Nonalcoholic fatty liver disease (NAFLD) can affect both adults and children. With the current worldwide epidemic of pediatric obesity, pediatric NAFLD is increasingly being diagnosed. It is not ...exactly identical to NAFLD in adults, and these differences may be due in part to the occurrence of hepatic metabolic derangements typical of NAFLD during periods of active growth (infancy, mid-childhood and puberty). The natural history of pediatric NAFLD is not yet known; however, children with pediatric NAFLD can develop cirrhosis. Although details of disease mechanism in pediatric NAFLD remain unclear, hyperinsulinemia with insulin resistance appears to be critical. Determining the pathogenesis of pediatric NAFLD is likely to enhance our understanding of NAFLD in all age groups and may identify new treatment opportunities. Finding effective ways to prevent pediatric NAFLD is an important issue for children’s health.
Purpose of Review
Exciting developments relating to Wilson disease (WD) have taken place with respect to both basic biological and clinical research. This review critically examines some of these ...findings and considers their implications for current thinking about WD. It is not a comprehensive review of WD as a clinical disorder.
Recent Findings
The structure of the gene product of
ATP7B
, abnormal in WD, is being worked out in detail, along with a broader description of how the protein ATP7B (Wilson ATPase) functions in cells including enterocytes, not only in relation to copper disposition but also to lipid synthesis. Recent population studies raise the possibility that WD displays incomplete penetrance. Innovative screening techniques may increase ascertainment. New strategies for diagnosing and treating WD are being developed. Several disorders have been identified which might qualify as WD-mimics.
Summary
WD can be difficult to diagnose and treat. Insights from its pathobiology are providing new options for managing WD.
Rumination is a robust vulnerability to depression and potential treatment target. However, we know relatively little about rumination in daily life. This study tested the validity of a new approach ...for assessing daily episodes of rumination, the Day Reconstruction Method for Rumination (DRM-R). Participants (N = 127) who were either high or low in neuroticism completed baseline self-report measures (e.g., depression, trait rumination). Next, they completed the DRM-R by reconstructing the previous day into a series of "scenes," identifying discrete episodes of rumination, and responding to follow-up items about each episode. 78.6% of high neuroticism participants reported experiencing discrete periods of rumination, 80.0% reported constant ruminative thoughts in the back of their heads, and 68.6% reported ruminative thoughts of fluctuating intensity. Time spent ruminating was moderately correlated with trait measures of rumination and worry. Findings provide preliminary evidence that the DRM-R is a valid method for assessing discrete episodes of rumination in daily life. The DRM-R may reveal, ideographically, the relationship between specific thought content and features of ruminative episodes (e.g., length, frequency). Further research is needed to establish whether the DRM-R can detect changes in rumination across multiple days and how it corresponds with traditional daily diary methods and ecological momentary assessment.
Public Significance Statement
Rumination is a form of repetitive thinking that is involved in depression and other mental health problems. Our study evaluated a new way of gathering information about ruminative thoughts that could help us to better understand how people experience rumination in daily life.
The liver plays an important role in the disposition of copper. Most dietary copper passes through the liver where it can be used for protein and energy production or excreted through the biliary ...route. Because copper is a prooxidant, its intracellular handling is tightly managed. In Wilson disease, in which synthesis of ceruloplasmin and biliary excretion of copper are defective, copper accumulates in the liver and leads to progressive liver damage. The features of hepatic Wilson disease are highly variable. The spectrum of liver disease includes mild inflammation, fatty liver, an autoimmune disorder, and cirrhosis. Wilson disease thus resembles drug hepatotoxicity, and indeed it can be regarded as a prototypic example of endogenous hepatotoxicity. Biomarkers developed for detecting drug hepatotoxicity may be relevant to Wilson disease. Biomarkers developed through metalloproteomics, which for copper seeks to define a set of proteins that have copper-binding capacity, or through genomic studies may also be relevant to Wilson disease and other disorders of copper handling, whether copper is deficient or overloaded.
Because pharmacologic treatment for Wilson disease must be consistent and lifelong, access to an alternative supply of trientine through the Special Access Programme was urgently needed. A different ...formulation of trientine, which cost less than Syprine did in 2013, was identified by some specialist clinicians with help from the Patented Medicine Prices Review Board, Alberta Health and Wellness, and the Canadian Organization for Rare Disorders, and this formulation was added to the list of drugs authorized under the Special Access Programme. Valeant Canada chose to reduce Syprine's price to its previous (2013) level, subsequent to public outcry initiated by Canadian hepatologists.9 Whether Syprine's price will remain fixed at that level is unknown; in the US, Valeant raised the drug's price again in July 2014.10 Although we seem to have overcome the trientine crisis for now, the situation described calls attention to important problems related to access to orphan drugs. Problems with access can arise with both older orphan drugs like trientine and newer orphan drugs like ivacaftor, the recently developed treatment for a subset of patients with cystic fibrosis,11 albeit perhaps somewhat differently. The challenge is that many drugs for rare diseases have small volumes and simply do not attract generic competition. As a result, competition cannot be relied on to ensure long-term access at reasonable prices. Generally, higher prices for rare-disease treatments are tolerated on the assumption that they permit manufacturers to recoup costs. But when generic competition fails to arrive, as in the case of trientine, an older drug with established safety and effectiveness, manufacturers remain free to charge what the market will bear. Valeant did not have to justify the price change in terms of expenditures or value. Payers tend to decide on reimbursement of new drugs with a view to their therapeutic value, and for orphan drugs, rarity is sometimes a consideration.12 But for older drugs, prices should reflect the cost of secure, stable and safe production, and nothing more. Second, the orphan drug framework should address the needs of Canadians who rely on the Special Access Programme to obtain essential medicines. The program is used for several hundred drugs, in part because the Canadian market is not large enough to attract some very specialized drugs. Facilitating the process of obtaining a Health Canada Notice of Compliance through the creation of a regulatory pathway for orphan drugs could, in theory, help to increase insurability of essential drugs and also help to increase competition. Given the experience under the US orphan drug system, however, additional measures may be required to ensure meaningful competition and achieve greater control of prices. One strategy for older, unpatented yet essential orphan drugs may be for the provinces and territories to work together to seek out alternative suppliers from international markets, with assistance from the Patented Medicine Prices Review Board. Another strategy, applicable to future orphan drugs developed in whole or in part with public research funds, is to attach stipulations for reasonable pricing to those funds, as recently proposed in the US.12 Downstream, manufacturers of orphan drugs could be required to account for their research and development expenditures to determine an appropriate rate of return20 for new orphan drugs. As Canada moves to design its framework for orphan drugs, it must provide for sustainable access to essential products on reasonable terms, and this will likely involve a set of innovative strategies.
Most infants with biliary atresia (BA) require liver transplantation (LT) after hepatoportoenterostomy (HPE), including those who initially clear jaundice. The aim of the present study was to ...identify clinical and routine laboratory factors in infants with BA post-HPE that predict native liver survival at 2 years.
A retrospective cohort study was conducted in 217 patients with BA undergoing HPE in Sydney, Australia and Toronto, Canada between January 1986 and July 2009. Univariate and multivariate logistic regression using backwards-stepwise elimination identified variables at 3 months after HPE most associated with 2-year native liver survival.
Significant variables (P < 0.05) on univariate analysis included serum total bilirubin (TB) and albumin at 3 months post-HPE, bridging fibrosis or cirrhosis on initial liver biopsy, ascites of <3 months post-HPE, type 3 BA anatomy, age at HPE of >45 days, change in length z scores within 3 months of HPE, and center. On multivariate analysis, TB (P < 0.0001) and albumin (P = 0.02) at 3 months post-HPE, and center (P = 0.0003) were independently associated with native liver survival. Receiver operating characteristic analysis revealed an optimal cut-off value of TB <74 μmol/L (4.3 mg/dL; area under the receiver operating characteristic curve 0.8990) and serum albumin level >35 g/L (3.5 mg/dL; area under the receiver operating characteristic curve 0.7633) to predict 2-year native liver survival. TB and albumin levels 3 months post-HPE defined 3 groups (1: TB ≤74 μmol/L, albumin >35 g/L; 2: TB ≤74 μmol/L, albumin ≤35 g/L; 3: TB >74 μmol/L) with distinct short- and long-term native liver survival rates (log-rank P < 0.001). Length z scores 3 months post-HPE were poorer for group 2 than group 1 (-0.91 vs -0.30, P = 0.0217) with similar rates of coagulopathy.
Serum TB and albumin levels 3 months post-HPE independently predicted native liver survival in BA when controlling for center. Serum albumin level <35 g/L in infants with BA who were no longer jaundiced at 3 months post-HPE was a poor prognostic indicator. Poorer linear growth and absence of significant coagulopathy suggest a role for early aggressive nutritional therapy in this group.
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