午夜福利1000集合

DOWN a few drinks, and then a few more, and do it again the next night and
the next, and your liver may end up inflamed and scarred. But take the main type
of liver cell, hepatocytes, and soak them alone in the lab in alcohol at the
kinds of concentrations found in a drinker鈥檚 blood, and there are no signs of
this kind of damage. So what is going on?

It turns out that it isn鈥檛 alcohol itself that destroys livers, but the toxic
free radicals and inflammatory substances released as the body struggles to deal
with it. What鈥檚 more, the severity of this response varies greatly from
individual to individual. The efficiency of your alcohol-metabolising enzymes,
your diet, your sex, the strength of your immune response and, most surprisingly
of all, the number and type of bacteria that live in your gut may all determine
whether you鈥檒l succumb to liver disease or survive a lifetime of propping up the
bar.

A third of heavy drinkers鈥攍oosely defined on both sides of the Atlantic
as those who put away more than five or six drinks a day鈥攄evelop alcoholic
hepatitis, a life-threatening inflammatory condition, and a fifth get the fatal
accumulation of scar tissue that is cirrhosis. But because there are few nerves
in the liver, most people have no idea that alcohol is messing with theirs until
the damage is at an advanced stage.

If you drink regularly for a few weeks, deposits of fat will build up in your
liver. These are probably harmless, and disappear with abstinence. Yet continue
drinking heavily, and for reasons that no one really understands, your liver may
suddenly become inflamed, your abdomen will start to hurt all over, and you will
feel sick. This is alcoholic hepatitis.

Unchecked, the inflammation causes massive tissue damage and scarring. This
is bad news, since the liver is not only the body鈥檚 detox unit but also its
principal protein factory, energy store and metaboliser of cholesterol.

Finally, you could end up with cirrhosis. In the later stages, you may itch
all over as toxins and fluids accumulate, bleed internally, become confused and
unconscious, and die.

In the US, up to 24 000 deaths a year from cirrhosis are blamed on alcohol.
In Britain, the official number is 2000. 鈥淏ut this is probably a gross
underestimate,鈥� says Michael Arthur, a hepatologist at the University of
Southampton.

Researchers don鈥檛 yet have a complete picture of how drink damages the liver,
but they do know that the liver makes huge numbers of free radicals as enzymes
such as acetaldehyde dehydrogenase and cytochrome P450 break down alcohol. The
alcoholic liver also produces massive excesses of messenger chemicals that
trigger inflammation and scarring, and the production of yet more free
radicals.

On the rampage

Free radicals are normally mopped up within milliseconds by natural
antioxidants such as glutathione, vitamin E and vitamin C. But when they are
produced to excess, they overwhelm those chemical defences and set to work
vandalising DNA, cell membranes and the mitochondria that serve as cells鈥�
powerhouses, inducing what researchers call 鈥渙xidative stress鈥�. Add to this the
fact that a poor diet tends to leave alcoholics low on natural antioxidants, and
the scene is set for serious harm.

Free radicals are inherently unstable, and until recently it was impossible
to measure them accurately. But this September Garret FitzGerald and his
colleagues at the University of Pennsylvania, Philadelphia, reported that urine
levels of isoprostanes, which are released when fat is attacked by free
radicals, are a good indicator of oxidative stress (The Journal of Clinical
Investigation, vol 104, p 805). In acute alcoholic poisoning, isoprostanes
may soar to astronomical levels, FitzGerald says. Even in healthy volunteers
drinking just enough to take them over the legal driving limit, levels of
isoprostanes can increase as much as threefold, although no one knows whether
this means that moderate drinking can lead to tissue damage. Curiously, one
recent study has found that in rats daily light alcohol consumption appears to
improve liver repair
(New Scientist, 13 November, p 17).

For those who already have alcohol-induced hepatitis, trials to see whether
antioxidants can reduce the damage caused by free radicals are already under
way. Martin Phillips and John O鈥橤rady of the Institute of Liver Studies at
King鈥檚 College Hospital, London, expect to have results from one such trial
within months. Separate studies in healthy volunteers will compare the oxidative
stress triggered by red wine, which contains antioxidants, with alcoholic drinks
that do not.

But free radicals are only half the story. The inflammatory chemicals also
appear to do some damage, although precisely how is controversial. One
possibility is that they wake up another type of liver cell鈥攖he stellate
cells that control the formation of scar tissue. This scar tissue is meant to
patch up the damaged liver but if there is too much it blocks normal cell
function.

Bizarre as it may sound, gut bacteria may be partly responsible for revving
up one key inflammatory chemical in the first place. In rats, alcohol makes the
gut 鈥渓eaky鈥�, allowing large amounts of endotoxin, a poison produced by bacteria
that live in the gut, to reach the liver. Once the endotoxin gets there,
specialist immune cells called Kupffer cells sound the alarm, spewing out a soup
of inflammatory proteins.

In a misguided defence operation, one of these chemicals, tumour necrosis
factor alpha, spurs the release of more toxic free radicals. Mice that are
genetically engineered to lack a receptor molecule for TNF-alpha are resistant
to alcohol-induced liver disease (New Scientist, 9 October, p 10), and
in rats, antibodies that block TNF-alpha reduce liver damage, according to
studies by Ronald Thurman at the University of North Carolina, Chapel Hill.

But perhaps Thurman鈥檚 most provocative finding is that antibiotics that wipe
out gut bacteria also protect rats against liver damage. Should people with
alcohol-induced hepatitis be given antibiotics, then? No, says Thurman: the
treatment given to the rats is not practical for humans, not least because gut
bacteria are essential for normal digestion.

Worse to come

Another inflammatory chemical, interleukin-8, is released by hepatocytes in
response to acetaldehyde, a breakdown product of alcohol, according to Nick
Sheron and his colleagues at the University of Southampton. Interleukin-8 lures
neutrophils, a type of white blood cell, into the liver, releasing more
TNF-alpha and worsening the inflammation and the oxidative damage. Other
researchers have found that people produce different amounts of interleukin-8,
which may help account for some of the variation in susceptibility to liver
disease.

Diet could be another reason. Rats fed large amounts of polyunsaturated fats
such as sunflower oil are far more likely to get alcoholic liver disease than
rats that eat saturated fats, according to Amin Nanji at Beth Israel Deaconess
Medical Center in Boston. Still, rats get only a pale imitation of the human
disease even when alcohol is pumped directly into their stomachs 24 hours a day,
so researchers would rather wait for more information before hazarding any
guesses about whether this means a bacon sandwich is a better accompaniment to
an evening鈥檚 drinking than focaccia with tomatoes and olive oil.

There鈥檚 one more thing to bear in mind if you鈥檙e hell-bent on drinking to
excess: it鈥檚 better not to be female鈥攁nd not just, as is often claimed,
because you鈥檙e likely to be smaller. In women, a key stomach enzyme, alcohol
dehydrogenase, doesn鈥檛 function as efficiently as in men, so drink for drink a
woman鈥檚 liver gets hit with more concentrated blasts of alcohol.

And Thurman has found that, in rats at least, oestrogen stimulates Kupffer
cells, triggering an inflammatory reaction similar to the one triggered by
bacterial endotoxin. What, if anything, this means for women鈥檚 drinking habits
during the monthly cycle, while taking the pill or on HRT, is a big unknown. 鈥淲e
need clinical studies now,鈥� says Thurman. Others are sceptical: the world is not
full of women suffering inflammatory liver disease because of normal oestrogen
levels, says Sheron.

In reality, there is an awful lot about alcohol-induced liver disease that
remains a mystery. 鈥淭his is a complicated area, and sadly people have tended to
ignore it because it was deemed self-induced,鈥� says Phillips. Nevertheless, in
the last few years there have been enough new discoveries to show that the
standard, one-size-fits-all advice on safe drinking鈥攏ot more than 4 units
a day for men, 3 units for women according to the Department of 午夜福利1000集合 in
Britain鈥攊s absurdly crude. In future, people may get their own personal
safe limits that take into account all the many factors that alter
susceptibility, says Phillips. 鈥淎nd some people would probably be advised never
to drink.鈥�