Distinctive HLA-II association with primary biliary cholangitis on the Island of Sardinia

Background: The HLA DRB1*08 allele associated with primary biliary cholangitis (PBC) among Caucasians is of low frequency in the Sardinian population. Objective: The aim of our study was to type a cohort of PBC patients from the island of Sardinia for HLA class II antigens. Methods: Twenty Sardinian patients affected by PBC, 14 with autoimmune hepatitis (AIH) and 89 healthy controls (HCs) were typed for HLA class II alleles by dot-blot analysis. Results: The PBC-associated HLA DRB1*08 allele was detected in none of the studied individuals. The DRB1*0301–DQB1*0201 was the prevalent HLA haplotype, detected in 19 (47.5%) out of 40 PBC haplotypes (OR = 3.0; 95% CI 1.5–6.2) and in 11 (39.3%) out of 28 AIH haplotypes (OR = 2.2; 95% CI 0.94–5.0), but in only 41 (23%) out of 178 HC haplotypes. Moreover, PBC patients showed an increased frequency of homozygosity for the DQB1*0201 allele (35% compared with 6.7% of the HCs; OR = 7.5; 95% CI 2.2–25.7). The frequency of the DRB1*11 allele in the PBC group was about half of that seen in the Sardinian HCs (7.5% vs 15.7%) (p = ns). Conclusions: Our study confirmed the low frequency of the HLA DRB1*08 allele among Sardinians, either in the general population or PBC patients. The high prevalence of the HLA DRB1*0301–DQB1*0201 haplotype is a distinctive genetic feature of PBC among Sardinians. Our study strengthens the hypothesis that still unknown genetic, epigenetic, and environmental factors must be involved in the pathogenesis of different HLA-associated liver diseases, and it represents a pathfinder that warrants exploration in a future extensive study

Anti-Actin IgA Antibodies Identify Celiac Disease Patients with a Marsh 3 Intestinal Damage among Subjects with Moderate Anti-TG2 Levels

A new diagnostic tool (algorithm-1) for coeliac disease (CD) permitting the diagnosis without performing the duodenal biopsy has been recently proposed by the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). It combines symptoms associated with CD, high anti-transglutaminase type 2 antibody (anti-TG2) levels, anti-endomysium-IgA antibodies (EMA), and at-risk HLA. Our aims were (i) to evaluate retrospectively in 227 individuals (149 CD patients and 78 controls) the algorithm-1, (ii) to reduce the number of duodenal biopsies among CD patients for whom algorithm-1 is not applicable through the addition of antiactin IgA antibodies (AAA-IgA), and (iii) to evaluate prospectively algorithm-1 and AAA-IgA in 50 patients with suspected CD. Algorithm-1 identified 70 out of 149 CD patients with Marsh 3 lesions. Adding AAA-IgA to the remaining patients with anti-TG2 levels comprised between 4 and 10 times upper limit of normal (ULN) allowed the detection of further 20 patients with a Marsh 3 damage. In our prospective study, algorithm-1 identified 23 out of 50 patients, whilst further 7 were recognized adding AAA-IgA. We confirm that algorithm-1 may avoid the duodenal biopsy in many CD patients and underscores the usefulness of AAA-IgA in reducing the number of duodenal biopsies in patients with moderate anti-TG2 levels

Autoantibodies against CYP-2C19: A Novel Serum Marker in Pediatric De Novo Autoimmune Hepatitis?

Diagnosis of de-novo autoimmune hepatitis (AIH) after orthotopic liver transplantation (OLT) is challenging especially in absence of hyper--globulinemia. Circulating autoantibodies are not sensitive nor specific in de-novo AIH, but when positive increase the diagnostic probability. We report the discovery of novel liver microsomal (LM) autoantibodies against CYP-2C19 in a 9-year-old boy with “de novo” AIH developed 7 years after OLT. Graft dysfunction presented with hypertransaminasemia (up to 400 IU/L), while serum γ-globulins remained within the normal range for age. Liver histology and response to high dose prednisone (2mg/kg/day) with the addition of azathioprine therapy further supported the diagnosis of de-novo AIH. Autoantibodies investigation by indirect immunofluorescence (IF) on rodent tissues showed a novel staining pattern involving the pericentral liver zone and sparing the renal tissue. Human but not rat liver proteins immunoblottings allowed us to characterize the novel LM antibodies and to identify CYP-2C19 as human antigen. The finding offers insights into the controversial discussion about autoimmunity versus alloreactivity with regard to the pathogenesis of de-novo AIH. Correct information on human versus rat tissue antigens tested by methods other than IF for antibodies detection may have significant implications for the correct diagnosis and management of patients followed up after OLT

Utility of Anti-actin Iga Antibody in Combination with the New ESPGHAN Guidelines for Coeliac Disease Diagnosis

AIM: An option to reduce the number of duodenal biopsies in the diagnosis of coeliac disease (CD) has recently been reported by the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition. New criteria showed that the duodenal biopsy may be avoided in presence of symptoms, high anti-transglutaminase type 2 antibody (anti-TG2) levels, anti-endomysial antibodies (EMA) and at-risk HLA, whilst biopsy still remains mandatory for individuals with moderate and low anti-TG2 levels. In this study, we considered the addition of serum measurement of anti-actin IgA antibody (AAA-IgA) to the new criteria, with the aim of further reducing the number of duodenal biopsies. METHODS: One hundred and forty consecutive symptomatic CD children and 78 controls were studied. All subjects were classified according to the new criteria with the addition of AAA-IgA levels and results were compared with the outcome of duodenal biopsy. RESULTS: The biopsies from the sixty-four individuals (out of 218) identified by the new criteria, presence of symptoms, anti-TG2 levels >10 times upper limit of normal (ULN), positive EMA and at-risk HLA, showed CD with a Marsh 3 lesion. In the remaining individuals, the addition of AAA-IgA allowed the detection of further 20 CD patients with a Marsh 3 damage when moderate (4 to 10 times ULN) but not low anti-TG2 levels were present. CONCLUSIONS: Our study confirms that the new criteria may avoid the duodenal biopsy in many CD patients. Moreover, although our finding needs to be confirmed, positivity for AAA-IgA may further reduce the number of duodenal biopsies in moderate anti-TG2 levels