January 14, 2011

Journal of Viral Hepatitis
Early View (Articles online in advance of print)

J. Fung, C.-L. Lai, D. K.-H. Wong, W.-K. Seto, I. Hung, M.-F. Yuen

Article first published online: 7 JAN 2011
DOI: 10.1111/j.1365-2893.2010.01428.x
© 2011 Blackwell Publishing Ltd

Author Information
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
*Correspondence: Prof Man-Fung Yuen, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China. E-mail: mfyuen@hkucc.hku.hk

Abstract

Keywords:
chronic hepatitis B;fibroscan;liver stiffness;longitudinal;transient elastography

Summary.  For patients with chronic hepatitis B (CHB) infection, changes in liver stiffness measurement (LSM) over time are not known. We examined changes longitudinally in a cohort of patients. Four hundred and twenty-six patients with CHB underwent transient elastography. Patients were followed regularly, and repeat elastography was performed at 3 years. Hepatitis serology, viral load and routine liver biochemistry were monitored. Of the 426 patients, 38 (9%) were hepatitis B e-antigen (HBeAg)-positive, 293 (69%) were HBeAg-negative and 95 (22%) were patients with prior hepatitis B surface antigen (HBsAg) seroclearance. A total of 110 patients received oral antiviral therapy. There was a significant decline of LSMs at the follow-up measurement compared to baseline (6.1 vs 7.8 kPa respectively, P = 0.002) in treated patients who had elevated alanine aminotransferase (ALT) at baseline and subsequent normalization after 3 years (normal ALT limit being 30 U/L for males and 19 U/L for females). In nontreated patients, only the patients with persistently normal ALT at both time points had significantly lower LSMs at the follow-up measurement compared to baseline: 4.9 vs 5.3 kPa, respectively, in patients who remained positive for HBsAg (P = 0.005) and 5.1 vs 5.4 kPa, respectively, in patients who had HBsAg seroclearance (P = 0.026). In patients who remained positive for HBsAg, independent factors associated with a significant decline in LSM of ≥1 kPa included antiviral therapy (P = 0.011) and the ALT levels at the follow-up time point (P = 0.024). Thus, in patients with CHB, a significant decline in LSM after 3 years was observed in treated patients with ALT normalization and in untreated patients who had persistently normal ALT. Antiviral therapy and follow-up ALT levels were independent significant factors associated with a decline in LSM.

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Journal of Viral Hepatitis
Early View (Articles online in advance of print)

C. Stasi, A. L. Zignego, G. Laffi, M. Rosselli

Article first published online: 7 JAN 2011
DOI: 10.1111/j.1365-2893.2010.01418.x
© 2011 Blackwell Publishing Ltd

Author Information
Department of Internal Medicine, University of Florence, Florence, Italy
*Correspondence: Cristina Stasi, MD, Dipartimento di Medicina Interna, Viale G.B. Morgagni, 85, 50134 Firenze, Italy. E-mail: cristina.stasi@unifi.it

Abstract

Keywords:
chronic viral hepatitis;cytokines;interferon;interleukins;psychological disorders

Summary.  Psychiatric symptoms are commonly identified in patients with viral hepatitis. They may have been present prior to the onset of disease and may include symptoms related to addiction issues. Furthermore, the virus and antiviral therapy, in particular interferon, may induce or modify psychiatric symptoms. Recent data support chronic hepatitis C replication in the brain and subsequent changes of cerebral metabolite spectra and magnetic resonance alterations. In chronic viral hepatitis and in other chronic inflammatory diseases, an alteration of the neuro-endocrine-immune system response has been observed. Catecholamines and glucocorticoids modulate this immune/inflammatory reaction. Psychiatric assessment and monitoring before, during and after antiviral therapy can identify patients whose psychiatric symptoms preclude therapy, and those who may benefit from psychopharmacological therapy and counselling, thereby improving therapeutic results. This review will discuss current insights into the complex interplay between cytokines, liver and brain in chronic viral hepatitis closely associated with psychiatric issues, especially in the case of antiviral therapy, with the aim of indicating future research and possible treatments.

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Hepatologists test drug on advanced liver cancer patients

2:03 p.m. EST, December 28, 2010

Hepatologists at the University of Florida have begun a new clinical trial in search of a better way to treat patients who have advanced, inoperable primary liver cancer but have trouble tolerating standard doses of the only drug available to help them.

Funded through a $650,000 grant from Bayer HealthCare Pharmaceuticals Inc. and Onyx Pharmaceuticals Inc., the makers and marketers of Sorafenib — the only FDA-approved drug for advanced liver cancer — the six-month, randomized pilot study will evaluate whether patients with a dual diagnosis of cirrhosis and liver cancer are better able to tolerate the drug if given doses that differ from the manufacturer's recommendation.

"The study will provide evidence for physicians about whether we can deliver more of the drug, improve tolerability and reduce adverse events by slowly introducing it," said study leader Roniel Cabrera, M.D., M.Sc., an assistant professor in the UF College of Medicine's division of gastroenterology, hepatology and nutrition.

UF and its Clinical and Translational Science Institute are coordinating the study, which will be carried out at 10 sites that include major Florida centers such as the University of South Florida, the University of Miami, the Florida Hospital, in collaboration with the University of Central Florida, and the Mayo Clinic in Jacksonville. The team hopes to develop a national academic consortium dedicated to advancing clinical and translational research efforts in hepatocellular carcinoma, the most common form of primary liver cancer.

"This study is very much targeting an unmet need in oncology, and it has the potential to clarify if we actually have the right dose for the medication," said Thom George, M.D., director of gastrointestinal oncology in the division of hematology/oncology at the UF College of Medicine, who is not directly involved in the study. "It may help answer the question of whether more patients will derive benefit from the treatment if we just go a little slower with the dosing."

Liver cancer, the fifth most common cancer and the third leading cause of cancer-related deaths, is a major global health problem. Despite new therapies, every year there are more than 600,000 new cases worldwide, and almost the same number of related deaths. Hepatocellular carcinoma is the leading cause of death among people who have chronic liver disease.

Many patients are diagnosed with advanced liver cancer at the same time they are diagnosed with cirrhosis, and that complicates treatment, since what works against one disease can worsen the other. When the cancer is advanced, treatment options are limited — surgery is impossible, and the most useful option left is the pill Sorafenib. It doesn't cure cancer, but in clinical studies, patients who took it survived for three to four months longer, on average, than untreated patients.

Manufacturers recommend a dose of two 200-milligram tablets twice a day. In practice, however, those doses are too high for patients with advanced disease to tolerate. The dosing recommendation is based on clinical studies in patients whose cirrhosis was under control. But "real life" patients show up at clinics with much worse cirrhosis and have negative reactions to the drug, including severe fatigue, skin rashes, gastrointestinal bleeding and worsening of liver function. That can be compounded by cirrhosis symptoms such as fatigue, confusion, fluid buildup in the abdomen and legs, and gastrointestinal bleeding.

"You can see how all those things can add up," Cabrera said.

In such patients, physicians have to discontinue therapy or give less than recommended.

Cabrera and colleagues will investigate whether a "ramp up" strategy that starts with one pill a day then adds a pill a week can improve how well patients tolerate the drug, the length of time they are able to remain on it, the amount they are able to handle overall without negative effects and the effect on the cancer being treated.

"This study will take patients who are not the most healthy, and see if there is a better way to still give them every chance to increase the benefits they receive from the medication and decrease the risk," George said. "That could potentially allow them to remain functional and be part of society and continue to work and provide for their families."

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Full findings are published in the January 2011 issue of Hepatology, a journal of the American Association for the Study of Liver Diseases.

Alcoholic liver disease (ALD) -- ranging from alcoholic fatty liver to alcohol induced liver fibrosis and cirrhosis -- accounts for more than 50% all chronic liver disease in industrialized countries and was responsible for over 25,000 deaths in the U.S. alone in 2005. Studies have shown that while all heavy drinkers display signs of hepatitis steatosis (fatty liver), only 10% to 35% of alcoholics develop hepatic inflammation, with up to 20% progressing to cirrhosis. Further medical evidence suggests a link between PNPLA3 gene variation and liver fat content; specifically the single nucleotide polymorphism (SNP) rs738409 was reported previously to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of European and Native American descent.

The German research team led by Jochen Hampe, MD, from Christian-Albrechts-Universit├Ąt Kiel determined the genotype and allele frequencies of PNPLA3 rs738409 in 1043 alcoholics with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Cirrhosis and steatosis was determined by liver biopsy and standard diagnostic testing. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were established using routine clinical chemistry testing.

Participants were categorized as alcoholic liver cirrhosis (ALC); alcoholics with liver steatosis on ultrasound and elevation of ALT as alcoholic liver damage (ALD); alcoholic liver steatosis and normal liver enzyme levels as alcoholic fatty liver (AFL); and alcoholics with normal appearance of the liver on ultrasound and normal liver enzyme levels as alcoholic controls.

Researchers discovered that SNP rs738409 was strongly over-represented in patients with ALC and ALD compared to alcoholics without liver damage. Additionally, the frequency of allele PNPLA3 rs738409 in AFL participants was lower than in alcoholics without steatosis and normal liver enzymes. "Our findings show PNPLA3 rs738409 carriers represent a subpopulation of high risk individuals susceptible to progression from clinically silent alcoholic liver disease to obvious cirrhosis," Dr. Hampe concluded. "Carriers of this risk allele should be targeted for future pharmaceutical treatments and non-pharmacological interventions."

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