November 24, 2011

Published: October 16, 2011. Imperial College London

Researchers have identified a large number of areas in the human genetic code that are involved in regulating the way in which the liver functions, in a new study of over 61,000 people, published today in the journal Nature Genetics.

The work is an international collaboration led by Imperial College London and it identifies 42 genetic regions associated with liver function, 32 of which had not been linked to liver function before. The work should lead to a better understanding of precisely what goes wrong when the liver ceases to work normally. Ultimately, it could point the way to new treatments that can improve the function of the liver and help to prevent liver damage.

The liver is the body's largest internal organ and the British Liver Trust estimates that around two million people in the UK have a liver problem at any one time. The liver carries out hundreds of different tasks, including making proteins and blood clotting factors, and helping with digestion and energy release. It also purifies the blood of bacteria, and of the by-products of digestion, alcohol and drugs.

In the new genome-wide association study, the researchers compared the genetic makeup of over 61,000 people, in order to identify areas of the genetic code that were associated with liver function.

The team assessed the function of the volunteers' livers by looking at the concentrations of liver enzymes in their blood. People who have liver damage have high concentrations of these enzymes, which are associated with an increased risk of conditions such as cirrhosis, type 2 diabetes and cardiovascular disease.

Dr John Chambers, the lead author of the study from the School of Public Health at Imperial College London, said: "The liver is a central hub in the body and because it has so many diverse functions, it is linked to a large number of conditions. Our new study is a big step towards understanding the role that different genes play in keeping the liver working normally, and towards identifying targets for drugs that can help prevent the liver from functioning abnormally or becoming susceptible to disease."

The researchers identified 42 areas on the genetic code associated with liver function and they then went on to pinpoint 69 associated genes within these areas. Some of the genes are known to play a part in other functions in the body, including inflammation and immunity, and metabolising glucose and carbohydrates.

Professor Jaspal S Kooner, the senior author of the study from the National Heart and Lung Institute at Imperial College London, said: "This massive international research effort provides in-depth new knowledge about the genes regulating the liver. We are particularly excited about the genes whose precise role we don't yet know. Investigating these further should help us to fill in the gaps in our understanding about what happens when the liver ceases to function normally and how we might be able to tackle this."

Professor Paul Elliott, also a senior author of the study, from the School of Public Health at Imperial College London, said: "Liver problems affect a huge number of people and they can have a devastating effect on a person's quality of life. This study represents a vast discovery that opens up multiple new avenues for research."

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HepatologyVolume 54, Issue 5, pages 1527–1537, November 2011

Marc G. Ghany1,*,§, Hae-Young Kim2, Anne Stoddard2, Elizabeth C. Wright3, Leonard B. Seeff4, Anna S.F. Lok5, the HALT-C Trial Group

Article first published online: 28 OCT 2011
DOI: 10.1002/hep.24550
Copyright © 2011 American Association for the Study of Liver Diseases

Abstract

Predicting clinical outcomes in patients with chronic hepatitis C is challenging. We used the hepatitis C long-term treatment against cirrhosis (HALT-C) trial database to develop two models, using baseline values of routinely available laboratory tests together with changes in these values during follow-up to predict clinical decompensation and liver-related death/liver transplant in patients with advanced hepatitis C. Patients randomized to no treatment and who had ≥2-year follow-up without a clinical outcome were included in the analysis. Four variables (platelet count, aspartate aminotransferase [AST]/alanine aminotransferase [ALT] ratio, total bilirubin, and albumin) with three categories of change (stable, mild, or severe) over 2 years were analyzed. Cumulative incidence of clinical outcome was determined by Kaplan-Meier analysis and Cox regression was used to evaluate predictors of clinical outcome. In all, 470 patients with 60 events were used to develop models to predict clinical decompensation. Baseline values of all four variables were predictive of decompensation. There was a general trend of increasing outcomes with more marked worsening of laboratory values over 2 years, particularly for patients with abnormal baseline values. A model that included baseline platelet count, AST/ALT ratio, bilirubin, and severe worsening of platelet count, bilirubin, and albumin was the best predictor of clinical decompensation. A total of 483 patients with 79 events were used to evaluate predictors of liver-related death or liver transplant. A model that included baseline platelet count and albumin as well as severe worsening of AST/ALT ratio and albumin was the best predictor of liver-related outcomes. Conclusion: Both the baseline value and the rapidity in change of the value of routine laboratory variables were shown to be important in predicting clinical outcomes in patients with advanced chronic hepatitis C. (HEPATOLOGY 2011;)

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Living with chronic illness during the holiday season

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Posted on KevinMD.com

In the U.S., we’re getting ready to celebrate Thanksgiving. Soon, people around the world will turn their attention to the holiday season. Chronic health problems can take a toll on relationships any time of the year. Most people have to experience unrelenting pain or illness themselves before they understand how debilitating it is, physically and mentally. Loved-ones (by whom I mean family and close friends) may be in some form of denial about what’s happened to you, or they may be scared and worried about the future. Bottom line, suffering from a chronic condition can be an ongoing crisis—for you and for those you’re close to.

That crisis can come to a head during the holidays when people’s expectations of one another are high and when stress levels for everyone are likely to be off the charts for any number of reasons—health, financial, relationship issues. If you’re like me, during the rest of the year, you carefully limit interactions with others in order to manage your symptoms; on a typical day, your most complex decision may be to choose between showering and shopping! But when the holidays arrive, you’re suddenly thrust into the middle of a lively and chaotic social scene where you’re expected to participate in a range of activities, often for days in a row. A bit of advance warning to loved-ones can go a long way toward minimizing stress levels over unrealistic expectations.

I know that this piece won’t apply to everyone. One of the heartbreaking consequences of living with chronic pain and illness is that some people are unable to be with loved-ones at all during the holidays, either because people are too disabled by their pain or illness to be able to gather with others, or because family and close friends having drifted out of their lives. I know the pain of that isolation; I’ll be writing about it in my next piece.

For those of you who are able to gather with others, the holidays can be a recipe for double disaster—the increase in activity exacerbates your physical symptoms, while coping with sadness, frustration, and maybe even guilt about your physical limitations gives rise to emotional pain. No wonder many people with health problems dread the approaching holidays.

If you’re one of the many people with chronic health problems who don’t look sick, the initiative is with you to make your condition visible. Here are some suggestions for helping loved-ones understand what your life is like and for giving them a heads-up on what to expect from you during the holidays.

Share information with them from the Internet or from books

Often the best way to educate loved-ones about chronic pain and illness is to use a neutral source because it takes the emotional impact out of the communication. A quick web search will yield a host of organizations devoted to every conceivable medical problem. Print out select pages or forward a few links to family and close friends. Alternatively, if you have a book about your condition, photocopy the pages that cover what you’d like them to know about you. In your accompanying note, keep it “light”—you could joke that “there won’t be a test.” But also make it clear that this favor you’re asking is important to you.

Write a letter

Many years ago, two friends of mine were in couples therapy. They weren’t able to speak to each other about their marital problems without one of them shutting down emotionally and the other reacting by shouting recriminations. Their therapist told them to write letters to each other expressing their feelings and their concerns about the marriage. It turned out to be a major first step in healing their relationship.

If you decide to write a letter, be sure it’s not accusatory. In composing it, use the word “I” more than the word “you.” Without complaining, express how difficult it’s been for you to adjust to this unexpected change in your life and how you wish you could be as active as you once were during the holidays.

You could briefly describe what your day-to-day life is like, including how unpredictable your condition is which means that you can’t know for sure how you’ll feel on the day of the actual gathering no matter how much you rest in advance. (This is the hardest concept for most loved-ones to comprehend—that we can spend weeks before a big event in full “rest mode,” but still feel very sick when the day arrives.)

I would end by telling them what to expect from you during the holidays—that you may have to skip some events, that you may have to excuse yourself right after eating to go lie down, that you may have to come late and leave early. In my experience, spelling out my limitations ahead of time is helpful not just to others, but to me, because I find it much easier to exercise the self-discipline it takes to excuse myself from a room full of people if I know that at least some of them are already expecting it.

P.S. It will be tempting to send an email, and if you have a lot of people you want to communicate with, it may be the most feasible way to reach everyone. But one thing’s for sure: people will read a handwritten letter, antiquated document that it’s become!

Find that ONE ally and enlist his or her help

If you have just one close friend or family member who understands what you’re going through, enlist his or her help in explaining your condition and your limitations. Before the holidays start, you could ask your ally to talk to loved-ones on your behalf or to be present when you talk to them. Ask your ally to be supportive if you have to excuse yourself in the middle of a gathering, or even to let you know if you’re wilting (as we call it in my household). It’s so helpful for me to be “prompted” by my ally because, when I start to overdo things, adrenaline kicks in which fools me into thinking I’m doing fine. But using adrenaline to get by just sets me up for a bad crash later on.

Your ally may be a close friend or family member who’s just waiting for you to enlist his or her help. Think long and hard before you decide there’s no such person in your life.

In the end, you may have to recognize that some loved-ones may never accept your limitations

Some family and close friends may refuse to accept that you’re disabled by pain or illness. I know this from personal experience and it hurts. Try to recognize that this inability is about them, not you. Don’t let their doubt make you doubt yourself. Your medical condition may trigger their own fears about illness and mortality, or they may be so caught up in problems in their own lives that they’re not able to see their way clear to empathize with you.

Just as you can’t force people to love you, you can’t force people to accept you. But getting angry at them just exacerbates your own symptoms. That’s why it’s important to protect yourself from allowing their lack of understanding to continually upset you. Think of it as protecting yourself from another chronic condition: chronic anger.

The physical suffering that accompanies chronic pain and illness is hard enough to endure without adding emotional suffering to it. When I feel let down family or close friends, the first thing I do is acknowledge how much it hurts. Then I reflect on the many possible reasons for their behavior. Finally, I work on genuinely wishing them well. These three steps immediately lessen my emotional suffering.

As you experiment with these suggestions, treat yourself kindly. Don’t blame yourself if one of them doesn’t work out. Instead, give yourself credit for having had the courage to try! My heartfelt wish is that your loved-ones come to understand and accept your limitations, but that if they don’t, you’ll be able to accept them as they are without bitterness.

Toni Bernhard was a law professor at the University of California—Davis, serving six years as the law school’s dean of students. She is the author of How to Be Sick: A Buddhist-Inspired Guide for the Chronically Ill and Their Caregivers and can be found online at HowToBeSick.com.

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