive

Absent

May be absent / variable

Slide 41 · Anemia may be the first recognized manifestation

Small-bowel mucosal damage

Reduced nutrient uptake

Iron / vitamin deficiency

Anemia and fatigue

Clinical recognition may begin outside gastroenterology.

Slide 42 · Dermatitis herpetiformis links skin and gut

A characteristic itchy, blistering eruption may accompany celiac disease.

The disease is an extraintestinal manifestation of gluten-related immunity.

The gastrointestinal phenotype can be clinically subtle.

The source refers to the dermatology chapter for skin-specific morphology.

Slide 43 · Pediatric disease may follow gluten introduction

Classic pediatric presentation may begin after gluten enters the diet.

Typical onset between 6 and 24 months in classic cases.

Young children may develop abdominal distention, irritability and chronic diarrhea.

Failure to thrive and muscle wasting reflect significant malabsorption.

Slide 44 · Nonclassical childhood symptoms delay recognition

Older-child complaints

Consequences to recognize

Recurrent abdominal pain

Nausea or vomiting

Bloating or constipation

Iron-deficiency anemia

Short stature

Delayed puberty

Arthralgia or aphthous stomatitis

Slide 45 · Growth failure is a clinical expression of malabsorption

Reduced nutrient uptake

Insufficient material for growth

Chronic mucosal inflammation

Persisting intestinal dysfunction

Childhood disease burden

Poor weight gain or short stature

Slide 46 · Adult and pediatric patterns are not identical

Dimension

Adults

Children

Clinical recognition

Often atypical or silent

Classic and nonclassical forms

Typical prominent clues

Anemia, bloating, fatigue

Distention, growth impairment, pain

Important extraintestinal clues

Dermatitis herpetiformis, anemia

Short stature, delayed puberty, anemia

Slide 47 · Diagnostic reasoning requires concordant evidence

Compatible clinical context

Serologic evidence

Small-bowel morphology

Integrated interpretation

No single morphologic alteration is sufficient in isolation.

Slide 48 · Anti-TG2 IgA is the main serologic test

Noninvasive serology is generally performed before biopsy.

IgA antibodies to tissue transglutaminase 2 as the most sensitive serologic test.

An antibody result requires interpretation in its clinical setting.

Serologic response can also track the effect of dietary gluten exclusion.

Slide 49 · Antiendomysial IgA provides additional evidence

IgA antiendomysial antibodies may be present.

This is an additional disease-associated serologic marker.

The result supports the immune-mediated diagnosis alongside other data.

Serologic markers complement rather than replace careful histopathologic interpretation.

Slide 50 · IgA deficiency changes test selection

Suspected celiac disease

Consider the reliability of IgA-based serology

If IgA deficient

IgG anti–tissue transglutaminase may be detected

Interpretation

Integrate with biopsy and clinical features

Slide 51 · HLA typing is most useful for exclusion

Both DQ2 and DQ8 absent

DQ2 and/or DQ8 present

Strongly argues against celiac disease.

Useful negative predictive information.

Indicates susceptibility, not certainty.

Does not independently confirm celiac disease.

Slide 52 · Integrating serology with biopsy

Serologic finding

Biopsy finding

Interpretive caution

Celiac-associated antibodies

Compatible mucosal triad

Joint evidence supports diagnosis

Antibodies without atrophy

May represent latent disease

Avoid equating positive serology with atrophy

IEL increase without specific antibodies

Nonspecific mucosal pattern

Investigate other causes of enteritis

Slide 53 · Gluten-free diet removes the driving exposure

Strict dietary exclusion of gluten is the principal treatment

Withdrawal removes the antigenic trigger.

Clinical manifestations and anti-TG2 antibody titers typically improve.

Mucosal structure can recover with time.

Slide 54 · Clinical and mucosal recovery are not instantaneous

Remove dietary gluten

Symptoms begin to improve

Antibody titers decrease

Mucosa may normalize

Normal or near-normal mucosal histology within approximately 6–24 months.

Slide 55 · A gluten-free diet may reduce long-term sequelae

Improvement in nutrient absorption may correct anemia.

Long-term skeletal complications may become less likely.

The source identifies potential benefits for female infertility.

Dietary treatment may also reduce certain malignancy risks.

Slide 56 · Refractory sprue changes the clinical question

Refractory sprue refers to loss of response despite a strict gluten-free diet.

Persistent or recurrent symptoms demand reassessment.

Refractory disease can be a precursor to enteropathy-associated T-cell lymphoma.

Do not assume every recurrence represents inadvertent gluten exposure.

Slide 57 · Enteropathy-associated T-cell lymphoma

An aggressive lymphoma arising from intestinal intraepithelial T lymphocytes

Celiac disease increases its risk.

The relevant cellular lineage is the cytotoxic intraepithelial T-cell compartment.

Refractory symptoms warrant attention to this complication.

Slide 58 · Small-intestinal adenocarcinoma risk also increases

Celiac disease is associated with an elevated risk of small-intestinal adenocarcinoma.

Cancer may present with new or recurrent gastrointestinal complaints.

Loss of a previously good response to diet requires evaluation.

The source does not provide a specific individual risk prediction.

Slide 59 · Alarm features on a strict gluten-free diet

Recurrent abdominal pain

Consider refractory disease or another process

Persistent diarrhea

Re-evaluate malabsorption and mucosal pathology

Unexplained weight loss

Investigate refractory sprue and malignancy

Slide 60 · Villous atrophy has alternative etiologies

Celiac-related pattern

Overlapping conditions

Villous loss

Crypt hyperplasia

Increased intraepithelial lymphocytes

Viral enteritis may show overlap.

Other nonceliac enteropathies may alter villi.

Specific serology and clinical context discriminate.

Slide 61 · Compare celiac disease with autoimmune enteropathy

Feature

Celiac disease

Autoimmune enteropathy (neighbor topic)

Main mechanism

Gluten + HLA-associated mucosal immunity

Immune-regulatory defects may predominate

Clinical setting

Adults or children

Often severe childhood diarrhea

Tissue caution

IEL increase; villous atrophy

Overlapping enteropathy; neutrophils may occur

Slide 62 · Case 1: Anemia without prominent diarrhea

Hypothetical teaching vignette

An adult with persistent fatigue has anemia. Gastrointestinal symptoms are modest. Celiac-associated serology is positive, and duodenal sampling shows villous shortening with increased intraepithelial lymphocytes.

Which mechanism best connects the biopsy to the anemia?

Slide 63 · Case 1: The injury impairs absorption

Mucosal surface loss and immature enterocytes impair nutrient uptake.

Villous atrophy reduces the functioning absorptive area.

Crypt hyperplasia accompanies accelerated turnover of immature epithelium.

The combination can cause nutrient deficiency even without florid diarrhea.

Slide 64 · Case 2: Symptoms despite dietary treatment

Hypothetical teaching vignette

A patient with established celiac disease previously improved on a strict gluten-free diet but now develops recurrent abdominal pain, persistent diarrhea and weight loss despite continued adherence.

What important complications must be considered?

Slide 65 · Case 2: Reassess for refractory disease or cancer

Refractory sprue and malignancy are important considerations.

Refractory sprue represents a loss of clinical response to gluten exclusion.

Enteropathy-associated T-cell lymphoma is an aggressive associated malignancy.

Small-intestinal adenocarcinoma is another recognized cancer risk.

Slide 66 · The causal chain in one view

Gluten-derived peptides

TG2 modification + HLA presentation

CD4 / CD8 immune response

Villous injury + malabsorption

Understanding the immune mechanism explains both biopsy changes and clinical phenotype.

Slide 67 · Morphology and diagnosis: Final synthesis

Villous atrophy

Crypt hyperplasia

Intraepithelial lymphocytosis

Increased lamina propria inflammatory cells commonly accompany fully developed disease.

Slide 68 · Source and visual attribution

Primary text: Robbins, Cotran & Kumar, Pathologic Basis of Disease, 11th edition (2026).

The malabsorption framework and autoimmune-enteropathy comparison use adjacent textbook sections.

Original native PowerPoint schematics depict conceptual mechanisms and mucosal architecture—not clinical specimens.

No textbook figures or clinical micrographs were reproduced.