Diagnostic clues in patients with clinical malabsorption and pathological small intestinal villous atrophy: Immune-mediated type and beyond

Table 6 Diagnostic clues of patients with small intestinal villous atrophy and malabsorption

Type of enteropathy	Clinical features	Laboratory or imaging features	Endoscopic features	Histological/molecular features on duodenal biopsy	Treatment
Immuno-mediated
CeD	Malabsorption, chronic diarrhea and extraintestinal manifestations	Positive serology for TTA, EmA, or DGP; HLA-DQ2/DQ8 typing	Nonspecific, VA, scalloping, flattening, and fissuring of the mucosal folds, mosaic mucosal pattern, and increased vascularity	VA, Increased IEL, Hypertrophic crypt (polyclonal IELs in RCD I and monoclonal IELs in RCD II)	GFD ± (budesonide and other agents for RCD)
AIE	Severe diarrhea, malabsorption with weight loss and electrolyte imbalance unresponsive to dietary restrictions	Anti-enterocyte and/or anti-goblet cell antibodies	Nonspecific, VA, edema, hyperemia; sometimes erosion, nodular changes, scalloping of plicae, mosaic mucosa; rarely ulcer	VA, decreased goblet and or Paneth cells, apoptotic bodies, lymphoplasmacytic infiltration ± increased IEL, neutrophilic infiltration	Glucocorticoid ± immunosuppressants
CVID	Chronic diarrhea, onset after age 2, recurrent respiratory infections	marked decrease of IgG and IgA ± low IgM	VA, edema, nodular changes	VA, lack of plasma cells, lymphoid follicles, lymphocytosis, apoptotic bodies	Immunoglobulin replacement, infection control
IEI	Miscellaneous, multisystem involvement	Genetic test might find pathogenic mutations	Variable	Various	Targeted treatments for specific mutation
Lymphoproliferative
EATL	Related to CeD, diarrhea, abdominal pain, malaise, weight loss, fever, night sweats, obstruction, perforation, bleeding, more common in Asian population	PET-CT scan, Monoclonal T cells on flow cytometry	Edema, VA, large circumferential ulcers, sometimes plaques and strictures, rarely tumor masses	VA, large malignant cells, variable cytologic atypia and pleomorphic, mixed inflammatory infiltration, necrosis, vascular destruction, high Ki-67, low MATK, NKp46+, cytoplasmic CD3+, CD2+, CD7+, CD103+, CD30+, TIA-1+, perforin+, granzyme-B+, CD4-, CD5-, CD8-, CD56-, Surface CD3- and surface TCR-	Chemotherapy
MEITL	Diarrhea, abdominal pain, malaise, weight loss, fever, night sweats, obstruction, more common in Western population	PET-CT scan, Monoclonal T cells on flow cytometry	deep ulcer, rigid intestinal segments or VA, swollen, mosaic mucosa, shallow ulcers	Monomorphic, medium-sized malignant cells with epitheliotropism, rare necrosis, high Ki-67, high MATK, NKp46+, CD3+, CD4-, CD5-, CD8+, CD56+, CD30-, TIA1+/-, perforin+/-, granzyme-B+, TCRγδ (> TCRαβ)	Chemotherapy
ITCL/LPD-GI	Protracted, persistent course, chronic diarrhea, abdominal pain, weight loss	Monoclonal T cells on flow cytometry	Nonspecific, nodular mucosa, erythema, erosion, ulcers or near normal	Small, mature, and clonal T-cell only infiltrate into lamina propria, without epitheliotropism or necrosis, low Ki-67, NKp46-, CD3+, CD5+, CD4+/-, CD8+/-, CD56-, monoclonal TCRαβ	No agreement (observation or steroid or chemotherapy)
INKLPD-GI	Asymptomatic or abdominal pain, hematochezia, diarrhea, diverticulosis	Absence of EBV	Superficial erosions, ulcers, erythematous or nodular or hyperemia mucosa	Infiltration of medium-sized atypical lymphoid cells in the lamina propria, without necrosis or vascular destruction, CD4-, CD5-, CD56+, absent TCR	Observation
IPSID	Malabsorption, chronic diarrhea, abdominal pain, subfebrile stages, finger clubbing, in developing countries	Immunoelectrophoresis and immunoselection detect α-heavy chain proteins, elevated serum IgA	Mild, atrophic nodular mucosa, thickening of intestinal folds, edema	variable degrees of VA, infiltration of clonal lympho-plasmacytes at variable stages ± lymph nodal Involvement	Antibiotics, chemotherapy
Infectious
Tropical sprue	Malabsorption, related to tropical and subtropical regions	malabsorption of ≥ 2 unrelated nutrients (e.g., anemia, D-xylose absorption, fecal fat estimation, serum vitamin B12 and folate levels)	Normal or mild changes	VA, increased IEL, Increased eosinophils in lamina propria	Antibiotics + vitamin B12 and folic acid supplementation
Whipple’s disease	Migratory arthralgia affecting large peripheral joints, followed diarrhea (steatorrhea), weight loss, fever, finally neurological involvement	PCR detection, absent rheumatoid factor, anti-citrullinated protein antibodies, or other autoantibodies,	Nonspecific changes	PAS-positive macrophage infiltration of the lamina propria, observation of T. whipplei bacilli	Antibiotics
Comorbid CMV infection	Gastrointestinal bleeding, diarrhea in immunocompromised individuals1	CMV IgM (IgG)+, CMV DNA+	Ulcerative, polypoid lesions	CMV inclusion bodies (owl’s eye), IHC staining+	Antiviral agents
Giardiasis	Malabsorption of different severity, in developing regions/immunocompromised individuals	Antigen testing, PCR detection, microscopic exams for stool	Near-normal or VA, nonspecific changes	Direct identification of parasite, neutrophilic infiltration, increased IEL, VA, lymphoid aggregates	Antiparasitic agents
Iatrogenic
ARB induced enteropathy	Severe malabsorption, weight loss, suggestive history of pharmacology	To rule out other diseases	Near-normal or VA, nonspecific changes	VA, similar to CeD/AIE	Drug withdrawal
GVHD	Severe diarrhea or nausea, vomiting, history of transplantation	To rule out other diseases (e.g., infections)	Near-normal or VA, nonspecific changes	epithelial apoptosis, crypt losses, and denudation, sparse inflammatory infiltration	Glucocorticoid ± immunosuppressants
Inflammatory (not prominent VA or malabsorption)
Crohn’s disease	Abdominal pain, chronic bloody diarrhea, fever, malabsorption, etc.	CT/MRI reconstruction of small intestine	Segmental lesions, longitudinal ulcer, pebble-like appearance, stricture, fistula	Transmural inflammation, crypt abscess, ulcer, noncaseous granulomas	5-ASA, glucocorticoid ± immunosuppressants ± biological therapy
EGE	Abdominal pain, nausea, vomiting, diarrhea or serous effusion or obstruction with history of atopy and allergies	Elevated eosinophil in blood or effusion, increased IgE	Nonspecific changes	Eosinophil infiltration	Special diet, Anti-allergy treatment, glucocorticoid ± immunosuppressants
Collagenous sprue	Malabsorption, watery diarrhea, weight loss	To rule out other diseases	VA, nonspecific changes	Duodenal VA, subepithelial collagen deposition, increased IEL	GFD, corticosteroid, immunosuppression
Idiopathic
IVA 1	Transient course, diarrhea, weight loss, dyspepsia, infectious triggers	To rule out all other diseases	Normal or VA or mild changes	VA	None, spontaneous remission
IVA 2	Persistent course, malabsorption	To rule out all other diseases	VA or nonspecific changes	VA, nonlymphoproliferative	Immunosuppressants
IVA 3	Persistent course, severe malabsorption	To rule out all other diseases	VA or nonspecific changes	VA, lymphoproliferative features, monoclonal TCR	Immunosuppressants, consult hematologist

¹Immunocompromised patients include recipients of solid organ or hematopoietic stem cell transplants, individuals with primary immunodeficiency or human immunodeficiency virus infection, those who have undergone chemotherapy or radiotherapy within the past six months, and patients receiving prolonged immunosuppressive therapy.

CeD: Celiac disease; TTA: Tissue transglutaminase; EmA: Endomysium antibodies; DGP: Deamidated gliadin peptides; AIE: Autoimmune enteropathy; IEL: Intraepithelial lymphocytes; VA: Villous atrophy; GFD: Gluten-free diet; RCD: Refractory celiac disease; CVID: Common variable immunodeficiency; IEI: Inborn errors of immunity; IPSID: Immunoproliferative small intestinal disease; EATL: Enteropathy-associated T-cell lymphoma; CT: Computed tomography; PET: Positron emission tomography; MATK: Megakaryocyte-associated tyrosine kinase: MEITL: Monomorphic epitheliotropic intestinal T-cell lymphoma; ITCL/LPD-GI: Indolent T-cell lymphoma/Lymphoproliferative disorder of the gastrointestinal tract; INKLPD-GI: Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract; EBV: Epstein-Barr virus; PCR: Polymerase chain reaction; CMV: Cytomegalovirus; IHC: Immune histochemistry; ARB: Angiotensin receptor blocker; GVHD: Graft-vs-host disease; EGE: Eosinophilic gastroenteritis; MRI: Magnetic resonance imaging; 5-ASA: 5-aminosalicylic acid; IVA: Idiopathic villous atrophy; T. whipplei: Tropheryma whipplei; TCR: T-cell receptor.