Clinical manifestations, diagnosis and long-term prognosis of adult autoimmune enteropathy: Experience from Peking Union Medical College Hospital

Table 1 Different criteria proposed for diagnosing autoimmune enteropathy

Unsworth and Walker-Smith[9] proposed in 1985	Akram et al[8], proposed in 2007	Sharma et al[7], proposed in 2018	Schiepatti et al[6], proposed in 2022
(1) Protracted diarrhea and severe enteropathy; (2) No response to exclusion diet or total parenteral nutrition; (3) Evidence of predisposition to autoimmune disease (presence of circulating autoantibodies and/or associated disease also thought to be autoimmune); and (4) No severe immunodeficiency	(1) Adult-onset chronic diarrhea (> 6 wk’ duration); (2) Malabsorption; (3) Specific small bowel histology, partial/complete villous blunting, deep crypt lymphocytosis, increased crypt apoptotic bodies, minimal intraepithelial lymphocytosis (IEL means > 40 per 100 epithelial cells); (4) Exclusion of other causes of villous atrophy including celiac disease, refractory sprue, and intestinal lymphoma; and (5) Anti-enterocyte (AE) and/or anti–goblet cell (AG) antibodies. Criteria 1-4 are required for a definite diagnosis of AIE. Presence of AE and/or AG antibodies is an important diagnostic support, but their absence does not exclude the diagnosis of AIE	(1) Adult-onset protracted diarrhea (> 6 wk) not responsive to any dietary exclusion; (2) Associated with specific small-bowel histology, villous atrophy, minimal IEL, increased crypt apoptotic bodies, absence of goblet or Paneth cells; and (3) Systematic exclusion of other causes of villous atrophy including CD or RCD (based on combination of celiac serology, HLA typing, histopathology features, and response to GFD), drug-induced enteropathy (based on history of starting medication and its correlation with symptoms, duration of treatment, histopathology and effect after discontinuation), common variable immunodeficiency-associated enteropathy (based on total immunoglobulin titers and histopathology [presence of plasma cells, lymphoid aggregates]), collagenous sprue and colitis (based on histopathology), and intestinal lymphoma	The following criteria must be satisfied for the diagnosis: (1) Severe malabsorption symptoms (chronic diarrhea, weight loss, nutritional deficiencies and electrolyte imbalance) unresponsive to any dietary restriction; (2) Frank villous atrophy unresponsive to any dietary restriction; (3) IgA/IgG positive enterocyte antibodies (indirect immunofluorescence on human/monkey jejunum); (4) Negative celiac serology; and (5) Exclusion of other causes of villous atrophy
			The following criteria were considered supportive for the diagnosis: (1) History of associated autoimmune conditions; (2) Clinical response to immunosuppressive treatments; (3) Deep crypt lymphocytosis and/or plasma cells infiltration, neutrophilic cryptitis ± crypt microabscesses and lack/decrease of Paneth cells on duodenal histology; (4) Positive serum anti-AIE 75 KD antibodies (ELISA) or nonorgan specific autoantibodies; and (5) Absence of severe immunodeficiencies, diagnostic role of serum antigoblet cells antibodies, involvement of other sites of the GI tract and some duodenal histopathological features (include intraepithelial lymphocytes count, crypt hyperplasia and crypt apoptotic bodies, lack of gamma-delta T cells and depletion of goblet cells)

IEL: Intraepithelial lymphocyte; CD: Celiac disease; RCD: Refractory celiac disease; HLA: Human leukocyte antigen; GFD: Gluten-free diet; ELISA: Enzyme-linked immuno sorbent assay.

Table 2 Demographic and clinical manifestations of adult autoimmune enteropathy patients

Onset age (yr)		45.5 (IQR: 30.8-53.5)
Diarrhea duration (months)		4.0 (IQR: 2.0-6.0)
Weight loss (kg)		17.0 (IQR: 11.3-29.0)
BMI (kg/m2)		17.9 (IQR: 16.4-19.1)
Vomit		81% (13/16)
Abdominal pain		50% (8/16)
Fever		50% (8/16)
Hypovolemic shock		38% (6/16)
Wernicke encephalopathy		19% (3/16)
Acute kidney injury		50% (8/16)
Anemia	Anemia	81% (13/16)
	Mild	44% (7/16)
	Moderate	31% (5/16)
	Severe	6% (1/16)
Hypoalbuminemia		88% (14/16)
Electrolyte disturbance	Hypokalemia	94% (15/16)
	Hyponatremia	69% (11/16)
	Hypocalcemia	94% (15/16)
	Hypomagnesemia	44% (4/9)
Endocrine disorders	Thyroid dysfunction	14% (2/14)
	Abnormal blood glucose	0% (0/14)
Inflammatory indicators	Elevated WBC	75% (12/16)
	Elevated hsCRP	50% (8/16)
	Elevated ESR	50% (8/16)
Liver function	Elevated ALT	50% (8/16)
Fecal OB test	Positive	81% (13/16)
	Negative	19% (3/16)
Fecal Sultan III staining	Positive	56% (9/16)
	Negative	44% (7/16)
D-xylose absorption test	Positive	100% (13/13)
Complement	Decreased C3	73% (11/15)
	Decreased C4	7% (1/15)
IgA	Elevated	25% (4/16)
	Normal	75% (12/16)
IgM	Elevated	6% (1/16)
	Decreased	25% (4/16)
	Normal	69% (11/16)
IgG	Elevated	19% (3/16)
	Normal	81% (13/16)
IgE	Elevated	43% (3/7)
	Normal	57% (4/7)
AE antibody		0% (0/2)
AG antibody		0% (0/6)
Other antibodies	Celiac	8% (1/13)
	ANA	7% (1/14)
	ANCA	8% (1/13)

IQR: Interquartile range; BMI: Body mass index; WBC: White blood cell; hsCRP: High-sensitivity C-reactive protein; ESR: Erythrocyte sedimentation rate; ALT: Alanine transferase; Fecal OB test: Fecal occult blood test; IgA: Immunoglobulin A; IgM: Immunoglobulin M; IgG: Immunoglobulin G; IgE: Immunoglobulin E; AE: Anti-enterocyte; AG: Anti–goblet cell; ANA: Antinuclear antibodies; ANCA: Anti-neutrophil cytoplasmic antibody; IBD: Inflammatory bowel disease; ASCA: Anti-Saccharomyces cerevisiae antibodies; APAB: Anti-pancreatic antibody.

Table 3 Characteristics of diarrhea in autoimmune enteropathy patients

Patients	Gender	Age	Stool frequency (/d)	Stool volume (mL/d)	Character of stool	Fasting test	Gluten-free diet
P1	F	39	10+	3000-5000	Watery, with undigested food residue	Positive (100-300 mL)	Partial response
P2	F	46	8-10	1000	Watery, with undigested food residue	Negative	Untested
P3	F	44	2-10	500-1000	Watery	Negative	Untested
P4	M	48	8-10	500-3000	Watery	Positive (50 mL)	Untested
P5	M	30	10+	2000-4000	Watery	Positive (300-400 mL)	Untested
P6	M	26	10-20	1000+	Watery	Negative	Untested
P7	M	55	10+	2000-5000	Watery	Negative	Untested
P8	F	56	4-8	1000	Watery, with undigested food residue	Untested	Untested
P9	F	26	7-20	4000-5000	Watery	Negative	Untested
P10	F	50	10+	2000-3000	Watery	Untested	Untested
P11	F	59	7-8	4000-5000	Watery	Untested	Untested
P12	F	22	10-20	1000-2000	Watery	Negative	No response
P13	F	45	10-20	3000-4000	Watery	Negative	Untested
P14	F	33	10-20	1500	Watery	Negative	Untested
P15	F	49	10+	1000-1700	Watery, with undigested food residue	Negative	No response
P16	M	60	10+	3000-5000	Watery	Negative	No response

Table 4 Gastrointestinal manifestations in adult autoimmune enteropathy patients under endoscopy

Duodenum (under gastroscopy)	Edema	94% (15/16)
	Villous blunting	94% (15/16)
	Hyperemia	88% (14/16)
	Nodular changes	63% (10/16)
	Erosion	56% (9/16)
	Scalloping of plicae	50% (8/16)
	Mosaic mucosa	31% (5/16)
	Ulcer	13% (2/16)
Small intestine (under enteroscopy)	Edema	100% (3/3)
	Villous blunting	100% (3/3)
	Nodular changes	67% (2/3)
	Erosion	0% (0/3)
	Ulcer	0% (0/3)
Ileum (under colonoscopy)	Villous blunting	79% (11/14)
	Edema	71% (10/14)
	Hyperemia	29% (4/14)
	Erosion	20% (3/14)
	Nodular changes	14% (2/14)
	Ulcer	7% (1/14)
Stomach (under gastroscopy)	Ulcer	6% (1/16)
Colon (under colonoscopy)	Hyperemia	36% (5/14)
	Erosion	29% (4/14)
	Edema	29% (4/14)
	Ulcer	14% (2/14)
Rectum (under colonoscopy)	Erosion	14% (2/14)
	Edema	14% (2/14)
	Hyperemia	14% (2/14)
	Ulcer	7% (1/14)