Pete had a truly awful Christmas. A few weeks earlier he was diagnosed with cirrhosis of the liver and the news was still sinking in while all around him the alcohol-fuelled festivities were in full swing. “I don’t even drink,” he told the specialist incredulously when given the diagnosis. Surely only hardened alcoholics get cirrhosis?
In November, feeling tired and washed-out, he had gone to see his doctor. Apart from being overweight he seemed to be in good health. Yet blood tests indicated he was anaemic and an endoscopy revealed a burst blood vessel in his gullet, a sign of cirrhosis, the final stage of liver disease. Weeks later Pete’s abdomen swelled alarmingly as it filled with fluid – another sign – and a liver biopsy confirmed the diagnosis. He was only 35.
Being told you have liver disease always comes as a huge shock. “It’s almost a grief reaction you see in people, because of the stigma,” says David Jones of the Freeman Hospital liver unit in Newcastle upon Tyne, UK, who is treating Pete (not his real name). “But there are over a hundred causes of liver disease that aren’t alcohol-related. That’s just the stereotype. It’s not even the commonest we see any more.”
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In the coming decades, more and more of us are likely to receive the same bad news as Pete. As many as 1 in 10 may already have liver disease, in many cases without realising it. While most people know liver disease can be caused by drinking too much or by infection with a hepatitis virus, few realise that simply being a bit overweight can also damage your liver – and due to the rising tide of obesity in affluent countries, this is set to become a huge problem. It has already overtaken alcohol and viral infections as the main cause of liver disease.
The good news is that the liver’s powers of regeneration are even greater than we thought. Most people with fatty liver disease could turn things around just by changing their lifestyle. And there are now tantalising signs that doctors may be able to halt or even reverse the final stage of liver disease, cirrhosis, for which the only available treatment was thought to be a transplant.
These discoveries are certainly timely. Liver function tests carried out as part of national health surveys in the US over the past two decades show that between 5 and 10 per cent of Americans have liver disease. About two-thirds have non-alcoholic fatty liver disease (NAFLD), while most of the remaining cases are due to excessive drinking and viral hepatitis. Even 10 per cent may be an underestimate, because not everyone with the disease has the abnormally high levels of liver enzymes in their blood that the tests measure (see “Have you got it?”). Pete’s liver function tests were initially normal.
Rich countries such as the UK and Australia, where the rising tide of obesity has followed closely that in the US, are likely to have similar numbers of people with undiagnosed fatty liver disease. It is no longer unusual for liver specialists in the UK to see people in their 20s and 30s with the disease, says Jones. “We’re even seeing children with liver cirrhosis resulting from obesity. These are extreme cases, but they’re not so extreme any more as to be once-in-a-lifetime events.”
“I don’t think any child should have fatty liver disease. It flashes warning lights,” says Eve Roberts of the Hospital for Sick Children in Toronto, Canada, who knows of about 20 children who have progressed to full-blown cirrhosis. Many others may go on to develop cirrhosis as adults. “There is a lack of awareness among the public and doctors. This is going to be the most important chronic liver disease in adults and children in North America. If we’re seeing 15 to 20 per cent or so of the population obese, then we’re going to see a huge increase in the prevalence of this disease.” Jones predicts an exponential increase in the coming decades. “It’s starting as a trickle but will build into a flood.”
One reason doctors are just waking up to the scale of the problem is that the liver is a truly phenomenal organ. It performs a string of vital functions, including carbohydrate and lipid metabolism, bile production and the breakdown of toxins. It can continue functioning adequately despite extensive damage and can regenerate from as little as a fifth of its original volume. This resilience may be its undoing, because people with diseased livers may show only mild symptoms or none at all until it is too late.
“The heavy drinker or overweight person who thinks ‘I must be alright because I feel alright’ is completely wrong,” says Chris Day, another liver specialist at the Freeman Hospital liver unit. “Your liver could be two-thirds rotted and you’d still feel fine.”
“Your liver could be two-thirds rotted and you’d still feel fine”
What symptoms there are in the early stages are vague: fatigue, insomnia, memory loss, difficulty concentrating, itching, abdominal pain. “The message that these might be warning signs of liver disease has been slow to filter through to GPs and the public,” says Day. People associate liver disease with jaundice and abdominal swelling, but these only appear in advanced cases.
While the effects of alcohol and viruses on the liver have long been clear, the dangers of obesity have started to be recognised only recently. It is still not clear how an excess of fat harms the liver. The leading theory is that it causes oxidative stress, triggering long-term inflammation and scar formation, or fibrosis.
Normally, fatty acids are released into the bloodstream from fat tissue when insulin levels fall between meals and are absorbed when insulin levels rise while food is being digested. In someone who is overweight and has become insulin-resistant, however, the bloodstream is constantly awash with fatty acids. The liver tries to fix this both by storing more fat and by stepping up its oxidation of fatty acids. Toxic free radicals are a by-product of oxidation, and it is these highly reactive molecules that are thought to damage liver cells and trigger inflammation.
Alcohol exacerbates the effect. “Alcohol and obesity interact to produce more damage than either alone,” says Ian Gilmore, a liver specialist at the Royal Liverpool University Hospital, UK. “Drinking is probably more dangerous in fat people than thin people.”
Whether the damage is caused by alcohol, fat or a virus, the effect is much the same. Holes appear in the liver’s structure as cells called hepatocytes – the organ’s workhorses – die. The tissue then becomes inflamed as immune cells move in and tell fibre-producing cells called hepatic stellate cells to multiply and plug the gaps with scar tissue. The longer the inflammation persists, the more scar tissue builds up. Eventually, it can overwhelm the entire structure of the liver, obstructing blood flow. This is cirrhosis.
As the liver fails, patients become emaciated, develop jaundice and abdominal swelling, and experience nausea and confusion. They may die as a result of burst blood vessels in their gullet or stomach, or develop liver cancer. “Liver cirrhosis is absolutely horrendous,” says Derek Mann, who leads the liver group at Newcastle University, UK. “It’s a horrible thing to die of.”
At present the only option is a liver transplant, but there are nowhere near enough organs to meet demand. Many people die waiting. “We cannot even begin to scratch the surface,” says Jones. “That’s why the pressure for alternative approaches is so desperate. Transplantation cannot possibly cope with the burden of all this.”
There is cause for optimism, though. Until recently it was thought that scarring, or fibrosis, was irreversible. Then John Iredale of the University of Southampton, UK, found that if a liver is still reasonably healthy the scars will gradually disappear if you remove the cause of the damage. What happens, his team showed in 1998, is that in the absence of signals from immune cells, the fibre-producing stellate cells self-destruct and the surrounding hepatocytes divide to fill the gaps.
What this means is that most people with early-stage disease could turn it around by themselves. “If you stop the underlying process – for example, if you’re an alcoholic and you stop drinking, or have obesity-related disease and you lose weight – then the body naturally has the capacity to break down the scars of cirrhosis,” says Jones. The formula is familiar – eat healthily and take more exercise.
Mann is proof that it works. Three or four years ago he was given liver function tests for an unrelated clinical issue. “They came back sky-high,” he recalls, “and I was asked whether I drank a lot of alcohol.” He didn’t. An ultrasound scan revealed fatty liver disease.
Luckily for Jones, his doctor (and colleague) was none other than John Iredale. “John told me, ‘It’s very simple, you need to lose a couple of stone – get down to the gym and change your diet’.” He took the advice and his liver enzymes are now back to normal levels.
As soon as it was discovered that fibrosis can be reversed, the hunt was on for a drug that would block the signals that keep the stellate cells alive, the idea being to accelerate the healing process. A drug called sulphasalazine, used since the 1950s to treat inflammatory conditions such as rheumatoid arthritis, was already known to inhibit one of the chemical signals that promote scarring. In 2005, a team led by Mann, then at the University of Southampton, UK, tested the drug on rats with liver fibrosis and discovered that just a single dose accelerated the animals’ recovery (Gastroenterology, vol 128, p 108).
A small-scale trial of sulphasalazine for liver disease is now being planned in Southampton. Around 20 patients with alcoholic liver cirrhosis who have stopped drinking will be given sulphasalazine and have their progress monitored. “It will simply be a quick check to see it doesn’t make them any worse, and if it makes them better then, bingo!” enthuses Mann.
If the trial goes well, it will be extended to take in more patients. There are, however, some doubts over whether the drug will prove effective in people. There are two big barriers.
The first is that in the animal study the drug was injected directly into the abdomen, whereas people take it in pill form – and gut bacteria are known to break the drug into two parts. “Both must be present in a single molecule to do their work,” says Matthew Wright, a member of the Newcastle team.
However, it is known that some sulphasalazine gets into the bloodstream intact. And if not enough reaches the liver in one piece, Wright reckons it would be simple to tweak the molecule to ensure that the two parts hold together more tightly in the gut.
A potentially more serious problem is that the drug’s targets – the hepatic stellate cells – sit right next to hepatocytes, whose job it is to break down foreign molecules such as sulphasalazine. But Wright thinks there is an answer to this too. In 2005 he was part of a team that generated a monoclonal antibody that binds to hepatic stellate cells but not to hepatocytes. Hook the antibody up to sulphasalazine or a similar molecule and it could ensure that the drug reaches high enough concentrations just where it is needed and nowhere else.
Even if sulphasalazine or a similar drug proves effective, it won’t stop people dying from cirrhosis unless the underlying cause of the damage, be it alcohol, viral infection or obesity, is removed too. Jones has a simple message for patients who come to him with fatty liver disease: “I put the fear of God into them, then I send them off to buy a heart rate monitor and to exercise. I tell them it’s the best £50 they’ll ever spend. And patient after patient comes back with normalised liver function tests. They feel a lot better, the tiredness goes away. It’s quite extraordinary.”
A coffee or four a day…
“Doctors have a saying that everything you enjoy is either illegal, immoral or bad for you, so it’s nice to discover that coffee is good for you,” says Arthur Klatsky, an epidemiologist at Kaiser Permanente in Oakland, California. His team has found that drinking four cups of coffee a day reduces the risk of non-alcoholic cirrhosis by 30 per cent and of alcoholic cirrhosis by 80 per cent.
The research, published last year, is the latest in a string of studies showing coffee protects the liver. “I haven’t the slightest idea what the mechanism is,” says Klatsky. “We don’t know for sure whether it’s caffeine or something else.”
Chris Day of Newcastle University in the UK thinks the effect could be due to the anti-inflammatory properties of theophylline, a breakdown product of caffeine. Most studies have failed to find any benefit from tea, which contains both theophylline and caffeine, but as Day laughingly points out, the studies were done in the US, “where tea is notoriously as weak as bathwater”.
Have you got it?
“Most people with liver disease don’t look like they’ve got liver disease,” says David Jones of the Freeman Hospital liver unit in Newcastle upon Tyne, UK. The early signs include symptoms we all experience sometimes: tiredness during the day and insomnia at night, difficulty concentrating, flu-like symptoms, itchiness, abdominal pain. “One of the reasons why these symptoms are so common is that liver disease is common,” he says.
Diagnosis is far from easy. Standard liver function tests measure levels of various liver enzymes in the blood – high levels strongly suggest some form of disease. The tests come back negative in most patients with fatty liver disease, however, and they can occasionally throw up false positives.
A doctor can sometimes detect an enlarged liver simply by feeling the abdomen, but this is tricky in overweight people – those most likely to get liver disease. A fatty liver can show up as a bright patch on an ultrasound scan but taking a liver sample is the only way to be sure someone has the scarring that underlies serious liver disease – and biopsies are painful, sample only a tiny part of the liver and cause fatal bleeding in around 1 in 10,000 patients.
So doctors are crying out for a non-invasive, reliable test. One possible solution is an antibody created at the University of Aberdeen, UK, in 2005 that binds to the scar-forming cells (Journal of Hepatology, vol 42, p 888). If the antibodies were hooked up to metal beads and injected into a patient, MRI scans should reveal the extent of any scarring throughout the entire liver.
