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Liver disease

In the second article on liver disease, Dr George Webster answers questions from GP Dr Melanie Wynne-Jones on hepatitis C and prescribing issues

In the second article on liver disease, Dr George Webster answers questions from GP Dr Melanie Wynne-Jones on hepatitis C and prescribing issues

1 What is the current epidemiology for hepatitis C? What are the long-term health risks to patients and neonates? Which tests indicate active infection/past infection/carrier status? What action should be taken for each type of result? Are all patients with haemophilia screened for hepatitis C?

There are 150 million people infected with hepatitis C virus (HCV) worldwide. Transmission is through infected blood products and unclean needles. Transmission via the former has been virtually eliminated in the UK since blood screening was introduced in 1990, hence the reason that more than 90 per cent of haemophiliacs infected with hepatitis C were treated pre-1990.

More than 60 per cent of UK cases where unclean needles are the cause relate to prior drug use. But in Egypt, where 15 per cent of the population has hepatitis C, inadequate needle usage in healthcare programmes is to blame. Risk of transmission sexually, and mother-to-baby is less than 6 per cent, higher if there is co-infection with HIV. There is no clear route of infection in 20 per cent in the UK. Acute hepatitis C (with jaundice) occurs in less than 15 per cent of patients. Most are asymptomatic following exposure but chronic infection is seen in 50-80 per cent. Hepatitis C is now the major cause of end-stage liver disease and cirrhosis, the latter usually developing more than 20 years after exposure, and often with co-factors (such as alcohol misuse, HIV, hepatitis B). Hepatocellular cancer (HCC) develops in 4 per cent every year following development of hepatitis C cirrhosis.Anti-HCV antibody confirms previous exposure, but hepatitis C RNA is required to demonstrate active chronic infection.ALT/AST are often only mildly elevated. Hepatitis C genotype influences treatment duration and response. Genotype 1 is worst (hence longer treatment required) and 2 and 3 are best.In a patient with chronic hepatitis C it is important to reassure that disease is very slowly progressive and that treatment is increasingly effective. It is also vital to explain the need to reduce compounding effects to a minimum – stop or minimise alcohol, as this greatly increases the risk of cirrhosis. Consider liver biopsy in all patients.The current best treatment of pegylated interferon and ribavirin controls infection in more than 80 per cent with hepatitis C genotype 2 or 3 after a six-month course, and up to 55 per cent with genotype 1 after a 12-month course. End-stage-cirrhosis due to hepatitis C is now the commonest indication for liver transplant in UK.

2 How often should we monitor patients with liver disease who take statins? If someone has mildly deranged LFTs (stable) can they take a statin at all? At what relative/absolute rise in LFTs should we stop prescribing statin? What is likely to happen then?

Mildly deranged LFTs should not preclude statin use, not least as the patient's hyperlipidaemia may be the cause of their fatty liver and LFT abnormalities.

To put in context, hepatotoxicity occurs in less than 3 per cent of patients on statins, and is usually manifested by increased ALT/AST. Acute liver failure is extremely rare, and risks appear to be dose related. Prior LFT abnormality is not strongly linked with subsequent hepatotoxicity on statins, and so statins should not be excluded.Most hepatotoxicity occurs within 12 weeks, so check LFTs monthly for three months, then every three months. Discontinue the drug if AST/ALT increase to three times baseline. Look for an alternative cause if improvement does not occur over six to eight weeks.

3 Can patients taking methotrexate and azathioprine take statins – how could we tell whether these drugs or the statins make the LFTs abnormal?

Implicating any drug as the cause of liver injury can usually only be made by demonstrating a deterioration of LFTs after the drug was given. This requires pre-treatment LFTs. If the patient is already on a potentially hepatotoxic drug it is vital to check LFTs before starting a statin.

Definitively implicating a particular drug might be possible only once it is reintroduced, but this should in most cases be strictly avoided as further idiosyncratic reactions may be extremely severe.Worsening LFTs after several drugs have been started at once (for instance multi-drug TB treatment) is a management headache. The ideal would be to stop all the drugs and restart them individually, but if this not possible, the pragmatic approach is usually to stop the drug most commonly associated with LFT derangement. A range of drugs may interact with statins, including erythromycin, ciclosp-orin, diltiazem and fibrates. It is important to check for possible interactions in the BNF prior to co-prescribing.

4 A patient came in to see me having read a JAMA report on the internet, which says regular paracetamol can derange LFTs in healthy people and may be risky to those who take other drugs that affect the liver, drink significant amounts of alcohol or have impaired liver function. Can you give any do's and don'ts, any advice on co-prescribing, and reassurances for patients?

The study showed that more than 30 per cent of healthy individuals taking paracetamol 4g/day for 14 days developed raised ALT (the levels settled after stopping the drug). No biopsies were performed, and there was no clinical evidence of significant or permanent liver injury. This study should not be interpreted as confirming that sub-toxic paracetamol use causes significant liver disease, and patients should be reassured.

Paracetamol remains one of the safest analgesics in patients with significant liver disease. NSAIDs may cause liver injury and renal failure; opiates may worsen confusion and encephalopathy.

5 Should moderately unwell patients with undiagnosed jaundice be admitted or investigated by the GP first?

If baseline bloods (FBC, clotting, U&Es, LFTs, hepatitis A, B, C) and ultrasound can be urgently organised by the GP, this should be done. Your local hepatologist/gastroenterologist is always keen to see patients urgently with 'new onset jaundice', and most would plan an urgent review within days.

There is a wide range of causes (and treatments) and prompt investigation is necessary. Acute hepatitis A may just require bed rest at home while acute liver failure or obstructive jaundice always requires admission and management.

6 We have a patient who has had a liver transplant and attends a regional centre for monitoring. Are there any special problems we should look out for?

There is a myriad of potential problems, particularly in the early post-transplant period, but they can broadly be categorised into:

• graft rejection• drug toxicity• infections (often related to immunosuppression) • disease recurrence.

Symptoms may be non-specific and finding the exact cause often requires hospital investigation (for instance biopsy). As the patient's GP you should expect close liaison with the liver centre and transplant team.

7 What is the current success rate for surgery to remove metastases – removal success and effect on survival? Who is suitable (type of cancer, degree of involvement ) and who isn't? Is there anything else GPs need to know?

The main role of metastasis liver surgery is in colorectal cancer, as 50 per cent of cases are complicated at some stage by liver metastases, and surgery is having an increasing role in their management.

Resection is possible in only 10-20 per cent of patients with liver metastases, but approximately 30 per cent of these will survive five years (compared with 2 per cent without surgery). Recent data suggests that these results might be improved further by post-operative chemotherapy.Contraindications to resection include:

• more than four metastases• extrahepatic metastases• significant background liver disease.

Surgery must aim to completely resect metastases. There is no benefit in palliative incomplete resection. The role of other ablative treatments (such as radiofrequency ablation) is promising but not established, and not an alternative to surgery if complete resection is possible.

8 What symptoms and investigations should alert us to autoimmune hepatitis? How common is it, how is it treated, and what is the outlook?

Autoimmune hepatitis classically occurs in young women (female:male ratio four to one) with associated other autoimmune disease (for instance thyroid, arthritis, ulcerative colitis), but any group can be affected. A prevalence of 50-100 per million is reported

It may present with jaundice due to acute hepatitis, but in most the disease is indolent and slowly progressive, with non-specific symptoms including fatigue and vague abdominal pain. Characteristic blood tests show hepatitis (raised ALT/AST), with autoantibodies (anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASM) present at >1:80 titre, and raised serum immunoglobulin G. Liver biopsy is required in all, but there are no completely diagnostic features. Cirrhosis is present on biopsy in more than 30 per cent.Prior to immunosuppression, there is only 50 per cent five-year survival, but this figure has now greatly improved with treatment (steroids, maybe with azathioprine). Prolonged treatment for more than two years is required (often with azathioprine monotherapy) even if there has been a prompt initial response. Liver transplantation is effective for 10 per cent of those who progress despite immunosuppression.

George Webster is a consultant and honorary lecturer in gastroenterology and hepatology at University College London Hospitals – he is co-author of the Oxford Handbook of Gastroenterology and Hepatology (Oxford University Press 2006)

Competing interests Prior to 2002, Dr Webster received honoraria from GlaxoSmithKline to lecture on hepatitis B

Take-home points

• There is no clear route of infection in hepatitis C in 20 per cent of cases. In patients with chronic hepatitis C the disease is very slowly progressive in the majority and treatment is increasingly effective.

• Most hepatotoxicity with statins occurs within 12 weeks.

• Paracetamol remains one of the safest analgesics in patients with significant liver disease.

• Resection is possible in 10-20 per cent of those with liver metastases from colorectal cancer but about 30 per cent of these will survive five years.

what i will do now

Dr Wynne-Jones responds to the answers to her questions

• Monitoring before and after statin prescribing causes us and patients a lot of work and concern. It's reassuring that adverse liver effects tend to occur sooner rather than later.

• I will encourage patients with abnormal liver function to opt for paracetamol rather than other painkillers.

• Jaundice is a difficult symptom to manage with current difficulties in obtaining urgent outpatient appointments and pressure to avoid hospital admissions. I shall feel more confident about initial investigations and when to hand over to secondary care.

• I will be less pessimistic about liver metastases.

• I will check autoantibodies more frequently in women who are tired all the time.

Dr Melanie Wynne-Jones is a GP trainer in Marple, Cheshire

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