C.M.J. van Nieuwkerk

Extrahepatic portal vein thrombosis: aetiology and determinants of survival

BACKGROUND Malignancy, hypercoagulability, and conditions leading to decreased portal flow have been reported to contribute to the aetiology of extrahepatic portal vein thrombosis (EPVT). Mortality of patients with EPVT may be associated with these concurrent medical conditions or with manifestations of portal hypertension, such as variceal haemorrhage. PATIENTS AND METHODS To determine which variables have prognostic significance with respect to survival, we performed a retrospective study of 172 adult EPVT patients who were followed over the period 1984–1997 in eight university hospitals. RESULTS Mean follow up was 3.9 years (range 0.1–13.1). Overall survival was 70% (95% confidence interval (CI) 62–76%) at one year, 61% (95% CI, 52–67%) at five years, and 54% (95% CI, 45–62%) at 10 years. The one, five, and 10 year survival rates in the absence of cancer, cirrhosis, and mesenteric vein thrombosis were 95% (95% CI 87–98%), 89% (95% CI 78–94%), and 81% (95% CI 67–89%), respectively (n=83). Variables at diagnosis associated with reduced survival according to multivariate analysis were advanced age, malignancy, cirrhosis, mesenteric vein thrombosis, absence of abdominal inflammation, and serum levels of aminotransferase and albumin. The presence of variceal haemorrhage and myeloproliferative disorders did not influence survival. Only four patients died due to variceal haemorrhage and one due to complications of a portosystemic shunt procedure. CONCLUSION We conclude that mortality among patients with EPVT is related primarily to concurrent disorders leading to EPVT and not to complications of portal hypertension.

The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes

Aliment Pharmacol Ther 2011; 34: 335–343

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Seroprevalence of Hepatitis E Virus in Autoimmune Hepatitis Patients in the Netherlands.

BACKGROUND AND AIMS In recent years chronic courses of hepatitis E virus (HEV) infection have been described in immunosuppressed individuals. This may implicate a potential role for HEV in the development of autoimmune diseases, including autoimmune hepatitis (AIH). Here we investigated the prevalence of HEV-antibodies in AIH patients in an endemic Central European country. METHODS HEV-specific immunoglobulin G (IgG) and HEV RNA were determined in 354 and 377 AIH patients, respectively. Clinical characteristics and disease outcome parameters were retrospectively collected. RESULTS No HEV viraemic patients were identified in this cohort. A total of 106 AIH patients (29.9%) tested positive for anti-HEV IgG, and this figure was slightly higher compared to the prevalence in a reference cohort including 5,329 healthy Dutch blood donors (26.7%; P>0.05). CONCLUSION This is the largest study on the association between HEV infection and AIH. Apparently silent HEV infection is present in a significant proportion of AIH patients, yet appears not to have significant clinical repercussions in this immune compromised group of patients. Nevertheless, since acute hepatitis E may present with histological and biochemical features of AIH, the possibility of a (concomitant) HEV infection should be considered in this category of patients.

938 PRIMARY SCLEROSING CHOLANGITIS IS A RISK FACTOR FOR COLORECTAL CANCER IN YOUNG ULCERATIVE COLITIS PATIENTS

G A A b st ra ct s age 65. Data were extracted from a comprehensive electronic medical record based on ICD9 coding and indexed terms. Results: There were 58 geriatric UC patients identified who underwent surgery. These patients had a mean age of 72 ± 5.6 years (range 65-87 years: males 34: females: 24). Mean duration of UC was 0-50 years (mean 9 ± 12 years SD). The majority of geriatric UC patients (79.3%; n=46) were diagnosed with UC after age 65 years, while 20.6% (n=12) had been diagnosed with UC before age 65. Patient demographics included 89.7% white, 1.7% African American and 8.6% unknown race. Among operative UC patients, 29.3% were positive for Clostridium difficile (C Diff) infection at the time of surgery. Colon carcinoma was noted in 22.4% of the geriatric UC operations. Patterns of bowel surgeries in the geriatric UC cohort included: Proctocolectomywith ileostomy (60.6%); hemicolectomy (14%), Ileocolectomy/partial colectomy (12.7%). Colectomy with Ileal pouch-anal anastomosis (6.6%); Hartmann closure with colostomy (6.1%). Operative mortality in the geriatric UC patients was 5% during the surgical admission. Length of stay for the UC surgery admissions was 10.9 ± 11.4 days(SD). Conclusion: Our study demonstrates that C Diff infection or colon cancer was associated with majority of geriatric UC operations. Operative mortality was significant, occurring in 5% of patients. A majority of geriatric UC patients requiring surgery demonstrated new onset disease, suggesting a more aggressive phenotype tends to present in the elderly age group.

A Case of Autoimmune Hepatitis and Bisphosphonate-Related Osteonecrosis of the Jaw

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease of unknown aetiology usually requiring long-term immunosuppressive therapy. We present the case of an AIH patient who received long-term corticosteroids and azathioprine. As treatment for concomitant osteoporosis she was also treated with potent intravenous bisphosphonate (BP). This treatment was complicated by the development of BP-related osteonecrosis of the jaw (BRONJ). BRONJ is an uncommon complication of BP treatment regimes that occurs at increased frequency in the presence of other risk factors, including chronic inflammatory conditions. Our patient suffered from a severe and complicated clinical course of BRONJ which, despite adequate therapy, resulted in death of the patient. Here we discuss the risk factors for the development and clinical course of BRONJ in AIH and the implications for management of these patients.

PRIMARY SCLEROSING CHOLANGITIS IS ASSOCIATED WITH PANCOLITIS AND NOT BACKWASH ILEITIS

Background and aims: PSC-IBD is reported to represent a distinct phenotype of IBD characterized by colitis, rectal sparing and backwash ileitis, but this has so far not been confirmed in large well-phenotyped cohorts. The aim of this study was to assess the IBD phenotype associated with PSC in a large Dutch PSC cohort using endoscopic and histopathological criteria. Methods: PSC cases were identified and ascertained, fulfilling well-established serological, histological and radiological criteria in 30 hospitals in The Netherlands. IBD location was recorded according to the Montreal classification. To assess the occurrence of backwash ileitis a subgroup analysis was performed in 40 cases and 80 ageand sex-matched IBD controls with at least one complete ileocolonoscopy including terminal ileum histology, reviewing 370 endoscopy and pathology reports written between 2001 and 2010. Results: 324 (64%) of a total of 506 PSC patients had coexistent IBD, mainly ulcerative colitis (UC, 72%). 147 (80%) of the PSC-UC patients had a pancolitis, 28 (15%) a left sided colitis and eight (4%) a proctitis. Sixty (95%) PSC-Crohns disease (CD) patients had an (ileo)colitis and three ileitis only (5%). In the subgroup analysis of 40 PSC-IBD patients twenty-seven (68%) PSC-UC patients were identified, as well as twelve (30%) PSC-CD patients and one (2%) PSC-undetermined IBD patient. Twenty-five (93%) PSC-UC patients had a pancolitis, compared to thirty-three (61%) matched UC patients (p = 0.034). Left sided colitis was seen in seventeen (32%) UC controls and in none of the PSC-UC patients (p = 0.001). Backwash ileitis was seen in only one (4%) PSC-UC patient and in none of the UC controls. Conclusion: PSC-IBD represents a distinct IBD phenotype. The majority of Dutch PSC-UC patients have a pancolitis. In case of PSC-CD, colonic inflammation is involved in 95% of patients. Backwash ileitis is not a prominent finding in Dutch PSC-UC cases.

Mycophenolate mofetil for patients with autoimmune hepatitis and overlap syndromes : authors' reply

SIRS, Garcia-Buey and Moreno-Otero nicely summarise the literature on mycophenolate mofetil (MM) in autoimmune hepatitis (AIH) and overlap syndromes. The Dutch Autoimmune Hepatitis Group (DAHG) shows that second-line MM induces remission in 67% of patients with AIH and intolerance to azathioprine (AZA). In AIH and AZA nonresponse, remission was achieved with MMF in only 13%, and all deaths, liver transplantations and decompensations of cirrhosis occurred in this group. Therefore, in AIH and AZA-nonresponse other options, including liver transplantation, seem more appropriate. This is consistent with the findings of Hennes et al. For all patients with overlap syndromes, MM appears a valuable treatment option. In the DAHG cohort, MM induced remission in 63% and 57%, and response in 15% and 14% after AZA intolerance and nonresponse respectively. Recently, adding MM and budesonide appeared beneficial in primary biliary cirrhosis (PBC) with insufficient response to ursodeoxycholic acid. Further investigations of MM in PBC and overlap seem warranted. As first-line therapy for AIH, one randomised controlled study indicates that budesonide with AZA induces more remission with less side-effects than prednisolone with AZA. However, despite the one prospective cohort with MM as first-line therapy in AIH, and the limitations of earlier studies, most evidence for first-line therapy in AIH still is with AZA and prednisolone. We therefore still consider prednisolone with AZA the first-line treatment in AIH and overlap syndromes until further randomised studies prove otherwise. In case of steroid side-effects, in the absence of cirrhosis, budesonide could be considered, although a prospective maintenance study against prednisolone is still lacking. As second-line therapy in case of AZA-intolerance in AIH, or for all overlap syndrome patients, MM with prednisolone appears useful, but not for AIH with AZA nonresponse. In contrast to AZA, MM is contraindicated in pregnancy.

Mycophenolate mofetil for patients with autoimmune hepatitis and overlap syndromes: authors’ reply: Letters to the Editors

SIRS, Garcia-Buey and Moreno-Otero nicely summarise the literature on mycophenolate mofetil (MM) in autoimmune hepatitis (AIH) and overlap syndromes. The Dutch Autoimmune Hepatitis Group (DAHG) shows that second-line MM induces remission in 67% of patients with AIH and intolerance to azathioprine (AZA). In AIH and AZA nonresponse, remission was achieved with MMF in only 13%, and all deaths, liver transplantations and decompensations of cirrhosis occurred in this group. Therefore, in AIH and AZA-nonresponse other options, including liver transplantation, seem more appropriate. This is consistent with the findings of Hennes et al. For all patients with overlap syndromes, MM appears a valuable treatment option. In the DAHG cohort, MM induced remission in 63% and 57%, and response in 15% and 14% after AZA intolerance and nonresponse respectively. Recently, adding MM and budesonide appeared beneficial in primary biliary cirrhosis (PBC) with insufficient response to ursodeoxycholic acid. Further investigations of MM in PBC and overlap seem warranted. As first-line therapy for AIH, one randomised controlled study indicates that budesonide with AZA induces more remission with less side-effects than prednisolone with AZA. However, despite the one prospective cohort with MM as first-line therapy in AIH, and the limitations of earlier studies, most evidence for first-line therapy in AIH still is with AZA and prednisolone. We therefore still consider prednisolone with AZA the first-line treatment in AIH and overlap syndromes until further randomised studies prove otherwise. In case of steroid side-effects, in the absence of cirrhosis, budesonide could be considered, although a prospective maintenance study against prednisolone is still lacking. As second-line therapy in case of AZA-intolerance in AIH, or for all overlap syndrome patients, MM with prednisolone appears useful, but not for AIH with AZA nonresponse. In contrast to AZA, MM is contraindicated in pregnancy.

Mycophenolate mofetil for patients with autoimmune hepatitis and overlap syndromes

SIRS, Garcia-Buey and Moreno-Otero nicely summarise the literature on mycophenolate mofetil (MM) in autoimmune hepatitis (AIH) and overlap syndromes. The Dutch Autoimmune Hepatitis Group (DAHG) shows that second-line MM induces remission in 67% of patients with AIH and intolerance to azathioprine (AZA). In AIH and AZA nonresponse, remission was achieved with MMF in only 13%, and all deaths, liver transplantations and decompensations of cirrhosis occurred in this group. Therefore, in AIH and AZA-nonresponse other options, including liver transplantation, seem more appropriate. This is consistent with the findings of Hennes et al. For all patients with overlap syndromes, MM appears a valuable treatment option. In the DAHG cohort, MM induced remission in 63% and 57%, and response in 15% and 14% after AZA intolerance and nonresponse respectively. Recently, adding MM and budesonide appeared beneficial in primary biliary cirrhosis (PBC) with insufficient response to ursodeoxycholic acid. Further investigations of MM in PBC and overlap seem warranted. As first-line therapy for AIH, one randomised controlled study indicates that budesonide with AZA induces more remission with less side-effects than prednisolone with AZA. However, despite the one prospective cohort with MM as first-line therapy in AIH, and the limitations of earlier studies, most evidence for first-line therapy in AIH still is with AZA and prednisolone. We therefore still consider prednisolone with AZA the first-line treatment in AIH and overlap syndromes until further randomised studies prove otherwise. In case of steroid side-effects, in the absence of cirrhosis, budesonide could be considered, although a prospective maintenance study against prednisolone is still lacking. As second-line therapy in case of AZA-intolerance in AIH, or for all overlap syndrome patients, MM with prednisolone appears useful, but not for AIH with AZA nonresponse. In contrast to AZA, MM is contraindicated in pregnancy.