Alexandra Heurgué-Berlot

Sequential presentation of primary biliary cirrhosis and autoimmune hepatitis.

Background Primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome is used to describe the coexistence of both diseases, with either a sequential or a simultaneous presentation in the same patient. Available studies have focused on the simultaneous form, whereas there is limited information on sequential PBC-AIH. We carried out a retrospective study of patients who sequentially developed PBC-AIH overlap syndrome. Methods The medical data of 1065 patients diagnosed with PBC (n=483) and AIH (n=582) were retrospectively analyzed. Results A sequential development of PBC-AIH was observed in 19 (1.8%) patients after a mean of 6.5 (1–14) years of follow-up. AIH developed in 12 (2.5%) PBC patients, whereas PBC occurred in seven (1.2%) patients with AIH. The baseline serologic and histological findings of patients who developed PBC-AIH were similar to those of patients with typical PBC or AIH. Eighteen patients were treated with a combination of ursodeoxycholic acid (UDCA) and immunosuppression after the diagnosis of PBC-AIH was established. One patient showed a spontaneous resolution of hepatitic flare under UDCA therapy. Biochemical remission was achieved in 16 patients, whereas three progressed to decompensated cirrhosis and required liver transplantation. Conclusion The sequential overlap of PBC-AIH can occur during the follow-up of patients with pure PBC or AIH. In our cohort, we could not identify any factors that predicted the development of this rare condition. The combination of UDCA and immunosuppression seems to be an appropriate therapy in the setting of PBC-AIH.

Drug-induced autoimmune-like hepatitis: a case of chronic course after drug withdrawal.

Dear Editor, We read with interest the review by Albert J. Czaja on drug-induced autoimmune-like hepatitis [1]. As underlined by the author, the outcome is usually favourable after drug withdrawal, either spontaneously or after a few months of corticosteroid therapy. In contrast with classical autoimmune hepatitis, drug-induced disease does not require longterm immunosuppressive treatment [1, 2]. We report here a rare exception to this rule in a patient with minocyclineinduced autoimmune-like hepatitis which self-perpetuates after drug withdrawal. A 17-year-old male patient was treated for acne vulgaris with minocycline 100 mg/day for 2 months, then 50 mg/day for 1 month from August to October 2005. He had no previous history of liver disease, intravenous drug or alcohol abuse. His liver blood tests controlled 2 years before were in the normal range. At the end of minocycline treatment, a laboratory workup was performed and showed elevated serum levels of alanine aminotransferase (ALT 464 IU/l, normal \ 46), aspartate aminotransferase (AST 293 IU/l, normal \ 49), gamma-glutamyl transpeptidase (GGT 188 UI/l, normal \ 88), alkaline phosphatase (AP 343 UI/l, normal \ 290) and normal bilirubin level (11 lmol/l). His prothrombin index was 67% and gammaglobulins were elevated (31 g/l). The blood eosinophil count rose to 804/ll. Anti-nuclear and anti-smooth muscle antibodies were positive at a titre of 1/6,400 and 1/400, respectively, whereas anti-liver/kidney microsomal and anti-mitochondria antibodies were negative. Anti-native DNA antibodies were slightly positive using the Farr test (6 IU/ml, normal \ 4). Serologies for hepatitis A, B, C, Epstein-Barr virus and cytomegalovirus were negative. Abdominal ultrasound sonography was normal. A liver biopsy was performed and showed features of chronic hepatitis with portal and lobular lymphoplasmocytic infiltrate, rosette formation, peacemeal necrosis and centralportal bridging necrosis. In addition, bile duct damage with lymphocytic cholangitis and ductular proliferation were observed. The diagnosis of auto-immune hepatitis induced by minocycline was made. Treatment with prednisone 40 mg/day was initiated. Serum aminotransferases normalised within 1 month. Prednisone was gradually reduced and stopped after 4 months. Three months later, there was a relapse with serum ALT level of 105 IU/l, AST of 73 IU/l and GGT of 104 IU/l. Gamma globulins were elevated (25 g/l). Prednisone was reintroduced at 30 mg/day with azathioprine 125 mg/day. On the basis of histological bile duct damage, ursodeoxycholic acid 1,000 mg/day was added. His serum levels of aminotransferases and GGT returned to normal within 3 months. Prednisone was stopped after 6 months and the patient was maintained on azathioprine and ursodeoxycholic acid. From 2007 to 2009, periods of poor compliance translated into transient increased levels of aminotransferases. In October 2010, the liver tests were normal. The prothrombin index was 88% and serum albumin was 41 g/l. However, immunological abnormalities were still present. Serum immunoglobulin G was elevated (21.3 g/l). Anti-nuclear and anti-smooth muscle antibodies were positive at titres of 1/3,200 and 1/400, respectively. Anti-native DNA antibodies were positive (50 IU/ml, normal \ 4). During the following 2-month period, the compliance rate was very poor, i.e. less A. Heurgue-Berlot (&) B. Bernard-Chabert G. Thiefin Department of Hepato-Gastroenterology, CHU Reims, Reims, France e-mail: aheurgue@chu-reims.fr

Late autoimmune hepatitis after hepatitis C therapy.

Background De-novo or reactivated autoimmune hepatitis (AIH) has been reported during or a short time after administration of interferon (IFN) in patients treated for hepatitis C (HCV). Reports on AIH during long-term follow-up after IFN treatment are scarce. Patients and methods Patients diagnosed with both HCV and AIH were identified in clinical databases of four gastroenterology departments. The medical records of patients diagnosed with AIH after IFN therapy were retrospectively assessed. Results Five patients (four female, one male) with a mean age of 50 years (range: 34–59) were identified. AIH developed at a mean duration of 4.8 years (range: 1–10) after HCV therapy. Three of five patients had a sustained viral response to antiviral therapy, whereas two were nonresponders. All patients were treated with immunosuppressive therapy after being diagnosed with AIH. Biochemical remission was achieved in four patients; however, one patient had an aggressive course and died despite immunosuppressive therapy. We could not identify any risk factors associated with the development of AIH. Conclusion AIH may develop in patients treated with IFN, not only during or after a short time from therapy but also after a long time from discontinuation of therapy.

The Periscreen Strip Is Highly Efficient for the Exclusion of Spontaneous Bacterial Peritonitis in Cirrhotic Outpatients

Objectives:We aimed to assess the performance of a new strip (Periscreen) for the rapid diagnosis of spontaneous bacterial peritonitis (SBP).Methods:Ascitic fluid (AF) of cirrhotic patients hospitalized between March 2014 and August 2015 was independently tested by two readers using the new strip, which has four colorimetric graduations (negative, trace, small, and large). SBP was diagnosed on neutrophils in ascites>250/mm3. Ascites not related to portal hypertension were excluded.Results:Overall, 649 patients from 21 French centers were included and 1,402 AF (803 AF samples from 315 outpatients and 599 samples from 334 inpatients) were assessed. Eighty-four AF samples (17 AF in 9 outpatients and 67 AF in 31 inpatients) were diagnosed as SBP. The prevalence of SBP was 6% (2.1% in outpatients vs. 11.2% in inpatients; P<0.001) and 7.2% in patients with symptoms suggestive of SBP (3% in outpatients vs. 11.3% in inpatients; P<0.001). The κ value for inter-reader agreement was 0.81 (95% confidence interval: 0.77–0.84) when using the “trace” threshold. Considering discordant results (n=131) as positive to interpret the diagnostic performance of the strip at the “trace” threshold, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 91.7, 57.1, 12.0, and 99.1%, respectively. At this “trace” threshold, sensitivity and NPV were both 100% in outpatients, and 89.5 and 97.9% in inpatients, respectively. At the “small” threshold, sensitivity, specificity, PPV and NPV were 81.0, 85.9, 25.9 and 98.7%, respectively.Conclusions:The Periscreen strip is a rapid and highly efficient tool for excluding SBP in the outpatient setting.

Proximal predominance of small bowel injury associated with uncoated low-dose aspirin therapy: a video capsule study in chronic users.

Background and aim Only a limited number of studies have evaluated the small intestinal damage associated with chronic low-dose aspirin (LDA) therapy. We assessed, using capsule endoscopy, the prevalence and the characteristics of small bowel damage in chronic LDA users compared with patients taking an anticoagulant (AC) and those taking no antithrombotic drugs. Patients and methods We retrospectively reviewed 75 capsule endoscopy recordings from three groups of patients with unexplained iron-deficient anemia: 28 patients receiving LDA, 15 receiving an AC, and 32 not receiving any antithrombotic drug. The severity and location of small intestinal mucosal breaks were assessed in a blinded manner by two endoscopists. Results All LDA users received uncoated aspirin. The number of small bowel mucosal breaks in patients receiving LDA (median 1, extremes 0–125) was significantly higher than that in those taking an AC (0, 0–1) (P=0.0005) or no antithrombotic drugs (0, 0–23) (P<0.0001). The prevalence of patients with mucosal breaks was higher in the LDA group (71.4%) than in the AC group (20%, P=0.001) and the control group (12.5%, P=0.000005). Mucosal breaks in LDA users were predominant in the first tertile of the small bowel. The difference between groups was significant only for mucosal breaks located in the first tertile (P<0.0001). Conclusion About two-thirds of uncoated LDA chronic users with anemia have mucosal breaks in the small bowel. These lesions are predominant in the proximal part, suggesting a topical toxic effect of uncoated LDA.

Clinical implications of antimitochondrial antibody seropositivity in autoimmune hepatitis: a multicentre study.

Background/aim Antimitochondrial antibody (AMA) positivity is the serological marker of primary biliary cholangitis (PBC), but can also be sporadically detected in autoimmune hepatitis (AIH). Little is known about the clinical significance of AMA in AIH. Patients and methods We recruited 47 AMA-positive AIH cases from several centres and compared them with 264 well-characterized Italian AIH patients. Cases with any features of PBC were excluded. Results In univariate analysis, AMA-positive AIH patients were older (46 vs. 36, P=0.002) and more responsive to immunosuppression (74 vs. 59%, P=0.05), but no differences were observed between the two groups after logistic regression using AMA as a dependent variable. None of the AMA-positive AIH patients showed signs of evolving PBC features after a median follow-up of up 47 months. AMA was detected in combination with all serological AIH markers except antiliver kidney microsome type 1 and antiliver cytosol type 1. AMA was the only marker of autoimmunity in eight cases. Conclusion We found no differences between AIH with and without AMA. The groups had similar clinical, biochemical and histological features. AMA-positive AIH patients did not evolve towards PBC. In some cases, AMA was the only autoantibody.

Accuracy of calprotectin using the Quantum Blue Reader for the diagnosis of spontaneous bacterial peritonitis in liver cirrhosis: Calprotectin and spontaneous bacterial peritonitis

We aimed to evaluate the accuracy of the dosage of calprotectin in ascitic fluid (AF) using the Quantum Blue assay, for the prompt diagnosis of spontaneous bacterial peritonitis (SBP).

Ménétrier's disease: Long-term remission with lanreotide.

Ménétriers disease is a rare hypertrophic gastropathy, causing protein leak. An overexpression of transforming growth factor alpha is involved. In inhibiting the epidermal growth factor receptor, cetuximab and somatostatin analogues are the two most promising treatments, allowing to avoid radical gastrectomy. We report the case of a patient with a sustained clinical remission after treatment with lanreotide, but without complete endoscopic healing. We discuss the available therapeutic options and present a literature review of somatostatin analogues for the treatment of Ménétriers disease.

Overlap syndrome and connective tissue diseases.

To the Editor, We read with interest the article by Efe et al. [1] on the development of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) overlap syndrome in three patients with connective tissue disease. It is well established that organ-specific and multisystemic autoimmune disorders may develop in patients with pure AIH or PBC and diagnostic screening for concurrent autoimmune diseases is recommended in these patients. The case report by Efe et al. [1] suggests that the same concept of ‘‘mosaic of autoimmunity’’ [2] applies to patients with AIH/CBP overlap syndrome. In order to bring additional information about the prevalence of multisystemic and hepatic autoimmune disease association, we analyzed our consecutive series of 82 patients with AIH, 63 with PBC, and 25 with AIH/PBC overlap syndrome. As shown in Table 1, we found that one patient (4%) in 25 with overlap syndrome had a multisystemic autoimmune disease compared to ten (12.2%) and 11 (17.5%) in those with pure AIH and PBC, respectively. We confirmed that systemic lupus erythematosus was more frequent in AIH patients and Sjögren’s syndrome was more frequent in PBC patients. In our series, the only case of connective tissue disease associated with AIH/PBC overlap syndrome was observed in a patient with rheumatoid arthritis who developed secondarily an AIH/PBC overlap syndrome. The diagnosis was made according to the biological and histological criteria proposed by Chazouillères et al. [3]. The patient had serum alanine aminotransferase and gamma-glutamyl-transpeptidase levels five times above the upper limit of normal and serum gamma-globulins at 26 g/l (N:6–11 g/l). Anti-nuclear antibodies were positive at a titer of 1/3,200. Anti-smooth muscle and antimitochondrial antibodies were negative. The liver biopsy showed lymphocyte and plasma cell infiltration in portal areas with piecemeal necrosis, portal fibrosis, and lymphocytic destructive cholangitis. After failure of corticosteroid and azathioprine treatment, the patient was successfully treated with cyclosporine. We also observed in our cohort that organ-specific immune disorders, mainly autoimmune thyroiditis, were present at the same extent in patients with AIH/PBC overlap syndrome (40%) and in patients with pure AIH (30.5%) or PBC (23.8%) (Table 1). According to Efe et al. [1] and our own data, it appears that the association of connective tissue disease with autoimmune liver disease is not restricted to patients with pure AIH and CBP but also concerns patients with AIH/ PBC overlap syndrome. Although limited, available data suggest that AIH, PBC, and overlap syndrome share the same propensity to develop extrahepatic autoimmune disorders, including multisystemic diseases, which favors the view that overlap syndrome is not a separate entity in the spectrum of autoimmune liver diseases. A. Heurgué-Berlot (&) B. Bernard-Chabert G. Thiéfin Department of Hepato-Gastroenterology, CHU Reims, Reims, France e-mail: aheurgue@chu-reims.fr