Prevalence and clinical outcomes of the 46/1 haplotype, Janus kinase 2 mutations, and ten-eleven translocation 2 mutations in Budd-Chiari syndrome and their impact on thrombotic complications post liver transplantation.

Latent myeloproliferative disorders (MPDs) can be identified by Janus kinase 2 (JAK2) mutations in patients with idiopathic Budd-Chiari syndrome (BCS). The incidence and clinical outcomes of JAK2 mutations, novel ten-eleven translocation 2 (TET2) mutations, and the 46/1 haplotype in BCS are unknown for liver transplantation (LT). We undertook molecular studies of 66 patients presenting with BCS and correlated the results with the clinical outcomes. An overt MPD was present in 20% of the cases, and a latent MPD confirmed by the presence of a JAK2 mutation was detected in 45%. Testing for a TET2 mutation identified MPDs at the molecular level in another 7% of the subset of patients with BCS who were evaluated. The 46/1 haplotype frequency was significantly greater in BCS patients versus the general population (P < 0.001). The presence of JAK2 and TET2 mutations had no impact on 1-year survival. Thirty-six patients underwent LT, and 12 developed liver-related thrombotic complications (33%). Ten of these 12 patients required retransplantation. Retransplantation was more likely in those patients who developed liver-related thrombotic complications (P < 0.001). A JAK2 mutation was highly associated with the development of thrombotic complications after LT (P = 0.005). In conclusion, the presence of JAK2V617F predicts hepatic and extrahepatic thrombotic complications after LT. Testing for TET2 mutations can identify another 7% of idiopathic BCS patients with molecular MPDs.

A diagnosis fifteen years in the making.

A 52-year-old male with a diagnosis of non-alcoholic fatty liver disease re-engages with the medical system and is found to have an unexpected diagnosis.

The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients.

BACKGROUND: Increased oxidative stress and subsequent mitochondrial damage are important pathways for liver damage in chronic hepatitis C virus (HCV) infection; consequently, therapies that decrease mitochondrial oxidative damage may improve outcome. The mitochondria-targeted anti-oxidant mitoquinone combines a potent anti-oxidant with a lipophilic cation that causes it to accumulate several-hundred fold within mitochondria in vivo. AIMS: In this phase II study, we investigated the effect of oral mitoquinone on serum aminotransferases and HCV RNA levels in HCV-infected patients. METHODS: Thirty HCV patients who were either non-responders or unsuitable candidates for standard-of-care (pegylated interferon plus ribavirin) were randomized to receive mitoquinone (40 or 80 mg) or placebo once daily for 28 days, and serum aminotransferases and HCV RNA levels were measured. RESULTS: Both treatment groups showed significant decreases in absolute and percentage changes in serum alanine transaminase (ALT) from baseline to treatment day 28 (P<0.05). There was also a significant difference between incremental area under the curve for ALT between baseline and day 28 for the 40 mg treatment group against placebo (P<0.05). The differences in plasma ALT activity from baseline to day 28 in both mitoquinone groups compared with placebo did not reach significance (P>0.05). There was no change in HCV load on mitoquinone treatment. CONCLUSIONS: Administration of the mitochondria-targeted anti-oxidant mitoquinone significantly decreased plasma ALT and aspartate aminotransferase in patients with chronic HCV infection, and this suggests that mitoquinone may decrease necroinflammation in the liver in these patients. As mitochondrial oxidative damage contributes to many other chronic liver diseases, such as steatohepatitis, further studies using mitochondria-targeted anti-oxidants in HCV and other liver diseases are warranted.

Low vaccination in rural Sindh, Pakistan: A case of refusal, ignorance or access?

INTRODUCTION: Pakistan is suffering from low routine childhood immunization (RI) coverage, meriting a systematic examination of community acceptance and barriers towards vaccination with a view to inform responsive strategies. We examine community perspectives on RI for children 0-23 months of age, unveiling community beliefs, health systems barriers and willingness to actively seek immunization services. METHODS: A qualitative study was conducted in the rural under-resourced district of Tando Muhammad Khan of Pakistan's Sindh province. 12 focus group discussions were conducted to probe immunization perceptions and experience: 6 with female caregivers of children <2 years and 6 with Lady Health workers (LHWs). An adapted Health Access Livelihood Framework guided data collection, qualitative data were thematically coded using inductive analysis and findings were triangulated across caregivers and LHWs. RESULTS: Caregivers were either indifferent to vaccination or had an unmet need to know more, with few reporting outright refusals to vaccinate. Caregiver beliefs were characterized by a lack of awareness and a confusion of RI with Polio and a fear of side effects. Religious beliefs were not major considerations. Second, health systems issues of hurried and infrequent vaccination encounters, driven by LHWs' poor capability to handle the vaccine counter-narrative, interrupted vaccine delivery to villages. These challenges were exacerbated by interruptions due to the Polio campaigns. Third, time and public transport constrained access to the Extended Program on Immunization centers. However, female caregivers usually took decisions on vaccination without recourse to male household members, with child's health viewed to be the main concern. CONCLUSIONS: An ineffective vaccination narrative, low LHW capability and prioritization of RI, intermittent outreach vaccination encounters, and overshadowing of RI activities by Polio campaigns limit the uptake of childhood RI services. We contend that critical attention is required for post-immunization messaging, client-centric services, positive immunization experiences and the availability of vaccination encounters.

Health systems changes after decentralisation: progress, challenges and dynamics in Pakistan.

Decentralisation is widely practised but its scrutiny tends to focus on structural and authority changes or outcomes. Politics and process of devolution implementation needs to be better understood to evaluate how national governments use the enhanced decision space for bringing improvements in the health system and the underlying challenges faced. We use the example of Pakistan's radical, politically driven provincial devolution to analyse how national structures use decentralisation opportunities for improved health planning, spending and carrying out transformations to the health system. Our narrative draws on secondary data sources from the PRIMASYS study, supplemented with policy roundtable notes from Pakistan. Our analysis shows that in decentralised Pakistan, health became prioritised for increased government resources and achieved good budgetary use, major strides were made contextualised sector-wide health planning and legislations, and a proliferation seen in governance measures to improve and regulate healthcare delivery. Despite a disadvantaged and abrupt start to devolution, high ownership by politicians and bureaucracy in provincial governments led to resourcing, planning and innovations. However, effective translation remained impeded by weak institutional capacity, feeble federal-provincial coordination and vulnerability to interference by local elites. Building on this illustrative example, we propose (1) political management of decentralisation for effective national coordination, sustaining stable leadership and protecting from political interfere by local elites; (2) investment in stewardship capacity in the devolved structures as well as the central ministry to deliver on new roles.

Severe jaundice following treatment with ezetimibe.

Ezetimibe is a cholesterol-lowering agent that modulates intestinal absorption of sterols. It is well tolerated but hepatic toxicity has been reported when ezetimibe is used in conjunction with a statin medication. In this case report, we report severe isolated hyperbilirubinaemia occurring in a patient with occult cirrhosis, probably owing to nonalcoholic steatohepatitis, who was treated with ezetimibe alone. The adverse event started after ezetimibe therapy was initiated and resolved when the drug was stopped. We propose a mechanism for this reaction and believe that liver function should be monitored in patients with abnormal liver tests who are treated with ezetimibe, even if they are not on concomitant treatment with a statin.

Dietary copper restriction in Wilson's disease.

Dietary copper restriction has long been considered an important aspect of treatment for Wilson's disease (WD). However, evidence supporting this approach is limited. There are no published randomised controlled trials examining this recommendation due to rarity of the disease and variable presentation. This review summarises current knowledge on the absorption and regulation of copper in humans and its relevance to patients with WD. Studies have demonstrated that as the level of dietary copper increases, the proportion absorbed decreases. This observation implies that 'high copper' foods that WD patients are generally advised to avoid would need to be consumed in large amounts to impact markedly on the quantity absorbed. Dietary copper restriction is unlikely to reduce the amount absorbed significantly and is not only difficult to manage but restricts food groups unnecessarily, detracting from the provision of substrates essential for improving nutritional status in a nutritionally compromised group. Medical management for WD is effective in compliant patients, allowing stabilisation of the liver disease. Based on current evidence, dietary copper restrictions in stable WD patients who are adherent to medical therapy are unnecessary with two food exceptions (shellfish and liver).

Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.

BACKGROUND & AIMS: The natural history of chronic portomesenteric (PM) and portosplenomesenteric (PSM) venous thrombosis is defined poorly. Therapeutic options are limited, and are directed at the prevention of variceal bleeding and the control of abdominal pain related to gastrointestinal hyperemia. METHODS: Patients with extensive PM and PSM thrombosis were reviewed retrospectively to evaluate the efficacy of medical therapy and to determine which clinical variables had prognostic significance regarding long-term survival. RESULTS: Sixty patients, with a median age at diagnosis of 44 years (range, 18-68 y), were assessed. The median follow-up period was 3.5 years (range, 0.2-32.0 y). The overall survival rate was 73.3%, with 1- and 5-year survival rates of 81.6%, and 78.3%, respectively. One- and 5-year survival rates, excluding patients who died from malignancy-related causes, were 85.7% and 82.1%, respectively. Factors associated with improved survival included treatment with beta-blockers (P = .02; odds ratio [OR], .09; 95% confidence interval [CI], 0.01-0.70) and anticoagulation (P = .005; OR, 0.01; 95% CI, <0.01 to 0.26). Eighteen patients in total were anticoagulated, including 8 patients who had variceal bleeding, all of whom underwent endoscopic band ligation of esophageal varices before anticoagulation. By using Cox regression analysis, variables associated with reduced survival were the presence of ascites (P = .001; OR, 42.6; 95% CI, 5.03-360), and hyperbilirubinemia (P = .01; OR, 13.8; 95% CI, 1.9-100) at presentation. Six patients died of variceal hemorrhage. CONCLUSIONS: Patients with chronic PM and PSM venous thrombosis without underlying malignancy have an acceptable long-term survival. Treatment with beta-blockers and anticoagulation appears to improve outcome.