Collagenous Sprue

Complex MONDO:0044092 Show in embeddings browser Enteropathy Malabsorption disorder

Collagenous sprue is a rare malabsorptive small-bowel disorder defined histologically by abnormal deposition of a thickened subepithelial collagen band beneath the surface epithelium, accompanied by villous atrophy and intraepithelial lymphocytosis, with entrapment of lamina propria cellular elements within the band. Patients present with prolonged watery diarrhea, weight loss, malnutrition and severe malabsorption, and laboratory evidence of hypoalbuminemia, hypokalemia and anemia. Exposure to a drug associated with sprue-like enteropathy — most often an angiotensin receptor blocker — is common in reported cases. The disorder is associated with, but not equivalent to, celiac disease: it is frequently refractory to a gluten-free diet and occurs in patients who are celiac-seronegative and HLA-DQ2/DQ8-negative. Its aetiology and molecular pathogenesis remain uncharacterized.

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3
Pathophys.
7
Phenotypes
3
Gaps
1
Genes
7
Medical Actions
3
Differentials
5
References
2
Deep Research
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Discussions and Knowledge Gaps

3
Which cells deposit the collagen band in collagenous sprue, and what shifts the balance between matrix synthesis and matrix turnover in favour of accumulation?
KNOWLEDGE GAP OPEN fibrogenic_mediators_uncharacterized
Attached to
pathophysiology#Subepithelial collagen deposition with entrapment of lamina propria elements genetic#
This entry previously carried five gene records — TGFB1, MMP1, MMP9, TIMP1 and TJP1 — each asserting a direction of change (TGF-beta driven fibroblast activation, reduced MMP activity, elevated TIMP1, reduced ZO-1). Every one of them was supported only by a histology sentence that named no gene, transcript or protein, and two of those sentences came from papers about collagenous gastritis and ARB-induced gastritis rather than about collagenous sprue. The records have been removed rather than re-sourced, because the searches run for this re-curation found no study that measures any of these mediators in collagenous sprue tissue. The model is plausible and is imported wholesale from collagenous colitis and from general gut-fibrosis biology; importing it was how the entity confusion this issue tracks got in. It is recorded here as an open question so that a future study can reinstate the nodes with real measurements.
Resolving this needs tissue-level work — immunohistochemistry or transcriptomics on collagenous sprue duodenal biopsies against celiac and normal controls — not another literature pass.
Show evidence (2 references)
PMID:21523258 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Future studies are needed to more precisely define molecular and genetic biomarkers that identify homogeneous groups and permit the development of improved treatment strategies for this increasingly recognized disorder."
A review of collagenous sprue stating that the molecular and genetic biomarkers are still undefined, which is the gap recorded here.
PMID:27486523 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Little is known about the aetiology and pathogenesis of this disease."
Independent statement that the pathogenesis is uncharacterized.
Is there an HLA association with collagenous sprue that is independent of its co-occurrence with celiac disease?
CONTROVERSY OPEN hla_association_is_inherited_from_celiac
Attached to
genetic#HLA-DQA1
Referral series report celiac disease in up to 89% of collagenous sprue patients, which makes an HLA-DQ2/DQ8 enrichment inevitable without implying that HLA predisposes to the collagen band. The one series that typed all its patients found them uniformly DQ2/DQ8-negative and celiac-seronegative, and concluded that collagenous sprue should be separated from celiac disease. The two positions are both cited on the HLA-DQA1 record, one as SUPPORT and one as REFUTE. Ascertainment is the likely explanation for the difference — the 89% figure comes from a celiac referral centre's pathology database — but no study has tested that.
Show evidence (2 references)
PMID:19641452 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Collagenous sprue evolved on a background of CD in 4 cases. There was no history of CD in others and these cases may be the result of a biologic insult other than gluten sensitivity."
A series in which only a third of cases arose on a celiac background, supporting a celiac-independent route into the disorder.
PMID:21631278 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Its exact etiology is still under investigation, and its relationship with classic celiac disease and other refractory, spruelike intestinal disorders remains controversial."
States that the relationship to celiac disease is itself contested, which is the controversy recorded here.
Should pulmonary hemosiderosis be listed as a differential diagnosis of collagenous sprue?
CURATION TODO RESOLVED pulmonary_hemosiderosis_differential_removed
Attached to
differential_diagnoses#
No. The record has been removed. It claimed that "collagenous sprue can have pulmonary manifestations through shared immune mechanisms" and cited a sentence about collagenous colitis that mentions no lung disease; nothing in the collagenous sprue literature reviewed for this re-curation reports pulmonary involvement. The entry is almost certainly a confusion with the celiac disease / idiopathic pulmonary hemosiderosis (Lane-Hamilton syndrome) association, which belongs to celiac disease and not to collagenous sprue, and which is not a differential diagnosis in either case — it is a comorbidity. Recorded rather than silently dropped so the concept is not re-nominated.
Resolution: Removed in the #10630 re-curation. If a collagenous sprue case with pulmonary hemosiderosis is ever reported, it belongs in a comorbidity or association record, not in differential_diagnoses.
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Pathophysiology

3
Mucosal immune activation with intraepithelial lymphocytosis
Small-bowel biopsies in collagenous sprue show intraepithelial lymphocytosis and a lamina propria infiltrate that may include plasma cells, neutrophils and eosinophils, alongside the collagen band and villous atrophy. Clonal T-cell populations are detectable in a majority of tested cases, and clinical response to thiopurines — whose active metabolite induces T-cell apoptosis — is the main functional argument for a T-cell-driven process. The immune activation is dissociable from celiac disease: it occurs in patients with negative celiac serology and without the HLA-DQ2/DQ8 haplotypes. The upstream trigger is unknown.
intraepithelial lymphocyte CL:0002496 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intraepithelial lymphocyte (CL:0002496). CL:0002496 is a cell type from the Cell Ontology. plasma cell CL:0000786 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology. eosinophil CL:0000041 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves eosinophil, annotated with mature eosinophil (CL:0000041). CL:0000041 is a cell type from the Cell Ontology.
T cell mediated immune response GO:0002292 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves T cell mediated immune response, annotated with T cell differentiation involved in immune response (GO:0002292). GO:0002292 is a biological process from the Gene Ontology. response to cytokine GO:0034097 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves response to cytokine (GO:0034097). GO:0034097 is a biological process from the Gene Ontology.
small intestinal mucosa UBERON:0002108 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in small intestinal mucosa, annotated with small intestine (UBERON:0002108). UBERON:0002108 is an anatomical location from the Uberon multi-species anatomy ontology. lamina propria UBERON:0000030 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lamina propria (UBERON:0000030). UBERON:0000030 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (4 references)
PMID:27486523 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Increased numbers of plasma cells, neutrophils and/or eosinophils can be present in the lamina propria."
Names the lamina propria infiltrate curated on this node, in a review of the collagenous sprue literature written by the authors of a dedicated case series.
PMID:19641452 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Small intestinal biopsies showed subepithelial collagen deposition with varying degrees of villous atrophy and varying numbers of intraepithelial lymphocytes."
Twelve-case series reporting intraepithelial lymphocytosis in collagenous sprue biopsies directly, rather than in a sibling collagenous disease.
PMID:19641452 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Clonal T-cell populations were identified in 5 of 6 cases tested."
Supports a T-cell-driven process in collagenous sprue; note the same series found no lymphoma on follow-up, so clonality here is not itself a malignancy finding.
+ 1 more reference
Subepithelial collagen deposition with entrapment of lamina propria elements
The defining lesion is a thickened band of collagen beneath the surface epithelium of the small bowel, confirmed as collagen by histochemical and ultrastructural study, which entraps capillaries, inflammatory cells and fibroblasts. Band thickness varies widely between cases and does not track symptom severity. The cellular and molecular drivers of the deposition — the fibroblast or myofibroblast population responsible, and the balance of collagen synthesis against matrix turnover — have not been characterized in collagenous sprue itself; see the `fibrogenic_mediators_uncharacterized` discussion.
myofibroblast CL:0000186 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myofibroblast, annotated with myofibroblast cell (CL:0000186). CL:0000186 is a cell type from the Cell Ontology. capillary endothelial cell CL:0002144 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves capillary endothelial cell (CL:0002144). CL:0002144 is a cell type from the Cell Ontology.
positive regulation of collagen biosynthetic process GO:0032965 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves positive regulation of collagen biosynthetic process, annotated with regulation of collagen biosynthetic process (GO:0032965). GO:0032965 is a biological process from the Gene Ontology. extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology.
subepithelial lamina propria UBERON:0000030 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in subepithelial lamina propria, annotated with lamina propria (UBERON:0000030). UBERON:0000030 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (3 references)
PMID:21631278 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Collagenous sprue is a severe malabsorptive disorder, histologically characterized by small intestinal villous and crypt atrophy, and a subepithelial collagen deposit, thicker than 12 µm, that entraps lamina propria cellular elements."
States the defining lesion of this node, including the entrapment of lamina propria elements, for collagenous sprue specifically.
PMID:20082473 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Histochemical stains and ultrastructural studies have confirmed that these deposits contain collagens."
Establishes that the subepithelial deposits are collagen, rather than an unspecified hyaline material.
PMID:19855376 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Subepithelial collagen thickness was mildly (n=6), moderately (n=10), or markedly (n=3) increased and villous atrophy was total (n=13) or subtotal (n=6)."
Quantifies the range of collagen thickening and villous atrophy across a 19-patient collagenous sprue series.
Epithelial detachment and villous atrophy
The collagen band is accompanied by epithelial detachment from the basement membrane and by villous atrophy that is total in roughly half of reported cases, producing the flattened mucosal lesion responsible for malabsorption. Histologic severity does not correlate with symptom severity, and histologic recovery lags clinical response to treatment — in one series the villous architecture normalized fully in only one of four clinically improved patients. Whether tight-junction proteins are involved has not been examined in collagenous sprue.
cell junction organization GO:0034330 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves cell junction organization (GO:0034330). GO:0034330 is a biological process from the Gene Ontology. epithelial cell differentiation GO:0030855 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves epithelial cell differentiation (GO:0030855). GO:0030855 is a biological process from the Gene Ontology.
duodenal mucosa UBERON:0002108 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in duodenal mucosa, annotated with small intestine (UBERON:0002108). UBERON:0002108 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (3 references)
PMID:27486523 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"In addition to a thickened collagenous band, villous atrophy, intraepithelial lymphocytosis, detachment of the epithelium and entrapment of capillaries, inflammatory cells and fibroblasts within the collagen band can be found."
Names epithelial detachment alongside villous atrophy as a feature of the collagenous sprue lesion.
PMID:27486523 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"The degree of histological abnormality in collagenous sprue does not correlate with the severity of the clinical symptoms."
Supports the dissociation between the histologic lesion and the clinical picture that this node records.
PMID:20082473 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Pathologically, a severe to variably severe "flattened" mucosal biopsy lesion with distinctive sub-epithelial deposits in the lamina propria region is detected."
Describes the flattened mucosal lesion that underlies malabsorption in collagenous sprue.
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Phenotypes

7
Blood 1
Anemia FREQUENT HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41854086 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
Pooled hemoglobin across reported collagenous sprue patients.
PMID:27486523 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Laboratory investigations showed anaemia, hypocalcaemia and hypoalbuminaemia."
Laboratory findings in a biopsy-confirmed collagenous sprue patient.
Digestive 3
Chronic watery diarrhea VERY_FREQUENT Chronic diarrhea HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhea (HP:0002028), qualified as temporality chronic. HP:0002028 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (3 references)
PMID:41854086 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Symptoms were prolonged (median 36 weeks) with prominent diarrhea (median 6.5 stools/day) and frequent malnutrition and edema."
Pooled patient-level analysis of 99 collagenous sprue cases quantifying diarrhea frequency and duration.
PMID:27620860 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Overall CS patients were more symptomatic with 17 (81.0%) patients with diarrhea and 15 (71.4%) with unintentional weight loss."
Gives the proportion with diarrhea in a 21-patient collagenous sprue cohort compared directly against celiac disease and collagenous colitis.
PMID:19855376 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"5 of 15 (33%) lacked diarrhea (atypical presentation), including 2 of 6 (33%) with active (untreated) celiac disease and 3 of 9 (33%) with refractory celiac disease"
Records the diarrhea-negative presentation, so the VERY_FREQUENT frequency band is not read as universal.
Malabsorption VERY_FREQUENT HP:0002024 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malabsorption (HP:0002024). HP:0002024 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41854086 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
Pooled laboratory data across 99 collagenous sprue patients establishing severe malabsorption.
PMID:20082473 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Collagenous sprue has traditionally been defined as a small intestinal mucosal disorder characterized by persistent diarrhea, severe malabsorption with multiple nutrient deficiencies and progressive weight loss."
Places severe malabsorption with multiple nutrient deficiencies in the definition of the disorder.
Protein-losing enteropathy FREQUENT HP:0002243 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protein-losing enteropathy (HP:0002243). HP:0002243 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41854086 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"Symptoms were prolonged (median 36 weeks) with prominent diarrhea (median 6.5 stools/day) and frequent malnutrition and edema."
Frequent edema in a pooled collagenous sprue cohort with a median albumin of 2.9 g/dL. Graded INDIRECT because enteric protein loss is the inference drawn from hypoalbuminemia plus edema in an enteropathy, not a reported measurement.
PMID:27486523 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Main symptoms are unintentional weight loss, hypoalbuminaemia, diarrhoea, bloating and anaemia."
Lists hypoalbuminaemia among the cardinal features, which is the observable consequence of the protein loss curated here.
Metabolism 1
Hypoalbuminemia FREQUENT HP:0003073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoalbuminemia (HP:0003073). HP:0003073 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41854086 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
Reports the pooled median serum albumin directly.
PMID:27486523 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Main symptoms are unintentional weight loss, hypoalbuminaemia, diarrhoea, bloating and anaemia."
Names hypoalbuminaemia among the cardinal features of collagenous sprue.
Constitutional 1
Abdominal pain OCCASIONAL HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27486523 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Patient 1, a 77-year-old woman, presented with fatigue, unintentional weight loss of 10 kg in 4 months, loss of appetite, abdominal pain and varying stool consistency."
A biopsy-confirmed collagenous sprue patient presenting with abdominal pain. This replaces a quote from a collagenous gastritis cohort that had been asserted for collagenous sprue.
Growth 1
Weight loss VERY_FREQUENT HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27620860 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Overall CS patients were more symptomatic with 17 (81.0%) patients with diarrhea and 15 (71.4%) with unintentional weight loss."
Quantifies unintentional weight loss in a collagenous sprue cohort.
PMID:27486523 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Main symptoms of collagenous sprue are unintentional weight loss and diarrhoea."
Names weight loss as one of the two cardinal symptoms of collagenous sprue.
🧬

Genetic Associations

1
HLA-DQA1 (Contested susceptibility locus, inherited through the celiac association)
Gene: HLA-DQA1 hgnc:4942 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HLA-DQA1 (hgnc:4942). hgnc:4942 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (3 references)
PMID:19855376 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"Seventeen (89%) had celiac disease and two had unclassified sprue; 9 of 17 (53%) celiac disease patients had refractory disease"
In this referral series almost all collagenous sprue patients had celiac disease, which carries the HLA-DQ2/DQ8 restriction. Graded INDIRECT: the HLA claim follows from the celiac diagnosis rather than from HLA typing reported here.
PMID:27486523 REFUTE DIRECT PRIMARY RESULT Human Clinical
"None of the patients had ever had coeliac-specific antibodies, and all were negative for HLA-DQ2 and HLA-DQ8 phenotype."
Four consecutive biopsy-confirmed collagenous sprue patients were all HLA-DQ2/DQ8-negative, so the haplotypes are not required for the disorder. This is the direct refutation of an HLA-restricted model of collagenous sprue.
PMID:27486523 REFUTE DIRECT PRIMARY RESULT Human Clinical
"Evaluating the cases in this study, all four patients were negative for HLA-DQ2 and HLA-DQ8, with negative coeliac serology, which proves that CS can occur in the absence of CD."
The authors' own statement that collagenous sprue occurs without celiac disease, which is the link the HLA association depends on.
💊

Medical Actions

7
Gluten-free diet
Action: gluten-free dietNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gluten-free diet, annotated with Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Platform: Behavioral / lifestyle
A gluten-free diet is standard first-line management, reflecting both the frequent co-occurrence with celiac disease and the fact that collagenous sprue is often first mistaken for it. Response is partial: fewer than half of patients improve on diet alone, and failure to respond is one of the features that raises the diagnosis.
Show evidence (2 references)
PMID:19855376 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Overall, 8 of 19 (42%) responded to gluten-free diet, including 2 of 9 (22%) with refractory celiac disease and 10 responded to immunomodulatory therapy, including 6 of 9 (67%) with refractory celiac disease."
Quantifies gluten-free diet response, and the larger response to immunomodulatory therapy, in a collagenous sprue series.
PMID:20082473 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Often, an initial diagnosis of celiac disease is considered but no continued response to treatment with a gluten-free diet occurs."
States the characteristic loss of response to a gluten-free diet, which is why diet alone is not sufficient management.
Corticosteroids (Budesonide)
Action: topical corticosteroid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is topical corticosteroid therapy (NCIT:C122078), qualified as therapeutic agent budesonide; route of administration gastrointestinal route. NCIT:C122078 is a clinical intervention from the NCI Thesaurus. Ontology label: Topical Corticosteroid Therapy NCIT:C122078
Platform: Small molecule
Corticosteroids, alone or combined with a gluten-free diet, are the mainstay of treatment, and budesonide is the agent used when topical gastrointestinal activity is wanted. Symptomatic response is common and often rapid.
Show evidence (3 references)
PMID:27620860 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Twenty CS patients received treatments, including the combination of gluten-free diet (GFD) and corticosteroids (n = 12), GFD only (n = 2), and corticosteroids only (n = 6). All CS patients showed symptomatic reliefs with treatment."
Direct treatment-outcome data for corticosteroids in a collagenous sprue cohort. This replaces a microscopic colitis pathogenesis sentence that named no treatment.
PMID:41854086 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Treatment commonly combined nutritional rehabilitation (often parenteral nutrition), gluten-free diet, withdrawal of suspected medications and corticosteroids."
Establishes corticosteroids as part of the usual regimen across five decades of reported cases.
PMID:27486523 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Three patients were treated with a combination of 6-TG and budesonide, and 1 patient received 6-TG only. All patients improved remarkably."
Names budesonide specifically as the corticosteroid used in collagenous sprue.
Thiopurines (Azathioprine/6-Thioguanine)
Action: immunosuppressive therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunosuppressive therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: azathioprine CHEBI:2948 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses azathioprine (CHEBI:2948). CHEBI:2948 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Thiopurines are used for collagenous sprue that does not respond to diet and steroids. Thioguanine with or without budesonide produced clinical improvement in all four patients of the only dedicated series, with histologic normalization of the collagen band in two and full villous recovery in one; symptoms recurred on withdrawal in one patient and remitted again on rechallenge.
Show evidence (2 references)
PMID:27486523 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Normalisation of the thickened basement membrane was found in 2 patients and complete histological improvement including full recovery of villi was found in 1 patient."
Histologic outcome of thioguanine treatment in biopsy-confirmed collagenous sprue. This replaces a quote that described a patient's presentation and mentioned no thiopurine.
PMID:27486523 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"At least one positive experience with another thiopurine, azathiopurine, together with steroids is described in the literature, with clinical and total histological improvement."
Supports the azathioprine arm of this record. Graded INDIRECT because it is the authors' report of someone else's case rather than their own result.
Anti-TNF-α Therapy
Action: immunosuppressive therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunosuppressive therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: infliximab NCIT:C1789 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses infliximab (NCIT:C1789). NCIT:C1789 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anti-TNF monoclonal antibody therapy appears in the collagenous sprue treatment literature as one of several options tried in refractory disease. No series reports its outcome separately, so this record is a catalogue entry rather than an established therapy.
Show evidence (1 reference)
PMID:27486523 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"A variety of therapeutic options have been described, including a GFD, milk-free diet, corticosteroids (including budesonide SR), sulfasalazine, cyclosporine, azathioprine, high-dose proton pump inhibitor and monoclonal tumour necrosis factor-α antibody"
Places anti-TNF antibody among the reported treatment options for collagenous sprue. Graded INDIRECT because the sentence catalogues options without reporting an outcome; the same paragraph adds that no adequate therapy has been found. Replaces a collagenous gastritis symptom quote that named no treatment.
Calcineurin Inhibitors (Tacrolimus)
Action: immunosuppressive therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunosuppressive therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: tacrolimus CHEBI:61049 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tacrolimus, annotated with tacrolimus (anhydrous) (CHEBI:61049). CHEBI:61049 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Tacrolimus is a calcineurin inhibitor reported for severe, treatment-refractory collagenous sprue with intestinal failure. The evidence is a single case.
Show evidence (1 reference)
PMID:39046809 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"A 25-year-old male presented with chronic watery diarrhea and severe intestinal failure due to collagenous sprue. Treatments, including immunosuppressants and a gluten-free diet, were ineffective. Tacrolimus shows promise in treating refractory cases."
Single-patient report of tacrolimus in refractory collagenous sprue with intestinal failure.
Medication discontinuation (Olmesartan withdrawal)
Action: medication managementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is medication management, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Reviewing the medication list and withdrawing a suspected culprit — in practice usually an ARB — is part of first-line management, and symptomatic improvement after withdrawal is the rule in drug-associated cases.
Show evidence (3 references)
PMID:41854086 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"CS is profoundly morbid but frequently improves with early recognition, medication review and withdrawal, aggressive nutritional support and steroid-based therapy, although relapse and mortality remain substantial."
Places medication review and withdrawal in the management of collagenous sprue, and keeps the authors' caveat about relapse and mortality attached.
PMID:39606500 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"This case report highlights the diagnostic challenges and clinical features of CS in a 74-year-old woman, whose symptoms resolved following cessation of olmesartan. The case emphasizes the importance of recognizing medication-induced forms of the disease"
Documents symptom resolution in collagenous sprue after the culprit ARB was stopped.
PMID:35945664 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"Following drug cessation, symptomatic improvement occurred in all 11 cases for which follow-up data were available. Histological resolution occurred in five of eight cases with follow-up gastric biopsies"
Dechallenge outcome in an ARB-injury cohort in which 11 of 13 patients with duodenal biopsies had duodenal involvement including collagenous sprue. Graded INDIRECT because the reported follow-up biopsies are gastric, so the histologic resolution figure is not a collagenous sprue measurement.
Nutritional support and supplementation
Action: nutritional supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is nutritional supplementation, annotated with Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Nutritional rehabilitation, frequently including parenteral nutrition, is a routine part of management and is needed more often than in celiac disease or collagenous colitis.
Show evidence (2 references)
PMID:41854086 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Treatment commonly combined nutritional rehabilitation (often parenteral nutrition), gluten-free diet, withdrawal of suspected medications and corticosteroids."
Establishes nutritional rehabilitation, often parenteral, as a usual component of collagenous sprue treatment.
PMID:27620860 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"CS patients had higher rates for disease-related temporary total parenteral nutrition (TPN) use (38.1% vs. 1.1% vs. 1.0%, P < 0.0001) and disease-related hospitalization (52.4% vs. 3.3% vs. 8.2%, P < 0.0001) than that in CD and CC patients."
Quantifies parenteral nutrition use in collagenous sprue against its two closest differentials, which is the evidence that this is a disease-specific need.
🌍

Environmental Factors

2
Medications (Angiotensin II Receptor Blockers)
ARB exposure, olmesartan most often, is the best-characterized trigger. Drug withdrawal is part of first-line management.
Show evidence (4 references)
PMID:41854086 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Exposure to medications associated with sprue-like enteropathy was common when reported (30/38, 79%), most often angiotensin receptor blockers."
Quantifies how often a drug exposure — usually an ARB — is present in reported collagenous sprue cases.
PMID:39606500 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"This case report highlights the diagnostic challenges and clinical features of CS in a 74-year-old woman, whose symptoms resolved following cessation of olmesartan. The case emphasizes the importance of recognizing medication-induced forms of the disease"
Dechallenge case demonstrating olmesartan as a direct trigger, with resolution after withdrawal.
PMID:26997446 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"This syndrome is characterized by severe diarrhea and sprue-like histopathologic findings in the intestine, often with increased subepithelial collagen."
Links the ARB-associated enteropathy to increased subepithelial collagen, which is the lesion that defines collagenous sprue.
+ 1 more reference
Medications (NSAIDs and clofazimine)
Reported as suggested associations only. This record was previously titled "Proton Pump Inhibitors and NSAIDs" and cited a quote that named neither; PPIs are dropped because the same literature lists high-dose PPI as an attempted *treatment* for collagenous sprue, not as a trigger.
Show evidence (1 reference)
PMID:27486523 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"A relationship with the usage of non-steroidal anti-inflammatory drugs (NSAIDs), olmesartan and clofazimine, has also been suggested."
Names NSAIDs and clofazimine as suggested drug associations of collagenous sprue. Graded INDIRECT because the authors report these as suggestions in the literature rather than as a measured association.
🔬

Biochemical Markers

4
Serum albumin (Decreased)
Context: Diagnostic and monitoring indicator of malabsorption severity; pooled median 2.9 g/dL across reported cases.
Show evidence (1 reference)
PMID:41854086 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
Direct pooled measurement of serum albumin in collagenous sprue.
Hemoglobin (Decreased)
Context: Marker of the anemia accompanying malabsorption; pooled median 11.95 g/dL.
Show evidence (1 reference)
PMID:41854086 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
Direct pooled measurement of hemoglobin in collagenous sprue.
Serum potassium (Decreased)
Context: Marker of severe secretory/osmotic stool losses; pooled median 2.6 mEq/L, which is in the range that prompts inpatient repletion.
Show evidence (1 reference)
PMID:41854086 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
Direct pooled measurement of serum potassium in collagenous sprue. This record replaces a Serum iron row whose quote reported neither iron nor a deficiency.
Tissue transglutaminase (tTG) antibodies (Usually negative)
Context: Helps separate collagenous sprue from celiac disease, though a minority of patients are seropositive because the two conditions co-occur.
Show evidence (2 references)
PMID:27486523 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Repeated coeliac serology in our clinic showed no antibodies against tissue transglutaminase and endomysium and no IgA deficiency."
A collagenous sprue patient in whom repeat tTG and endomysial serology was negative, which is what led to the celiac diagnosis being withdrawn.
PMID:27620860 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Positive celiac serology was noted in 5 (23.8%) CS patients."
Quantifies the seropositive minority, supporting "usually negative" rather than "negative" as the recorded presence.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Collagenous Sprue:

Celiac disease MONDO:0005130
Overlapping Features Celiac disease shares chronic diarrhea, weight loss and villous atrophy with collagenous sprue and frequently co-occurs with it, so the two are separated histologically by the subepithelial collagen band rather than clinically. Most collagenous sprue patients are celiac-seronegative, and collagenous sprue patients are more symptomatic and need parenteral nutrition and hospitalization far more often than celiac patients.
Distinguishing Features
  • Subepithelial collagen band present in collagenous sprue, absent in celiac disease
  • Positive tTG and endomysial antibodies in most celiac patients; positive in about a quarter of collagenous sprue patients
  • HLA-DQ2/DQ8 restriction in celiac disease; collagenous sprue occurs in DQ2/DQ8-negative patients
  • Sustained response to gluten-free diet in celiac disease; fewer than half of collagenous sprue patients respond to diet alone
Show evidence (3 references)
PMID:27620860 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Collagenous sprue patients had more severe clinical presentation than patients with CD and CC and therefore had higher demand for temporary TPN and hospitalization."
Head-to-head comparison of collagenous sprue against celiac disease and collagenous colitis, which is the discriminating clinical observation curated here.
PMID:27486523 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"CS should be separated from coeliac disease."
The authors' conclusion that the two are distinct entities, reached from uniformly negative celiac serology and HLA typing in their patients.
PMID:40177217 SUPPORT DIRECT BACKGROUND Human Clinical
"The presence of a subepithelial collagen band on histology differentiates CS from celiac disease, as both have villous blunting."
States the histologic discriminator. Marked BACKGROUND: the sentence is the case report's framing of established practice, not its own finding.
Microscopic colitis Not Yet Curated MONDO:0000702
Overlapping Features Collagenous colitis, the collagen-band subtype of microscopic colitis, is the colonic counterpart of the same lesion and co-occurs with collagenous sprue in a substantial fraction of cases, so the distinction is one of site and extent rather than of a different process. Colonic biopsies are therefore part of the workup rather than an alternative to small-bowel biopsy.
Distinguishing Features
  • Collagen band in colonic mucosa in collagenous colitis, small-bowel mucosa in collagenous sprue
  • Villous atrophy is intrinsic to collagenous sprue and absent from a purely colonic process
  • Concurrent collagenous colitis is present in a large minority of collagenous sprue patients, so the two are not mutually exclusive
Show evidence (2 references)
PMID:19641452 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Seven cases were associated with collagenous colitis and 1 also had features of lymphocytic colitis."
Quantifies the overlap with microscopic colitis in a collagenous sprue series, replacing a quote taken from a collagenous colitis review.
PMID:21523258 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"In collagenous sprue, concomitant collagen deposits may also occur in gastric or colonic mucosal sites (or both), indicating that this unusual mucosal process may be very heterogeneous and far more extensive in the intestinal tract than previously appreciated."
Supports treating the gastric and colonic collagenous lesions as extensions of the same process rather than as separate diseases to be excluded.
Refractory celiac disease Not Yet Curated MONDO:0018353
Overlapping Features Refractory celiac disease and collagenous sprue both present as villous atrophy that does not respond to a gluten-free diet, and they overlap: about half of the celiac patients in one collagenous sprue series had refractory disease. The collagen band separates them histologically, and aberrant intraepithelial lymphocyte phenotypes — the hallmark of type II refractory celiac disease — were absent throughout that series.
Distinguishing Features
  • Subepithelial collagen band present in collagenous sprue
  • Phenotypically aberrant intraepithelial lymphocytes in type II refractory celiac disease, not found in collagenous sprue
  • Documented celiac disease with initial gluten-free diet response precedes refractory celiac disease
Show evidence (3 references)
PMID:19855376 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Seventeen (89%) had celiac disease and two had unclassified sprue; 9 of 17 (53%) celiac disease patients had refractory disease"
Quantifies the overlap between collagenous sprue and refractory celiac disease.
PMID:19855376 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Phenotypically aberrant intraepithelial lymphocytes were not detected in any case."
Supports the distinguishing feature: the aberrant IEL phenotype that defines type II refractory celiac disease was absent from every collagenous sprue case here.
PMID:41341547 SUPPORT DIRECT BACKGROUND Human Clinical
"The clinical course of celiac disease may be complicated by the development of additional conditions such as microscopic colitis, refractory celiac disease or collagenous sprue."
Places the three conditions as alternative complications of celiac disease, which is why they must be differentiated. Marked BACKGROUND: the sentence is this case report's framing of established knowledge.
{ }

Source YAML

click to show 
name: Collagenous Sprue
creation_date: '2026-01-19T21:03:46Z'
description: >-
  Collagenous sprue is a rare malabsorptive small-bowel disorder defined
  histologically by abnormal deposition of a thickened subepithelial collagen band
  beneath the surface epithelium, accompanied by villous atrophy and intraepithelial
  lymphocytosis, with entrapment of lamina propria cellular elements within the band.
  Patients present with prolonged watery diarrhea, weight loss, malnutrition and
  severe malabsorption, and laboratory evidence of hypoalbuminemia, hypokalemia and
  anemia. Exposure to a drug associated with sprue-like enteropathy — most often an
  angiotensin receptor blocker — is common in reported cases. The disorder is
  associated with, but not equivalent to, celiac disease: it is frequently refractory
  to a gluten-free diet and occurs in patients who are celiac-seronegative and
  HLA-DQ2/DQ8-negative. Its aetiology and molecular pathogenesis remain
  uncharacterized.
category: Complex
disease_term:
  preferred_term: collagenous sprue
  term:
    id: MONDO:0044092
    label: collagenous sprue
parents:
- Enteropathy
- Malabsorption disorder
has_subtypes: []
pathophysiology:
- name: Mucosal immune activation with intraepithelial lymphocytosis
  description: >-
    Small-bowel biopsies in collagenous sprue show intraepithelial lymphocytosis and a
    lamina propria infiltrate that may include plasma cells, neutrophils and
    eosinophils, alongside the collagen band and villous atrophy. Clonal T-cell
    populations are detectable in a majority of tested cases, and clinical response to
    thiopurines — whose active metabolite induces T-cell apoptosis — is the main
    functional argument for a T-cell-driven process. The immune activation is
    dissociable from celiac disease: it occurs in patients with negative celiac
    serology and without the HLA-DQ2/DQ8 haplotypes. The upstream trigger is unknown.
  cell_types:
  - preferred_term: intraepithelial lymphocyte
    term:
      id: CL:0002496
      label: intraepithelial lymphocyte
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  - preferred_term: eosinophil
    term:
      id: CL:0000041
      label: mature eosinophil
  biological_processes:
  - preferred_term: T cell mediated immune response
    term:
      id: GO:0002292
      label: T cell differentiation involved in immune response
  - preferred_term: response to cytokine
    term:
      id: GO:0034097
      label: response to cytokine
  locations:
  - preferred_term: small intestinal mucosa
    term:
      id: UBERON:0002108
      label: small intestine
  - preferred_term: lamina propria
    term:
      id: UBERON:0000030
      label: lamina propria
  evidence:
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased numbers of plasma cells, neutrophils and/or eosinophils can be present in the lamina propria."
    explanation: >-
      Names the lamina propria infiltrate curated on this node, in a review of the
      collagenous sprue literature written by the authors of a dedicated case series.
  - reference: PMID:19641452
    reference_title: "Collagenous sprue: a clinicopathologic study of 12 cases."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Small intestinal biopsies showed subepithelial collagen deposition with varying degrees of villous atrophy and varying numbers of intraepithelial lymphocytes."
    explanation: >-
      Twelve-case series reporting intraepithelial lymphocytosis in collagenous sprue
      biopsies directly, rather than in a sibling collagenous disease.
  - reference: PMID:19641452
    reference_title: "Collagenous sprue: a clinicopathologic study of 12 cases."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clonal T-cell populations were identified in 5 of 6 cases tested."
    explanation: >-
      Supports a T-cell-driven process in collagenous sprue; note the same series found
      no lymphoma on follow-up, so clonality here is not itself a malignancy finding.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the 6-TG metabolites is 6-thioguanine-triphosphate, which is part of the 6-thioguaninenucleotides (6-TGN), and induces T-cell apoptosis, using a mitochondrial pathway"
    explanation: >-
      The authors' stated rationale for treating collagenous sprue with thioguanine.
      Graded INDIRECT: the mechanism is the drug's, and the inference that T cells drive
      the disease follows from the clinical response rather than from a measurement.
- name: Subepithelial collagen deposition with entrapment of lamina propria elements
  description: >-
    The defining lesion is a thickened band of collagen beneath the surface epithelium
    of the small bowel, confirmed as collagen by histochemical and ultrastructural
    study, which entraps capillaries, inflammatory cells and fibroblasts. Band
    thickness varies widely between cases and does not track symptom severity. The
    cellular and molecular drivers of the deposition — the fibroblast or myofibroblast
    population responsible, and the balance of collagen synthesis against matrix
    turnover — have not been characterized in collagenous sprue itself; see the
    `fibrogenic_mediators_uncharacterized` discussion.
  cell_types:
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  - preferred_term: capillary endothelial cell
    term:
      id: CL:0002144
      label: capillary endothelial cell
  biological_processes:
  - preferred_term: positive regulation of collagen biosynthetic process
    term:
      id: GO:0032965
      label: regulation of collagen biosynthetic process
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  locations:
  - preferred_term: subepithelial lamina propria
    term:
      id: UBERON:0000030
      label: lamina propria
  evidence:
  - reference: PMID:21631278
    reference_title: "Collagenous sprue: a rare, severe small-bowel malabsorptive disorder."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Collagenous sprue is a severe malabsorptive disorder, histologically characterized by small intestinal villous and crypt atrophy, and a subepithelial collagen deposit, thicker than 12 µm, that entraps lamina propria cellular elements."
    explanation: >-
      States the defining lesion of this node, including the entrapment of lamina propria
      elements, for collagenous sprue specifically.
  - reference: PMID:20082473
    reference_title: Update on collagenous sprue.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Histochemical stains and ultrastructural studies have confirmed that these deposits contain collagens."
    explanation: >-
      Establishes that the subepithelial deposits are collagen, rather than an
      unspecified hyaline material.
  - reference: PMID:19855376
    reference_title: "Collagenous sprue is not always associated with dismal outcomes: a clinicopathological study of 19 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subepithelial collagen thickness was mildly (n=6), moderately (n=10), or markedly (n=3) increased and villous atrophy was total (n=13) or subtotal (n=6)."
    explanation: >-
      Quantifies the range of collagen thickening and villous atrophy across a
      19-patient collagenous sprue series.
- name: Epithelial detachment and villous atrophy
  description: >-
    The collagen band is accompanied by epithelial detachment from the basement
    membrane and by villous atrophy that is total in roughly half of reported cases,
    producing the flattened mucosal lesion responsible for malabsorption. Histologic
    severity does not correlate with symptom severity, and histologic recovery lags
    clinical response to treatment — in one series the villous architecture normalized
    fully in only one of four clinically improved patients. Whether tight-junction
    proteins are involved has not been examined in collagenous sprue.
  biological_processes:
  - preferred_term: cell junction organization
    term:
      id: GO:0034330
      label: cell junction organization
  - preferred_term: epithelial cell differentiation
    term:
      id: GO:0030855
      label: epithelial cell differentiation
  locations:
  - preferred_term: duodenal mucosa
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to a thickened collagenous band, villous atrophy, intraepithelial lymphocytosis, detachment of the epithelium and entrapment of capillaries, inflammatory cells and fibroblasts within the collagen band can be found."
    explanation: >-
      Names epithelial detachment alongside villous atrophy as a feature of the
      collagenous sprue lesion.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of histological abnormality in collagenous sprue does not correlate with the severity of the clinical symptoms."
    explanation: >-
      Supports the dissociation between the histologic lesion and the clinical picture
      that this node records.
  - reference: PMID:20082473
    reference_title: Update on collagenous sprue.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathologically, a severe to variably severe \"flattened\" mucosal biopsy lesion with distinctive sub-epithelial deposits in the lamina propria region is detected."
    explanation: >-
      Describes the flattened mucosal lesion that underlies malabsorption in collagenous
      sprue.
phenotypes:
- name: Chronic watery diarrhea
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >-
    Prolonged watery diarrhea is the dominant presenting symptom, reported in roughly
    four out of five patients, with a median symptom duration of months before
    diagnosis. A minority of patients present without diarrhea.
  evidence:
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms were prolonged (median 36 weeks) with prominent diarrhea (median 6.5 stools/day) and frequent malnutrition and edema."
    explanation: >-
      Pooled patient-level analysis of 99 collagenous sprue cases quantifying diarrhea
      frequency and duration.
  - reference: PMID:27620860
    reference_title: Comparison of clinical features, treatment, and outcomes of collagenous sprue, celiac disease, and collagenous colitis.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall CS patients were more symptomatic with 17 (81.0%) patients with diarrhea and 15 (71.4%) with unintentional weight loss."
    explanation: >-
      Gives the proportion with diarrhea in a 21-patient collagenous sprue cohort
      compared directly against celiac disease and collagenous colitis.
  - reference: PMID:19855376
    reference_title: "Collagenous sprue is not always associated with dismal outcomes: a clinicopathological study of 19 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "5 of 15 (33%) lacked diarrhea (atypical presentation), including 2 of 6 (33%) with active (untreated) celiac disease and 3 of 9 (33%) with refractory celiac disease"
    explanation: >-
      Records the diarrhea-negative presentation, so the VERY_FREQUENT frequency band is
      not read as universal.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
    temporality: CHRONIC
- name: Weight loss
  category: Systemic
  frequency: VERY_FREQUENT
  description: >-
    Unintentional, often marked weight loss secondary to malabsorption and chronic
    diarrhea, reported in about seven of ten patients.
  evidence:
  - reference: PMID:27620860
    reference_title: Comparison of clinical features, treatment, and outcomes of collagenous sprue, celiac disease, and collagenous colitis.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall CS patients were more symptomatic with 17 (81.0%) patients with diarrhea and 15 (71.4%) with unintentional weight loss."
    explanation: >-
      Quantifies unintentional weight loss in a collagenous sprue cohort.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Main symptoms of collagenous sprue are unintentional weight loss and diarrhoea."
    explanation: >-
      Names weight loss as one of the two cardinal symptoms of collagenous sprue.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- name: Abdominal pain
  category: Gastrointestinal
  frequency: OCCASIONAL
  description: >-
    Abdominal or epigastric pain is reported in individual cases but is not among the
    cardinal features, and no cohort study quantifies it. Frequency is set to
    OCCASIONAL on case-level evidence alone.
  evidence:
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 1, a 77-year-old woman, presented with fatigue, unintentional weight loss of 10 kg in 4 months, loss of appetite, abdominal pain and varying stool consistency."
    explanation: >-
      A biopsy-confirmed collagenous sprue patient presenting with abdominal pain. This
      replaces a quote from a collagenous gastritis cohort that had been asserted for
      collagenous sprue.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
- name: Malabsorption
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >-
    Severe malabsorption with multiple nutrient deficiencies is intrinsic to the
    definition of the disorder and drives the biochemical picture of hypoalbuminemia,
    hypokalemia and anemia.
  evidence:
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
    explanation: >-
      Pooled laboratory data across 99 collagenous sprue patients establishing severe
      malabsorption.
  - reference: PMID:20082473
    reference_title: Update on collagenous sprue.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Collagenous sprue has traditionally been defined as a small intestinal mucosal disorder characterized by persistent diarrhea, severe malabsorption with multiple nutrient deficiencies and progressive weight loss."
    explanation: >-
      Places severe malabsorption with multiple nutrient deficiencies in the definition
      of the disorder.
  phenotype_term:
    preferred_term: Malabsorption
    term:
      id: HP:0002024
      label: Malabsorption
- name: Protein-losing enteropathy
  category: Gastrointestinal
  frequency: FREQUENT
  description: >-
    Enteric protein loss with consequent hypoalbuminemia and edema. Note the
    curation caveat: the pooled series reports edema and a median albumin of 2.9 g/dL
    but does not report faecal alpha-1-antitrypsin clearance or another direct measure
    of enteric protein loss, so the protein-losing mechanism is inferred from the
    albumin-plus-edema picture rather than measured. A dedicated case report of
    collagenous sprue presenting as protein-losing enteropathy exists (PMID:25514205)
    but its abstract carries no quotable finding beyond the title.
  evidence:
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms were prolonged (median 36 weeks) with prominent diarrhea (median 6.5 stools/day) and frequent malnutrition and edema."
    explanation: >-
      Frequent edema in a pooled collagenous sprue cohort with a median albumin of
      2.9 g/dL. Graded INDIRECT because enteric protein loss is the inference drawn from
      hypoalbuminemia plus edema in an enteropathy, not a reported measurement.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Main symptoms are unintentional weight loss, hypoalbuminaemia, diarrhoea, bloating and anaemia."
    explanation: >-
      Lists hypoalbuminaemia among the cardinal features, which is the observable
      consequence of the protein loss curated here.
  phenotype_term:
    preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
- name: Anemia
  category: Hematologic
  frequency: FREQUENT
  description: >-
    Anemia accompanying malabsorption, with a pooled median hemoglobin just under
    12 g/dL.
  evidence:
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
    explanation: >-
      Pooled hemoglobin across reported collagenous sprue patients.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory investigations showed anaemia, hypocalcaemia and hypoalbuminaemia."
    explanation: >-
      Laboratory findings in a biopsy-confirmed collagenous sprue patient.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
- name: Hypoalbuminemia
  category: Metabolic
  frequency: FREQUENT
  description: >-
    Low serum albumin, with a pooled median of 2.9 g/dL, reflecting malabsorption and
    enteric protein loss.
  evidence:
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
    explanation: >-
      Reports the pooled median serum albumin directly.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Main symptoms are unintentional weight loss, hypoalbuminaemia, diarrhoea, bloating and anaemia."
    explanation: >-
      Names hypoalbuminaemia among the cardinal features of collagenous sprue.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
biochemical:
- name: Serum albumin
  presence: Decreased
  context: >-
    Diagnostic and monitoring indicator of malabsorption severity; pooled median
    2.9 g/dL across reported cases.
  evidence:
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
    explanation: >-
      Direct pooled measurement of serum albumin in collagenous sprue.
- name: Hemoglobin
  presence: Decreased
  context: Marker of the anemia accompanying malabsorption; pooled median 11.95 g/dL.
  evidence:
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
    explanation: >-
      Direct pooled measurement of hemoglobin in collagenous sprue.
- name: Serum potassium
  presence: Decreased
  context: >-
    Marker of severe secretory/osmotic stool losses; pooled median 2.6 mEq/L, which is
    in the range that prompts inpatient repletion.
  evidence:
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings reflected severe malabsorption (median albumin 2.9 g/dL; potassium 2.6 mEq/L; hemoglobin 11.95 g/dL)."
    explanation: >-
      Direct pooled measurement of serum potassium in collagenous sprue. This record
      replaces a Serum iron row whose quote reported neither iron nor a deficiency.
- name: Tissue transglutaminase (tTG) antibodies
  presence: Usually negative
  context: >-
    Helps separate collagenous sprue from celiac disease, though a minority of patients
    are seropositive because the two conditions co-occur.
  evidence:
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeated coeliac serology in our clinic showed no antibodies against tissue transglutaminase and endomysium and no IgA deficiency."
    explanation: >-
      A collagenous sprue patient in whom repeat tTG and endomysial serology was
      negative, which is what led to the celiac diagnosis being withdrawn.
  - reference: PMID:27620860
    reference_title: Comparison of clinical features, treatment, and outcomes of collagenous sprue, celiac disease, and collagenous colitis.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Positive celiac serology was noted in 5 (23.8%) CS patients."
    explanation: >-
      Quantifies the seropositive minority, supporting "usually negative" rather than
      "negative" as the recorded presence.
genetic:
- name: HLA-DQA1
  gene_term:
    preferred_term: HLA-DQA1
    term:
      id: hgnc:4942
      label: HLA-DQA1
  association: Contested susceptibility locus, inherited through the celiac association
  relationship_type: SUSCEPTIBILITY
  notes: >-
    The HLA link to collagenous sprue is entirely indirect: it is inherited from the
    frequent co-occurrence with celiac disease, which is HLA-DQ2/DQ8-restricted. No
    study has typed HLA in an unselected collagenous sprue cohort and found an
    association independent of celiac disease, and the one series that typed all its
    patients found them uniformly DQ2/DQ8-negative. Both directions are cited below.
  evidence:
  - reference: PMID:19855376
    reference_title: "Collagenous sprue is not always associated with dismal outcomes: a clinicopathological study of 19 patients."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventeen (89%) had celiac disease and two had unclassified sprue; 9 of 17 (53%) celiac disease patients had refractory disease"
    explanation: >-
      In this referral series almost all collagenous sprue patients had celiac disease,
      which carries the HLA-DQ2/DQ8 restriction. Graded INDIRECT: the HLA claim follows
      from the celiac diagnosis rather than from HLA typing reported here.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: REFUTE
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the patients had ever had coeliac-specific antibodies, and all were negative for HLA-DQ2 and HLA-DQ8 phenotype."
    explanation: >-
      Four consecutive biopsy-confirmed collagenous sprue patients were all
      HLA-DQ2/DQ8-negative, so the haplotypes are not required for the disorder. This is
      the direct refutation of an HLA-restricted model of collagenous sprue.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: REFUTE
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evaluating the cases in this study, all four patients were negative for HLA-DQ2 and HLA-DQ8, with negative coeliac serology, which proves that CS can occur in the absence of CD."
    explanation: >-
      The authors' own statement that collagenous sprue occurs without celiac disease,
      which is the link the HLA association depends on.
environmental:
- name: Medications (Angiotensin II Receptor Blockers)
  notes: >-
    ARB exposure, olmesartan most often, is the best-characterized trigger. Drug
    withdrawal is part of first-line management.
  effect: Triggers collagenous sprue in exposed patients; withdrawal is followed by
    clinical improvement
  evidence:
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exposure to medications associated with sprue-like enteropathy was common when reported (30/38, 79%), most often angiotensin receptor blockers."
    explanation: >-
      Quantifies how often a drug exposure — usually an ARB — is present in reported
      collagenous sprue cases.
  - reference: PMID:39606500
    reference_title: Pathognomonic Features of Olmesartan-Induced Collagenous Sprue Resulting in Severe Small Bowel Malabsorption.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case report highlights the diagnostic challenges and clinical features of CS in a 74-year-old woman, whose symptoms resolved following cessation of olmesartan. The case emphasizes the importance of recognizing medication-induced forms of the disease"
    explanation: >-
      Dechallenge case demonstrating olmesartan as a direct trigger, with resolution
      after withdrawal.
  - reference: PMID:26997446
    reference_title: "Olmesartan-associated sprue-like enteropathy: a systematic review with emphasis on histopathology."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "This syndrome is characterized by severe diarrhea and sprue-like histopathologic findings in the intestine, often with increased subepithelial collagen."
    explanation: >-
      Links the ARB-associated enteropathy to increased subepithelial collagen, which is
      the lesion that defines collagenous sprue.
  - reference: PMID:26997446
    reference_title: "Olmesartan-associated sprue-like enteropathy: a systematic review with emphasis on histopathology."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "It is also not well established if other ARBs cause such a syndrome, although case reports suggest they can."
    explanation: >-
      Qualifies the class-wide claim: the evidence outside olmesartan is case-level, so
      "and other ARBs" is weaker than the olmesartan association.
- name: Medications (NSAIDs and clofazimine)
  notes: >-
    Reported as suggested associations only. This record was previously titled
    "Proton Pump Inhibitors and NSAIDs" and cited a quote that named neither; PPIs are
    dropped because the same literature lists high-dose PPI as an attempted
    *treatment* for collagenous sprue, not as a trigger.
  effect: Suggested, not established, triggers
  evidence:
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "A relationship with the usage of non-steroidal anti-inflammatory drugs (NSAIDs), olmesartan and clofazimine, has also been suggested."
    explanation: >-
      Names NSAIDs and clofazimine as suggested drug associations of collagenous sprue.
      Graded INDIRECT because the authors report these as suggestions in the literature
      rather than as a measured association.
treatments:
- name: Gluten-free diet
  description: >-
    A gluten-free diet is standard first-line management, reflecting both the frequent
    co-occurrence with celiac disease and the fact that collagenous sprue is often
    first mistaken for it. Response is partial: fewer than half of patients improve on
    diet alone, and failure to respond is one of the features that raises the
    diagnosis.
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:19855376
    reference_title: "Collagenous sprue is not always associated with dismal outcomes: a clinicopathological study of 19 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, 8 of 19 (42%) responded to gluten-free diet, including 2 of 9 (22%) with refractory celiac disease and 10 responded to immunomodulatory therapy, including 6 of 9 (67%) with refractory celiac disease."
    explanation: >-
      Quantifies gluten-free diet response, and the larger response to immunomodulatory
      therapy, in a collagenous sprue series.
  - reference: PMID:20082473
    reference_title: Update on collagenous sprue.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Often, an initial diagnosis of celiac disease is considered but no continued response to treatment with a gluten-free diet occurs."
    explanation: >-
      States the characteristic loss of response to a gluten-free diet, which is why
      diet alone is not sufficient management.
  treatment_term:
    preferred_term: gluten-free diet
    term:
      id: NCIT:C15447
      label: Dietary Intervention
- name: Corticosteroids (Budesonide)
  description: >-
    Corticosteroids, alone or combined with a gluten-free diet, are the mainstay of
    treatment, and budesonide is the agent used when topical gastrointestinal activity
    is wanted. Symptomatic response is common and often rapid.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:27620860
    reference_title: Comparison of clinical features, treatment, and outcomes of collagenous sprue, celiac disease, and collagenous colitis.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty CS patients received treatments, including the combination of gluten-free diet (GFD) and corticosteroids (n = 12), GFD only (n = 2), and corticosteroids only (n = 6). All CS patients showed symptomatic reliefs with treatment."
    explanation: >-
      Direct treatment-outcome data for corticosteroids in a collagenous sprue cohort.
      This replaces a microscopic colitis pathogenesis sentence that named no treatment.
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment commonly combined nutritional rehabilitation (often parenteral nutrition), gluten-free diet, withdrawal of suspected medications and corticosteroids."
    explanation: >-
      Establishes corticosteroids as part of the usual regimen across five decades of
      reported cases.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients were treated with a combination of 6-TG and budesonide, and 1 patient received 6-TG only. All patients improved remarkably."
    explanation: >-
      Names budesonide specifically as the corticosteroid used in collagenous sprue.
  treatment_term:
    preferred_term: topical corticosteroid therapy
    term:
      id: NCIT:C122078
      label: Topical Corticosteroid Therapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C1909
          label: Pharmacologic Substance
      value:
        preferred_term: budesonide
        term:
          id: NCIT:C1027
          label: Budesonide
    - predicate:
        preferred_term: route of administration
        term:
          id: NCIT:C38114
          label: Route of Administration
      value:
        preferred_term: gastrointestinal route
        term:
          id: NCIT:C38209
          label: Enteral Route of Administration
- name: Thiopurines (Azathioprine/6-Thioguanine)
  description: >-
    Thiopurines are used for collagenous sprue that does not respond to diet and
    steroids. Thioguanine with or without budesonide produced clinical improvement in
    all four patients of the only dedicated series, with histologic normalization of
    the collagen band in two and full villous recovery in one; symptoms recurred on
    withdrawal in one patient and remitted again on rechallenge.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Normalisation of the thickened basement membrane was found in 2 patients and complete histological improvement including full recovery of villi was found in 1 patient."
    explanation: >-
      Histologic outcome of thioguanine treatment in biopsy-confirmed collagenous sprue.
      This replaces a quote that described a patient's presentation and mentioned no
      thiopurine.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "At least one positive experience with another thiopurine, azathiopurine, together with steroids is described in the literature, with clinical and total histological improvement."
    explanation: >-
      Supports the azathioprine arm of this record. Graded INDIRECT because it is the
      authors' report of someone else's case rather than their own result.
  treatment_term:
    preferred_term: immunosuppressive therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azathioprine
      term:
        id: CHEBI:2948
        label: azathioprine
- name: Anti-TNF-α Therapy
  description: >-
    Anti-TNF monoclonal antibody therapy appears in the collagenous sprue treatment
    literature as one of several options tried in refractory disease. No series
    reports its outcome separately, so this record is a catalogue entry rather than an
    established therapy.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  evidence:
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "A variety of therapeutic options have been described, including a GFD, milk-free diet, corticosteroids (including budesonide SR), sulfasalazine, cyclosporine, azathioprine, high-dose proton pump inhibitor and monoclonal tumour necrosis factor-α antibody"
    explanation: >-
      Places anti-TNF antibody among the reported treatment options for collagenous
      sprue. Graded INDIRECT because the sentence catalogues options without reporting
      an outcome; the same paragraph adds that no adequate therapy has been found.
      Replaces a collagenous gastritis symptom quote that named no treatment.
  treatment_term:
    preferred_term: immunosuppressive therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: infliximab
      term:
        id: NCIT:C1789
        label: Infliximab
- name: Calcineurin Inhibitors (Tacrolimus)
  description: >-
    Tacrolimus is a calcineurin inhibitor reported for severe, treatment-refractory
    collagenous sprue with intestinal failure. The evidence is a single case.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:39046809
    reference_title: Successful Long-Term Treatment of Collagenous Sprue With Tacrolimus in a 25-Year-Old With Severe Intestinal Failure.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 25-year-old male presented with chronic watery diarrhea and severe intestinal failure due to collagenous sprue. Treatments, including immunosuppressants and a gluten-free diet, were ineffective. Tacrolimus shows promise in treating refractory cases."
    explanation: >-
      Single-patient report of tacrolimus in refractory collagenous sprue with intestinal
      failure.
  treatment_term:
    preferred_term: immunosuppressive therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tacrolimus
      term:
        id: CHEBI:61049
        label: tacrolimus (anhydrous)
- name: Medication discontinuation (Olmesartan withdrawal)
  description: >-
    Reviewing the medication list and withdrawing a suspected culprit — in practice
    usually an ARB — is part of first-line management, and symptomatic improvement
    after withdrawal is the rule in drug-associated cases.
  evidence:
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "CS is profoundly morbid but frequently improves with early recognition, medication review and withdrawal, aggressive nutritional support and steroid-based therapy, although relapse and mortality remain substantial."
    explanation: >-
      Places medication review and withdrawal in the management of collagenous sprue, and
      keeps the authors' caveat about relapse and mortality attached.
  - reference: PMID:39606500
    reference_title: Pathognomonic Features of Olmesartan-Induced Collagenous Sprue Resulting in Severe Small Bowel Malabsorption.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case report highlights the diagnostic challenges and clinical features of CS in a 74-year-old woman, whose symptoms resolved following cessation of olmesartan. The case emphasizes the importance of recognizing medication-induced forms of the disease"
    explanation: >-
      Documents symptom resolution in collagenous sprue after the culprit ARB was
      stopped.
  - reference: PMID:35945664
    reference_title: The histological spectrum of ARB-induced gastritis.
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following drug cessation, symptomatic improvement occurred in all 11 cases for which follow-up data were available. Histological resolution occurred in five of eight cases with follow-up gastric biopsies"
    explanation: >-
      Dechallenge outcome in an ARB-injury cohort in which 11 of 13 patients with
      duodenal biopsies had duodenal involvement including collagenous sprue. Graded
      INDIRECT because the reported follow-up biopsies are gastric, so the histologic
      resolution figure is not a collagenous sprue measurement.
  treatment_term:
    preferred_term: medication management
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Nutritional support and supplementation
  description: >-
    Nutritional rehabilitation, frequently including parenteral nutrition, is a routine
    part of management and is needed more often than in celiac disease or collagenous
    colitis.
  evidence:
  - reference: PMID:41854086
    reference_title: "Collagenous sprue across five decades (1970-2025): a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment commonly combined nutritional rehabilitation (often parenteral nutrition), gluten-free diet, withdrawal of suspected medications and corticosteroids."
    explanation: >-
      Establishes nutritional rehabilitation, often parenteral, as a usual component of
      collagenous sprue treatment.
  - reference: PMID:27620860
    reference_title: Comparison of clinical features, treatment, and outcomes of collagenous sprue, celiac disease, and collagenous colitis.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "CS patients had higher rates for disease-related temporary total parenteral nutrition (TPN) use (38.1% vs. 1.1% vs. 1.0%, P < 0.0001) and disease-related hospitalization (52.4% vs. 3.3% vs. 8.2%, P < 0.0001) than that in CD and CC patients."
    explanation: >-
      Quantifies parenteral nutrition use in collagenous sprue against its two closest
      differentials, which is the evidence that this is a disease-specific need.
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
differential_diagnoses:
- name: Celiac disease
  disease_term:
    preferred_term: celiac disease
    term:
      id: MONDO:0005130
      label: celiac disease
  description: >-
    Celiac disease shares chronic diarrhea, weight loss and villous atrophy with
    collagenous sprue and frequently co-occurs with it, so the two are separated
    histologically by the subepithelial collagen band rather than clinically. Most
    collagenous sprue patients are celiac-seronegative, and collagenous sprue patients
    are more symptomatic and need parenteral nutrition and hospitalization far more
    often than celiac patients.
  distinguishing_features:
  - Subepithelial collagen band present in collagenous sprue, absent in celiac disease
  - Positive tTG and endomysial antibodies in most celiac patients; positive in about a
    quarter of collagenous sprue patients
  - HLA-DQ2/DQ8 restriction in celiac disease; collagenous sprue occurs in DQ2/DQ8-negative
    patients
  - Sustained response to gluten-free diet in celiac disease; fewer than half of
    collagenous sprue patients respond to diet alone
  evidence:
  - reference: PMID:27620860
    reference_title: Comparison of clinical features, treatment, and outcomes of collagenous sprue, celiac disease, and collagenous colitis.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Collagenous sprue patients had more severe clinical presentation than patients with CD and CC and therefore had higher demand for temporary TPN and hospitalization."
    explanation: >-
      Head-to-head comparison of collagenous sprue against celiac disease and collagenous
      colitis, which is the discriminating clinical observation curated here.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "CS should be separated from coeliac disease."
    explanation: >-
      The authors' conclusion that the two are distinct entities, reached from uniformly
      negative celiac serology and HLA typing in their patients.
  - reference: PMID:40177217
    reference_title: "Coexisting Collagenous Sprue and Celiac Disease: A Case Report."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of a subepithelial collagen band on histology differentiates CS from celiac disease, as both have villous blunting."
    explanation: >-
      States the histologic discriminator. Marked BACKGROUND: the sentence is the case
      report's framing of established practice, not its own finding.
- name: Microscopic colitis
  disease_term:
    preferred_term: microscopic colitis
    term:
      id: MONDO:0000702
      label: microscopic colitis
  description: >-
    Collagenous colitis, the collagen-band subtype of microscopic colitis, is the
    colonic counterpart of the same lesion and co-occurs with collagenous sprue in a
    substantial fraction of cases, so the distinction is one of site and extent rather
    than of a different process. Colonic biopsies are therefore part of the workup
    rather than an alternative to small-bowel biopsy.
  distinguishing_features:
  - Collagen band in colonic mucosa in collagenous colitis, small-bowel mucosa in
    collagenous sprue
  - Villous atrophy is intrinsic to collagenous sprue and absent from a purely colonic
    process
  - Concurrent collagenous colitis is present in a large minority of collagenous sprue
    patients, so the two are not mutually exclusive
  evidence:
  - reference: PMID:19641452
    reference_title: "Collagenous sprue: a clinicopathologic study of 12 cases."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven cases were associated with collagenous colitis and 1 also had features of lymphocytic colitis."
    explanation: >-
      Quantifies the overlap with microscopic colitis in a collagenous sprue series,
      replacing a quote taken from a collagenous colitis review.
  - reference: PMID:21523258
    reference_title: Collagenous sprue.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "In collagenous sprue, concomitant collagen deposits may also occur in gastric or colonic mucosal sites (or both), indicating that this unusual mucosal process may be very heterogeneous and far more extensive in the intestinal tract than previously appreciated."
    explanation: >-
      Supports treating the gastric and colonic collagenous lesions as extensions of the
      same process rather than as separate diseases to be excluded.
- name: Refractory celiac disease
  disease_term:
    preferred_term: refractory celiac disease
    term:
      id: MONDO:0018353
      label: refractory celiac disease
  description: >-
    Refractory celiac disease and collagenous sprue both present as villous atrophy
    that does not respond to a gluten-free diet, and they overlap: about half of the
    celiac patients in one collagenous sprue series had refractory disease. The
    collagen band separates them histologically, and aberrant intraepithelial
    lymphocyte phenotypes — the hallmark of type II refractory celiac disease — were
    absent throughout that series.
  distinguishing_features:
  - Subepithelial collagen band present in collagenous sprue
  - Phenotypically aberrant intraepithelial lymphocytes in type II refractory celiac
    disease, not found in collagenous sprue
  - Documented celiac disease with initial gluten-free diet response precedes refractory
    celiac disease
  evidence:
  - reference: PMID:19855376
    reference_title: "Collagenous sprue is not always associated with dismal outcomes: a clinicopathological study of 19 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventeen (89%) had celiac disease and two had unclassified sprue; 9 of 17 (53%) celiac disease patients had refractory disease"
    explanation: >-
      Quantifies the overlap between collagenous sprue and refractory celiac disease.
  - reference: PMID:19855376
    reference_title: "Collagenous sprue is not always associated with dismal outcomes: a clinicopathological study of 19 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypically aberrant intraepithelial lymphocytes were not detected in any case."
    explanation: >-
      Supports the distinguishing feature: the aberrant IEL phenotype that defines type
      II refractory celiac disease was absent from every collagenous sprue case here.
  - reference: PMID:41341547
    reference_title: "[Collagenous Sprue, Collagenous Gastritis, and an Uncommon Association with Inflammatory Bowel Disease: A Case Report]."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical course of celiac disease may be complicated by the development of additional conditions such as microscopic colitis, refractory celiac disease or collagenous sprue."
    explanation: >-
      Places the three conditions as alternative complications of celiac disease, which
      is why they must be differentiated. Marked BACKGROUND: the sentence is this case
      report's framing of established knowledge.
discussions:
- discussion_id: fibrogenic_mediators_uncharacterized
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Subepithelial collagen deposition with entrapment of lamina propria
    elements
  - genetic#
  prompt: >-
    Which cells deposit the collagen band in collagenous sprue, and what shifts the
    balance between matrix synthesis and matrix turnover in favour of accumulation?
  rationale: >-
    This entry previously carried five gene records — TGFB1, MMP1, MMP9, TIMP1 and
    TJP1 — each asserting a direction of change (TGF-beta driven fibroblast activation,
    reduced MMP activity, elevated TIMP1, reduced ZO-1). Every one of them was
    supported only by a histology sentence that named no gene, transcript or protein,
    and two of those sentences came from papers about collagenous gastritis and
    ARB-induced gastritis rather than about collagenous sprue. The records have been
    removed rather than re-sourced, because the searches run for this re-curation found
    no study that measures any of these mediators in collagenous sprue tissue. The
    model is plausible and is imported wholesale from collagenous colitis and from
    general gut-fibrosis biology; importing it was how the entity confusion this issue
    tracks got in. It is recorded here as an open question so that a future study can
    reinstate the nodes with real measurements.
  evidence:
  - reference: PMID:21523258
    reference_title: Collagenous sprue.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Future studies are needed to more precisely define molecular and genetic biomarkers that identify homogeneous groups and permit the development of improved treatment strategies for this increasingly recognized disorder."
    explanation: >-
      A review of collagenous sprue stating that the molecular and genetic biomarkers
      are still undefined, which is the gap recorded here.
  - reference: PMID:27486523
    reference_title: The first cases of collagenous sprue successfully treated with thioguanine.
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Little is known about the aetiology and pathogenesis of this disease."
    explanation: >-
      Independent statement that the pathogenesis is uncharacterized.
  notes: >-
    Resolving this needs tissue-level work — immunohistochemistry or transcriptomics on
    collagenous sprue duodenal biopsies against celiac and normal controls — not another
    literature pass.
- discussion_id: hla_association_is_inherited_from_celiac
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - genetic#HLA-DQA1
  prompt: >-
    Is there an HLA association with collagenous sprue that is independent of its
    co-occurrence with celiac disease?
  rationale: >-
    Referral series report celiac disease in up to 89% of collagenous sprue patients,
    which makes an HLA-DQ2/DQ8 enrichment inevitable without implying that HLA
    predisposes to the collagen band. The one series that typed all its patients found
    them uniformly DQ2/DQ8-negative and celiac-seronegative, and concluded that
    collagenous sprue should be separated from celiac disease. The two positions are
    both cited on the HLA-DQA1 record, one as SUPPORT and one as REFUTE. Ascertainment
    is the likely explanation for the difference — the 89% figure comes from a celiac
    referral centre's pathology database — but no study has tested that.
  evidence:
  - reference: PMID:19641452
    reference_title: "Collagenous sprue: a clinicopathologic study of 12 cases."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Collagenous sprue evolved on a background of CD in 4 cases. There was no history of CD in others and these cases may be the result of a biologic insult other than gluten sensitivity."
    explanation: >-
      A series in which only a third of cases arose on a celiac background, supporting a
      celiac-independent route into the disorder.
  - reference: PMID:21631278
    reference_title: "Collagenous sprue: a rare, severe small-bowel malabsorptive disorder."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Its exact etiology is still under investigation, and its relationship with classic celiac disease and other refractory, spruelike intestinal disorders remains controversial."
    explanation: >-
      States that the relationship to celiac disease is itself contested, which is the
      controversy recorded here.
- discussion_id: pulmonary_hemosiderosis_differential_removed
  kind: CURATION_TODO
  status: RESOLVED
  attaches_to:
  - differential_diagnoses#
  prompt: >-
    Should pulmonary hemosiderosis be listed as a differential diagnosis of collagenous
    sprue?
  rationale: >-
    No. The record has been removed. It claimed that "collagenous sprue can have
    pulmonary manifestations through shared immune mechanisms" and cited a sentence
    about collagenous colitis that mentions no lung disease; nothing in the collagenous
    sprue literature reviewed for this re-curation reports pulmonary involvement. The
    entry is almost certainly a confusion with the celiac disease / idiopathic
    pulmonary hemosiderosis (Lane-Hamilton syndrome) association, which belongs to
    celiac disease and not to collagenous sprue, and which is not a differential
    diagnosis in either case — it is a comorbidity. Recorded rather than silently
    dropped so the concept is not re-nominated.
  resolution_note: >-
    Removed in the #10630 re-curation. If a collagenous sprue case with pulmonary
    hemosiderosis is ever reported, it belongs in a comorbidity or association record,
    not in differential_diagnoses.
references:
- reference: PMID:22728033
  title: Severe spruelike enteropathy associated with olmesartan.
  findings: []
- reference: PMID:19764099
  title: Free perforation of the small intestine in collagenous sprue.
  findings: []
- reference: PMID:35485780
  title: "[Collagenous sprue in a patient with severe diarrhoea, malnutrition and acute renal failure]."
  findings: []
- reference: PMID:25514205
  title: "A rare cause of protein losing enteropathy: collagenous sprue."
  findings: []
- reference: PMID:37070112
  title: "Collagenous sprue: a rare cause of watery diarrhea and villous atrophy - case report."
  findings: []
notes: >-
  Collagenous sprue is defined by a histologic lesion rather than by an aetiology, and
  more than one route appears to lead to it: an ARB or other drug exposure, a
  background of celiac disease, and — in patients who are celiac-seronegative and
  HLA-DQ2/DQ8-negative — neither. The entry therefore records the drug trigger and the
  celiac association as separate, non-exclusive contributions rather than as one causal
  chain. Prognosis is not uniform: a referral series reported good outcomes with only
  one death, while the pooled five-decade analysis reports 23% mortality among patients
  with known vital status, and the difference is likely ascertainment.
review_notes: >-
  Evidence re-curated 2026-09-16 against monarch-initiative/dismech#10630, which found
  that only 9 of 35 evidence items supported the claim they were attached to; the rest
  quoted real papers about collagenous gastritis, collagenous colitis, microscopic
  colitis or ARB-induced gastritis and asserted the finding for collagenous sprue. All
  six DOI:10.1093/ecco-jcc/jjab123 items and the PMID:34272945 duplicate of the same
  microscopic colitis review are gone, so the citation is no longer split across a
  gate-covered and a skip_prefixes form. Five gene records with no molecular evidence
  (TGFB1, MMP1, MMP9, TIMP1, TJP1) were removed and the open question recorded as the
  `fibrogenic_mediators_uncharacterized` discussion; the `Pulmonary hemosiderosis`
  differential was removed and the reasoning recorded as
  `pulmonary_hemosiderosis_differential_removed`. A `Serum iron` biochemical record
  whose quote reported neither iron nor a deficiency was replaced by `Serum potassium`,
  which the pooled series measures. The one remaining sibling-disease citation
  (PMID:35945664, ARB-induced gastritis) is kept only on medication withdrawal, graded
  INDIRECT, with the gastric-versus-duodenal limitation stated in its explanation.
📚

References & Deep Research

References

5
PMID:22728033
Severe spruelike enteropathy associated with olmesartan.
No top-level findings curated for this source.
PMID:19764099
Free perforation of the small intestine in collagenous sprue.
No top-level findings curated for this source.
PMID:35485780
[Collagenous sprue in a patient with severe diarrhoea, malnutrition and acute renal failure].
No top-level findings curated for this source.
PMID:25514205
A rare cause of protein losing enteropathy: collagenous sprue.
No top-level findings curated for this source.
PMID:37070112
Collagenous sprue: a rare cause of watery diarrhea and villous atrophy - case report.
No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

  • Name: Collagenous Sprue
  • Category: Complex
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 42

Key Pathophysiology Nodes

  • Mucosal immune activation with intraepithelial lymphocytosis
  • Epithelial barrier dysfunction and tight junction disruption
  • Subepithelial collagen deposition and fibrotic remodeling
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1016/j.humpath.2015.12.001
  • DOI:10.1016/j.mayocp.2012.06.003
  • DOI:10.1093/ecco-jcc/jjab123
  • DOI:10.20524/aog.2017.0146
  • DOI:10.3748/wjg.15.4446
  • DOI:10.3748/wjg.v16.i3.296
  • DOI:10.4103/jnsbm.jnsbm_184_17
  • DOI:10.52787/agl.v54i3.383
  • DOI:10.7759/cureus.72571
Falcon ▸
Pathophysiology description
Edison Scientific Literature 30 citations 2026-01-19T15:23:26.487644

Pathophysiology description Collagenous sprue (CS) is a rare enteropathy of the small intestine defined by villous atrophy with a thickened, irregular subepithelial collagen band (>10 μm) that may entrap capillaries and stromal cells, accompanied by intraepithelial lymphocytosis and lamina propria inflammation; endoscopically, diffuse villous blunting and scalloping may be seen, but diagnosis requires histology (trichrome) (mirakhor2021collagenousenteritis–analternative pages 1-3, moreno2024spruecolágenogastritis pages 1-2, moreno2024spruecolágenogastritis pages 4-5). Clinically, patients present with chronic watery diarrhea, profound weight loss, malabsorption, protein‑losing enteropathy, anemia, and hypoalbuminemia; CS often mimics celiac disease but typically shows negative celiac serology and poor response to a gluten‑free diet (mirakhor2021collagenousenteritis–analternative pages 1-3, moreno2024spruecolágenogastritis pages 1-2, mirakhor2021collagenousenteritis–analternative pages 3-4).

Core Pathophysiology - Primary mechanisms: (1) mucosal immune activation with increased intraepithelial lymphocytes (IELs) and lamina propria inflammation; (2) epithelial barrier injury with crypt apoptosis and tight‑junction perturbation; and (3) fibroblast/myofibroblast activation leading to excessive extracellular matrix (ECM) deposition and a diagnostic subepithelial collagen band, plausibly due to TGF‑β–driven profibrotic signaling together with an imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, zabana2022pathogenesisofmicroscopic pages 10-11, valatas2017stromalandimmune pages 3-4, xiao2009collagenousspruea pages 3-4). - Dysregulated pathways: Evidence (largely inferential and by analogy to collagenous colitis and intestinal fibrosis) supports roles for TGFB1 signaling, increased TIMP1 with relative reductions/restrictions in MMP1/9 activity, IL‑15/TNF‑α–associated IEL activation and epithelial apoptosis, and barrier protein disruption (ZO‑1/TJP1) (zabana2022pathogenesisofmicroscopic pages 10-11, burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, valatas2017stromalandimmune pages 3-4, xiao2009collagenousspruea pages 3-4). - Affected cellular processes: epithelial apoptosis and tight‑junction impairment; fibroblast→myofibroblast differentiation with α‑SMA expression and increased collagen I production; impaired fibrolysis due to MMP/TIMP imbalance; immune cell infiltration (IELs, plasma cells, eosinophils) (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, valatas2017stromalandimmune pages 3-4, xiao2009collagenousspruea pages 3-4, moreno2024spruecolágenogastritis pages 4-5).

Recent developments and latest research (prioritize 2023–2024) - 2024 case‑based review emphasizes CS’s association with collagenous gastritis/colitis, autoimmune comorbidities, and severe complications (ulceration, perforation, lymphoma), while also noting some recent reports of favorable responses to immunosuppression (Spanish; full text with diagnostic details including the >10 μm band cutoff and entrapped capillaries) (Sep 2024, Acta Gastroenterológica Latinoamericana; https://doi.org/10.52787/agl.v54i3.383) (moreno2024spruecolágenogastritis pages 1-2, moreno2024spruecolágenogastritis pages 4-5, moreno2024spruecolágenogastritis pages 2-4). - 2024 case report of olmesartan‑induced collagenous sprue underscores medication‑triggered disease and rapid clinical improvement after drug withdrawal, reinforcing drug‑induced immune/injury mechanisms (Oct 2024, Cureus; https://doi.org/10.7759/cureus.72571) (goshgarian2024pathognomonicfeaturesof pages 1-2). - Ongoing synthesis from foundational studies continues to support immune‑mediated mechanisms including IEL activation, crypt apoptosis, and epithelial barrier protein alterations (ZO‑1/TJP1) in ARB enteropathy overlapping with CS (Human Pathology 2016; https://doi.org/10.1016/j.humpath.2015.12.001) (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, burbure2016olmesartanassociatedspruelikeenteropathy pages 3-5).

Current applications and real‑world implementations - Diagnostic criteria and practice: Recognition that the collagen band threshold >10 μm with trichrome positivity and entrapped capillaries, paired with villous atrophy and intraepithelial lymphocytosis, is key for diagnosis; multi‑segment evaluation (stomach, colon) is advocated when CS is suspected (moreno2024spruecolágenogastritis pages 4-5, sharma2018collagenousgastritisa pages 1-2, mirakhor2021collagenousenteritis–analternative pages 3-4). - Medication review and withdrawal: Systematic collection of medication history, particularly ARBs such as olmesartan, PPIs, and NSAIDs, and prompt withdrawal in suspected drug‑induced cases; many patients exhibit clinical and histologic reversal within months (Mayo Clinic Proc 2012; Hum Pathol 2016) (rubiotapia2012severespruelikeenteropathy pages 5-7, burbure2016olmesartanassociatedspruelikeenteropathy pages 3-5). - Immunosuppression: Corticosteroids (including budesonide) remain first‑line in many reports; refractory cases may respond to thiopurines or TNF‑α inhibitors, though evidence derives from case series and case reports (mirakhor2021collagenousenteritis–analternative pages 3-4, xiao2009collagenousspruea pages 5-6).

Expert opinions and analysis from authoritative sources - Mayo Clinic series: Olmesartan‑associated sprue‑like enteropathy likely reflects a delayed cell‑mediated immune reaction in genetically predisposed patients (frequent HLA‑DQ2), with histologic overlap with CS (villous atrophy, IELs, collagen band); clinical and histologic recovery follows drug cessation (Aug 2012, Mayo Clinic Proceedings; https://doi.org/10.1016/j.mayocp.2012.06.003) (rubiotapia2012severespruelikeenteropathy pages 5-7, rubiotapia2012severespruelikeenteropathy pages 3-4). - Systematic review emphasis: Immune‑mediated injury plus epithelial barrier disruption (including reports of ZO‑1/TJP1 alterations) underlie ARB enteropathy; frequent collagen deposition links drug‑induced enteropathy to CS phenotype (Apr 2016, Human Pathology; https://doi.org/10.1016/j.humpath.2015.12.001) (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, burbure2016olmesartanassociatedspruelikeenteropathy pages 5-7, burbure2016olmesartanassociatedspruelikeenteropathy pages 3-5). - Intestinal fibrosis frameworks: In gut fibrosis, TGF‑β–driven myofibroblast activation, TIMP1 upregulation, and reduced MMP activity drive ECM accumulation—mechanisms broadly consistent with the collagen band in CS (Apr 2017, Annals of Gastroenterology; https://doi.org/10.20524/aog.2017.0146) (valatas2017stromalandimmune pages 3-4, valatas2017stromalandimmune pages 2-3).

Relevant statistics and data from recent studies - Demographics: Reported across ages 2–85 years with ~2:1 female predominance; many cases severe with marked weight loss and malnutrition (2021 summary; 2024 case review) (mirakhor2021collagenousenteritis–analternative pages 1-3, moreno2024spruecolágenogastritis pages 2-4). - Histologic thresholds: Normal subepithelial collagen band ~5–7 μm; cutoff >10 μm used to define CS; bands of 10–20 μm or more with entrapped capillaries and stromal cells are typical (2024 case review) (moreno2024spruecolágenogastritis pages 4-5). - Drug association prevalence: In early cohorts of olmesartan enteropathy, approximately one‑third of a CS cohort was exposed to olmesartan at or near diagnosis, and most improved after discontinuation (2012 Mayo Clinic Proceedings) (rubiotapia2012severespruelikeenteropathy pages 5-7).

Mechanistic model of disease progression - Initiation: Environmental/drug triggers (notably ARBs) or autoimmune milieu initiate mucosal immune activation; many patients lack celiac serology and fail gluten‑free diet, implicating alternative triggers (rubiotapia2012severespruelikeenteropathy pages 5-7, mirakhor2021collagenousenteritis–analternative pages 1-3). - Epithelial insult and immune activation: Increased IELs and cytokine signaling (e.g., IL‑15, TNF‑α, IL‑6) drive crypt epithelial apoptosis; barrier dysfunction is supported by reports of ZO‑1/TJP1 disruption (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, burbure2016olmesartanassociatedspruelikeenteropathy pages 3-5). - Stromal remodeling: TGF‑β–driven fibroblast→myofibroblast differentiation increases COL1A1 and TIMP1 with relatively reduced MMP1/9 activity, favoring ECM accumulation and subepithelial collagen band formation (zabana2022pathogenesisofmicroscopic pages 10-11, valatas2017stromalandimmune pages 3-4, xiao2009collagenousspruea pages 3-4). - Tissue architecture and clinical phenotype: Collagen band (>10 μm) entrapping capillaries/cells and villous atrophy produce severe malabsorption, protein‑losing enteropathy, and weight loss; multi‑segment involvement (gastritis/colitis) and complications (ulceration, perforation, lymphoma) may ensue (moreno2024spruecolágenogastritis pages 4-5, moreno2024spruecolágenogastritis pages 1-2, rubiotapia2012severespruelikeenteropathy pages 3-4).

Key Molecular Players - Genes/Proteins (HGNC): TGFB1 (TGF‑β1), MMP1, MMP9, TIMP1, COL1A1, TJP1 (ZO‑1), TNF (TNF‑α), IL15, IL6; HLA‑DQA1/DQB1 (HLA‑DQ2/8 susceptibility in drug‑induced SLE) (zabana2022pathogenesisofmicroscopic pages 10-11, burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, rubiotapia2012severespruelikeenteropathy pages 5-7, xiao2009collagenousspruea pages 3-4). - Chemical entities (CHEBI): glucocorticoids (budesonide), thiopurines (azathioprine/6‑thioguanine), anti‑TNF agents; olmesartan (ARB), NSAIDs and PPIs as potential modifiers/triggers (mirakhor2021collagenousenteritis–analternative pages 3-4, rubiotapia2012severespruelikeenteropathy pages 5-7, burbure2016olmesartanassociatedspruelikeenteropathy pages 3-5, moreno2024spruecolágenogastritis pages 4-5). - Cell types (CL): Intraepithelial lymphocytes (CD8+ IELs), enterocytes, lamina propria plasma cells/eosinophils, subepithelial myofibroblasts (α‑SMA+), fibroblasts (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, valatas2017stromalandimmune pages 3-4, moreno2024spruecolágenogastritis pages 4-5). - Anatomical locations (UBERON): Small intestinal mucosa (duodenum, jejunum), lamina propria (subepithelial region), with possible involvement of gastric and colonic mucosa (moreno2024spruecolágenogastritis pages 4-5, sharma2018collagenousgastritisa pages 1-2, moreno2024spruecolágenogastritis pages 1-2).

Biological Processes (GO annotation candidates) - ECM organization and collagen fibril organization; regulation of collagen biosynthetic process (TGFB1‑mediated) (valatas2017stromalandimmune pages 3-4, zabana2022pathogenesisofmicroscopic pages 10-11). - Regulation of proteolysis and extracellular matrix disassembly (MMP/TIMP balance) (zabana2022pathogenesisofmicroscopic pages 10-11, valatas2017stromalandimmune pages 2-3). - Epithelial cell apoptotic process and regulation of cell‑cell junction organization (TJP1/ZO‑1 alteration) (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, burbure2016olmesartanassociatedspruelikeenteropathy pages 3-5). - T cell–mediated immune response; response to cytokines (IL‑15, TNF‑α, IL‑6) (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, burbure2016olmesartanassociatedspruelikeenteropathy pages 3-5).

Cellular Components - Subepithelial lamina propria (site of collagen band); epithelial tight junctions (ZO‑1/TJP1); extracellular space/ECM; fibroblast stress fibers (α‑SMA cytoskeleton) (moreno2024spruecolágenogastritis pages 4-5, burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, valatas2017stromalandimmune pages 3-4).

Disease Progression - Sequence: trigger (often medication) → IEL‑driven/immune activation and epithelial apoptosis with barrier loss → TGF‑β–driven myofibroblast activation with net ECM accumulation (↑TIMP1/↓MMP) → subepithelial collagen band and villous atrophy → malabsorption/protein loss → complications (ulceration/perforation; occasional lymphoma) (rubiotapia2012severespruelikeenteropathy pages 5-7, zabana2022pathogenesisofmicroscopic pages 10-11, rubiotapia2012severespruelikeenteropathy pages 3-4, moreno2024spruecolágenogastritis pages 1-2). - Phases: (i) inflammatory/immune injury; (ii) fibrogenic remodeling; (iii) established collagen band with severe malabsorption; (iv) potential regression if drug withdrawn and/or immunosuppression, although course is heterogeneous (rubiotapia2012severespruelikeenteropathy pages 5-7, mirakhor2021collagenousenteritis–analternative pages 3-4, freeman2010updateoncollagenous pages 1-2).

Phenotypic Manifestations (HP terms) - Chronic diarrhea (HP:0002028), Weight loss (HP:0001824), Malabsorption (HP:0002242), Protein‑losing enteropathy (HP:0005226), Anemia (HP:0001903), Hypoalbuminemia (HP:0003073), Villous atrophy on small intestinal biopsy (HP:0011472) (mirakhor2021collagenousenteritis–analternative pages 1-3, moreno2024spruecolágenogastritis pages 4-5, mirakhor2021collagenousenteritis–analternative pages 3-4).

Cell type involvement (CL terms) - Intraepithelial lymphocyte, small intestine (CL:0009101); Intestinal epithelial cell (CL:0002563); Subepithelial myofibroblast (often annotated as intestinal myofibroblast; related: CL:0000186 fibroblast, with α‑SMA+ phenotype) (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, valatas2017stromalandimmune pages 3-4).

Anatomical locations (UBERON terms) - Duodenum (UBERON:0002114), Jejunum (UBERON:0002115), Intestinal lamina propria (UBERON:0001982), Gastric mucosa (UBERON:0001275), Colonic mucosa (UBERON:0001155) (moreno2024spruecolágenogastritis pages 4-5, moreno2024spruecolágenogastritis pages 1-2, sharma2018collagenousgastritisa pages 1-2).

Chemical entities (CHEBI) - Olmesartan (CHEBI:7791), Nonsteroidal anti‑inflammatory drug (CHEBI:35475), Proton pump inhibitor (CHEBI:50784), Budesonide (CHEBI:3160), Azathioprine (CHEBI:2955), 6‑Thioguanine (CHEBI:9565), Infliximab/adalimumab (anti‑TNF biologics; protein therapeutics) (rubiotapia2012severespruelikeenteropathy pages 5-7, mirakhor2021collagenousenteritis–analternative pages 3-4, moreno2024spruecolágenogastritis pages 4-5).

Evidence items with PMIDs/DOIs/URLs and quotes - “Collagenous sprue … characterized by … villous atrophy and a thick subepithelial collagen band … diagnosis requires endoscopy with biopsy.” (2021; source includes endoscopic and histologic description) (mirakhor2021collagenousenteritis–analternative pages 1-3). - “A normal subepithelial collagen band is 5–7 μm … a diagnostic cutoff … >10 μm … with entrapped capillaries and stromal cells … Masson trichrome positive.” (Sep 2024; Acta Gastroenterol Latinoam; https://doi.org/10.52787/agl.v54i3.383) (moreno2024spruecolágenogastritis pages 4-5). - “Olmesartan‑associated sprue‑like enteropathy … mediated primarily by a delayed, cell‑mediated immune mechanism … TGF‑β perturbation hypothesized … high prevalence of HLA‑DQ2 among cases … histology shows villous atrophy … in some cases collagen deposition … recovery after stopping olmesartan.” (Aug 2012; Mayo Clin Proc; https://doi.org/10.1016/j.mayocp.2012.06.003) (rubiotapia2012severespruelikeenteropathy pages 5-7, rubiotapia2012severespruelikeenteropathy pages 3-4). - “Proposed roles for IL‑15 signaling and disruption of tight junction protein ZO‑1, implying both immune activation and epithelial barrier dysfunction … frequent increase in subepithelial collagen … overlap with autoimmune enteropathy … reverses after cessation of olmesartan.” (Apr 2016; Hum Pathol; https://doi.org/10.1016/j.humpath.2015.12.001) (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, burbure2016olmesartanassociatedspruelikeenteropathy pages 3-5). - “ECM accumulation in collagenous enteropathy likely reflects increased collagen I synthesis and impaired degradation via MMP/TIMP imbalance; TGFB1, TIMP1 upregulated with restricted MMP1/9 activity.” (Jul 2022; J Crohn’s & Colitis; https://doi.org/10.1093/ecco-jcc/jjab123) (zabana2022pathogenesisofmicroscopic pages 10-11); supported by gut fibrosis frameworks (Apr 2017; Ann Gastroenterol; https://doi.org/10.20524/aog.2017.0146) (valatas2017stromalandimmune pages 3-4). - Complications: reports of ulceration, perforation, and lymphoma associations in CS (Sep 2009; WJG; https://doi.org/10.3748/wjg.15.4446) and 2024 review (rubiotapia2012severespruelikeenteropathy pages 3-4, moreno2024spruecolágenogastritis pages 1-2).

Embedded artifact | Mechanism / Process | Key molecules / genes (HGNC) | Cell types (CL) | Tissue / Anatomy (UBERON) | Evidence summary (1–2 sentences) | Strongest recent/landmark sources (year, journal, URL) with context IDs | |---|---|---|---|---|---| | Subepithelial collagen band formation: MMP/TIMP imbalance & TGF-β signaling | TGFB1, MMP1, MMP9, TIMP1, COL1A1 | Myofibroblasts (α-SMA+), fibroblasts, fibrocytes | Small intestinal mucosa (duodenum/jejunum) lamina propria | Reports show increased collagen I synthesis with upregulated TGFB1 and TIMP1 and relatively reduced MMP activity, producing diagnostic >10 μm subepithelial collagen bands and steroid-responsive fibrosis. | Zabana Y et al., 2022, J Crohn's & Colitis; https://doi.org/10.1093/ecco-jcc/jjab123 (zabana2022pathogenesisofmicroscopic pages 10-11); Valatas V et al., 2017, Ann Gastroenterol; https://doi.org/10.20524/aog.2017.0146 (valatas2017stromalandimmune pages 3-4); Xiao Z et al., 2009 (xiao2009collagenousspruea pages 3-4) | | Intraepithelial lymphocytosis & mucosal immune activation; IL-15 / TNF-α with epithelial apoptosis & barrier (ZO-1/TJP1) disruption | IL15, TNF (TNF), IFNG, IL6, TJP1 (ZO-1) | Intraepithelial lymphocytes (IELs; CD8+), enterocytes, antigen-presenting cells | Small intestinal epithelium (duodenal mucosa) | Many cases show increased IELs and cytokine-driven epithelial injury (crypt apoptosis) and reports of tight-junction (ZO-1/TJP1) disruption, linking immune activation to barrier loss and enteropathy. | Rubio-Tapia A et al., 2012, Mayo Clin Proc; https://doi.org/10.1016/j.mayocp.2012.06.003 (rubiotapia2012severespruelikeenteropathy pages 5-7); Burbure N et al., 2016, Hum Pathol; https://doi.org/10.1016/j.humpath.2015.12.001 (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3); Mirakhor E et al., 2021 (mirakhor2021collagenousenteritis–analternative pages 1-3) | | Drug-induced (olmesartan) immune-mediated sprue-like enteropathy progressing to collagenous sprue | AGTR1, TGFB1, HLA-DQA1 / HLA-DQB1 (HLA-DQ2/8 associated) | CD4+ / CD8+ T cells, IELs, myofibroblasts | Small intestine (duodenum/jejunum); possible multi-segment involvement (stomach, colon) | Case series link olmesartan exposure to severe villous atrophy with IELs and frequent subepithelial collagen; clinical and histologic reversal after drug cessation supports a drug-triggered immune/injury mechanism with fibrotic remodeling in susceptible patients. | Rubio-Tapia A et al., 2012, Mayo Clin Proc; https://doi.org/10.1016/j.mayocp.2012.06.003 (rubiotapia2012severespruelikeenteropathy pages 5-7); Burbure N et al., 2016, Hum Pathol; https://doi.org/10.1016/j.humpath.2015.12.001 (burbure2016olmesartanassociatedspruelikeenteropathy pages 7-8); Goshgarian MA et al., 2024, Cureus; https://doi.org/10.7759/cureus.72571 (goshgarian2024pathognomonicfeaturesof pages 1-2) | | Myofibroblast activation (α-SMA+) and ECM overproduction in gut fibrosis | ACTA2 (α-SMA), TGFB1, PDGFA/PDGFR, CTGF, IL17A | Subepithelial myofibroblasts (α-SMA+), fibroblasts, recruited circulating fibrocytes | Lamina propria of small intestine (jejunal/duodenal mucosa) | TGF-β and proinflammatory cytokines drive fibroblast-to-myofibroblast differentiation, upregulate collagen/fibronectin and TIMP1, and reduce fibrolysis, producing persistent ECM accumulation in fibrotic/ collagenous lesions. | Valatas V et al., 2017, Ann Gastroenterol; https://doi.org/10.20524/aog.2017.0146 (valatas2017stromalandimmune pages 3-4); related experimental/ECM studies summarized in systematic reviews (valatas2017stromalandimmune pages 2-3) | | Multisegment collagenous gastroenteritides (gastritis/colitis associations) and complications (ulceration, perforation, lymphoma) | COL1A1, COL3A1, COL5A1, MMP/TIMP axes, TGFB1; IgG4 (plasma cell phenotype reported) | Plasma cells (IgG4+ in some series), IELs, lamina propria inflammatory cells | Stomach (gastric mucosa), small intestine, colon | Case series document collagen deposition across gastric, small-bowel and colonic sites (collagenous gastritis/enteritis/colitis) with clinical complications including ulceration, perforation, and reported associations with intestinal lymphoma in select cohorts. | Moreno ML et al., 2024, Acta Gastroenterol Lat Am; https://doi.org/10.52787/agl.v54i3.383 (moreno2024spruecolágenogastritis pages 1-2); Freeman HJ, 2010, World J Gastroenterol; https://doi.org/10.3748/wjg.v16.i3.296 (freeman2010updateoncollagenous pages 1-2); Freeman & Webber, 2009 (free perforation) (rubiotapia2012severespruelikeenteropathy pages 3-4) |

Table: Concise mechanistic evidence mapping for collagenous sprue: lists processes, genes/proteins, cell/tissue context, short evidence summaries, and landmark citations (with URLs and context IDs) to support ontology annotation and further research.

Notes and limitations - Collagenous sprue remains rare; mechanistic evidence is drawn from case series/case reports, fibrotic gut biology, and microscopic colitis analogies. Prospective molecular profiling in CS is limited; proposed pathways (IL‑15/TJP1, TGFB1/MMP/TIMP) reflect best current evidence and related disease models (burbure2016olmesartanassociatedspruelikeenteropathy pages 1-3, zabana2022pathogenesisofmicroscopic pages 10-11, valatas2017stromalandimmune pages 3-4).

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