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The Health Report -Important new liver research
The findings from the Centenary Institute and Concord Hospital in Sydney could make transplantation easier; enable hepatitis C to be treated more effectively and maybe also autoimmune diseases like insulin dependent diabetes and rheumatoid arthritis.
Scientists at the Centenary Institute and Concord Hospital in Sydney have found that our liver is a black hole for rogue immune cells. Read Transcript
Deferasirox Can Improve Liver Fibrosis, Necroinflammation
By: MARY ANN MOON, Internal Medicine News Digital Network
Oct 1
This improvement occurred independently of patients’ treatment response as measured by liver iron concentration, which suggests that some of the drug’s benefit is independent of its iron-clearing ability. The improvements also were seen regardless of patients’ hepatitis C virus (HCV) antibody status at baseline, said Dr. Deugnier of University Hospital Pontchaillou in Rennes, France, and his associates (Gastroenterology 2011 October [doi:10.1053/j.gastro.2011.06.065]).
"To our knowledge, this is the first analysis which demonstrates regression of fibrosis in patients with beta-thalassemia during iron chelation therapy," they noted. The study was sponsored by Novartis, maker of deferasirox.
"The overall improvement in liver fibrosis and necroinflammation with deferasirox treatment seen in this study is striking," given that there is scant evidence in the literature that any medication can reverse fibrosis.
The investigators performed a secondary analysis of data on 219 subjects participating in two 1-year trials. One trial involved patients with beta-thalassemia major who had received 1 year of either deferasirox or deferoxamine therapy, and the other involved patients with various transfusion-dependent anemias, including beta-thalassemia, who had received 1 year of treatment with deferasirox.
In Dr. Deugnier’s study, the subjects with beta-thalassemia were followed as they continued on deferasirox after the trials concluded, because the data collected so far showed that a 1-year course of therapy may not be long enough to reveal changes in the extent or severity of fibrosis.
All the study subjects were at least 2 years of age at baseline and were receiving eight or more blood transfusions per year. All underwent liver biopsy at baseline and after 3 years of deferasirox treatment, and 210 had evaluable biopsy samples.
A total of 134 patients were classified as response successes on the basis of their liver iron concentrations, while the other 76 were deemed to be response failures by this measure.
However, fibrosis staging scores improved in both groups – the response successes and failures. Overall, 122 patients, 56% of the entire study population, showed stabilization of liver fibrosis and another 59 (27%) showed regression of fibrosis.
Fibrosis stabilized in 60% of response successes and 49% of response failures, while it regressed in 26% of response successes and 30% of response failures.
This lack of correlation between liver iron concentrations and improvements in fibrosis suggests that deferasirox’s effect on fibrosis may be independent of its ability to remove iron. It is possible that the drug exerts a direct effect on the pathophysiologic mechanisms that moderate fibrosis, the researchers said.
"Recent studies have shown an inhibitory effect of deferasirox on the transcriptional nuclear factor NF-KB35, a protein which also has been shown to be implicated in the development of fibrosis of the lung. Further molecular biology studies are required to explore this hypothesis," they noted.
Deferasirox also improved liver fibrosis regardless of subjects’ HCV status. The fibrosis stabilized in 47% of HCV-positive and 57% of HCV-negative patients, and it regressed in 30% of HCV-positive and 27% of HCV-negative patients. Thus, infection with this virus does not appear to diminish the drug’s effectiveness.
Ishak necroinflammatory grading scores improved by a mean of 1.3 points in the study population overall. As with fibrosis, inflammation did not correlate with liver iron concentrations. And as with fibrosis, necroinflammatory scores improved in both HCV-positive and HCV-negative patients.
Patients who took deferasirox showed a mean decrease from 40.9 to 29.6 IU/L in mean serum alanine aminotransferase (ALT), a marker of hepatocellular damage. Improvements in ALT correlated with decreases in liver iron concentrations, so that only patients classified as response successes by this measure showed significant reductions in ALT as well.
The study findings "are encouraging and warrant further studies to investigate the potential effects of deferasirox in preventing iron-induced tissue fibrosis in organs other than the liver, such as endocrine organs or the heart. In support of this concept, recent preclinical data in which deferasirox treatment was administered to an iron-overloaded gerbil model were associated with attenuated cardiac fibrosis," Dr. Deugnier and his colleagues wrote.
Most of the authors disclosed relationships with Novartis; several authors are employees of the company and others receive honoraria, lecture fees, or grants from Novartis.
By: MARY ANN MOON, Internal Medicine News Digital Network
Oct 1
In patients who have chronic hepatitis C and undergo liver biopsy, the presence of Mallory-Denk bodies – hepatocyte cytoplasmic inclusions that occur in several chronic liver diseases – is independently associated with progression of liver fibrosis, Dr. Mina O. Rakoski and her colleagues reported in the October issue of Clinical Gastroenterology and Hepatology.
In addition, patients in whom serial liver biopsies show an increase in the number of Mallory-Denk bodies over time are more likely to have clinical decompensation and progression to cirrhosis than patients who have no Mallory-Denk bodies or who have a stable or decreasing number of them over time.
Little is known about Mallory-Denk bodies, and it is still unclear whether they "represent a benign epiphenomenon of hepatocyte injury" or are actual modifiers of disease progression. Their major constituents are keratin polypeptides 8 and 18, which "likely play an essential cytoprotective role in the liver," said Dr. Rakoski of the University of Michigan, Ann Arbor, and her associates.
In mice, gender and genetic background play critical roles in the formation of Mallory-Denk bodies. In humans, genes that encode keratin, including KRT8 and KRT18, have been associated with susceptibility to end-stage liver disease, increased fibrosis in chronic hepatitis C, and increased severity of primary biliary cirrhosis, they noted.
To explore the potential prognostic value of Mallory-Denk bodies in biopsy samples, Dr. Rakoski and her colleagues analyzed data from the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) trial. This was a multicenter prospective randomized controlled trial involving 1,050 patients with chronic hepatitis C and advanced fibrosis or cirrhosis.
The HALT-C study subjects underwent liver biopsy at baseline, 18 months, and 3 years, and were followed for a median of 6 years to track their clinical and histologic outcomes. The presence or absence of Mallory-Denk bodies was recorded by expert pathologists reviewing the biopsy samples.
A total of 158 subjects (15%) had Mallory-Denk bodies present in baseline biopsy samples. Their presence was associated with laboratory markers of severe disease, including low platelets, low albumin, high AFP, and high AST/ALT ratio. It also was associated with histologic markers of severe disease, including greater periportal fibrosis, greater pericellular fibrosis, steatosis, and higher inflammation scores.
A subset of 844 HALT-C patients was studied longitudinally, and 719 of these patients showed no Mallory-Denk bodies on baseline biopsy. In all, 61 of these subjects (8.5%) did show Mallory-Denk bodies on repeat biopsy ("MDB gain").
MDB gain was significantly associated with increased fibrosis and steatosis on repeat biopsy, as well as with diabetes, female gender, and Hispanic ethnicity. The association with gender and ethnicity suggest that genetic factors play an important but as yet unknown role in MDB formation.
Of 125 patients who had Mallory-Denk bodies on baseline biopsy, 101 (81%) showed fewer inclusions on repeat biopsy ("MDB loss"). This loss was associated with a lower BMI, less baseline fibrosis, the absence of diabetes, and the absence of smoking.
It is unknown why some patients showed MDB loss over time, nor why these patients did not show improved outcomes. It is possible that the loss of MDB actually reflected liver sampling errors. It also is possible that some unknown environmental or genetic factor caused the resolution of the inclusions but did not impact overall outcomes, Dr. Rakoski and her colleagues said.
In a subset of 58 patients with MDB gain over time, half developed an adverse clinical outcome. In contrast, only 15% of subjects who did not have MDB developed an adverse clinical outcome, a significant difference.
By comparison, in a subset of 88 patients with MDB loss over time, 23% developed an adverse clinical outcome, whereas 32% of those who did not have MDB loss developed an adverse clinical outcome – a nonsignificant difference. Thus, MDB loss was not associated with either good or adverse clinical outcomes.
Histologic outcomes also were assessed in a subset of 447 patients in the longitudinal analysis. In all, 67% of those who showed MDB gain over time developed an adverse histologic outcome, compared with only 28% of patients who did not show MDB gain over time. This difference was highly significant.
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, and Hoffmann-La Roche (now Genentech). The investigators reported no conflicts of interest.
Date: 01 Oct 2011 -Liver re-transplantation generally has an inferior outcome compared with a patient's first transplant, due to the technical demands of the surgery and because patients are often sicker than they were at the time of their first procedure.
UCLA researchers, basing their work on 26 years worth of patient data from UCLA, sought to develop a scoring system for risk stratification of patients in need of a liver re-transplant, in the hopes of improving patient selection for scarce livers......
October 2011
HCV Advocate Newsletter
October 2011
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Pharmasset: 98% to 100% Cure Rates
Alan Franciscus, Editor-in-Chief
HealthWise: Reducing the Cost of Hepatitis C Treatment
Lucinda K. Porter, RN
Disability & Benefits: Medicare Enrollment Explained
Jacques Chamber, CLU
HCV Snapshots
Lucinda K. Porter, RN
Clinical Trials
Alan Franciscus, Editor-in-Chief
What is Hemolytic Uremic Syndrome?
Hemolytic uremic syndrome is a severe, life-threatening complication of an E. coli bacterial infection that was first described in 1955, and is now recognized as the most common cause of acute kidney failure in childhood. E. coli O157:H7 is responsible for over 90% of the cases of HUS that develop in North America. In fact, some researchers now believe that E. coli O157:H7 is the only cause of HUS in children. HUS develops when the toxin from E. coli bacteria, known as Shiga-like toxin (SLT) [1,2], enters cells lining the large intestine. The Shiga-toxin triggers a complex cascade of changes in the blood. Cellular debris accumulates within the body’s tiny blood vessels and there is a disruption of the inherent clot-breaking mechanisms. The formation of micro-clots in the blood vessel-rich kidneys leads to impaired kidney function and can cause damage to other major organs...continue reading..
September 26, 2011 — Risk for depression may decrease as coffee consumption increases, new research suggests.
In a 10-year cohort study of more than 50,000 older women, investigators found that compared with those who drank 1 cup or less of caffeinated coffee per week, those who drank 2 to 3 cups per day had a 15% decreased risk for depression, and those who drank 4 cups or more had a 20% decreased risk.
"This is one of the first major studies to look to this relationship," lead author Michel Lucas, PhD, RD, epidemiologist/nutritionist at Harvard School of Public Health in Boston, Massachusetts, told Medscape Medical News.. continue reading
Arch Intern Med. 2011;171:1571-1578. Abstract
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