Therapeutic Guidelines Liver Disorders

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Welcome to this Australian Prescriber podcast. I'm Dr Justin Coleman a GP on the Tiwi Islands, and we're here to talk about what's new and what's changed with livers. Now, never before have I started the podcast with a quote that my grandmother who enjoyed a wine used to quote Shakespeare, "With mirth and laughter let old wrinkles come," I’m now that age, obviously, "And let my liver rather heat with wine / Than my heart call with mortifying groans." Letting your liver heat was presumably a euphemism for raised LFTs back in the day, and there is indeed a notable connection between liver disease and our hearts giving out mortifying groans, which we'll explore today. And today I'm speaking all about livers and I'm hoping my guest will avoid too many groans. I have with me Professor Alex Thompson who's a hepatologist and Director of gastroenterology at my own old alma mater St Vincent's Hospital in Melbourne. Alex, welcome to the podcast.

Thanks Justin. It's good to speak to you.

Back in Elizabethan England, they recognised alcohol as a liver toxin, but we hadn't invented our alphabet soup of hepatitis viruses and non-alcoholic fatty liver disease. Just wondering, where do they rank in terms of health impact in modern day Australia, the various types of liver disease that you see?

Well, the three most common causes of liver disease are fatty liver disease, which we'll be talking about today, as well as alcoholic liver disease and still viral hepatitis.

Well, you're a member of the Liver Expert Group at Therapeutic Guidelines who published an update for eTG Liver disorders, so perhaps we'll start with the viral hepatitis, and with my apologies to all the other letters, I think I'll skip straight to C because C's where rapid change has taken place. What's the overall big change that's happened over the last few years?

Well, the really big change is the introduction in 2016 of new oral antiviral treatments that can cure hepatitis C. So we've seen a dramatic shift from interferon-based treatments that were used in the 1990s and the noughties. These were injectable treatments that cause lots of side effects, cured about 50% of the people, and really, because of the side effects, only a small minority of people were eligible. With the introduction of these new treatments that are once-daily oral pills, for 8–12 weeks, that have cure rates of 95–100%, and because they are so well tolerated, everyone is a candidate for treatment. We now have the lofty goal of eliminating hep C as a public health threat in Australia, and over the last five years, since the introduction of these medications, we've taken really significant steps towards doing that.

But there are still some challenges in Australia. Hepatitis C is a disease, mainly of people who inject drugs. These people are often marginalised and not engaged with medical care, and so to achieve elimination, we need to work really hard to engage high-risk individuals through opioid substitution clinics, through safe injecting rooms, through homeless persons programs, in hepatitis C testing and treatment. The other venue where there are a lot of people living with hepatitis C are the prisons, and one of the really forward-thinking steps that the Commonwealth Government took was to make these new treatments available to people who are in prison.

Yeah, we live in exciting times, I think, and it's wonderful to see that that is on the cards. And I think GPs out there in the community are good at hopefully tapping into some of these more difficult populations in terms of their access to healthcare.

That has been the other really significant shift that hepatitis C treatment has moved from specialists prescribing in hospitals to community prescribing by GPs. And now the majority of hepatitis C scripts are written by GPs and GPs are really going to lead the way in terms of us achieving our hepatitis C elimination goals in Australia.

When we do order a hep C test, I generally order a hep C antibody, but there's a suggestion now that we should be ordering an RNA test on the same pathology form.

So hepatitis C antibody tests tell us about exposure, but they don't tell us whether an individual is still infected with hepatitis C and about 25% of people will spontaneously clear hepatitis C. What we recommend is that you order a hepatitis C antibody test with reflex testing for hepatitis C RNA if the antibody test is positive. And that avoids one of the steps in that cascade of care and the requirement for multiple appointments we know can be a barrier to people engaging with hepatitis C.

And it's reassuring to know that that's not over-testing in the sense that the lab won't do the test if the hep C antibody test is negative, they won't go on to the RNA. Is there anyone we shouldn't be treating, or essentially our goal is to treat everyone who we identify as having hep C?

These treatments are so well tolerated that really everyone is a treatment candidate. The only people that we would say are no longer treatment candidates are people who are diagnosed in the terminal phase of their life when they have a very short life expectancy.

And of those people we're looking at treating, which in particular do you think we should be referring off to hepatologists because the treatment decisions may be more specialised?

So, very few. The vast majority of people living with hepatitis C now do not need specialist involvement. Of course, specialists are interested to be involved in hepatitis C care. And I think it's useful for GPs to have a specialist partner whom they can ask questions about or can consult with. The people that we would be interested still to see, however, are people with cirrhosis and here we're interested to see the individuals because of the need for follow-up [ care of the cirrhosis after the hepatitis C is cured, so that involves liver cancer screening, screening for portal hypertension and oesophageal varices in particular. We would also be interested to see people with hepatitis B co-infection. Only a small number of hepatitis C-infected people also have hepatitis B, but there is a small risk of hepatitis B reactivation in these individuals, and I think they are a population for whom specialist involvement is useful.

Then finally, there are a very small number of people who fail first-line treatments with these new direct-acting antiviral agents, and I think there's a role for specialist care in those individuals. Of course, people with decompensated liver disease, this is a now vanishingly small number of individuals in Australia, the drugs have been available for four years, but they should be managed by specialists as well.

So we have a person who's confirmed hep C virus, RNA positive, and presumably we repeat the test to make sure it's not a false positive. What else do we have to look at or assess before we start treatment?

So just firstly, I don't think you do need to repeat the RNA test. The RNA tests these days are very accurate. And if you've got an RNA positive individual with a history of injecting drug use, you can assume they have chronic hepatitis C and they are a candidate for treatment. And particularly in people who inject drugs, there is a risk of forward transmission of the infection, and so we’re keen to treat those individuals as soon as possible.

The other steps that are important to test for hepatitis B and HIV co-infection, as part of our comprehensive blood-borne virus screen, and to perform a liver fibrosis assessment, which nowadays we would do non-invasively, would be very rare for people to need a liver biopsy for liver fibrosis assessment, and so we now use clinical biomarker algorithms based on simple blood tests, such as the APRI score or the FIB-4 score. And then if you have access to liver FibroScan, which is liver elastography to measure the stiffness of the liver, it's also an excellent tool for assessing liver fibrosis.

And then the last thing to check is there is a potential for drug–drug interactions between hepatitis C medications and other medications. And there is a very useful online tool developed by the University of Liverpool in the United Kingdom, which allows us to check for drug–drug interactions. But that's really it. They're the four key steps: confirm hepatitis C RNA positivity, perform a liver fibrosis assessment to screen for cirrhosis, check for hepatitis B and HIV co-infection, and check for drug–drug interactions. Once you've done those four things, you're good to go.

Looking at the APRI, that's the AST to Platelet Ratio Index test, versus FirbroScan, which of those do we choose, and when. Is that availability?

Yeah, so the APRI is based on the serum AST and the blood platelet count, so this is a score that can be calculated in everyone based on routine blood tests, and so that is the triage score we would recommend GPs use. It's really useful for excluding cirrhosis, so in individuals with a low APRI score, they're very unlikely to have cirrhosis, and the critical threshold is one. So an APRI of <1 is a very good marker for excluding cirrhosis. People with an APRI score of >1 have a higher risk of cirrhosis, but may not have cirrhosis. And so they need a second test. And the most accurate test is FibroScan or liver elastography. The reason we don't recommend that as the first-line tool for everyone is because it's an expensive piece of equipment and there is limited access to the FibroScans in the community. I should also mention Hepascore. That's used extensively in Western Australia, free of charge, and it's a blood test with similar performance characteristics to the APRI score that can be used to screen for liver fibrosis.

Okay. So then we put the patient on 12 weeks of therapy.

So the two first-line treatments are the combination of glecaprevir and pibrentasivr, which is a three-pill, once-a-day regimen for eight weeks' duration, and then the second first-line regimen is a combination of sofosbuvir and velpatasvir, which is a one-pill once-a-day for 12 weeks' regimen. Both have cure rates of greater than 95% in clinical trials, as well as real-world experience. And for people with no cirrhosis, they don't need any monitoring on treatment, we confirm hepatitis C cure by testing for HCV RNA, 12 weeks after treatment. And if the HCV RNA is negative 12 weeks after treatment, then the individual is cured. It's important to appreciate that the hepatitis C antibody tests remain positive. So it's important for clinicians to understand, and also patients to know, that at 12 weeks post-treatment, if the RNA is negative, they are cured, but the hep C antibody test will still remain positive, just reflecting previous exposure.

A very useful brief, but neat summary. Back to the Therapeutic Guidelines now, in terms of hepatitis B, what are your key messages there for GPs?

The key messages are that diagnosis rates are lower than we'd like them in Australia, just as for hepatitis C, there are populations in Australia who have high risk for hepatitis B exposure. For instance, people who were born in South-East Asia have a higher prevalence of hepatitis B. People with ethnicities that have a higher prevalence of hepatitis B should be screened. And so screening and engagement in care is really important. The major reason people with hepatitis B die related to the hepatitis B nowadays is liver cancer. And all people with hepatitis B should be screened for liver cancer once they reach a certain age.

So when you say screening for hepatocellular carcinoma, in practice how's that done?

The most important test is a liver ultrasound every six months. The doubling time of liver cancers when they're present is such that an ultrasound every six months is the appropriate interval, and then serum alpha-fetoprotein is also used in combination with ultrasound. Ultrasound is the most accurate and the most important test to do, but we find serum alpha-fetoprotein, whilst it has false positives and false negatives, provides some useful information.

The first-line treatments for hepatitis B have been available in Australia for more than 10 years. The first-line drugs are entecavir and tenofovir. One important thing that has changed over the last five years or so is our approach to management of hepatitis B in pregnant women to reduce the risk of vertical transmission. We now know that women with a very high hepatitis B viral load should receive tenofovir therapy in the third trimester of pregnancy to drop the viral load and reduce the risk of vertical transmission. Now, all babies still need to receive HBIG and the first dose of the hepatitis B vaccine as soon as possible after delivery, but we know that in women with a high viral load, the addition of tenofovir in the third trimester of pregnancy really prevents vertical transmission when used with HBIG and vaccination.

Moving on to non-alcoholic fatty liver disease. And I must say for me as a GP, I find this a relatively unexciting diagnosis in the sense that the majority of people who have it I would hopefully be treating anyway, looking at causes of obesity, or trying to reduce that central adiposity and reduce cardiovascular risk. It does seem to be, very much, a growing diagnosis over the last, perhaps, ten years or so. How important do you think it is to make this diagnosis in the sense of it changing our management?

Look, you make a really good point that fatty liver disease is now the most common cause of liver disease in Australia and the prevalence in Australian adults is estimated to be in the order of 30%. And the prevalence has dramatically risen with the obesity and the diabetes epidemics. As hepatologists, what we are concerned about is that, even though only a minority of people with fatty liver disease will have significant liver scarring and be at risk of liver cirrhosis and liver-related morbidity, as the prevalence of fatty liver disease increases, that small percentage becomes a very large absolute number of individuals.

So what we're focused on is identifying those people with fatty liver disease who are at risk of liver-related complications, and they're the people who have at least moderate liver fibrosis. So you're exactly right, that the management of fatty liver disease is addressing diabetic control, addressing cardiovascular risk and lifestyle measures to reduce weight. And so our approach to fatty liver disease is to triage patients into those who have at least moderate liver fibrosis, and they should be referred for hepatology care, as opposed to those who have minimal liver fibrosis for whom those lifestyle issues can be managed in primary care.

Okay. So we're really looking at normal high-quality primary care management plus screening to try to pick that percentage who do have fibrosis or more advanced liver problems.

And we use similar tools to those we've discussed in hepatitis C to triage patients for their risk of advanced liver disease. So we use the blood biomarkers again, such as APRI, we use the Hepascore test, and we use liver FibroScan.

So look, we've covered probably the big three, hepatitis B, C, and non-alcoholic fatty liver disease. There are more things, of course, updated in Therapeutic Guidelines. One of them, which we won't have time to discuss in detail, but I do like the fact that there's now a list of incidental liver lesions, because of course we're doing more and more liver ultrasounds, far more than when I started out as a GP and other liver investigations, CTs etc. And we certainly do come up with liver cysts and haemangiomas, benign tumours. So I think it's good for us to have some reference point as to what we do need to worry about and don't need to worry about.

Yeah, I agree. This is a really useful addition to the Therapeutic Guidelines. The other thing that's changed is the resolution and the accuracy of ultrasound and CT scan over the last decade. And so we are seeing a lot more particularly small lesions that previously might not have been diagnosed. This is a source of anxiety for patients and GPs and also an increasing source of referral to hospital. So there's some advice on how to be confident about which lesions need further investigation and referral.

Professor Alex Thompson, thank you so much for your time today. I think that was a short, punchy, and to-the-point update on liver disorders. Thanks for coming on the podcast.

Okay. Thanks for your time, Justin. Thanks for inviting me.

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My guests’ views are their own and don’t represent Australian Prescriber, and my views are certainly all mine.