Summary

Although mild disturbances in the way the liver functions are very common when we start taking a new drug (or a combination of new drugs), it usually takes an unfortunate chain of events for these drugs to cause serious liver injury or death: a drug (or a combination of drugs) that is prone to cause liver damage; missed appointments and/or poor monitoring; and often existing, but perhaps undiscovered, liver damage coupled with excessive alcohol consumption.

All about the liver

The liver is an immensely resilient organ. It has to be: every foreign substance taken in by the body is processed by the liver, which is the body's chemical processing plant, energy stockpile and recycling station.

It is the only major organ that will regenerate from a bit of itself, and usually has a big enough reserve of surplus liver cells (called hepatocytes) to deal with the toughest reprocessing job. It takes old red blood cells that have passed their sell-by date, extracts the iron-containing pigment, and in a piece of biochemical thriftiness, makes a bitter green fluid called bile out of them which is used to digest fatty foods. It stores energy in the form of glycogen - a form of glucose.

And its cells contain several hundred different enzymes from the cytochrome P450 family. Each of these has expertise in transforming a particular class of drugs into substances that can be more easily eradicated by the body - usually by chopping or adding bits that make them more soluble in water.

And that, generally, is where the trouble lies. Some drugs are processed nice and tidily and get excreted without fuss. But in others, the soluble liver product (called a metabolite) is more toxic than the original drug itself.

The best-known example is alcohol, where a different enzyme called alcohol dehydrogenase turns it into the more soluble but much more poisonous chemical acetaldehyde. In the short-term, the result is a hangover, but long-term (chronic) alcohol abuse can lead to fibrosis and cirrhosis.

Fibrosis and cirrhosis

A number of chronic conditions can eat away at the liver's reserve: chronic hepatitis B and C, alcohol and drug abuse, and even an autoimmune condition in which the body's own defences attack the liver can destroy liver cells. These turn into scar tissue (fibrosis) and eventually the whole liver can become hard and inelastic, its channels blocked and its processing capability down to a fraction of what it should be (cirrhosis).

“Fibrosis does not in itself make it more likely you will get liver damage from a drug,” explains Dr Gary Brook, Head of Department in GU and HIV Medicine at northwest London's Central Middlesex Hospital, and co-author of several British HIV Association's (BHIVA) guidelines on hepatitis co-infections and liver transplantation. “But if you already have fibrosis you have less spare capacity. For example, although nevirapine is the anti-HIV drug most often associated with liver damage, even efavirenz (Sustiva), the other non-nucleoside, can cause severe liver damage in about 3% of patients. If you already have some fibrosis, however, this risk rises to about 8%. In our experience, being coinfected with chronic viral hepatitis B or C - the main cause of fibrosis in people with HIV - can double or triple the risk of drug-induced liver injury.”

Other factors, and alcohol in particular, can tip the balance decisively. “Even in patients with quite severe liver damage,” says Dr Brook, “paracetamol is safe as long as you don't overdose. But in someone who drinks a lot, an 'overdose' might only be twelve 500mg tablets a day; 50% more than the recommended maximum dose.” This can happen, for example, if you are combining paracetamol with other cold remedies that also contain the drug.

Which drugs can damage the liver?

All drugs have the potential to hurt the liver, including many used by HIV-positive people, but there are no definitive data that can provide a pecking order of drug-induced liver injury, not even in a group of patients as intensively-studied as those living with HIV.

“Our figures come mainly from drug trials,” says Dr Brook. "Unfortunately no-one has done large enough studies to pick out which drugs cause the most problems in the real world.”

To help remedy this situation, in 2004 the United States National Institute of Health (NIH) began a three-year study of patients who suffer severe liver injury due to both prescription and over-the-counter medications, but results aren't yet available. And in Europe, the body responsible for licensing new drugs, the European Medicines Evaluation Agency (EMEA), is now monitoring liver toxicity in HIV-positive people based on the model of one that already exists on lipodystrophy.

They have expanded the D:A:D (Data collection on adverse events of anti-HIV drugs) study - which currently monitors the frequency of heart attacks and strokes in people on HIV medication - to also look at drug-induced liver injury. Their preliminary findings, reported at the Thirteenth Conference on Retroviruses and Opportunistic Infections (CROI) held in Denver last month^[1], suggest some evidence of an increased risk of death due to drug-induced liver injury of 10% per year of anti-HIV therapy once latest CD4 counts had been adjusted for, although the investigators say that a longer study period is required before firm conclusions can be drawn . However, tha main risk factors for liver-related death were lox CD4 counts, chronic coinfection woth hepatitis B and C, and older age.

Currently the only information that helps identify individual drugs associated with serious drug-induced liver injury come from the World Health Organization (WHO) which keeps a database of around 5000 reports of deaths between 1968 to 2003 that appear to be caused by liver-toxic drugs^[2]. “It's a very ad-hoc collection of largely American cases,” comments Dr Brook, “but it does give an approximate guide to the most troublesome drugs. What's notable is that four anti-HIV drugs are in the Top Ten and another is a drug used to prevent and treat an AIDS-defining illness.”

WHO's Top Ten liver toxic drugs

1.  Paracetamol/acetaminophen (painkiller)
2. Troglitazone (anti-diabetes, now discontinued)
3. Valproic acid (anti-epilepsy; also being used as an experimental immune modulator in HIV)
4. Stavudine/d4T/Zerit (anti-HIV)
5. Halothane (anaesthetic, now discontinued)
6. Lamivudine/3TC/Epivir/Zeffix (anti-HIV, anti-hepatitis B)
7. Didanosine/ddI/Videx/Videx EC (anti-HIV)
8. Amiodarone/CordaroneX/Amyben (heart disease)
9. Nevirapine/Viramune (anti-HIV)
10. Cotrimoxazole/Septrin/Bactrim (antibiotic, used to prevent and treat Pneumocystis pneumonia/PCP)

It's important to remember that this list reflects the popularity of drugs as well as their absolute liver toxicity, which explains the high position on the list of the widely-used 3TC which is relatively less liver-toxic than, say, the less commonly-used nevirapine. Other drugs just outside the Top Ten include the painkiller diclofenac (Voltarol), the antibiotic amoxicillin/clavulanate (Augmentin), and the anti-tuberculosis (TB) drug isoniazid.

But virtually any drug can cause liver problems in at least a handful of people, and it's not only prescribed drugs that can cause drug-induced liver injury. Top of the list - and accounting for 30% of all cases reported to the WHO - is the over-the-counter painkiller and fever-reducer, paracetamol, which is also found in all kinds of cold remedies.

Recreational drugs can also cause liver injury. “When I was working in A&E,” recalls BHIVA hepatitis guidelines co-author, Dr Janice Main, who is a consultant in infectious diseases and general medicine at Imperial College School of Medicine at St Mary's Hospital, London, “we used to talk about 'hepatitis E'. This doesn't refer to a rare viral type, but to the liver damage we'd see that was caused by ecstasy every weekend. Cocaine overdoses can damage the liver, too.”

Even complementary therapies can be liver-toxic. Dr Main has seen liver failure due to the herb butterbur, used to treat hayfever and sinusitis. Herbs that have been banned in various countries due to their potentially liver-damaging properties include the tranquillising herb, kava-kava, and the Chinese herb ma huang, also known as ephedra.

How do you know if your liver is sick?

• Waste products the liver is failing to clear. The most important of these is bilirubin, the waste from old red blood cells. The yellowing appearance of jaundice, caused by an excess of bilirubin in the blood and tissues, is the surest sign that liver damage is severe and the drug needs to be stopped. “Jaundice is a key feature of predicting how severe liver damage is,” says Dr Brook. “The liver failure rate among patients with acute liver injury who have jaundice is about 11%.”
• Chemicals found in the liver that shouldn't be in the blood. These are the liver enzymes, which should normally sit inside cells doing their processing jobs, but which spill out when liver cells rupture and die. The most important one is ALT (alanine aminotransferase). This is an enzyme whose abnormal presence in the blood signals the rupture of liver cells. Normal levels are less than 40 IUs (international units) per litre. Over 200 IU suggests liver problems, but, says Dr Main, “we get really worried if it's in the thousands.”
• Chemicals the liver should be making, and isn't. The most important one of these is the protein albumin, a substance made in large quantities by the liver that regulates the body's fluid balance. “Albumin acts like a sponge,” explains Dr Main. “If there's not enough of it, you get ascites.” Ascites (pronounced a-site-ease) is the accumulation of fluid in the belly that is a sign of end-stage liver failure, and usually means a liver transplant is necessary. At this point the liver has come to the end of its reserves and has given up doing the most basic biochemical jobs (known as 'decompensation).

Liver function tests

Reference ranges can vary by labs.

However, there's usually plenty of time to remedy the situation before you begin to have symptoms of liver failure, which tend to occur in a specific sequence. "The first thing people often notice is severe loss of appetite, often with nausea,” says Dr Main. "If you're a smoker, you go off cigarettes too! Then you may notice you feel very fatigued and weak. Sometimes you get very itchy or may need to drink a lot of water. You may also notice yourself bruising easily - this is because the liver makes the factors that make blood clot. Light-coloured stools and dark urine usually herald the appearance of frank jaundice, often noticed first in the whites of the eyes."

"Eventually you would start to get fluid accumulation in the belly," Dr Main adds, "but by this time you hopefully will have gone to hospital.”

References

1. Weber R et al. Exposure to Antiretroviral Therapy and the Risk of Liver-related Death: Is there an Association? Results from the D:A:D Study. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 770, 2006.

2. Björnsson E et al. Suspected drug-induced liver fatalities reported to the WHO database. Digestive and Liver Disease 38(1): 33-38, 2006.