To screen or not to screen? Celiac antibodies in liver diseases

Table 1 Studies regarding the association of primary sclerosing cholangitis and celiac disease

Type of article	No. of patients	Symptoms	Celiac antibodies	Duodenal biopsy	Response to gluten-free diet	Liver biopsy	ERCP	Comorbidities	Country, year	Ref.
Case report	3	Weight loss, steatorrhoea	No	Typical1	Yes	Yes	Yes	2 Chronic ulcerative colitis	United States, 1988	Hay et al[35]
Abstract	69	Screening	55% AGA (+)	0/26 altered	-	-	-	-	Ireland, 1992	MacMathuna et al[46]
Case report	1	Diarrhea, weight loss, growth retardation	No	Typical1	Yes	Yes	Yes	Chronic colitis	France, 1995	Lacaille et al[37]
								Turner’s syndrome
Case report	2	Anemia	AGA IgA (+)	Villous atrophy	Yes	Yes	Yes	-	Italy, 1996	Fracassetti et al[36]
Case report	1	Diarrhea	No	Villous atrophy	Yes	Yes	Yes	Ulcerative colitis	Sweden, 1994	Tysk[41]
Case report	1	Folic acid deficiency	AGA (-)	Typical1		Yes	Yes	Ulcerative colitis	France, 1994	Brazier et al[44]
			EmA (+)					Hashimoto’s thyroiditis
Case report	2	Weight loss	EmA (+)	Typical1	Yes	Yes	Yes	-	Italy, 1998	Venturini et al[49]
Case report	1	Anemia	No	Not mentioned	Not mentioned	Yes	Yes	Rheumatoid arthritis	United Kingdom, 2001	Gow et al[50]
Case series	1	Diarrhea	tTG (+)	Villous atrophy	No adherence	Yes	Not mentioned	Not mentioned	Finland, 2002	Kaukinen et al[51]
		Protruding	EmA (-)
		abdomen
		Failure to thrive
Case report	2	Active screening for CD	EmA (+)	Typical1	Yes	Yes	Yes	Ulcerative colitis	Poland, 2002	Habior et al[43]
			tTG (+)
Prospective cohort	61	Active screening for CD	1.6% EmA (+)	100% (1/1) Typical1	Yes	Yes	Yes	-	Italy/Spain 2002	Volta et al[52]
			3.3% tTG (+)
Case report	2	Weight loss, steatorrhoea	EmA (+)	Villous atrophy	Yes	No	Yes	Ulcerative colitis	United Kingdom, 2003	Wurm et al[42]
Case report	1	Routine UDE	AGA (+)	Typical1	Yes	Yes	Yes	-	United States, 2004	Al-Osaimi et al[53]
			EmA (+)
Case report	1	Diarrhea	EmA (+)	Typical1	Yes	Yes	Yes	-	Spain, 2005	Cadahía et al[54]
Prospective cohort	155	Screening	3% EmA (+)	-	-	-	-	-	United States, 2008	Rubio-Tapia et al[48]
			9% tTG (+)
Case report	1	Short stature and anemia	tTG (+)	Typical1	Yes	Yes	No, MRC	-	Saudi Arabia, 2013	Al-Hussaini et al[55]

¹Vilous atrophy, crypt hyperplasia, lymphoplasmocytic infiltrate. ERCP: Endoscopic retrograde cholangio pancreatography; MRCP: Magnetic resonance cholangiopancreatography; AGA: Anti-gliadin antibody; EmA: Endomysial antibody; tTG: Tissue transglutaminase; CD: Celiac disease; UDE: Upper digestive endoscopy.

Table 2 Case reports² regarding the association of primary biliar cholangitis and celiac disease

Number of patients	Symptoms	Celiac antibodies	Duodenal biopsy	Response to gluten-free diet	Liver biopsy	AMA	Comorbidities	Country, year	Ref.
4	Weight loss, steatorrhea, anemia	No	Typical1	Yes	Yes	(+)	serum-IgA deficiency	Scotland, 1978	Logan et al[58]
1	Weight loss, diarrhea, anorexia	No	Typical1	Yes	Yes	No	-	United Kingdom, 1978	Lee et al[59]
1	Malabsorption	No	Typical1	Poor adherence	Yes	(+)	-	Canada, 1979	Iliffe et al[60]
1	Diarrhea, anemia, short stature		Subtotal villous atrophy	Yes, but PBC was diagnosed afterwards	Yes	(+)	-	Ireland, 1983	Shanahan et al[62]
1	Dermatitis herpetiformis	No	Typical1	Yes	Yes	(+)	Dermatitis herpetiformis	Norway, 1985	Gabrielsen et al[64]
1	Anemia	AGA (-)	Typical1	Yes	Yes	(+)	Renal tubular acidosis, Sjögren Syndrome	Ireland, 1987	Whitehead et al[68]
1	Weight loss, diarrhea	No	Typical1	Yes	Yes	(+)	-	United States, 1992	Ginn et al[69]
1	Weight loss, anemia	No	Typical1	Yes	Yes	(+)	-	Canada, 1994	Freeman[70]
1	Diarrhea	No	Typical1	Yes, but PBC was diagnosed afterwards	Yes	(+)	-	Germany, 1994	Löhr et al[196]
1	Diarrhea, weight loss	AGA (+)	Typical1	No	Yes	(+)	-	Spain, 1994	Gálvez et al[97]
1	Weight loss, steatorrhea	AGA (+)	Typical1	Yes	Yes	(+)	Bacterial overgrowth	United States, 1998	DiBaise et al[71]
		EmA (+)
1	Anemia	EmA (+)	Typical	Yes	Yes	No	-	United States, 2002	Sedlack et al[84]
1	Diarrhea, weight loss	EmA (+)	Typical1	Yes	Yes	(+)	Renal tubular acidosis, Sjögren Syndrome,	Italy, 2004	Fracchia et al[98]
							Graves’ disease
1	Inability to walk, anemia	AGA (-)	Typical1	Yes	Yes	(+)	Osteomalacic Myopathy	Turkey, 2008	Demirag et al[99]
		EmA (-)
1	Bone pain	AGA (+)	Typical1	Yes	Yes	(+)	Fanconi syndrome	Paris, 2008	Terrier et al[100]
		EmA (+)
		tTG (+)
1	Dispepsia	tTG (+)	Typical1	Yes	Yes	(+)	Helicobacter pylori	Italy, 2010	Abenavoli et al[83]
1	Diarrhea, bloating	EmA (+)	Typical1	Yes	Yes	(+)		India, 2013	Lodh et al[101]
		tTG (+)

¹Vilous atrophy, crypt hyperplasia, lymphoplasmocytic infiltrate;

²Case reports for which we had access to the full text. ERCP: Endoscopic Retrograde Cholangio Pancreatography; MRCP: Magnetic resonance cholangiopancreatography; AGA: Anti-gliadin antibody; EmA: Anti-endomysial antibody; tTG: Tissue transglutaminase.

Table 3 Research on screening celiac disease in patients with primary biliar cholangitis

Study	Screening method	Number of positive patients	Typical duodenal biopsy12	Response to gluten-free diet	Country, year	Ref.
Prospective	Duodenal biopsy	5/26 (19.2%)	19, 2%	No improvement in liver biochemestry	Sweden, 1982	Olsson et al[61]
Retrospective	Previous diagnose	2/18 (11.1%)	Not mentioned	No improvement in liver biochemestry or liver histology	Sweden, 1985	Löfgren et al[65]
Prospective	EmA IFI > 1:5	6/57 (11%) EmA (+)	7%	No improvement in liver biochemestry	Ireland, 1997	Dickey et al[73]
Prospective cohort	AGA IgG IgA > 1 AU	0/62 (0%) EmA (+)	0/0	-	United States/Italy	Volta et al[76]
	IgA EmA IFI	11/62 (16%) AGA (+)
Prospective	malabsorption, haematinic	4/67 (6%)	4/67 (6%)	No improvement in liver biochemestry	United Kingdom, 1998	Kingham et al[72]
	deficiency, positive antigliadin antibody,
	or CD family history
Prospective	AGA IgA > 25 AU/mL	4/11 (36, 4%) AGA IgA (+)	18%	-	Argentina, 1998	Niveloni et al[102]
	IgG > 28 AU/mL	1/11 (9%) AGA IgG (+)
	EmA IFI > 1:5	1/11 (9%) EmA (+)
Retrospective (stored sera)	EmA IFI > 1:5	10/378 (2.6%) EmA (+) + tTG (+)	1.30%	-	United Kingdom, 2000	Gillett et al[103]
	tTG IgA ELISA > 140 AU/mL	44/378 (11.6%) EmA (-) + tTG (+)
Prospective	EmA IFI	3/87 (3.4%) EmA (+)	0/17	-	Italy, 2002	Floreani et al[80]
	tTG IgA > 10 IU	24/87 (27.5%) tTG (+)
Prospective	AGA IgA > 50 U/mL	13/62 (21%) AGA (+)	0/10	-	Greece, 2002	Chatzicostas et al[78]
	AGA IgG > 50 U/mL	0/62 EmA (+)
	EmA IgA IFI ≥ 1:5	6/62 (10%) tTG (+)
	IgA tTG > 30 U/mL
Prospective cohort	EmA IFI > 1:5	7/173 (4%) EmA (+)	7/7	No improvement in liver biochemestry	Italy/Spain 2002.	Volta et al[52]
	tTG IgA > 7 AU	5/173 (2.9%) tTG (+)
	AGA IFI
Prospective cohort	IgA tTG > 7 AU	5/48 (10.4%) tTG (+)	-	-	Italy, 2003	Bizzaro et al[104]
	IgG anti-Ttg > 30 AU
	EmA IFI
	tTG < 1:100	7/115 (6.1%) tTG (+)	1/8	Duodenal histological improvement	Poland, 2003	Habior et al[105]
	EmA IFI	1/115 (0.9%) EmA (+)
	AGA Elisa	8/115 (7.0%) AGA (+)
Prospective cohort	Six different ELISA tTG	28/105 (26.7%) tTG IgA (+)	100% EmA (+)	-	Italy, 2006	Bizzaro et al[25]
		6/105 (5.7%) tTG IgG (+)	0% tTG (+)

¹Vilous atrophy, crypt hyperplasia, lymphoplasmocytic infiltrate;

²Only a small number of patients usually undergo intestinal biopsy. EmA: Anti-endomysial antibody; IIF: Indirect immunofluorescence; tTG: Anti-tissue transglutaminase; ELISA: Enzyme-linked immunosorbent assay; CD: Celiac disease; AGA: Anti-gliadin antibody.

Table 4 Case reports regarding the association of autoimmune hepatitis and celiac disease

Number of patients	Symptoms	AIH antibodies	Celiac antibodies	Duodenal biopsy	Response to gluten-free diet	Liver biopsy	Comorbidities	Country, year	Authors
1	Anemia, infection	ASM 1:500	AGA IgA and IgG (+)	Typical1	Yes2	Active chronic hepatitis	Erythroblastopenia	France, 2001	Bridoux-Henno et al[124]
		anti-vimentin 1:500	EmA (+)
1	Weight loss,	ANA 1:1280, p-ANCA 1:2560, SMA 1:1200, LKM1 1:50	Reticulin antibodies	Typical1	No, developed AIH despite of a gluten-free diet	Chronic inflammation	Thyrotoxicosis	Finland, 2002	Arvola et al[34]
	fatigue, abdominal pain, and diarrhea		to 1:2000			In the portal area and proliferation of the small hepatic
			AGA IgA (+)			Ductules. Patchy degeneration of the liver cells.
2	Diarrhea, abdominal enlargement and	ANA (+)	?	?	case 1: poor response to a	Acute hepatitis	-	Italy, 2003	Leonardi et al[125]
	failure to thrive.	SMA (+)			gluten-free diet for the treatment of hepatitis;	With portal bridging necrosis and fibrosis and a
		antiactine (+)			case 2: developed AIH despite the diet	Peri-portal inflammatory infiltrate of lymphocytes,
						Plasma cells and neutrophils
1	Elevated liver enzymes detected, hypesthesia of the left	ANA (+)	AGA (+)	Typical1	Poor adherence to diet	Moderately active, chronic hepatitis with	Cryoglobulinaemia	Switzerland, 2003	Biecker et al[126]
	foot, purpura and skin ulcers of both legs.		EmA (+)			Interface lesions and fibrosis of the portal tract,
						Bile duct lesions and ductular
						Proliferations.
1	Jaundice and pale stools.	All negative. Score probable	AGA IgA (+)	Typical1	Liver disease progressed despite the diet	Moderate to severe	.-	Italy, 2004	Iorio et al[127]
			AGA IgG (+)			lobular inflammatory activity, mononuclear portal
			Ema (+)			inflammation, interface hepatitis, and portal and periportal
			tTG IgA (+)			fibrosis with septae; rosetting of liver cells
						and some giant cells.
1	Ferropenia	-	tTG (+)	Villous atrophy	Elevation of aminotranferases despite the diet.	severe ymphocytic inflammatory infiltrate		Peru, 2006	Tagle et al[128]
	and elevation of aminotransferases.					with slight increase of collagen in
						portal tracts, foci of lobular necrosis and presence
						acidophilus bodies
1	Anorexia, severe diarrhea, rapid loss of weight,	ANA (+)	EmA (+)	Villous atrophy	Developed cirrhosis despite the diet	Cirrhosis	Holmes-Adie syndrome	Hungary, 2006	Csak et al[129]
	amenorrhea and anemia.	SMA (+)	tTG (+)
1	Jaundice	SMA (+)	AGA (+)	Typical1	Poor adherence to diet	Confirmed the diagnosis of acute AIH	Multiple sclerosis	Italy, 2008	Ferrò et al[130]
			EmA (+)
			tTG IgA (+) IgG (+)
1	Weight loss, anorexia, fatigue, and diarrhea.	ANA+++	AGA IgA (+)	Typical1	Liver disease was diagnosed on a gluten-free diet	Moderately active, chronic hepatitis with interface lesions	Autoimmune cholangitis overlap, Autoimmune thyroiditis	Turkey, 2009	Ozaslan et al[131]
			AGA IgG (+)			And fibrosis of the portal tracts, ductular injury and ductopenia.
			EmA (+)
			tTG (+)
1	Malaise,	ANA, SMA, LKM-1, mitochondrial, anti-LC1,	EmA (+)	Typical1	No, developed AIH despite of a gluten-free diet	Lymphoplasmacytic hepatitis (portal interface and lobular)	-	United Kingdom, 2009	Quail et al[132]
	intermittent pyrexia and vomiting, an urticarial-vasculitic	anti-SLA/LP, parietal cell	tTG (+)			With moderate to marked activity and minimal
	rash and joint pains.	antibodies, all negative				Chronicity (fibrosis stage 1/6).
1	Two miscarriages, iron deficiency anemia, osteopenia and alternating bowel habit, elevated aminotransferases	ANA +++, homogeneous; SMA ++, anti-dsDNA	EmA 1:160	Severe villous atrophy	Yes2	Chronic	Lupus	Italy, 2010	Tovoli et al[133]
		0.1527778				Active hepatitis with piecemeal necrosis and lympho-plasmacellular periportal infiltrate
1	anemia, weakness and high	ANA 1:640,	EmA (+)	Flat mucosa	No, developed acute liver failure	Severe fibrosis	None	Italy, 2013	Volta et al[134]
	aminotransferase levels	SMA 1:320,	tTG (+)
		pANCA 1:160
1	Miscontrol of diabetes	ANA 1:160	IgA tTG (+)	Typical1	Yes2	Moderate interface hepatitis and chronic inflammatory infiltrate, and foci of necrosis	Autoimmune thyroiditis and type 1 diabetes	Spain, 2016	Dieli-crimi et al[135]
	Altered liver enzymes		EmA (-)

¹Vilous atrophy, crypt hyperplasia, lymphoplasmocytic infiltrate;

²Patient under corticosteroids and azathioprine. AGA: Anti-gliadin antibody; EmA: Anti-endomysial antibody; tTG: Anti-tissue transglutaminase antibody; ANA: Anti-nuclear antibody; ASM: Anti-smooth muscle antibodies; anti-LP: Antibodies against liver pancreas; anti-SLA: Antibodies against soluble liver antigen.

Table 5 Research screening celiac disease in patients with autoimmune hepatitis

Study	Screening method	Number of positive patients	Typical duodenal biopsy12	Response to gluten-free diet	Country, year	Authors
Prospective cohort	AGA IgG IgA > 1 AU	8/181 (4.4%) EmA (+)	5/5	-	United States/Italy, 1998	Volta et al[76]
	IgA EmA IFI	7/181 (3.9%) AGA (+)
Retrospective	EmA	3/47 (6.4%)	3/3	-	Italy, 2005	Villalta et al[136]
	tTG IgA IgG
Retrospective	EmA	19/140 (14%)	?	No	Italy, 2008	Caprai et al[120]
	tTG IgA IgG
Retrospective	AGA IgA, IgG	5/40 (13%)	5/5	Mild decrease of transaminases, but never a complete normalization	Italy, 2008	Diamanti et al[137]
	EmA IgA
	tTG IgA
Retrospective	AGA IgA, IgG	7/15 (47%)	7/7	-	Turkey, 2009	Tosun et al[138]
	EmA IgA
	tTG IgA
Retrospective	?	3/278 (1.1%)	?	-	Germany, 2010	Teufel et al[139]
Prospective	IgA EmA IFI	4/26 (15%)	3/4	-	Egypt, 2011	El-Shabrawi et al[140]
	tTG ELISA
Retrospective	EmA IgA, IgG	15/79 (19%)	?	All of the 15 patients achieved sustained	Italy, 2013	Nastasio et al[122]
	tTG IgA, IgG			remission when treated with prednisone and azathioprine or cyclosporine
Prospective	tTG IgA ELISA	3/64 (4.7%) tTG (+)	3/3	-	Iran, 2014	Najafi et al[141]
Prospective	IgA EmA IIF	6 previous diagnoses	-	-	Netherlands, 2014	van Gerven et al[118]
	tTG ELISA	10/460 tTG + EmA + HLA
	HLA DQ2 DQ8	-3.50%

¹Vilous atrophy, crypt hyperplasia, lymphoplasmocytic infiltrate;

²Only a small number of patients usually undergo intestinal biopsy. EmA: Anti-endomysial antibody; IIF: Indirect immunofluorescence; tTG: Anti-tissue transglutaminase; ELISA: Enzyme-linked immunosorbent assay; HLA: Human leukocyte antigen; AGA: Anti-gliadin antibody.