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SPECIAL REPORT

Reducing the Recurrence of Episodes of Overt Hepatic Encephalopathy in Adult Patients Reducing the Recurrence of Episodes of Overt Hepatic Encephalopathy in Adult Patients The Liver – An Organ you can Damage Without Knowing it The Alphabetical Viruses That Damage the Liver (ABCDE) Fat Infiltration of the Liver and How it Can Cause Liver Damage with Secondary Damage to the Brain Brain Damage Caused by Liver Damage – the How and Why of Hepatic Encephalopathy

Norgine Pharmaceuticals Ltd have provided financial support by way of sponsorship for the production and distribution of this report. Norgine Pharmaceuticals Ltd had no editorial input into the content of the report other than a review for medical accuracy.

Published by Global Business Media


NICE has published Technology Appraisal Guidance TA337 for Rifaximin.1 Section 1.1; Rifaximin is recommended, within its marketing authorisation, as an option for reducing the recurrence of episodes of overt hepatic encephalopathy in people aged 18 years or older.1

TARGAXAN 550 mg film-coated tablets. REFER TO FULL SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) BEFORE PRESCRIBING Presentation: Film-coated tablet containing rifaximin 550 mg. Uses: Targaxan is indicated for the reduction in recurrence of episodes of overt hepatic encephalopathy in patients m 18 years of age. Dosage and administration: Adults 18 years of age and over: 550 mg twice daily, with a glass of water, with or without food for up to 6 months. Treatment beyond 6 months should be based on risk benefit balance including those associated with the progression of the patients hepatic dysfunction. No dosage changes are necessary in the elderly or those with hepatic insufficiency. Use with caution in patients with renal impairment. Contraindications: Contraindicated in hypersensitivity to rifaximin, rifamycin-derivatives or to any of the excipients and in cases of intestinal obstruction. Warnings and precautions for use: The potential association of rifaximin treatment with Clostridium difficile associated diarrhoea and pseudomembranous colitis cannot be ruled out. The administration of rifaximin with other rifamycins is not recommended.Rifaximin may cause a reddish discolouration of the urine. Use with caution in patients with severe (Child-Pugh C) hepatic impairment and in patients with MELD (Model for End-Stage Liver Disease)

score > 25. In hepatic impaired patients, rifaximin may decrease the exposure of concomitantly administered CYP3A4 substrates (e.g. warfarin, antiepileptics, antiarrhythmics, oral contraceptives). Ciclosporin may increase the rifaximin Cmax. Pregnancy and lactation: Rifaximin is not recommended during pregnancy. The benefits of rifaximin treatment should be assessed against the need to continue breastfeeding. Side effects: Common effects reported in clinical trials are dizziness, headache, depression, dyspnoea, upper abdominal pain, abdominal distension, diarrhoea, nausea, vomiting, ascites, rashes, pruritus, muscle spasms, arthralgia and peripheral oedema. Other effects that have been reported include: Clostridial infections, urinary tract infections, candidiasis, pneumonia cellulitis, upper respiratory tract infection and rhinitis. Blood disorders (e.g. anaemia, thrombocytopenia). Anaphylactic reactions, angioedemas, hypersensitivity. Anorexia, hyperkalaemia and dehydration. Confusion, sleep disorders, balance disorders, convulsions, hypoesthesia, memory impairment and attention disorders. Hypotension, hypertension and fainting. Hot flushes. Breathing difficulty, pleural effusion, COPD. Gastrointestinal disorders and skin reactions. Liver function test abnormalities. Dysuria, pollakiuria and proteinuria. Oedema. Pyrexia. INR abnormalities. Licensing and legal category: Legal category: POM. Cost: Basic NHS price ÂŁ259.23 for 56 tablets. MA number: PL 20011/0020.

For further information contact: Norgine Pharmaceuticals Limited, Norgine House, Moorhall Road, Harefield, Middlesex, UB9 6NS. Telephone: +44(0)1895 826606 E-mail: medinfo@norgine.com Ref: UK/XIF5/1215/0159 Date of preparation: Dec 2015 Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Medical Information at Norgine Pharmaceuticals Ltd on 01895 826606 Reference: 1. Available from: http://www.nice.org.uk/guidance/ta337 [Accessed January 2016]. Product under licence from Alfa Wassermann S.p.A. TARGAXAN is a registered trademark of the Alfa Wassermann group of companies, licensed to the Norgine group of companies. NORGINE and the sail logo are registered trademarks of the Norgine group of companies. UK/XIF5/0116/0160. Date of preparation: January 2016.


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

SPECIAL REPORT

Reducing the Recurrence of Episodes of Overt Hepatic Encephalopathy in Adult Patients Reducing the Recurrence of Episodes of Overt Hepatic Encephalopathy in Adult Patients

Contents

The Liver – An Organ you can Damage Without Knowing it The Alphabetical Viruses That Damage the Liver (ABCDE) Fat Infiltration of the Liver and How it Can Cause Liver Damage with Secondary Damage to the Brain Brain Damage Caused by Liver Damage – the How and Why of Hepatic Encephalopathy

Foreword

2

Dr Charles Easmon, Editor

Reducing the Recurrence of Episodes of Overt Hepatic Encephalopathy in Adult Patients

3

Dr Charles Easmon, Editor Published by Global Business Media

Published by Global Business Media Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org Publisher Kevin Bell Business Development Director Marie-Anne Brooks Editor Dr Charles Easmon Senior Project Manager Steve Banks Advertising Executives Michael McCarthy Abigail Coombes Production Manager Paul Davies For further information visit: www.globalbusinessmedia.org

The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated. Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor. While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles. © 2015. The entire contents of this publication are protected by copyright. Full details are available from the Publishers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical photocopying, recording or otherwise, without the prior permission of the copyright owner.

The Liver – An Organ you can Damage Without Knowing it

7

Dr Charles Easmon, Editor

The Alphabetical Viruses That Damage the Liver (ABCDE)

9

Jane Lucien, Medical Correspondent

Fat Infiltration of the Liver and How it Can Cause Liver Damage with Secondary Damage to the Brain

11

Dr Charles Easmon

Brain Damage Caused by Liver Damage – the How and Why of Hepatic Encephalopathy Jane Lucien, Medical Correspondent

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SPECIAL REPORT: TELEPHONY ACCESS AND AUTO BOOKING SOLUTIONS

Foreword T

HE LIVER is a vital but hidden organ. It is under

Liver expert Professor Roger Williams and team

assault from alcohol, obesity and viruses.

note that ‘Most liver services in the UK are provided

Mortality rates for liver disease have increased 400%

by gastroenterologists who may have as little as

since 1970 – mainly due to alcohol consumption. The

6 months training in liver disease, and by general

number of people admitted to hospital for alcohol-

physicians who have had no specialised liver training’.

related liver disease has almost doubled during the past decade. It is estimated that alcohol costs the English economy over £20 billion a year included in which is more than £2 billion of health care costs.

Even if we treated everyone with viral hepatitis today we still have large legacy of unknown and under managed cases. More are developing and some are coming from less developed nations. The brain is a complex organ protected by the skull

Being dependent on alcohol and using it harmfully

and a blood-brain barrier that acts as a gateway to

is associated with increased risk of physical and

stop noxious substances getting to the brain. The

mental health problems including liver disease,

healthy liver ensures that the blood-brain barrier is not

other gut problems, neurological and cardiovascular

overexposed to ammonia compounds but once the

disease, depression and anxiety disorders and

liver fails these compounds overwhelm the brain and

ultimately, premature death. It is estimated that 1 in 4

hence lead to encephalopathy. The brain is damaged

people aged between 16 and 65 in England consume

by the 3-pronged assault of alcohol, obesity and

alcohol in a way that is potentially or actually harmful

viruses on the liver.

to their health or well-being. Depending on the

We must identify cases of liver damage as early as

diagnostic criteria used, alcohol dependence

possible, stop liver damage where we can and where,

affects between 3% and 6% of people.

we cannot stop it, mitigate its effects with medications

Alcohol misuse is also an increasing problem

like rifaximin to reduce hepatic encephalopathy.

in children and young people, with over 24,000

Liver disease is something we can do something

treated in the NHS for alcohol-related problems in

about by drinking less alcohol, eating healthier and

2008 and 2009.

testing for and monitoring viral diseases.

Around 25% of the UK population are obese and many of these people also have non-alcohol fatty liver disease. There is a ’silent epidemic’ of both hepatitis B and C viral liver infections leading to liver damage.

Dr Charles Easmon Editor

Dr Charles Easmon is a medical doctor with 30 years’ experience in the public and private sectors. After qualifying as a physician, he developed his interests in occupational medicine, public health and travel diseases. His interest in liver disease is from both the public health point of view as recommended by the Hepatitis C Trust/The Lancet Commission on Liver Disease and the occupational health point of view.

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REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

Reducing the Recurrence of Episodes of Overt Hepatic Encephalopathy in Adult Patients Dr Charles Easmon, Editor

Introduction Liver disease is one of the big 5 killers in the Western world and worldwide is a major cause of death, disease and disability1. Whilst four of the big five (Stroke/Cancer/Lung/Heart Diseases) have seen declines, liver disease is the only one on the increase. Mortality rates for liver disease have increased 400% since 1970 – mainly due to alcohol consumption, and the number of people admitted to hospital for alcohol-related liver disease has almost doubled during the past decade. Around 25% of the UK population are obese and many of these people also have non-alcohol fatty liver disease. Britain has been called the Fat man2 (& Woman) of Europe. We have a major Public Health problem. Latest research shows that it is better not to get fat in the first place as the chances of reducing weight to normal, long term, are low. Sadly, we have a rising population of obese children. The list of unhealthy foods is increasing but we are all aware of the need to avoid excess sugar, saturated fats, ready meals etc. We are also all aware of the need for more regular aerobic exercise, but many make excuses to do as little as possible. We are aware of cardiac risk increasing with waist size but we must also remember

that every inch on the waistband represents more fat infiltration of the liver, and it is not just about clogged arteries. The UK has significant numbers of people infected with chronic viral hepatitis (B and C). The liver is an easy organ to damage without knowing that it has been damaged until too late. Viral infections, fat infiltration (obesity) and alcohol are amongst the main causes of liver damage and all have some aspects of preventability or harm reduction. Sadly, a lot of those with liver damage are not aware until too late and at this stage they are at severe risk of recurrent brain damage caused by hepatic encephalopathy as the liver’s ‘gateway’ protection system fails. Targaxan (Rifaximin-α) is a scientifically proven effective preventative to hepatic encephalopathy reducing recurrence of episodes of overt HE and hospital admissions in a cost effective manner.

The liver is an easy organ to damage without knowing that it has been damaged until too late. Viral infections, fat infiltration (obesity) and alcohol are amongst the main causes of liver damage

The Impact of Encephalopathy Hospital bed fees vary across the country but are in the hundreds of pounds. Anything that can reduce hospital admissions has real value, especially if, during those admissions, extensive supportive care is required for someone with hepatic encephalopathy, who may be confused and unable to care for themselves. Those who WWW.PRIMARYCAREREPORTS.CO.UK | 3


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

Anything that can reduce hospital admissions has real value, especially if, during those admissions, extensive supportive care is required for someone with hepatic encephalopathy, who may be confused and unable to care for themselves

are not admitted, disrupt their own lives and those of their families. The societal cost of hepatic encephalopathy is hard to measure but can be assumed to be very high.

Clinical Evidence in Support of the Use of Oral Targaxan (Rifaximin-α) to Prevent Hepatic Encephalopathy The key effectiveness study is Bass NM et al3, which examined the efficacy of rifaximin in preventing hepatic encephalopathy (HE) in patients with chronic liver disease. The study was a randomised, double blind, placebo controlled trial, comprising 299 patients who were in remission from recurrent HE due to chronic liver disease. Over a period of 6 months, 140 patients received rifaximin (550 mg, twice daily) and 159 patients received placebo. The key findings were summarised as follows: • Compared with placebo, rifaximin significantly reduced the risk of recurrent HE • Breakthrough HE episodes occurred in 22.1% of patients receiving rifaximin group compared with 45.9% of patients receiving placebo + lactulose • Rifaximin treatment was associated with a 58% relative reduction in risk of breakthrough HE compared with placebo + lactulose • In total, 13.6% of patients receiving rifaximin were hospitalised due to HE compared with 22.6% of patients receiving placebo + lactulose • The incidence of adverse events and serious adverse events was similar in the rifaximin and placebo groups The National Institute for Health and Care Excellence (NICE) March 2015 guidelines 4 4 | WWW.PRIMARYCAREREPORTS.CO.UK

endorse Rifaximin for reducing the recurrence of episodes of overt hepatic encephalopathy in people aged 18 years or older. In 2014 the Lancet published a commissioned report led by the world-renowned liver expert Professor Roger Williams 5 addressing liver disease in the UK. It was subtitled – ‘a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues in excess consumption of alcohol, obesity and viral hepatitis’. The report highlights liver disease as a national priority. The Welsh government has developed and published its Liver Disease Delivery plan6, which includes the use of Targaxan (Rifaximin-α). The Scottish Medical Consortium, which advises NHS Scotland7, led to the acceptance by NHS Scotland of Rifaximin for reducing the recurrence of episodes of overt hepatic encephalopathy in people aged 18 years or older.

Drug Safety In 2014, Mullen et al8, examined the safety and hospitalisation rate in hepatic encephalopathy (HE) patients receiving long-term rifaximin therapy. The study concluded that long-term treatment with rifaximin (550 mg, twice daily) provides a sustained reduction in overall rate of hospitalisation, including HE-related hospitalisations, without increased risk of adverse events. The median exposure to rifaximin in this study was 427 days.

Rifaximin Use in Primary Care and Shared Care The Lancet Commission report highlights a shortage of liver expertise across the UK and makes suggestions for how this situation can


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

be improved. In the interim, liver disease patients should ideally be diagnosed by a specialist and subsequent care shared with their General Practitioner (GP) following standard quality guidelines. In 2014 Preedy et al9, concluded that ‘Rifaximin is an effective maintenance therapy for HE patients with chronic liver disease, treated in a secondary care environment. Rifaximin treatment is associated with fewer HE-related hospital admissions and a reduction in total number of hospital bed days leading to potential healthcare savings’. GP’s should always feel comfortable in any prescribing and benefit from knowing if the therapy is cost-effective and has a low range of adverse effects. Targaxan (Rifaximin-α) is cost effective and its adverse effects profile is very similar to placebo.

Reduced Hospital Admissions and Improved Quality of Life In 2012 Valliani T et al10, showed a single centre experience of using rifaximin and concluded that over a 6 or 12 month period, rifaximin treatment reduced the number of HE-related hospital admissions per patient and the total length of stay (LOS) for each admission. In 2014 Goel A11 et al, concluded that ‘Rifaximin treatment in patients with HE, due to chronic liver disease, is associated with a significant reduction in hospital admissions and hospital bed day occupancy within a district general hospital setting, leading to major cost savings and improved clinical outcomes’ In 2013 Roach J et al12, showed that rifaximin treatment significantly reduces hospital admission rates in HE patients and was associated with a significant decrease in the length of hospital stay required for HE patients. This reduction in the number and length of hospital admissions was surmised to also be associated with increased quality of life due to reduced burden for patients and their families. In the same year Orr J, Perez F et al13, concluded that ‘Rifaximin treatment for secondary prevention of HE is cost-effective due to the overall reduction in number and length of emergency admissions associated with this approach to HE therapy’.

glass of water) as regular maintenance therapy for 6 months. As with many drugs, caution is advised in those with renal impairment. Avoid prescribing in those with hypersensitivity to rifaximin, rifamycin-derivatives or to any of the excipients and in cases of intestinal obstruction. Avoid prescribing in known cases of Clostridium difficile associated diarrhoea and pseudomembranous colitis. The liver specialist should ensure caution in patients with severe (Child-Pugh C) hepatic impairment and in patients with MELD (Model for End-Stage Liver Disease) score > 25.

If a patient is on oral oestrogenic contraceptives, it is recommended to take additional contraceptive precautions

Known Targaxan (Rifaximin-α) Side Effects Common effects reported in clinical trials are dizziness, headache, depression, dyspnoea, upper abdominal pain, abdominal distension, diarrhoea, nausea, vomiting, ascites, rashes, pruritus, muscle spasms, arthralgia and peripheral oedema. Other effects that have been reported include: Clostridial infections, urinary tract infections, candidiasis and pneumonia. Blood disorders e.g. anaemia, thrombocytopenia. Anaphylactic reactions, angioedemas, hypersensitivity. Hypo and hypertension. Pyrexia. Liver function abnormalities.

Non-Drug Approaches to Reducing Liver Damage Targaxan (Rifaximin-α) is now known as an effective therapy once the liver is damaged but we must also try to prevent this damage in the first place.

Public Health The British Medical Association14 (BMA) is advocating minimum pricing on alcohol especially to take the cheapest drinks off the market. There is a voluntary agreement with drink manufactures to encourage responsible drinking, but it can be argued that more needs to be done to change a dominant ‘drinking culture’. Many of our young enjoy binge-drinking on nights out and our colleges/universities often have a very ‘pro-drink’ culture. How to manage these issues is open to debate.

Prescribing Targaxan

Occupational Health

This is not a drug for children, pregnant or breastfeeding women. If a patient is on oral oestrogenic contraceptives, it is recommended to take additional contraceptive precautions, in particular if the oestrogen content of oral contraceptives is less than 50 µg. In those aged 18 or over the recommended dosage is two 550mg tablets per day (with a

Some work cultures are very ‘pro-drink’ and it can be hard to seem the odd one out by turning drinks down. Our military have a significant problem in civilian life but the problem often started whilst they were serving since, anecdotally, many soldiers say they are told to drink to ‘de-stress’ during their rest and recreation periods. WWW.PRIMARYCAREREPORTS.CO.UK | 5


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

Companies can encourage healthier eating. One excellent example is a Chief Medical Officer who ensured that all food in the canteen had traffic lights (red for the least healthy foods and green for the healthiest)

Some at risk of needle stick injuries (Hepatitis B) or bites find it hard to get a course of Hepatitis B vaccine and the pathways for this for police officers, care workers and others at risk should be improved as soon as possible. Companies can encourage healthier eating. One excellent example is a Chief Medical Officer who ensured that all food in the canteen had traffic lights (red for the least healthy foods and green for the healthiest). Many companies now encourage exercise schemes and find that allowing staff to compete amongst themselves or other companies can increase motivation to exercise and lose weight.

Summary Targaxan (Rifaximin-α) is a safe, cost-effective means of reducing hospital admissions and improving quality of life in the increasing number of UK adults with liver damage. At a cost of under £4,000 per patient per year it can save the NHS more than £20,000 per year. We need strategies like those of NHS Scotland to prevent liver damage occurring in the first place.

Personal Habits and Behaviours More of us need to exercise and lose weight. Too many drink alcohol routinely, without consideration to the units per week recommended levels, or having drink free’ days as recommended by the BMA. More can and should be encouraged to be test for Hepatitis B and C.

References: 1

http://www.bbc.co.uk/news/health-21667065 accessed 6/8/15

2

http://www.nhs.uk/livewell/loseweight/pages/statistics-and-causes-of-the-obesity-epidemic-in-the-uk.aspx accessed 6/8/15

3

Bass NM et al. N Engl J Med 2010; 362:1071-81

4

https://www.nice.org.uk/guidance/ta337 accessed 6/8/15

5

Williams R et al. Lancet. 2014 Nov 29;384(9958):1953-97

6

Liver Disease Delivery Plan, Editorial Team: Hugo van Woerden & Jane Salmon, Public Health Wales, and Andrew Yeoman on behalf of WAGE: Consultation Version. Journal / Citation Available from: http://wales.gov.uk/docs/dhss/consultation/141111liveren.pdf [accessed 6/8/15]

7

Scottish Medical Consortium. Advice regarding rifaximin 550mg film-coated tablets (TARGAXAN®). 2013. SMC No. (893/13). Available from: http://www.scottishmedicines.org.uk/SMC_Advice/Advice/893_13_rifaximin_Targaxan/rifaximin_Targaxan

8

Mullen et al. Clin Gastroenterol Hepatol 2014 Aug; 12(8): 1390-7

9

Preedy et al. Poster presentation. BASL Annual Meeting

10

Valliani T et al. Dr Falk Symposium, Germany. 2012. Abstract 81

11

Goel A et al. Gut 2014;63:A179-A180

12

Roach J et al. Falk Symposium: Liver Diseases in 2013: Advances in Pathogenesis and Treatment. 2013. Abstract 73

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13

Orr J et al. British Society of Gastroenterology Annual Conference. Poster presentation 2013

14

http://bma.org.uk/alcohol accessed 6/8/15


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

The Liver – An Organ you can Damage Without Knowing it Dr Charles Easmon, Editor

I

F YOU hit your head 10 times hard against a brick wall you would be aware of the damage you were causing, in fact you would stop before the 10th hit. This is because it is clear that you will harm yourself. However, the liver is a hidden organ that you can silently damage and not be aware of doing so for years until it is too late and you have either clear signs of liver disease or damage to a second organ because of it (the brain). Legendary footballer, George Best, managed to damage 2 livers, his own and the one donated. He illustrated the main cause of much Western liver damage, which is alcohol. We can quietly and consistently damage our liver without any apparent effect until it becomes scarred and we now show the evidence of the diseased organ which, by the way, can no longer process alcohol and so people at the scarred liver (cirrhosis) stage get drunk very easily after that!

What is the Liver and What Does it do? The liver sits under our right side rib cage (very rarely it is on the other side alongside a right sided heart). It is the largest gland and the largest solid organ in the normal body. It weighs between 1-3-1.8 kg. It has 2 parts or lobes (right and left). At any one time it holds over 10% of all the blood in the body. It has been estimated to have over 500 functions. It receives blood from our gastrointestinal tract and is connected to our gall bladder. It has impressive regenerative features. It breaks down food and coverts it to energy. It also detoxifies a lot of things before they return to the main blood stream. When healthy, it does all its many functions very efficiently. When damaged, it is as if toxins can bypass this filtration system and then cause damage to the brain. Damage starts with a reduction of effective liver cells and their replacement by scarred tissue (cirrhosis) – an increase in fibrous tissue or fat infiltration.

The liver is a hidden organ that you can silently damage and not be aware of doing so for years until it is too late

How Much Alcohol does it Take For Man/Woman, Transgender Person or Child to Damage their Liver? It seems that size matters, hence the Institute for Alcohol Studies1 advises lower limits for women than men. The current maximum guidance for men is 21 units per week and 14 for women, with a low daily maximum and advice to have drink-free days. This is not a target but a sensible estimate of the upper limit before we would expect any significant harm. Drinking habits matter so, although in France it may be quite normal for children to enjoy a glass of wine at the table with their parents, the quantity is moderate and controlled unlike that with binge drinking teens in the UK. Alcohol units are as follows. 1 unit = a small glass of wine, half a pint, a single measure of a spirit such as whisky.

Alcohol Our National Vice It is estimated that alcohol costs the English economy over £20 billion annually included in which is more than £2 billion of health care costs. WWW.PRIMARYCAREREPORTS.CO.UK | 7


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

It is estimated that 1 in 4 people aged between 16 and 65 in England consume alcohol in a way that is potentially or actually harmful to their health or well-being

Being dependent on alcohol and using it harmfully is associated with increased risk of physical and mental health problems including liver disease, other gut problems, neurological and cardiovascular disease, depression and anxiety disorders and ultimately, premature death. It is estimated that 1 in 4 people aged between 16 and 65 in England consume alcohol in a way that is potentially or actually harmful to their health or well-being. Depending on the diagnostic criteria used, alcohol dependence affects between 3% and 6% of people2. Alcohol misuse is also an increasing problem in children and young people, with over 24,000 treated in the NHS for alcoholrelated problems in 2008 and 2009.

Why Prohibition Doesn’t Work but Pricing out Cheap Alcohol Might The Americans tried banning alcohol for 13 years (Prohibition) but this just led to a boost in the gangster economy and a rise in toxic substances mixed in with illegal alcohol. It seems that overall levels of drinking stayed the same or increased. However, the British Medical Association believes that minimum pricing on alcohol3 will deter youngsters and the more desperate end of the market from accessing alcohol that is too cheap.

Why Does Liver Damage Matter? The Big 5 Killers In the Western world there are 5 main killers. Most people are aware of cancer, heart disease, stroke and lung disease but sadly few realise that the 5th is liver disease. We can do something about liver disease by drinking

less alcohol, eating healthier and testing for and monitoring viral diseases.

How Does a Damaged Liver Cause Problems to a Second Organ – The Brain? The brain is a complex organ protected by the skull and a blood-brain barrier that acts as a gateway to stop noxious substances getting to the brain. The healthy liver ensures that the bloodbrain barrier is not overexposed to ammonia compounds, but once the liver fails these compounds overwhelm the brain and hence lead to encephalopathy.

Is There Anything That Can Reduce The Risks of This Secondary Brain Damage? Rifaximin is thought to act by preventing the build up of ammonia by bacteria and hence reduces encephalopathy4.

What Are the Benefits of Rifaximin to the Individual and to Society? The societal cost of people with liver damage having a clear head and not suffering from encephalopathy is almost incalculable. The hospital savings are substantial and all at a cost per person per year of less than £4,0005.

Conclusions As a society we need to tackle alcohol abuse, obesity and viral diseases of the liver more robustly, but until we do there will be many more cases of liver failure and, in these, many more cases of encephalopathy that can be stopped or the cost reduced effectively by Rifaximin.

References:

8 | WWW.PRIMARYCAREREPORTS.CO.UK

1

http://tiny.cc/vovh3x accessed 6/8/15

2

http://www.nice.org.uk/guidance/qs11/chapter/Introduction-and-overview accessed 6/8/15

3

http://bma.org.uk/alcohol accessed 6/8/15

4

http://www.nice.org.uk/guidance/ta337/evidence accessed 6/8/15

5

Orr J et al. British Society of Gastroenterology Annual Conference. Poster presentation 2013


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

The Alphabetical Viruses That Damage the Liver (ABCDE) Jane Lucien, Medical Correspondent

S

O FAR we know of 5 main viral causes of liver inflammation. These 5 are known alphabetically as ABCDE. Two (A & E) are transmitted by dirty food and/or dirty water ingestion (‘Muck to mouth’) transmission. Two (B & C) are transmitted by blood and/or mucous fluids. These two can also be transmitted from mother to child at birth with a ticking time bomb effect over the next 20-30 years. The worst time to acquire hepatitis B infection is as a newborn baby because the chance of chronic infection is as high as 85% compared with 4% in adult infection1. Many Hepatitis B & C infections occur from unchecked blood transfusions, unsterile needles, unsterile tattoos, sexual intercourse or drug use which includes injection but also snorting cocaine because if the same straw is used by more than one person the virus can be transmitted via the mucous membranes. One (D) is technically a co-infection and only occurs in those already infected with Hepatitis B. It is important to identify and separately treat it as it makes the liver damage worse.

Why is Liver Damage More Likely With B & C Than A & E? Hepatitis A and Hepatitis E can be serious diseases causing deaths or prolonged illnesses (up to 6 months). E is particularly deadly to pregnant women and their fetuses2. Both can cause an acute liver failure but, fortunately, this is relatively rare and neither lingers for more than a few months. Hepatitis B & C are different in that they are the ‘silent epidemic’3 staying in the liver for years and over time leading to a percentage of liver failure and later to liver cancer. 20 years of infection can lead to damage or cancer so children affected in developing nations are dying in their 20s and 30s from these problems.

Without appropriate treatment or monitoring, 1 in 4 people with chronic Hepatitis B infection will die of liver cancer, cirrhosis or liver failure. One third of the world’s chronic Hepatitis B carriers live in China and it has the greatest burden of Hepatitis B and liver cancer.

Which Liver Viruses Can We Vaccinate Against? Currently, we can only vaccinate against two of the five. Hepatitis A requires two vaccines within a 3-5 year period for protection that probably lasts beyond 20 years. Hepatitis B requires 3 initial vaccines in a fast or slow regime. If the fast regime is used, an extra dose is required at 12 months and boosters after 5-10 years. The World Health Organisation (WHO) has described Hepatitis B as the 1st anti-cancer vaccine4. Many developing nations now include Hepatitis B vaccine as part of their childhood schedule. Advocates have suggested that the UK should do the same but so far our regulatory authorities have avoided taking this action routinely5. All medical staff exposed to exposure prone procedures are advised to have Hepatitis B vaccination for their own protection and for that of their patients. UK medical students are now tested for Hepatitis C infection6.

Without appropriate treatment or monitoring, 1 in 4 people with chronic Hepatitis B infection will die of liver cancer, cirrhosis or liver failure

What Liver Viruses Can We Treat? A & E are short-lived viral infections and generally do not need antiviral treatment, but just supportive therapies depending on the severity of the illness. We can now cure Hepatitis C and some people believe that we could actually eliminate it by 2030. Current thought is that Hepatitis B cannot be cured but can be managed. The problem is identifying the cases and patients putting up WWW.PRIMARYCAREREPORTS.CO.UK | 9


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

We must identify cases as early as possible, stop liver damage where we can and, where we cannot stop it, mitigate its effects with medications like Rifaximin to reduce hepatic encephalopathy

with prolonged medicine that has uncomfortable side effects. Antibiotics for bacteria have been used since the accidental discovery of Penicillin by Alexander Fleming. Drugs for viruses are in their relative infancy. Hepatitis C has different serotypes and the biggest change is to treat with drugs that stop viral replication, which can cure over 90% in 12 weeks. However, this treatment is expensive and not readily available on the NHS. 2 new oral drugs, Simeprevir & Sofosbuvir, stop the Hepatitis C virus replicating. When combined with the other recommended drugs, a treatment course costs between £27-70,0007. Other treatments include interferons and Ribavarin. Commonly reported adverse drug effects with these treatments include rash, itching, nausea, constipation, shortness of breath, photosensitivity and raised bilirubin. Hepatitis B also has different serotypes

How Common are B & C in the UK? Not enough people are tested to give us an accurate answer. WHO estimates that worldwide there are 400 million living with viral hepatitis, a liver disease that Imperial College estimates kills more people than malaria, Tuberculosis (TB) or HIV8. In the UK, estimates of those chronically infected with Hepatitis B range from 180,000 to 325,000 and most new cases are thought to occur in migrants who acquire their infection as children in their country of origin. Public Health England estimated that the UK had 214,000 Hepatitis C infections in 20149 but the Hepatitis C Trust notes that less than 50% of those infected are tested10.

Should More People Be Tested For Hepatitis Viruses? The answer is a definite ‘yes’ and both the Hepatitis C Trust and the British Liver Trust11 are keen advocates of this. Currently Scotland seems to be more advanced in its approach to viral Hepatitis management than England12.

The Ethical Choices of Expensive Treatment in a Cash Strapped Health Service Treating Hepatitis C alone with a curative drug would cost the National Health Service (NHS) more than £100 million13 but this pales compared to the lifetime cost of managing those with chronic liver diseases and liver cancer.

Lessons from Abroad Other countries have included routine childhood Hepatitis B vaccine into their schedule. Spain has decided to manage Hepatitis C cases with curative treatments14.

Will we find an F, G etc? The odds are that there are other viruses that affect the liver that we have not indentified yet and we could presume that the alphabetical tradition will persist.

The Way Forward Even if we treated, everyone with viral hepatitis today, we still have large legacy of unknown and under managed cases. More are developing and some are coming from less developed nations. We must identify cases as early as possible, stop liver damage where we can and, where we cannot stop it, mitigate its effects with medications like Rifaximin to reduce hepatic encephalopathy.

References: 1 2 3 4 5 6

7 8

9 10 11 12

13 14

10 | WWW.PRIMARYCAREREPORTS.CO.UK

http://tiny.cc/u2xj3x accessed 6/8/15 http://www.who.int/mediacentre/factsheets/fs280/en/ accessed 6/8/15 http://www.hepctrust.org.uk/about-hepatitis-c accessed 6/8/15 http://www.who.int/bulletin/volumes/88/1/08-065722/en/ accessed 6/8/15 http://www.ovg.ox.ac.uk/hepatitis-b-vaccine accessed 6/8/15 https://www.gov.uk/government/publications/new-healthcare-workers-clearance-for-hepatitis-b-and-c-tb-hiv accessed 6/8/15 http://tiny.cc/t4xj3x accessed 6/8/15 http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_5-5-2015-17-20-46 accessed 6/8/15 https://www.gov.uk/government/publications/hepatitis-c-in-the-uk accessed 6/8/15 http://www.hepctrust.org.uk/how-you-can-help-us accessed 6/8/15 http://www.britishlivertrust.org.uk/world-hepatitis-day-2015/ Accessed 6/8/15 http://www.scotpho.org.uk/health-wellbeing-and-disease/chronic-liver-disease/policy-context accessed 6/8/15 http://www.england.nhs.uk/2015/06/10/patients-hep-c/ accessed 6/8/15 Treatment guidelines for Hepatitis C in Spain Crespo-Casal, M; NLM. Revista española de sanidad penitenciaria17.2 (Oct 2015): 37-47


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

Fat Infiltration of the Liver and How it Can Cause Liver Damage with Secondary Damage to the Brain Dr Charles Easmon

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of conditions characterised by excess fat in the liver in the absence of alcohol consumption

Human Stuffed Livers Many people are upset about a practice that involves force-feeding ducks so that their liver gets stuffed with fat to produce the delicacy ‘foie gras’. Humans can stuff their livers with fat voluntarily or by much rarer accidents of genetics. Elvis Presley at his autopsy had a liver twice the normal size and most of the extra weight was caused by fat. Fat infiltration of the liver makes the liver less good at getting rid of toxins. In many cases it appears to be harmless but in some it leads to more severe liver disease and it can lead to brain damage from liver encephalopathy. Fat without inflammation and damage to the liver is known as ‘fatty liver’.

Liver Damage in the Non-Drinker Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of conditions characterised by excess fat in the liver in the absence of alcohol consumption1. Two main histological patterns of NAFLD are described: fatty liver alone and the condition caused by fat infiltration of the liver with inflammation and damage is known as NonAlcoholic SteatoHepatitis or NASH. What the name explains is that alcohol is not

the cause of the liver inflammation but that it is caused by fat infiltration. Many a doctor has done liver tests on a patient, which on return were abnormal, and the patient has become upset when the doctor has insisted that excessive drinking must have caused these results! Abnormal liver tests may be the first and only sign of this condition. Patients with NASH will often be overweight and have unhealthy eating habits. The advice is to lose weight, eat less fat, do more exercise, avoid alcohol and unnecessary medications and, over time, the monitored blood tests should improve to normal. NASH can occur in children. Our rising obesity epidemic in children is of major public health concern. To diagnose NASH and differentiate it from fatty liver, a biopsy is ideally required. But biopsies carry a risk of complications such as excessive bleeding, secondary infection and, very rarely, death. NASH affects 2-5% of Americans 2. The percentage in the UK is not known but if NAFLD is seen as a progression risk to NASH, the estimate of 1 in 5 people in the UK with the early stages of NAFLD is of great concern3. WWW.PRIMARYCAREREPORTS.CO.UK | 11


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

Latest research shows that it is better not to get fat in the first place as the chances of reducing weight to normal long term are low

Obesity and Liver Damage Britain has been called the fat man (and woman) of Europe. We have a major Public Health problem. Latest research shows that it is better not to get fat in the first place as the chances of reducing weight to normal long term are low. Sadly, we have a rising population of obese children. The list of unhealthy foods is increasing but we are all aware of the need to avoid excess sugar, saturated fats, ready meals etc. We are also all aware of the need for more regular aerobic exercise, but many make excuses to do as little as possible. We are aware of cardiac risk increasing with waist size, but we must also remember that every inch on the waistband represents more fat infiltration of the liver and it is not just about clogged arteries.

Public Health Prevention of NASH There is controversy over the possible introduction of a fat tax or a sugar tax. However, it can be shown that increasing prices of unhealthy products decreases consumption and has net societal benefit. In his book “Fast Food Nation”, Eric Schlosser4 shows the corrupt genius of those who increased consumption of unhealthy foods and drinks in the USA and we now know the price the USA is paying for that. Manufactures in the UK have also been smart with ‘Naughty but Nice’ type campaigns. Researchers such as Richard Thaler and colleagues in books like ‘Nudge’5 explain that choice architecture affects the choices people make. If healthier foods and drinks are accessible they will be chosen if positioned in the right places. In poorer areas of the UK, it is actually hard to find healthy food and, sadly, it is much more expensive than cheaper foods.

Current and Future Alternatives to Liver Biopsies The complications of liver biopsy are not insignificant and the costs are high as they have to be done in a hospital setting with provision for emergency should something go wrong. Because liver biopsy involves a small part of the liver it can be inaccurate if the wrong part of the liver is biopsied or if the operator is inexperienced. A less invasive approach to diagnose NASH or liver damage would be incredibly useful and potentially cost-effective. Scans with a technique similar to ultrasound6 can be used to measure hardness of the liver since a normal liver is soft and supple. These require no anaesthetic, have no side effects and take just 15 minutes.Blood biomarkers7 have also been shown to give reasonable accuracy for assessing degrees of liver damage.

Are All Fats Bad? Humans need some fat for insulation and energy. However, we now know that there are types of fat that are not good for us and many of these are not ‘natural’ to us. The biggest risk appears to be from ‘trans fats’8, which are a by-product of processing fat, and appear in scarily large numbers in processed foods and fast food. Trans fats have been found to raise the bad cholesterol and decrease the good cholesterol in our bodies9.

Conclusions Fat is not just a feminist issue – as Susie Orbach10 said, it is a societal issue. How we address rising waistbands, XXL sport shirts and such has an impact on our future healthcare costs, and many lives will be affected adversely by damage to a vital organ that some do not even realise they are harming with that tempting extra portion.

References: 1

http://www.worldgastroenterology.org/NAFLD-NASH.html accessed 6/8/15

2

http://tiny.cc/ze8h3x accessed 6/8/15

3

http://www.britishlivertrust.org.uk/liver-information/liver-conditions/non-alcohol-related-fatty-liver-disease/ accessed 6/8/15

4

http://www.amazon.co.uk/Fast-Food-Nation-All-American-Doing/dp/0141006870 accessed 6/8/15

5

https://nudges.wordpress.com/ accessed 6/8/15

6

http://www.liverandpancreas.co.uk/fibroscan.php accessed 6/8/15

7

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1386692/ accessed 6/8/15

8

http://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/in-depth/trans-fat/art-20046114 accessed 6/8/15

9

http://www.heartfoundation.org.au/healthy-eating/fats/Pages/trans-fats.aspx Accessed 6/8/15

10

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http://www.amazon.co.uk/Fat-Is-A-Feminist-Issue/dp/0099481936 accessed 6/8/15


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

Brain Damage Caused by Liver Damage – the How and Why of Hepatic Encephalopathy Jane Lucien, Medical Correspondent

A ‘foggy’ brain refers to an inability to think clearly and this can be one of many results of encephalopathy

The Brain The brain is our most important organ in that it makes us the individuals that we are and it differentiates us from other animals. It has fascinated religious thinkers, philosophers and scientists through the ages. We are learning more about it all the time. Some are even trying to replicate it! (The Human Brain Project1). Noble Prize winner Daniel Kahneman in his book ‘Thinking, Fast and Slow’2, helps us to understand that the brain has 2 key systems. One is methodical and slow. The other is emotional and fast. Often we think we have made decisions based on logic but we are more affected by the emotional part of the brain than we realise. The brain is a treasure that ideally we should not damage.

Damage to the Brain – Temporary and Permanent Encephalopathy is a very broad term that

refers to pathology in the brain that could be caused by or lead to actual structural damage to the brain or, more commonly, it describes alterations in mental function caused by temporary or permanent brain damage. Liver disease can lead to initial temporary and later permanent brain damage (hepatic encephalopathy). Since the brain does so much there is a lot that can go wrong.

Encephalopathy – Disordered Thinking, Sensations, Belief and Movements On a clear day you can see for miles and on a foggy day you might find it hard to see your own hand in front of your face. A ‘foggy’ brain refers to an inability to think clearly and this can be one of many results of encephalopathy. A person affected will feel lethargic, have difficulty concentrating, may have memory loss and often may feel flat. WWW.PRIMARYCAREREPORTS.CO.UK | 13


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

Alcohol can cause encephalopathy by many different and often combined methods

The brain controls our personality and behaviours. It is well recognised that damage to the frontal lobes leads to disinhibition and an increased tendency to violence. These and other ‘behavioural’ areas of the brain can be affected by encephalopathy. The brain also processes and interprets our senses. So encephalopathy can lead to abnormal vision, taste, touch etc and in some case false beliefs (delusions) or false perceptions (illusions). Motor functions can be affected by encephalopathy and these may manifest as slurred speech, repeated movements of a limb or the eyes.

How Could Hepatic Encephalopathy Affect a Patient’s Work Life? If not hospitalised at the time, patients may forget things and not be able to work efficiently. Because their thinking will not be clear they may make bad business decisions and bring their business close to or to actual ruin. They may be more distrustful of their staff or work mates and create unnecessary tensions with people they work with. They may be perceived as odd for slurred speech or uncontrollable movements of the limbs or the eyes. If their job involves specific cognitive skills, these may or may not be impaired, such as mathematical skills in an accountant. If their job involves specific motor skills these may or may not be impaired, such as fine manual skills in a carpenter. Such problems may ultimately lead to loss of work through perceived incompetence.

14 | WWW.PRIMARYCAREREPORTS.CO.UK

How Could Hepatic Encephalopathy Affect a Patient’s Home Life?’ Your patient may suffer significant mood swings, be disinhibited and thus cause major upset to their home life and their friends. They may at the time not be able to think through the negative consequences of their actions.

How Does Rifaximin Work to Reduce Hepatic Encephalopathy? The most likely method of action is the antibiotic effect reducing harmful bacteria, which would produce harmful ammonia in the brain3.

What are the Social and Financial Implications of this Benefit? As noted above the cost-effective use of Rifaximin leads to less work and home-related negative consequences of encephalopathy.

Does Science Support Rifaximin Use to Prevent Hepatic Encephalopathy? Many studies have now confirmed the benefits of Rifaximin4,5,6 and the National Institute for Health and Care Excellence (NICE) has endorsed its use in the NHS7. The key study by Bass et al was a 6-month, international, multicentre, randomised, double blind trial comparing Rifaximin with a placebo. It is clearly costeffective as there are less admissions and better quality of life for the individuals.


REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

different and often combined methods. Alcohol itself in excess is toxic to the liver. Heavy drinkers tend to ignore their nutrition and this may also have an effect on the liver. Extreme alcoholics become deficient in a vitamin called thiamine and this leads to a specific encephalopathy named after Wernicke8. The transformation of a patient with Wernicke’s encephalopathy by the correct treatment is apparently quite miraculous.

Is Liver Disease the Only Cause of Encephalopathy? There are many other causes of encephalopathy but the liver statistically is the most important. Other causes include high blood pressure, lack of oxygen, infections, vitamin deficiency, autoimmune attack, and many more. Interestingly, alcohol can cause encephalopathy by many

Conclusions

There are many other causes of encephalopathy but the liver statistically is the most important

The brain is a delicate organ that needs protecting. Normally the liver is part of the brain’s defense mechanism. When the liver fails, this defensive system is broken and toxins can cause damage to the brain. The cost-effective benefit of Rifaximin is to stop these toxic effects of liver encephalopathy. A key message is to avoid liver damage, as prevention is much better than cure.

References: 1

https://www.humanbrainproject.eu/en_GB Accessed 6/8/15

2

http://www.amazon.co.uk/Thinking-Fast-Slow-Daniel-Kahneman/dp/0141033576 accessed 6/8/15

3

http://www.nice.org.uk/guidance/qs11/chapter/Introduction-and-overview accessed 6/8/15

4

Bass NM et al. N Engl J Med 2010; 362:1071-81

5

Mullen et al. Clin Gastroenterol Hepatol 2014 Aug; 12(8): 1390-7

6

Goel A et al. Gut 2014; 63:A179-A180

7

https://www.nice.org.uk/guidance/ta337 accessed 6/8/15

8

http://www.nlm.nih.gov/medlineplus/ency/article/000771.htm accessed 6/8/15

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REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

Notes:

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REDUCING THE RECURRENCE OF EPISODES OF OVERT HEPATIC ENCEPHALOPATHY IN ADULT PATIENTS

Notes:

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