Background Nodular regenerative hyperplasia (NRH) is a rare liver disease causing non-cirrhotic intrahepatic portal hypertension (1). The knowledge of NRH is based mainly upon case reports. Although patients with NRH may remain asymptomatic, at least 50% develop life-threatening complications. Among the autoimmune diseases, SSc has been hypothesized to be associated with NRH. In SSc, microvascular injury is considered one of the earliest pathologic events, followed by inflammation and fibrosis. Similar mechanisms are supposed to be operative in NRH. Therefore, it might be hypothesized that NRH represents a yet unidentified vascular complication of SSc.
Objectives To investigate the prevalence and clinical phenotype of NRH in SSc.
Methods Published cases of SSc-NRH were identified by systematic literature review. Next, we screened the Zurich SSc cohort. In accordance with international guidelines, the diagnosis of NRH had to be established by liver biopsy showing a characteristic diffuse micronodular transformation without fibrous septa (2). SSc characteristics were derived from the EUSTAR database. Information on NRH was extracted from the patients' charts. The study was approved by the local institutional review board. For the statistical analysis, SPSS version 20 was used. Continues variables are presented as mean±SD or median+range. Categorical variables are given as absolute numbers and percentage.
Results The Pubmed search review retrieved 9 cases of SSc-NRH. In the Zurich cohort, 5 out of 278 patients with established SSc were diagnosed with NRH resulting in a prevalence of 1.8%. The main characteristics of all 14 patients are provided in Fig.1. The majority of patients was female (69.2%) with an average age of 44.5±12.3 years at diagnosis of SSc. Mean disease duration of SSc was 8.2±7 years when NRH was diagnosed. NRH occurred in both diffuse and limited cutaneous SSc. ACR/EULAR criteria were fulfilled by all patients. Of note, in the majority of patients, vascular features of SSc were present at the time point of the diagnosis of NRH including digital ulcers (ever 100%, active 71.4%), an active pattern on nailfold capillaroscopy (100%), and pulmonary hypertension (50%). The most prevalent auto-antibodies were anti-centromere (40%) and anti-U1nRNP (33%), whereas no patient was positive for anti-Scl70 or anti-RNA-Polymerase III. In the majority of patients, an elevation of AP and GGT (75%, 60%) was observed, whereas transaminases were not increased. Melaena and hematemesis occurred in 66.7%, resp. 50% of patients. Ultrasound detected ascites (60%) and splenomegaly (75%), but no pathologic liver morphology, although an increased stiffness was diagnosed by fibroscan (75%). Portal hypertension was diagnosed in 85.7% with oesophageal varices (70%) and variceal haemorrhage (44.4%) as main complications.
Conclusions NRH might represent a rare, yet clinically important, potentially life-threatening complication in SSc patients, especially in those with prominent vascular features and positivity for anti-centromere. Elevated levels of AP and GGT, ascites and splenomegaly by ultrasound and increased stiffness by fibroscan might alert to the presence of NRH. If suspected, the diagnosis should be confirmed by liver biopsy.
Hillaire S, et al. Gut 2002;
Steiner PE. Am J Pathol 1959
Disclosure of Interest B. Maurer: None declared, L. Graf: None declared, Y. Allanore Grant/research support from: Actelion, Bayer, Biogen Idec, Bristol-Myers Squibb, Genentech/ Roche, Inventiva, Medac, Pfizer, Sanofi/Genzyme, Servier and UCB., Consultant for: Actelion, Bayer, Biogen Idec, Bristol-Myers Squibb, Genentech/ Roche, Inventiva, Medac, Pfizer, Sanofi/Genzyme, Servier and UCB., R. Dobrota: None declared, S. Jordan: None declared, O. Distler Grant/research support from: Bayer, Sanofi, Ergonex, Boehringer Ingelheim, Actelion, Pfizer, Consultant for: 4 D Science, Actelion, Active Biotec, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Pharmacyclics, Pfizer, Serodapharm, Sinoxa,