People on liver transplant waitlist may be no worse off if they have used marijuana

People on liver transplant waitlist may be no worse off if they have used marijuana
Last Updated: 2018-02-08
By Lorraine L. Janeczko

NEW YORK (Reuters Health) - Candidates on the liver transplant (LT) waitlist who have used marijuana have no worse outcomes than their counterparts on the list who have not used it, a single-center study suggests.

"Unlike illicit drug use, marijuana use was not associated with worse outcomes on the LT waitlist. . . We found a high prevalence of historical marijuana use that did not have clear adverse effects on LT waitlist outcomes," lead author Prashant Kotwani of the University of California San Francisco School of Medicine and colleagues write in Transplantation, online January 10.

Continue reading: http://www.chronicliverdisease.org/reuters/article.cfm?article=20180208Other1065659537

Long-term trends of liver cancer mortality by gender in urban and rural areas in China: an age-period-cohort analysis

Long-term trends of liver cancer mortality by gender in urban and rural areas in China: an age-period-cohort analysis
Yuanyuan Sun, Yanhong Wang,Mengmeng Li, Kailiang Cheng, Xinyu Zhao, Yuan Zheng, Yan Liu,
Shaoyuan Lei, Li Wang

Full Text

View Online

Abstract
Objectives To provide an up-to-date overview of long-term trends of liver cancer mortality and evaluate the effects attributable to age, period and cohort in Chinese population stratified by gender and urban/rural areas.

Methods

Population and liver cancer mortality data were obtained based on the Disease Surveillance Points in China from 1991 to 2014. To examine the time trends of liver cancer mortality by gender in urban and rural areas in China, Joinpoint analysis was used to estimate the annual per cent change. The intrinsic estimator, a method of age-period-cohort analysis to estimate age, period and cohort effects simultaneously, was used to analyse the underlying mechanisms for liver cancer mortality trends in the aforementioned four groups.

Results

We observed a significant decline in liver cancer mortality for urban men (average annual per cent change (AAPC)=−1.1%, P<0.05) and urban women (AAPC=−1.4%, P<0.05), while the liver cancer mortality remained stable for rural men (AAPC=−0.1%, P>0.05) and rural women (AAPC=−0.9%, P>0.05). Compared with the 15–19 age group, the liver cancer mortality risk of the 85 and above age group increased 65 and 42 times for urban and rural men, and 102 and 70 times for urban and rural women. From the 1990–1994 period to the 2005–2009 period, the risk increased 56% and 92% for urban and rural men, and 30% and 74% for urban and rural women. Compared with period and cohort effects, age effects were the most influential factor in liver cancer mortality.

Conclusions

As the status of ageing population in China gets worse, the burden caused by liver cancer mortality could still be a great challenge for China in the future. The disparity of liver cancer mortality trends between urban and rural residents can be attributed to period effects, referring to the unequal medical levels and resources between urban and rural areas.

Continue to article: http://bmjopen.bmj.com/content/8/2/e020490

CORRECTED-Living-donor liver transplantation has long-term advantages in children

CORRECTED-Living-donor liver transplantation has long-term advantages in children
Last Updated: 2018-02-07

(Modifies headline and first paragraph, to clarify study findings, and adds new paragraph 6.)
By Will Boggs MD

NEW YORK (Reuters Health) - Living-donor liver transplantation has durable clinical and immunological benefits in pediatric transplant patients, according to a retrospective study.

"Our findings provide strong support for a more confident recommendation of living donor as the best option for children needing liver transplantation," said Dr. Eric M. Przybyszewski from Columbia University Medical Center, in New York City.

"Our data demonstrating that grafts from living donors have lower long-term immunologic risks compared to grafts from deceased donors provides support for this recommendation," he told Reuters Health by email.

Living-donor liver transplantation (LDLT) has been used successfully for pediatric recipients for nearly 30 years, yet long-term benefits have yet to be shown.

Continue reading: http://www.chronicliverdisease.org/reuters/article.cfm?article=20180207Other585275945

Regulation of insulin resistance and type II diabetes by hepatitis C virus infection: A driver function of circulating miRNAs.

J Cell Mol Med. 2018 Feb 7. doi: 10.1111/jcmm.13553. [Epub ahead of print]

Regulation of insulin resistance and type II diabetes by hepatitis C virus infection: A driver function of circulating miRNAs.
Singhal A1, Agrawal A2, Ling J1.

Abstract
Hepatitis C virus (HCV) infection is a serious worldwide healthcare issue. Its association with various liver diseases including hepatocellular carcinoma (HCC) is well studied. However, the study on the relationship between HCV infection and the development of insulin resistance and diabetes is very limited. Current research has already elucidated some underlying mechanisms, especially on the regulation of metabolism and insulin signalling by viral proteins. More studies have emerged recently on the correlation between HCV infection-derived miRNAs and diabetes and insulin resistance. However, no studies have been carried out to directly address if these miRNAs, especially circulating miRNAs, have causal effects on the development of insulin resistance and diabetes. Here, we proposed a new perspective that circulating miRNAs can perform regulatory functions to modulate gene expression in peripheral tissues leading to insulin resistance and diabetes, rather than just a passive factor associated with these pathological processes. The detailed rationales were elaborated through comprehensive literature review and bioinformatic analyses. miR-122 was identified to be one of the most potential circulating miRNAs to cause insulin resistance. This result along with the idea about the driver function of circulating miRNAs will promote further investigations that eventually lead to the development of novel strategies to treat HCV infection-associated extrahepatic comorbidities.

Full text: http://onlinelibrary.wiley.com/doi/10.1111/jcmm.13553/full

Clinical studies investigating the effect of vitamin E therapy in patients with NASH

Clinical Liver Disease

View issue TOC
Volume 11, Issue 1
January 2018
Pages 16–21

Clinical studies investigating the effect of vitamin E therapy in patients with NASH

Sebastian Larion M.D.,Sandeep Khurana M.B.B.S.

First published: 31 January 2018

DOI: 10.1002/cld.687

Abstract

Watch a video presentation of this article

Full Text

Download PDF

View online

Nonalcoholic steatohepatitis (NASH) is the inflammatory sequelae of fatty liver disease that is characterized histologically by steatosis with ballooning degeneration and lobular hepatitis. NASH and particularly fibrosis development are significantly associated with increased all-cause and liver-related mortality.[1, 2] By 2030, NASH is projected to affect more than 27 million patients in the United States and be attributed to 10.9% of all patient deaths.[3] Despite this major public health burden, no U.S. Food and Drug Administration–approved medications exist for the specific treatment of NASH, identifying an unmet need for a further understanding of disease-causing processes.

Continue reading........

'Virus-cracking' molecules advance fight against hepatitis B

Adam Zlotnick

'Virus-cracking' molecules advance fight against hepatitis B

BLOOMINGTON, Ind. -- Indiana University researchers have made an important step forward in the design of drugs that fight the hepatitis B virus, which can cause liver failure and liver cancer.

It's estimated that 2 billion people worldwide have had a hepatitis B virus infection in their lifetime, with about 250 million -- including 2 million Americans -- living with chronic infection. Although a vaccine exists, there is no cure.

The study, published Jan. 29 in the journal eLife, explains how the structure of the hepatitis B virus changes when bound to an experimental drug. Members of this new class of antiviral drug are now in clinical trials.

"Our discovery suggests that this same drug could attack hepatitis B virus on multiple fronts -- both preventing replication and killing new copies of the virus," said senior author Adam Zlotnick, a professor in the IU Bloomington College of Arts and Sciences' Department of Molecular and Cellular Biochemistry. "If we're smart, we can take advantage of the multiple ways this drug can work at the same time."

The research was led by Christopher Schlicksup, a graduate student in the department.

A virus reproduces by hijacking a host's cellular machinery to produce more of the virus. The majority of viruses protect their genetic material -- DNA or RNA -- inside a protein shell called a "capsid."

For the past 20 years, Zlotnick's lab has conducted research to stop viral infections by studying the physics of viruses, focusing on how capsids are formed.

"The reaction is a bit like throwing a deck of cards in the air to build the Taj Mahal -- a highly complex structure seemingly emerging from chaos," Zlotnick said. His work helped discover a class of molecules called core protein allosteric modulators, or CpAMs, that disrupt capsid protein assembly.

CpAM molecules attack viruses by causing their shells to assemble incorrectly, interrupting the life cycle of the virus. Previously, CpAMs were seen as only able to disrupt a virus during formation of the capsid, after which its DNA was protected inside a hard casing.

This new study finds the molecule can break apart this shell even after it has already assembled.

To make their discovery, IU scientists bound the CpAM to a chemical called TAMRA -- a crimson-colored dye used in some red lipstick -- to make it fluorescent and easier to detect in experiments. Using cryo-electron microscopy, they found the small CpAM molecule could make the large, soccer ball-shaped virus capsid bend and distort.

"The big implication is viral capsids aren't as impenetrable as previously thought," Zlotnick said. “The other implication, which may be even more important, is that if this type of interference works against hepatitis B virus, it might also work against other viruses.

"About half of known virus families have soccer ball-like capsids; examples include polio and herpes," he added. "This study may lead to better treatments against them since the mechanisms behind capsid disruption could lead to drugs against any of them."

Zlotnick also is the co-founder of Assembly Biosciences, a NASDAQ-listed company, which has CpAMs in clinical trials. Although the molecule used in this study isn't one of the molecules under clinical trial, Zlotnick said the mechanism sheds light on the behavior of the experimental drugs. Next, Zlotnick hopes to conduct similar studies on the CpAMs under clinical trial.

Additional IU authors on the study are Michael VanNieuwenhze, professor in the IU Bloomington College of Arts and Sciences' Department of Chemistry; Joseph Wang, assistant research professor in the Department of Molecular and Cellular Biochemistry; and Balasubramanian Venkatakrishnan, a postdoctoral researcher in Molecular and Cellular Biochemistry at the time of the study. Other authors are Samson Francis and William Turner of Assembly BioSciences. Schlicksup is the first author on the study.

This research was supported in part by the National Institutes of Health's National Institute of Allergy and Infectious Diseases.

Adam Zlotnick. Photo by James Brosher, IU Communications

Watch - Liver Cancer in patients with HCV

liverfoundation2010
Published on Feb 7, 2018

An American Liver Foundation Webinar Program

This webinar will discuss HCC (primary liver cancer) in patients with HCV, tests for diagnosis, risk for HCC after SVR, and which patients should undergo surveillance for HCC. 

https://www.youtube.com/watch?v=Z_AjxBi7Jsw&t=914s

FDA Statement - Kratom potential for abuse, addiction, and linked to 44 deaths

FDA Statement

Statement from FDA Commissioner Scott Gottlieb, M.D., on the agency’s scientific evidence on the presence of opioid compounds in kratom, underscoring its potential for abuse

Additional adverse events associated with kratom use identified.

Over the past several months, there have been many questions raised about the botanical substance known as kratom. Our concerns related to this product, and the actions we’ve taken, are rooted in sound science and are in the interest of protecting public health. However, we recognize that there is still much that is unknown about kratom, which is why we’ve taken some significant steps to advance the scientific understanding of this product and how it works in the body. Today, we’re providing details of some of the important scientific tools, data and research that have contributed to the FDA’s concerns about kratom’s potential for abuse, addiction, and serious health consequences; including death.

Notably, we recently conducted a novel scientific analysis using a computational model developed by agency scientists, which provided even stronger evidence of kratom compounds’ opioid properties. These kinds of models have become an advanced, common and reliable tool for understanding the behavior of drugs in the body. We also have learned more about deaths that involved kratom use, and have identified additional adverse events related to this product. This new data adds to our body of substantial scientific evidence supporting our concerns about the safety and abuse potential of kratom.

We have been especially concerned about the use of kratom to treat opioid withdrawal symptoms, as there is no reliable evidence to support the use of kratom as a treatment for opioid use disorder and significant safety issues exist. We recognize the need and desire for alternative treatments for both the treatment of opioid addiction, as well as the treatment of chronic pain. The FDA stands ready to evaluate evidence that could demonstrate a medicinal purpose for kratom. However, to date, we have received no such submissions and are not aware of any evidence that would meet the agency’s standard for approval.

The FDA’s PHASE model used to assess kratom

Federal agencies need to act quickly to evaluate the abuse potential of newly identified designer street drugs for which limited or no pharmacological data are yet available. This is why the FDA developed the Public Health Assessment via Structural Evaluation (PHASE) methodology – a tool to help us simulate, using 3-D computer technology, how the chemical constituents of a substance (such as the compounds/alkaloids found in kratom) are structured at a molecular level, how they may behave inside the body, and how they can potentially affect the brain. In effect, PHASE uses the molecular structure of a substance to predict its biological function in the body. For example, the modelling platform can simulate how a substance will affect various receptors in the brain based on a product’s chemical structure and its similarity to controlled substances for which data are already available.

Using this computational model, scientists at the FDA first analyzed the chemical structures of the 25 most prevalent compounds in kratom. From this analysis, the agency concluded that all of the compounds share the most structural similarities with controlled opioid analgesics, such as morphine derivatives.

Next, our scientists analyzed the chemical structure of these kratom compounds against the software to determine its likely biologic targets. The model predicted that 22 (including mitragynine) of the 25 compounds in kratom bind to mu-opioid receptors. This model, together with previously available experimental data, confirmed that two of the top five most prevalent compounds (including mitragynine) are known to activate opioid receptors (“opioid agonists”).

The new data provides even stronger evidence of kratom compounds’ opioid properties.

The computational model also predicted that some of the kratom compounds may bind to the receptors in the brain that may contribute to stress responses that impact neurologic and cardiovascular function. The agency has previously warned of the serious side effects associated with kratom including seizures and respiratory depression.

The third aspect of the model is the 3-D image we generate to look at not just where these compounds bind, but how strongly they bind to their biological targets. We found that kratom has a strong bind to mu-opioid receptors, comparable to scheduled opioid drugs.

So what does this body of scientific evidence mean? The FDA relies on this kind of sophisticated model and simulation to supplement its data on how patients react to drugs; often as a way to fully elucidate the biological activity of a new substance. The data from the PHASE model shows us that kratom compounds are predicted to affect the body just like opioids. Based on the scientific information in the literature and further supported by our computational modeling and the reports of its adverse effects in humans, we feel confident in calling compounds found in kratom, opioids.

Furthermore, this highlights the power of our computational model-based approach to rapidly assess any newly identified natural or synthetic opioids to respond to a public health emergency.

Learnings from reports of death associated with kratom

We’ve been carefully monitoring the use of kratom for several years, and have placed kratom products on import alert to prevent them from entering the country illegally. We have also conducted several product seizures. These actions were based, in part, on a body of academic research, as well as reports we have received, suggesting harm associated with its use. And we are not alone in our evaluation and our public health concerns. Numerous countries, states and cities have banned kratom from entering their jurisdictions. We described some of this information in a public health advisory in November 2017, in which we urged consumers not to use kratom or any compounds found in the plant.

Now, I’d like to share more information about the tragic reports we have received of additional deaths involving the use of kratom. Looking at the information we have received – including academic research, poison control data, medical examiner reports, social science research and adverse event reports – we now have 44 reported deaths associated with the use of kratom. This is an increase since our November advisory, which noted 36 deaths associated with these products. We’re continuing to review the newly received reports and will release those soon. But it’s important to note that these new reports include information consistent with the previous reports.

Today, we’re releasing the reports of the 36 deaths we referenced in November. These reports underscore the serious and sometimes deadly risks of using kratom and the potential interactions associated with this drug. Overall, many of the cases received could not be fully assessed because of limited information provided; however, one new report of death was of particular concern. This individual had no known historical or toxicologic evidence of opioid use, except for kratom. We’re continuing to investigate this report, but the information we have so far reinforces our concerns about the use of kratom. In addition, a few assessable cases with fatal outcomes raise concern that kratom is being used in combination with other drugs that affect the brain, including illicit drugs, prescription opioids, benzodiazepines and over-the-counter medications, like the anti-diarrheal medicine, loperamide. Cases of mixing kratom, other opioids, and other types of medication is extremely troubling because the activity of kratom at opioid receptors indicates there may be similar risks of combining kratom with certain drugs, just as there are with FDA-approved opioids.

However, unlike kratom, FDA-approved drugs have undergone extensive review for safety and efficacy, and the agency continuously tracks safety data for emerging safety risks that were previously unknown. So we have better information about the risks associated with these products; and can better inform the public of new safety concerns. For example, in August 2016, the FDA required a class-wide change to drug labeling to help inform health care providers and patients of the serious risks (including respiratory depression, coma and death) associated with the combined use of certain opioid medications and benzodiazepines. In June 2016, the agency also issued a warning that taking significantly high doses of loperamide, including through abuse or misuse of the product to achieve euphoria or self-treat opioid withdrawal, can cause serious heart problems that can lead to death. We also recently took steps to help reduce abuse of loperamide by requesting packaging restrictions for these products sold “over-the-counter.”

Taken in total, the scientific evidence we’ve evaluated about kratom provides a clear picture of the biologic effect of this substance. Kratom should not be used to treat medical conditions, nor should it be used as an alternative to prescription opioids. There is no evidence to indicate that kratom is safe or effective for any medical use. And claiming that kratom is benign because it’s “just a plant” is shortsighted and dangerous. After all, heroin is an illegal, dangerous, and highly-addictive substance containing the opioid morphine, derived from the seed pod of the various opium poppy plants.

Further, as the scientific data and adverse event reports have clearly revealed, compounds in kratom make it so it isn’t just a plant – it’s an opioid. And it’s an opioid that’s associated with novel risks because of the variability in how it’s being formulated, sold and used recreationally and by those who are seeking to self-medicate for pain or who use kratom to treat opioid withdrawal symptoms. We recognize that many people have unmet needs when it comes to treating pain or addiction disorders. For individuals seeking treatment for opioid addiction who are being told that kratom can be an effective treatment, I urge you to seek help from a health care provider. There are safe and effective, FDA-approved medical therapies available for the treatment of opioid addiction. Combined with psychosocial support, these treatments are effective. Importantly, there are three drugs (buprenorphine, methadone, and naltrexone) approved by the FDA for the treatment of opioid addiction, and the agency is committed to promoting more widespread innovation and access to these treatments to help those suffering from an opioid use disorder transition to lives of sobriety. There are also safer, non-opioid options to treat pain. We recognize that some patients have tried available therapies, and still have unmet medical needs. We’re deeply committed to these patients, and to advancing new, safe and effective options for those suffering from these conditions.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm595622.htm