Sarwa Darwish Murad

Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.

Data on the long‐term effects of interferon alfa (IFN) treatment on disease progression and mortality in patients with chronic hepatitis B (CHB) are limited. To evaluate factors that influence clinical outcome and survival, we performed a follow‐up study on 165 hepatitis B e antigen (HBeAg) positive CHB patients treated with IFN between 1978 and 2002. The median IFN dose was 30 megaunits (MU)/week (range, 2–70 MU/week), and the median duration of therapy was 16 weeks (range, 1–92 weeks). Response to treatment was defined as HBeAg loss within 12 months after the end of IFN therapy. Median follow‐up was 8.8 years (range, 0.3–24 years). Fifty‐four patients (33%) responded to IFN treatment. Relapse (HBeAg reactivation) occurred in 7 of the 54 (13%) responders. Fifty‐two percent of the responders lost hepatitis B surface antigen (HBsAg) as compared with 9% of the nonresponders (P < .001). Liver histology showed a decreased necroinflammatory activity and less progression of fibrosis in responders. Twenty‐six patients died during follow‐up. Hepatocellular carcinoma (HCC) was found in 8 patients, 6 of whom were nonresponders. Of the two responders who developed HCC, one patient had relapsed after discontinuation of therapy. Multivariate analysis showed significantly improved survival (relative risk (RR) of death 0.28, 95% CI 0.10–0.78) and reduced risk of developing HCC (RR 0.084, 95% CI 0.09–0.75) in responders. In conclusion, response to IFN therapy results in a prolonged clinical remission with an increased rate of HBsAg seroconversion and improved liver histology. Our results indicate that after correction for baseline factors, response to IFN therapy increases survival and reduces the risk of developing HCC. (HEPATOLOGY 2004;39:804–810.)

Etiology, management, and outcome of the Budd-Chiari syndrome

BACKGROUND The Budd-Chiari syndrome (BCS) is hepatic venous outflow obstruction. What is known about the syndrome is based on small studies of prevalent cases. OBJECTIVE To characterize the causes and treatment of incident BCS. DESIGN Consecutive case series of patients with incident BCS, enrolled from October 2003 to October 2005 and followed until May 2006. SETTING Academic and nonacademic hospitals in France, Spain, Italy, Great Britain, Germany, Belgium, the Netherlands, Portugal, and Switzerland. PATIENTS Persons older than 16 years with definite hepatic outflow obstruction diagnosed by imaging. Persons with hepatic outflow obstruction due to heart failure, sinusoidal obstruction syndrome, cancer, or liver transplantation were excluded. MEASUREMENTS Signs and symptoms; laboratory and imaging findings; diagnosis; treatment; and overall, transplantation-free, and intervention-free survival. RESULTS 163 incident cases of BCS were identified. Median follow-up was 17 months (range, 0.1 to 31 months). Most patients (84%) had at least 1 thrombotic risk factor, and many (46%) had more than 1; the most common was myeloproliferative disorders (49% of 103 tested patients). Patients were mainly treated with anticoagulation (140 patients [86%]), transjugular intrahepatic portosystemic shunting (56 patients [34%]), or liver transplantation (20 patients [12%]), and 80 patients (49%) were managed noninvasively. Only 3 patients underwent surgical shunting. The survival rate was 87% (95% CI, 82% to 93%) at 1 year and 82% (CI, 75% to 88%) at 2 years. LIMITATION Treatment was not standardized across all centers, and data on important clinical variables were missing for some patients. CONCLUSION Most patients with BCS have at least 1 thrombotic risk factor, and many have more than 1; myeloproliferative disorders are most common. One- and 2-year survival rates are good with contemporary management, which includes noninvasive therapies (anticoagulation and diuretics) and invasive techniques. Transjugular intrahepatic portosystemic shunting seems to have replaced surgical shunting as the most common invasive therapeutic procedure. PRIMARY FUNDING SOURCE Fifth Framework Programme of the European Commission.

The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases

Myeloproliferative diseases (MPDs) represent the commonest cause of splanchnic vein thrombosis (SVT), including Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT), but their diagnosis is hampered by changes secondary to portal hypertension, while their influence in the outcome of SVT remains unclear. We assessed the diagnostic and prognostic value of JAK2 and MPL515 mutations in 241 SVT patients (104 BCS, 137 PVT). JAK2V617F was found in 45% of BCS and 34% of PVT, while JAK2 exon 12 and MPL515 mutations were not detected. JAK2V617F was found in 96.5% of patients with bone marrow (BM) changes specific for MPD and endogenous erythoid colonies, but also in 58% of those with only one feature and in 7% of those with neither feature. Stratifying MPD diagnosis first on JAK2V617F detection would have avoided BM investigations in 40% of the patients. In BCS, presence of MPD carried significantly poorer baseline prognostic features, required hepatic decompression procedures earlier, but had no impact on 5-year survival. Our results suggest that JAK2V617F testing should replace BM investigations as initial test for MPD in patients with SVT. Underlying MPD is associated with severe forms of BCS, but current therapy appears to offset deleterious effects of MPD on the medium-term outcome.

Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome

Budd‐Chiari syndrome (BCS) is a rare disorder that is characterized by hepatic venous outflow obstruction. The aim of this study was to assess determinants of survival and to evaluate the effect of portosystemic shunting. In this international multicenter study, 237 patients with BCS, diagnosed between 1984 and 2001, were investigated. Univariate, multivariate, and time‐dependent Cox regression analyses were performed. Overall survival at 1, 5, and 10 years was 82% (95% CI, 77%–87%), 69% (95% CI, 62%–76%), and 62% (95% CI, 54%–70%), respectively. Encephalopathy, ascites, prothrombin time, and bilirubin were independent determinants of survival. A prognostic classification combining these factors could identify three classes of patients (classes I–III). The 5‐year survival rate was 89% (95% CI, 79%–99%) for class I, 74% (95% CI, 65%–83%) for class II, and 42% (95% CI, 28%–56%) for class III. Anticoagulants were administered to 72%; only for patients in class I was this associated with a trend toward improved survival (relative risk [RR], 0.14; 95% CI, 0.02–1.21). Portosystemic shunting was performed in 49% of the patients (n = 117); only for patients in class II, time‐dependent analyses suggested an improved survival (RR, 0.63; 95% CI, 0.26–1.49). In conclusion, at the time of diagnosis, patients with BCS can be classified into good (I), intermediate (II), and poor (III) prognostic classes, according to simple baseline clinical and laboratory parameters. Our results suggest an improved survival after surgical portosystemic shunting for patients with an intermediate prognosis (class II). (HEPATOLOGY 2004;39:500–508.)

Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers.

BACKGROUND & AIMS Excellent single-center outcomes of neoadjuvant chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma caused the United Network of Organ Sharing to offer a standardized model of end-stage liver disease (MELD) exception for this disease. We analyzed data from multiple centers to determine the effectiveness of this treatment and the appropriateness of the MELD exception. METHODS We collected and analyzed data from 12 large-volume transplant centers in the United States. These centers met the inclusion criteria of treating 3 or more patients with perihilar cholangiocarcinoma using neoadjuvant therapy, followed by liver transplantation, from 1993 to 2010 (n = 287 total patients). Center-specific protocols and medical charts were reviewed on-site. RESULTS The patients completed external radiation (99%), brachytherapy (75%), radiosensitizing therapy (98%), and/or maintenance chemotherapy (65%). Seventy-one patients dropped out before liver transplantation (rate, 11.5% in 3 months). Intent-to-treat survival rates were 68% and 53%, 2 and 5 years after therapy, respectively; post-transplant, recurrence-free survival rates were 78% and 65%, respectively. Patients outside the United Network of Organ Sharing criteria (those with tumor mass >3 cm, transperitoneal tumor biopsy, or metastatic disease) or with a prior malignancy had significantly shorter survival times (P < .001). There were no differences in outcomes among patients based on differences in surgical staging or brachytherapy. Although most patients came from 1 center (n = 193), the other 11 centers had similar survival times after therapy. CONCLUSIONS Patients with perihilar cholangiocarcinoma who were treated with neoadjuvant therapy followed up by liver transplantation at 12 US centers had a 65% rate of recurrence-free survival after 5 years, showing this therapy to be highly effective. An 11.5% drop-out rate after 3.5 months of therapy indicates the appropriateness of the MELD exception. Rigorous selection is important for the continued success of this treatment.

TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.

BACKGROUND & AIMS Budd-Chiari syndrome (BCS) is a rare and life-threatening disorder secondary to hepatic venous outflow obstruction. Small series of BCS patients indicate that transjugular intrahepatic portosystemic shunt (TIPS) may be useful. However, the influence of TIPS on patient survival and factors that predict the outcome of TIPS in BCS patients remain unknown. METHODS One hundred twenty-four consecutive BCS patients treated with TIPS in 6 European centers between July 1993 and March 2006 were followed until death, orthotopic liver transplantation (OLT), or last clinical evaluation. RESULTS Prior to treatment with TIPS, BCS patients had a high Model of End Stage Liver Disease and high Rotterdam BCS prognostic index (98% of patients at intermediate or high risk) indicating severity of liver dysfunction. However, 1- and 5-year OLT-free survival were 88% and 78%, respectively. In the high-risk patients, 5-year OLT-free survival was much better than that estimated by the Rotterdam BCS index (71% vs 42%, respectively). In the whole population, bilirubin, age, and international normalized ratio for prothrombin time independently predicted 1-year OLT-free survival. A prognostic score with a good discriminative capacity (area under the curve, 0.86) was developed from these variables. Seven out of 8 patients with a score >7 died or underwent transplantation vs 5 out of 114 patients with a score <7. CONCLUSIONS Long-term outcome for patients with severe BCS treated with TIPS is excellent even in high-risk patients, suggesting that TIPS may improve survival. Furthermore, we identified a small subgroup of BCS patients with poor prognosis despite TIPS who might benefit from early OLT.

Good long-term outcome of Budd-Chiari syndrome with a step-wise management

Budd‐Chiari syndrome (BCS) is a rare, life‐threatening disease caused by obstruction of hepatic venous outflow. The aim of the study was to assess long‐term outcome and identify prognostic factors in BCS patients managed by a step‐wise approach using anticoagulation, angioplasty/thrombolysis, transjugular intrahepatic portosystemic shunting (TIPS), and orthotopic liver transplantation (OLT). We reviewed long‐term data on 157 patients previously included by the European Network for Vascular Disorders of the Liver, a multicenter prospective study of newly diagnosed BCS patients in nine European countries. Patients were followed for a median of 50 months (range, 0.1‐74.0). During the study, 88 patients (56%) received at least one invasive intervention (22 patients angioplasty/thrombolysis, 62 TIPS, and 20 OLT) and 36 (22.9%) died. Most interventions and/or deaths occurred in the first 2 years after diagnosis. The Rotterdam score was excellent in predicting intervention‐free survival, and no other variable could significantly improve its prognostic ability. Moreover, BCS‐TIPS prognostic index (PI) score (based on international normalized ratio, bilirubin, and age) was strongly associated with survival and had a discriminative capacity, which was superior to the Rotterdam score. Conclusions: The current study confirms, in a large cohort of patients with BCS recruited over a short period, that a step‐wise treatment approach provides good long‐term survival. In addition, the study validates the Rotterdam score for predicting intervention‐free survival and the BCS‐TIPS PI score for predicting survival. (HEPATOLOGY 2013;)

Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: The Rotterdam study

Given that little is known about the prevalence of, and factors associated with, liver fibrosis in the general population, we aimed to investigate this in a large, well‐characterized cohort by means of transient elastography (TE). This study was part of the Rotterdam Study, a population‐based study among individuals ≥45 years. All participants underwent abdominal ultrasound and TE. Liver stiffness measurement (LSM) ≥8.0 kilopascals (kPa) was used as a cutoff suggesting clinically relevant fibrosis. Of 3,041 participants (age, 66.0 ± 7.6 years) with reliable LSM, 169 (5.6%) participants had LSM ≥8.0 kPa. Age (odds ratio [OR]: 2.40; 95% confidence interval [CI]: 1.72‐3.36; P < 0.001), alanine aminotransferase (ALT; OR, 1.24; 95% CI: 1.12‐1.38; P < 0.001), smoking (OR, 1.77; 95% CI: 1.16‐2.70; P = 0.008), spleen size (OR, 1.23; 95% CI: 1.09‐1.40; P = 0.001), hepatitis B surface antigen, or anti–hepatitis C virus positivity (OR, 5.38; 95% CI: 1.60‐18.0; P = 0.006), and combined presence of diabetes mellitus (DM) and steatosis (OR, 5.20; 95% CI: 3.01‐8.98; P < 0.001 for combined presence) were associated with LSM ≥8.0 kPa in multivariable analyses. The adjusted predicted probability of LSM ≥8.0 kPa increased per age decade, with probabilities ranging from 1.4% (0.9‐3.6) in participants ages 50‐60 years to 9.9% (6.8‐14.5) in participants >80 years. Participants with both DM and steatosis had the highest probabilities of LSM ≥8.0 kPa (overall probability: 17.2% [12.5‐23.4]; this probability did not increase with age [P = 0.8]). Conclusion: In this large population‐based study of older adults, LSM ≥8.0 kPa, suggestive of clinically relevant fibrosis, was present in 5.6% and was strongly associated with steatosis and DM. In the context of an aging population and an increased prevalence of DM and obesity, this study illustrates that liver fibrosis may become a more prominent public health issue in the near future. (Hepatology 2016;63:138–147)

Predictors of self-reported problem behaviours in Turkish immigrant and Dutch adolescents in the Netherlands

BACKGROUND Although many studies have compared psychopathology in different cultures, not much is known about factors that contribute to the observed differences. METHODS We compared self-reported emotional and behavioural problems in 363 Turkish immigrant and 1098 Dutch adolescents in the Netherlands and we evaluated the contribution of adolescent, parent, family and stress-related factors to the observed ethnic differences. Data were drawn from the Dutch version of the Youth Self-Report (YSR), as well as from Dutch and Turkish parental questionnaires. RESULTS Turkish girls scored higher on four of the eight YSR syndrome-scales, on the Internalising broadband scale and on total problems than Dutch girls. Turkish boys scored higher on three syndrome scales and on the Internalising scale, but scored less on Delinquent Behaviour than their Dutch peers. Ethnic differences for both sexes were most pronounced on the Withdrawn and Anxious/Depressed scales. Socio-economic measures, in particular education of the parents, contributed most to the explanation of ethnic differences on the Somatic Complaints scale for girls and Social Problem and Internalising scales for boys. On most scales, however, ethnic differences could not be explained by other factors. The distribution of some factors appeared to be more favourable (i.e., less frequent) for Turkish than for Dutch youths, such as referral of family members to mental health services. CONCLUSIONS Low educational levels of the parents play an important, yet not an exclusive role in explaining cross-cultural differences in emotional and behavioural problems in adolescents. In particular, differences in Withdrawn and Anxious/Depressed behaviour could not be explained by non-cultural factors. This study offers starting-points for future research on cultural-specific predictors of psychopathology in immigrants.

Paroxysmal nocturnal hemoglobinuria in Budd-Chiari Syndrome: Findings from a cohort study

BACKGROUND/AIMS A well recognized cause of Budd-Chiari syndrome (BCS) is paroxysmal nocturnal hemoglobinuria (PNH). PNH is an acquired disorder of hematopoietic stem cells, characterized by intravascular hemolysis and venous thrombosis. Testing for this hematological disorder should be considered in all BCS patients. METHODS Using data from the EN-Vie study, a multi-center study of 163 patients with BCS, we investigated the relationship between BCS and PNH in 15 patients with combined disease and compared the results to 62 BCS patients in whom PNH was excluded. RESULTS Median follow-up for the study group (n=77) was 20 months (range 0-44 months). BCS patients with PNH presented with a significantly higher percentage of additional splanchnic vein thrombosis (SVT) as compared to BCS patients without PNH (47% vs. 10%, p=0.002). During follow-up, type and frequency of interventions for BCS was similar between both groups. Six patients with BCS and PNH were successfully treated with a transjugular intrahepatic portosystemic shunt (TIPS). Of 15 patients with PNH, six underwent allogenic stem cell transplantation after diagnosis of BCS. PNH was successfully cured in five cases. There was no significant difference in survival between BCS patients with and without PNH. CONCLUSIONS This study shows that despite a higher frequency of additional SVT, short-term prognosis of BCS patients with PNH does not differ from BCS patients without PNH. Treatment with TIPS can be safely performed in patients with PNH. Stem cell transplantation appears to be a feasible treatment option for PNH in BCS patients.