Frequency of Non-cirrhotic Portal Fibrosis in Patients with Celiac Disease: A Single Center Experience From Northern India

To the editor, Portal hypertension is well known in patients with celiac disease (CeD). However, only a few patients with non-cirrhotic portal fibrosis (NCPF) are reported in patients with CeD.1Tanwar A. Gupta G.K. Chauhan V. et al.Celiac disease and portal hypertension: a causal association or just a coincidence?.J Clin Exp Hepatol. 2020 Jul-Aug; 10 (PMID 32655231, PMCID PMC7335706): 290-295https://doi.org/10.1016/j.jceh.2019.11.005Abstract Full Text Full Text PDF Scopus (4) Google Scholar The association between NCPF and CeD is uncommon, and the data on this issue are sparse. Accordingly, we undertook a study to know the frequency of NCPF among patients with CeD. The present study included 150 patients with CeD whose data were prospectively maintained on a questionnaire including demographic, clinical, biochemical, and histological parameters during a five-year period (2016–2021) in the Department of Gastroenterology at Sanjay Gandhi Postgraduate Institute of Medical Sciences. All patients underwent necessary tests to look for the presence of portal hypertension. Patients with portal hypertension, who had normal liver ultrasonography, patent splenoportal axis, and low liver stiffness value (<10 kPa), underwent liver biopsies and hepatic venous pressure gradient (HVPG) measurement. Asia Pacific Association for the Study of the Liver (APSAL) criteria were used to diagnose NCPF.2Sarin S.K. Kumar A. Chawla Y.K. et al.Noncirrhotic portal fibrosis/idiopathic portal hypertension: APASL recommendations for diagnosis and treatment.Hepatol Int. 2007 Sep; 1 (PMID 19669336. PMCID PMC2716836): 398-413https://doi.org/10.1007/s12072-007-9010-9Crossref PubMed Google Scholar Among 150 patients, three (2%) had NCPF. Their clinical, biochemical, and histological features are described here (Table 1). On examination, all of them had clinically palpable splenomegaly. Liver biopsies revealed periportal fibrosis in two patients and normal in one, suggesting the diagnosis of NCPF. Following a gluten-free diet (GFD), their symptoms improved.Table 1Clinical, Biochemical, and Histological Profile of All the Patients with Non-cirrhotic Portal Fibrosis (NCPF).Patient characteristicsPatient 1Patient 2Patient 3Age (years)273319SexFemaleFemaleFemalePresenting complaintsEasy fatigability and recurrent iron deficiency anemiaEasy fatigability and left hypochondrium painChronic diarrheaClinically palpable splenomegaly+++++++Hemoglobin (g/dL; normal12–16 g/dL)7.68.510.2Total leukocyte count (4500–11000/mm3)350024504100Platelet count (1.5–4.5/mm3)80,0001.4176,000Bilirubin mg/dL (total/conjugated)1.4/0.72.3/1.31.2/0.4SGOT/SGOT (U/L)40/3518/3234/24Alkaline phosphatase (U/L)25411559Albumin (g/dL)3.73.44.0INR1.621.431.63Anti-TTG (normal <3 Unit/mL)>10078112Concomitant autoimmune diseaseHypothyroidismNilSubclinical hypothyroidismLSM (kPa)119.19.8HVPG (mm of Hg) (normal < 5)987.5VaricesSmall esophageal varicesSmall esophageal varicesSmall esophageal varicesSpleen size (7.6–13 cm)222520PV diameter (<13 mm)161518Liver biopsyInconspicuous portal tract with fibrosisNormal liver biopsyPeri-portal tract fibrosisResponse to GFDDied of intestinal perforation after eight months of diagnosis after transient responseYesGained weight, anemia improvedYesDiarrhea improvedAMA: anti-mitochondrial antibody; ANA: antinuclear antibody; HVPG: hepatic venous pressure gradient; INR: international normalized ratio; kPa: kilopascal; LKM1: liver kidney microsomal antibody 1; SGOT: serum glutamic-oxalacetic transaminase; SGPT: serum glutamic-pyruvic transaminase; TTG: tissue transglutaminase; U/L: unit per liter.The normal values are given within brackets. Open table in a new tab AMA: anti-mitochondrial antibody; ANA: antinuclear antibody; HVPG: hepatic venous pressure gradient; INR: international normalized ratio; kPa: kilopascal; LKM1: liver kidney microsomal antibody 1; SGOT: serum glutamic-oxalacetic transaminase; SGPT: serum glutamic-pyruvic transaminase; TTG: tissue transglutaminase; U/L: unit per liter. The normal values are given within brackets. NCPF has been now classified as porto-sinusoidal vascular disease (PSVD).3De Gottardi A. Sempoux C. Berzigotti A. Porto-sinusoidal vascular disorder.J Hepatol. 2022 Oct; 77 (PMID 35690264): 1124-1135https://doi.org/10.1016/j.jhep.2022.05.033Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar PSVD encompasses a group of disorders that is characterized by lesions involving small vasculature of the liver or sinusoids because of underlying immune disorders, infections, or thrombophilia. A liver biopsy is mandatory to diagnose PSVD.3De Gottardi A. Sempoux C. Berzigotti A. Porto-sinusoidal vascular disorder.J Hepatol. 2022 Oct; 77 (PMID 35690264): 1124-1135https://doi.org/10.1016/j.jhep.2022.05.033Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Non-specific duodenal biopsies findings are common in patients with portal hypertension, and false positive celiac serology is also reported in patients with cirrhosis.4Maiwall R. Goel A. Pulimood A.B. et al.Investigation into celiac disease in Indian patients with portal hypertension.Indian J Gastroenterol. 2014 Nov; 33 (PMID 25231910): 517-523https://doi.org/10.1007/s12664-014-0501-zCrossref PubMed Scopus (18) Google Scholar But the combination of high anti-TTG, villous atrophy, and response to gluten therapy point toward the diagnosis of CeD. In our study, 2% of patients with CeD had NCPF. Similar results were found in a study from India. A study by Nijhawan et al. showed that of 363 patients with CeD, 12 (3.3%) had NCPF.5Nijhawan S. Katiyar P. Nagaich N. et al.Prevalence of associated disorders in Indian patients with celiac disease.Indian J Gastroenterol. 2013 Sep; 32 (PMID 23897517): 330-334https://doi.org/10.1007/s12664-013-0345-yCrossref PubMed Scopus (18) Google Scholar Other reports from India have shown similar presentations.6Sharma B.C. Bhasin D.K. Nada R. Association of celiac disease with non-cirrhotic portal fibrosis.J Gastroenterol Hepatol. 2006 Jan; 21 (PMID 16460500): 332-334https://doi.org/10.1111/j.1440-1746.2006.03296.xCrossref PubMed Scopus (17) Google Scholar Following GFD, symptomatic improvement was noted; however, the improvement of portal hypertension was not documented in most of the studies. The prevalence of autoimmune liver diseases like autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis is high among patients with CeD (4–11%).7Villalta D. Girolami D. Bidoli E. et al.High prevalence of celiac disease in autoimmune hepatitis detected by anti-tissue transglutaminase autoantibodies.J Clin Lab Anal. 2005; 19 (PMID 15645466): 6-10https://doi.org/10.1002/jcla.20047Crossref PubMed Scopus (89) Google Scholar,8Kingham J.G. Parker D.R. The association between primary biliary cirrhosis and coeliac disease: a study of relative prevalences.Gut. 1998; 42 (PMID 9518232): 120-122https://doi.org/10.1136/gut.42.1.120Crossref PubMed Scopus (190) Google Scholar The association between CeD and autoimmune liver diseases can be explained by underlying genetic predisposition and immunogenic mechanisms.9Kaukinen K. Halme L. Collin P. et al.Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure.Gastroenterology. 2002; 122 (PMID 11910339): 881-888https://doi.org/10.1053/gast.2002.32416Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar,10Manns M.P. Krüger M. Immunogenetics of chronic liver diseases.Gastroenterology. 1994; 106 (PMID 8194717): 1676-1697https://doi.org/10.1016/0016-5085(94)90427-8Crossref PubMed Scopus (141) Google Scholar Interestingly, patients with CeD and other autoimmune liver diseases share common HLA which was shown by Kaukinen et al..9Kaukinen K. Halme L. Collin P. et al.Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure.Gastroenterology. 2002; 122 (PMID 11910339): 881-888https://doi.org/10.1053/gast.2002.32416Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar In that study, 39% of patients with PBC with CeD and 58% of patients with PSC and CeD shared HLA DR3 DQ2 or DR4-DQ8. Hence, a GFD can reverse liver dysfunction in CeD which has been reported in earlier studies.9Kaukinen K. Halme L. Collin P. et al.Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure.Gastroenterology. 2002; 122 (PMID 11910339): 881-888https://doi.org/10.1053/gast.2002.32416Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar NCPF is uncommonly associated with CeD, and the presence of splenomegaly should prompt a physician to look for portal hypertension. SM and UCG have been involved in conceptualizing the study. SM, UCG, AM, PM, and AK have cared for and managed the patients. UCG has been the supervisor. PR and NK were involved in the pathology reporting. None of the other authors has any conflict of interest to declare concerning this paper. None.