Table 1

Aetiological classification of non-coeliac seronegative enteropathies with villous atrophy

Type of enteropathyClinical and laboratory featuresHistological/molecular features on duodenal biopsyDiagnostic testsTreatment
Immuno-mediated
Autoimmune enteropathySevere malabsorption with intractable diarrhoea, weight loss and electrolyte imbalance unresponsive to dietary restrictionsIELs can be reduced, decreased globet cells, lymphoplasmacytic infiltrate in lamina propria, neutrophilic cryptitisPositive anti-enterocyte antibodiesImmunosuppressants (steroids, azathioprine, infliximab) and parenteral nutritional support
Common variable immunodeficiencyMalabsorption of different severity, arising after age 2 years, poor response to vaccines, recurrent infections of upper airwaysAbsence of plasma cells, polymorphonuclear infiltrate of the lamina propria, GVHD-like lesions, Crohn’s like lesionsIgG <5 g/L+ low IgA or IgMSteroids, budesonide, immunoglobulin replacement therapy
Lymphoproliferative
EATL (type 1 and type 2)Severe malabsorption, abdominal pain, fever, bleeding, obstruction and/or perforation; type 1 usually associated to CD, unlike type 2Monoclonal population of T cells on IHC or flow cytometryInflammatory markers, abdomen CT/PET scan, capsule endoscopyConsult haematologist+chemotherapy
CD4+indolent lymphomasSevere malabsorption, abdominal pain, fever, bleeding, obstruction and/or perforation
  1. Expansion of T-CD4+CD3+CD8− monomorphic lymphocytes of the epithelium/lamina propria on IHC or flow cytometry

  2. Monoclonal beta/gamma-TCR

Inflammatory markers, abdomen CT/PET scan, capsule endoscopyConsult haematologist+chemotherapy
IPSIDMalabsorption syndrome of different severityTCR gamma/beta clonality on duodenal biopsy
Full thickness intestinal biopsy
Heavy chains of immunoglobulinConsult haematologist+chemotherapy+antibiotics
IatrogenicSevere malabsorption and suggestive pharmacological historyVA undistinguishable form CDDuodenal biopsy and drug withdrawalDrug withdrawal
Angiotensin type 2 receptor blockersSevere malabsorption and suggestive pharmacological historyVA undistinguishable form CDDuodenal biopsy and drug withdrawalDrug withdrawal
ChemotherapySevere malabsorption and suggestive pharmacological historyVA undistinguishable from CD, lamina propria fibrosisDuodenal biopsySteroids, consult oncologist to evaluate alternative regimens
RadiotherapySevere malabsorption and history of radiotherapyLamina propria fibrosisDuodenal biopsySteroids
GVHDSevere malabsorption and history of bone marrow transplantationCrypt cell necrosis, loss of epitheliumDuodenal biopsySteroids or budesonide
Infectious
GiardiasisMalabsorption syndrome of different severity. Consider immune-deficiencies as predisposing conditionsIdentification trophozoites on duodenal biopsyPCR from duodenal aspirate, positive stool specific immunoassayMetronidazole
HIV enteropathyKnown history of AIDS, presence of opportunistic infectionsDecrease CD4+ T lymphocytes, increase in CD8+ T lymphocytesHIV testAntiretroviral therapy, treatment of opportunistic infections
TuberculosisCough, ascites, night sweats, feverGranulomatous diseaseInterferon-gamma release assay, CT, ascetic fluid/sputum analysisSpecific anti-TB regimens
Whipple’s diseaseHistory of seronegative migratory arthritis preceding onset of severe malabsorption and fever, enlarged lymphnodes, neurological symptomsPAS+ macrophagic infiltration of the lamina propria
  • PAS positive macrophages on duodenal biopsies

  • Positive PCR for Tropheryma whipplei

Ceftriaxone/meropenem followed by TMP-SMX/hydroxychloroquine and doxycycline
Tropical sprueHistory of travel to/residency in endemic areas, anaemia with vitamin B12 and folate deficiencyIncreased plasma cells and eosinophils in lamina propria, changes in duodenum, jejunum and ileumDuodenal biopsy, VCE, exclusion of other causes of VATetracycline or doxycycline+folic acid
Inflammatory
Eosinophilic gastro-enteritisHistory of atopy and allergiesMassive eosinophilic infiltration on duodenal biopsyDuodenal biopsy and peripheral hyper eosinophiliaSteroids and dietary therapy
Collagenous sprueSevere malabsorptionVillous atrophy and subepithelial collagen depositionDuodenal biopsyGFD and immunosuppression (budesonide, prednisone, azathioprine)
Crohn’s diseaseChronic diarrhoea with blood, abdominal pain, fever, weight lossVillous atrophy, granulomasDuodenal biopsy, colonoscopy + biopsies, abdomen CT, entero-MRISteroids, antibiotics, azathioprine, biological therapy
Idiopathic
IVA 1—transient VA likely post-infectiveDiarrhoea, weight loss, dyspepsiaHistology usually undistinguishable from CDAbdominal CT, VCESpontaneous resolution within 6 months
IVA 2—persistent non-lymphoproliferative VASevere malabsorptionHistology usually undistinguishable from CDAbdominal CT, VCEImmunosuppressants
IVA 3—persistent VA with lymphoproliferative featuresSevere malabsorption, history of lymphoproliferative disordersHistology usually undistinguishable from CD, monoclonal rearrangement for gamma-TCRAbdominal CT, VCEImmunosuppressants, consider haematological consultation
  • CD, coeliac disease; CT, computed tomography; EATL, enteropathy associated T-cell lymphoma; GFD, gluten-free diet; GVHD, graft versus host disease; IELs, intraepithelial lymphocytes; IHC, immunohistochemistry; IPSID, immune-proliferative small intestinal disease; IVA, idiopathic villous atrophy; MEITL, monomorphic epitheliotropic T-cell lymphoma; MRI, magnetic resonance imaging; PAS, periodic acid Shiff staining; PET, positron emission tomography; PET, positron emission tomography; TMP-SMX, trimethoprim sulfamethoxazole; VA, villous atrophy; VCE, video-capsule endoscopy.