Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please can you give a brief introduction to alcoholic liver disease and outline the main stages of the condition?
Alcoholic liver disease (ALD) is one of the leading causes of death worldwide and also in the UK. As its name indicates this disease arises due to consuming excessive amounts of alcohol (80 g/day) over an extended period, normally 10-20 years.
There are 3 characteristic stages of ALD. Stage 1- fatty liver disease, where increased amounts of lipids are deposited in the hepatocytes. This arises due to imbalances in the cellular redox state as well as decreased fat oxidation and lipid export. Although only a few days of heavy drinking results in fatty liver, this stages is reversible once alcohol is abstained for a period of 2 weeks.
Stage 2 is called alcoholic hepatitis. This is generally a more serious and potentially severe form of liver disease. At this stage cell death is a prominent feature, infiltration of white blood cells as well as enlarged hepatocytes. Some collagen tissue also becomes deposited around the perivenous region of hepatocytes. Whilst alcoholic hepatitis is reversible those who binge drink at this stage can result in hospitalisation with death in up to 40% of alcoholics
The final stage is cirrhosis which again can take 2 forms, non-compensated (liver functioning) and decompensated (limited liver function). Liver scarring and formation of fibrotic nodules are key features at this stage. If alcoholics do not stop drinking, liver failure can ensue, with a liver transplant the only option.
What are the symptoms of alcoholic liver disease and how many people are thought to be affected?
The symptoms of ALD are quite difficult to identify and are generally non-specific, like feeling unwell. Only after the liver has become severely damaged will symptoms become noticeable. These include, jaundice (yellowing of the skin), muscle weight loss, swelling of the legs/ankles and abdomen, itchy skin, dark stools, confusion.
The number of people admitted to A&E for alcohol related problems was 1.2 million in 2012/13 costing the NHS £2.7 billion and economy £22 billion. The number of deaths attributed to liver disease is approximately 9000, of which alcohol is the main cause; this equates to 16 deaths/day. Liver disease is now the 5th commonest cause of death in the UK.
What is known about the mechanism by which alcohol causes damage to the liver?
Whilst there are key alterations occurring in ALD, the precise mechanisms for disease progression are still not completely understood.
Despite this lipid loading, increased free radical and acetaldehyde production, damaged mitochondria, increased apoptotic and necrotic cell death pathways, altered innate immune response and collagen production are key features.
Deficiencies in particular micronutrients and changes to the gut microbiota are also recent findings.
How much research is currently being carried out to increase our understanding of alcoholic liver disease?
In the UK funding into ALD has been quite limited in comparison to countries such as the USA, Germany and France. Here research is studying all aspects of disease development and progression, alcohol addiction, craving and withdrawal.
However, in the UK, recent research is focussed on developing new treatments for patients with acute alcoholic hepatitis, improved rehabilitation programmes for patients and investigations into genetic susceptibility.
What are the main treatments for alcoholic liver disease and how many patients require liver transplant?
The treatment for ALD depends on the degree of liver damage and state of alcohol dependency. New guidelines provided by EASL (European Association for the Study of the Liver) have suggested the following treatment modalities.
In patients who are alcohol-dependent but do not show severe liver damage then disulfiram, naltrexone and acamprosate can be given to reduce alcohol intake, together with counselling.
For patients with severe liver damage then baclofen is given. In additional nutritional therapy by supplying high protein diets is also suggested.
Patients with ALD and suffering from alcohol withdrawal are recommended benzodiazepines. Patients admitted for severe acute alcoholic hepatitis are given either steroids to reduce the inflammation or pentoxifylline to reduce the pro-inflammatory cytokine levels.
There are varied reports across the world regarding transplantation rates ranging from 20/yr in the UK to 50/year in Japan per institution. Larger cohorts have been studied over greater periods but this may under present the current trends.
Could you please outline the debate over transplantation in patients with alcoholism?
There are many causes whereby patients will require a Liver transplant. Apart from ALD these include non-alcoholic fatty liver disease, hepatitis B or C, primary sclerosing cholangitis, and hepatocellular carcinoma.
Therefore it is important that an alcoholic has actually abstained from alcohol. Current guidelines state that a minimum of 6 months without alcohol consumption is required.
The contentious issue is whether an alcoholic has actually abstained from drinking and whether they will resume drinking after a liver transplant. Blood tests such as liver function tests, GGT (Gamma glutamyltransferase) and %CDT (carbohydrate-deficient transferrin) and newer markers such as ETS (ethyl sulphate) can be used to verify no alcohol has been consumed.
In terms of resuming drinking after a transplant, again the data is not clear, but various studies suggest a recidivism range from 33-50%, which is quite high and approximately 10-15% of these will be heavy drinkers. An important factor affecting the recidivism is the period of abstinence prior to a transplant, i.e. longer the abstinence period the lower the risk of relapsing.
Why have patients with severe alcohol-associated hepatitis (SAAH) historically not been considered for transplants?
Generally it is difficult to identify SAAH patients who require a liver transplant at this stage. Most of the data is based on clinical findings as opposed to biopsy proven ASH, with only a small percentage will have reached decompensated ALD. It is thought that by using a multi-therapy approach of drugs, nutrition and counselling treatment, can assist admitted patients.
Many of these patients are also quite unwell, suffering from bacterial infection and ascites. They remain hospitalised for 3-6 months and are therefore not suitable for an immediate transplant.
Since there is inconsistent treatment practices across the UK implies patient outcomes are variable, adding to the lack of appropriate guidelines to follow.
In addition, alcoholic hepatitis can be reversible at this stage. However, in a small study of SAAH patients who did not respond to therapy, liver transplant was carried out which resulted in improved survival rates.
Could you please outline the pilot scheme that was recently announced in the UK for patients with SAAH? What are your thoughts on this?
The STOPAH (steroids or pentoxifylline for alcoholic hepatitis) trial is an important multi-centre study across the UK, investigating the benefits of steroids (prednisolone) and/or pentoxifylline for SAAH patients. Steroids have shown mixed results whereas studies with pentoxifylline are limited.
It is an important initiative since patients with SAAH have a poor prognosis once admitted to hospital, with mortality rates up to 50% at 28 days. It is the largest UK study treating 1200 patients with either pentoxifylline, steroids, both or placebo and supported with nutritional therapy, with mortality end points of 28 days, 90 days and one year. Patients admitted for SAAH will be given one of the treatments and followed for a year.
What excites you most about the current research into alcoholic liver disease?
Research into ALD has made great strides in terms of improved models for studying ALD that replicate all of the disease stages; and we now have biomarkers that detect recent alcohol consumption. This suggests we’ll have a better understanding of how to treat patients with ALD.
There are still several areas that require more intensive studies, including understanding the development of foetal alcohol syndrome, role of epigenetics, environmental factors, and new drugs to combat alcohol dependency.
What are your future research plans?
We are currently studying the initial stage of ALD, fatty liver since many of the biochemical and molecular alterations occur at this stage; therefore understanding these mechanisms will help us understand how the disease progresses. We are also looking into developing new therapies for SAAH and markers that can predict the degree of liver damage.
Where can readers find more information?
Good sources of information can be obtained from the British Liver Trust, NIAAA, patient.co.uk and for more detailed information, scientific journals such as Hepatology and journal of Hepatology.
The following websites contain useful information,
About Dr Vinood Patel
Dr Vinood B. Patel is currently a Senior Lecturer in Clinical Biochemistry at the University of Westminster and honorary fellow at King’s College London. He presently directs studies on metabolic pathways involved in liver disease, particularly related to mitochondrial energy regulation and cell death.
Research is being undertaken to study the role of nutrients, iron, alcohol and fatty acids in the development of liver disease.
Other areas of interest include development of novel biomarkers, understanding oxidative stress in Alzheimers and gastrointestinal dysfunction in autism.
Dr Patel graduated from the University of Portsmouth with a degree in Pharmacology and completed his PhD in protein metabolism from King’s College London in 1997.
His post-doctoral work was carried out at Wake Forest University Baptist Medical School studying structural-functional alterations to mitochondrial ribosomes, where he developed novel techniques to characterize their biophysical properties.
Dr Patel is a nationally and internationally recognized liver researcher and was involved in several NIH funded biomedical grants related to alcoholic liver disease.
Dr Patel has edited biomedical books in the area of nutrition and health prevention, autism, biomarkers and has published over 150 articles.