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

Table 1 Summary and comparison of the Marsh-Oberhuber and Corazza-Villanacci pathological classifications[16,18,20,21]

Marsh-Oberhuber				Corazza-Villanacci
Stage	IELs/100 enterocytes in Marsh	Crypts	Villi	Stage	IELs/100 enterocytes in Corazza	Villi
Type 0	< 40	Normal	Normal	None	< 25	Normal
Type 1	> 40	Normal	Normal	Grade A	> 25	Nonatrophic
Type 2	> 40	Hypertrophic	Normal
Type 3 (3a, 3b)	> 40	Hypertrophic	Mild to moderate blunting	Grade B1	> 25	Atrophic, villous-crypt ratio < 3:1
Type 3 (3c)	> 40	Hypertrophic	Severe blunting (flat)	Grade B2	> 25	Atrophic, villi no longer detectable
Type 4	< 40	Normal	Severe blunting (flat)	/	/	/

IELs: Intraepithelial lymphocytes.

Table 2 Pathological classification of autoimmune enteropathy[49]

Classification	Active chronic duodenitis	CeD-like	GVHD-like	Mixed/no predominant
Description[49]	Villous atrophy, expansion of the lamina propria by mixed but predominantly mononuclear inflammation (consisting of lymphocytes, plasma cells, and eosinophils), and neutrophilic cryptitis (with or without crypt abscesses); with or without increased apoptosis in the crypt epithelium. Plasma cells were the predominant cell within the lamina propria inflammatory infiltrate	Villous atrophy and marked IEL (> 40 lymphocytes/100 enterocytes)	Increased apoptosis in crypt epithelium (> 1 apoptotic figure per 10 crypts), with or without crypt dropout, with minimal inflammation	Admixture of ≥ 2 patterns or insufficient features to qualify for other patterns

CeD: Celiac disease; GVHD-like: Graft-vs-host disease-like; IEL: Intraepithelial lymphocyte.

Table 3 Summary of evolving definitions proposed for common variable immunodeficiency disease

Update	ESID and the PAGID in 1999[61]	IUIS in 2017[58]	ESID in 2019[62]	IUIS in 2019[59] and in 2022[60]	IUIS in 2024 (https://iuis.org/committees/iei/)
Description	Probable CVID (a marked decrease1 in serum IgG and IgA levels) and possible CVID (a marked decrease in one of the major isotypes, IgM, IgG, or IgA). Both need to fulfill all of the following criteria; (1) Onset of immunodeficiency at greater than 2 years of age; (2) Absent isohemagglutinins and/or poor response to vaccines; and (3) Excluded defined causes of hypogammaglobulinemia	Rename PIDs, including CVID, as IEIs. A total of 354 IEIs were categorized into 9 tables	At least one of the following: (1) Increased susceptibility to infection; (2) Autoimmune manifestations; (3) Granulomatous disease; (4) Unexplained polyclonal lymphoproliferation; and (5) Affected family member with antibody deficiency. And marked decrease of IgG and marked decrease of IgA with or without low IgM levels (measured at least twice; < 2 SD of the normal levels for their age). And at least one of the following: (1) Poor antibody response to vaccines (and/or absent isohemagglutinins); i.e., absence of protective levels despite vaccination where defined; and (2) Low switched memory B cells (< 70% of age-related normal value). And secondary causes of hypogammaglobulinemia have been excluded (e.g., infection, protein loss, medication, malignancy). And diagnosis is established after the fourth year of life (but symptoms may be present before). And no evidence of profound T-cell deficiency, defined as 2 of the following (y < years of life): (1) CD4 numbers/microliter: 2-6 years < 300, 6-12 years < 250, > 12 years < 200; (2) %naïve of CD4: 2-6 years < 25%, 6-16 years < 20%, > 16 years < 10%; and (3) T-cell proliferation absent	Increase to 416 and 485 IEI, respectively, and categorized into 10 tables	Increase to 555 IEI and categorized into 10 tables (similar to IUIS 2022). Unknown Genetic defect; Low IgG and IgA and/or IgM; Clinical phenotypes vary: Most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias and/or granulomatous disease

¹Marked decrease means at least 2 SD below the age-adjusted mean.

ESID: European Society for Immunodeficiencies; PAGID: Pan-American Group for Immunodeficiency; IUIS: International Union of Immunological Societies; CVID: Common variable immune deficiency; PIDs: Primary immunodeficiency diseases; IEIs: Inborn errors of immunity.

Table 4 Histopathological staging of immunoproliferative small intestinal disease

Stage	Small intestine involvement	Lymph nodal involvement (mesenteric, other abdominal and retroperitoneal, etc.)
Stage A (benign)	Infiltration of the lamina propria, predominantly by mature lymphocytes and plasma cells, accompanied by variable degrees of villous atrophy	Mature plasmocytic infiltration, with limited disruption of the lymph node architecture
Stage B (intermediate)	Infiltration extending beyond the mucosa, spreading into the submucosa, characterized by atypical lymphoplasmacytic cells and immunoblastic-like cells, often associated with total or subtotal villous atrophy	Atypical plasmocytic and immunoblastic infiltration, leading to total or subtotal architectural disruption of the lymph nodes
Stage C (malignant)	Proliferation of histiocytes (Hodgkin sarcoma) affecting all layers of the intestinal wall. Large masses are formed and transformed into malignant lymphoma	Sarcomatous proliferation, extensively disrupting the entire lymph node architecture

Histopathological staging of immunoproliferative small intestinal disease by Evangelista-Leite et al[104] and Galian et al[124].

Table 5 Grade system for graft-vs-host disease

GVHD	Grade 1	Grade 2	Grade 3	Grade 4
Description[156,157]	isolated apoptotic epithelial cells, without crypt loss	loss of isolated crypts, without loss of contiguous crypts	loss of 2 or more contiguous crypts	extensive crypt loss with mucosal denudation

GVHD: Graft-vs-host disease.

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.