Dr Jonathan Stenner

Non Alcoholic fatty liver Primary Associated with metabolic syndrome Secondary Drugs – Steroids, Amiodarone, Tamoxifen Metabolic/ Genetic – Lipodystrophies Nutritional – TPN, Rapid weight loss Small bowel disease- IBD, Bacterial overgrowth Environmental - petrochemicals

What does Non- alcoholic mean? What is fatty liver? Histopathological Accumulation of fat in the liver > 5-10% of total liver weight In clinical practice Abnormal LFTS Fatty liver on USS (not present if steatosis < 33%) What does Non- alcoholic mean? Daily alcohol consumption of < 20g/day 1 unit alcohol = 8g

General Population Imaging Type of Study Country Prevalence NAFLD% Prevalence of NASH% Autopsy Sweden 24 NR Hospital LB Spain 39 16 Hospital Imaging Romania 20 Outpatients Imaging Italy 53 General Population Imaging Germany 23 36 Bariatric Surgery Belgium France 74 78 27 14

Fibrosis progression rate was highly variable Largely benign Few good studies Largest study of paired liver biopsies (n=103 mean follow up 3.2 ±3 years) 37% progressed fibrosis stage 34% remained stable 29% regressed Mean rate of fibrosis progression 0.09 stages/year Adams et al J. Hep 2005 Fibrosis progression rate was highly variable

Extrapolation of data in autopsy and liver biopsy studies 20-30 % of general public have NAFLD Of whom 10-25% may have NASH 2-10% of these patients may be at risk of progressive liver fibrosis, cirrhosis and HCC

Data from Mediplus practices

Prevalence of NAFLD is similar in adults with (25%) and WITHOUT abnormalities of liver enzymes) 50% of NAFLD cases will be missed if abnormal LFTS are considered as a selection criteria Bedogni et al Hepatology 2005

Obese (36-78%) Diabetes Mellitus (43-62%) Patients with hyperlipidaemia (50%) Hypertension (30%) Metabolic Syndrome (50-83%) Insulin Resistance (80%)

Incidental finding of “bright liver on USS” Abnormal LFTs Suspect the diagnosis Diabetic Metabolic syndrome BMI > 30 Incidental finding of “bright liver on USS” > 33% steatosis Abnormal LFTs Mildly elevated ALT GGT often isolated elevation

Patients at risk to develop NASH with fibrosis: A. Age > 45 B. Obesity (BMI > 31-32) C. Diabetes Angulo et al. Independent predictors of liver fibrosis in patients with NASH. Hepatology. 2000; 30: 1356-1362.

Risk factors for advanced fibrosis at baseline ALT > 100 IU/ml AST:ALT ratio > 1.0 Platelet count < 150 x 109/ml Faster progression to advanced fibrosis BMI > 30 Type 2 Diabetes Mellitus Matteoni et al 1999

Peripheral stigmata of chronic liver disease Splenomegaly Cytopaenia Abnormal iron studies Diabetes and/or significant obesity in an individual over the age of 45

Argo CK, J Hepatol 2009

Secondary Care HCC screening varices follow up etc Abn LFTs Suspicion of NAFLD Fatty liver on USS LIVER OPD 1 History and exam Bloods USS LIVER OPD 2 Diagnosis NAFLD Risk Factor assessed ? Screening bloods and USS organised prior to referral LOW RISK OF FIBROSIS No risk factors Age < 45 BMI <30 With AST:ALT < 1 HIGH RISK OF FIBROSIS Age>45 DM or Obese AST:ALT > 1 Platelets < 150 PRIMARY CARE Management of BP Rx Hyperlipidaemia Yearly screening AST/ALT ALT>100 Ferritin > 400 2 occasions 3 months apart Platelets Abnormal LIVER BIOPSY NASH Mild fibrosis Cirrhosis Bridging fibrosis Bland Steatosis Standard Follow up Secondary Care HCC screening varices follow up etc

How to Treat? Second Hit First Hit NASH Insulin resistance Antioxidants Insulin Sensitizers Cytoprotectants Antihyperlipidemics Second Hit First Hit Steatosis NASH Insulin resistance ↑ Fatty acids Lipid peroxidation Weight Loss Diet/Exercise

348 male subjects with abn ALT (other causes excluded) Followed for 1 year after health advice re exercise and weight loss Patients who normalised ALT were followed for a further 2 years Weight loss of 5% improved ALT with OR 3.6 for ALT normalisation Maintainance of weight loss OR 4.6 for ALT normalisation Suzuki et al 2005

Palmer et al. Gastroenterology 1990 --39 obese patients, no primary liver disease --Retrospective analysis after weight loss --Lower ALT seen in patients with >10% weight loss Anderson et al. Journal Hepatology 1991 --41 obese patients with biopsy-proven NAFLD --Low calorie diet (~400 kcal/d) --Most improved, but 24% worse fibrosis/inflammation --Histological worsening associated with rapid weight loss

Can lead to sustained improvement in liver enzymes, histology, serum insulin levels, and quality of life. Improvement in steatosis following bariatric surgery Should not exceed approximately 1.6 kg per week in adults .

Metformin Marchesini et al. Lancet 2001 Nair et al. AP& T 2004 --20 patients, biopsy-proven NASH --14 metformin (500 tid) x 4 months; 6 controls --ALT & OGTT improved in metformin Nair et al. AP& T 2004 --22 patients, biopsy-proven NASH --Received metformin 20 mg/kg/d x 12 months --Improvement in ALT & insulin sensitivity --No improvement in liver histology

Non significant improvement in inflammatory markers No improvement in histological scoring ?transient in effect.

Rosiglitazone (FLIRT-1 and FLIRT-2) 1 year RCT 47% in Rosi group improved steatosis, 16% placebo 38% normalised ALT in Rosi group vs 7% placebo Concerns about long term effects especilaly weight gain

Laurin et al. Hepatology 1996- Clofibrate -No significant improvement in ALT or histology Basaranoglu et al. J.Heptol 1999- Gemfibrozil --74% patients in gemfibrozil group had lower ALT --30% patients no treatment group had lower ALT Naserimoghadam SSO - J Hepatol 2003 Probucol was associated with a significant reduction in serum aminotransferases No conclusive evidence of benefit

Statins

<Upper limit normal BASELINE ALT POSTBASELINE ALT (week 12) <ULN >x1 >x2 <Upper limit normal 56 58 6 8 1 1 P=0.78 >x1 14 12 33 38 9 7 >x2 1 1 9 9 5 9 Patients with Pravastatin Patients with Placebo No differences in baseline ALT values between groups Lewis 2007

1.9% 0.2% 4.7% 0.6% 6.4% 0.4% Cohort 2 (normal LFT + statins) Moderate elevation Severe elevation 1.9% 0.2% Cohort 2 (normal LFT + statins) P=0.002 NS Cohort 1 (elevated baseline LFT + statins) 4.7% 0.6% NS NS Cohort 3 (elevated LFT without statins) 6.4% 0.4% In summary, individuals with elevated LFT do not appear to have increased susceptibility to hepatotoxicity from statins.

Measure baseline ALT/AST Start statin if AST/ALT < 3 xULN Monitor AST/ALT at 6 and 12 weeks If AST/ALT < 3 x ULN continue or dose advance If AST/ALT > 3 x ULN recheck in 1 week if still elevated then dose reduce or stop If AST/ALT return to baseline then continue lower dose If stopped then rechallenge with lower dose of another statin

How to Treat? Second Hit First Hit NASH Insulin resistance Antioxidants Insulin Sensitizers Cytoprotectants Antihyperlipidemics Second Hit First Hit Steatosis NASH Insulin resistance ↑ Fatty acids Lipid peroxidation Weight Loss Diet/Exercise

Laurin et al. Hepatology 1996 --63% had improved ALT and steatosis --No significant improvement in inflammation/fibrosis Lindor et al. Hepatology 2004 --Randomized controlled double-blind study --168 patients with biopsy-proven NASH --No significant improvement in ALT or histology

Betaine Losartan Pentoxifylline Orlistat

Vitamin E Hasegawa et al. Aliment Pharmacol Ther 2001 --22 patients, 10 steatosis and 12 biopsy-proven NASH --6/12 standard diet followed by Vitamin E 100 IU tid x 12/12 --Steatosis group showed improvement in ALT after diet --Improvement in ALT after Vitamin E --40% NASH patients had histological improvement Kugelmas et al. Hepatology 2003 --16 patients with biopsy-proven NASH followed for 3 mo --9 received diet/exercise and Vitamin E 800 IU qd --7 diet/exercise only --Vitamin E conferred no significant improvement in ALT

247 non diabetic patients RCT for 96 weeks 80 Pioglitazone 30 mg daily 84 Vitamin E 800 IU daily 83 Placebo No difference in adverse events amongst groups Sanyal et al NEJM 2010

Sanyal et al NEJM 2010

Sanyal et al NEJM 2010

NAFLD is common, may be clinically silent, and is likely to increase NAFLD is a marker of metabolic syndrome and increased risk of CV disease Weight loss / exercise are the only proven treatments-?role of bariatric surgery Emerging evidence for antioxidants Other causes must be excluded!!!

Alcohol-use disorders: preventing harmful drinking ABOUT THIS PRESENTATION: This presentation has been written to help you raise awareness of the NICE clinical guideline on ‘Alcohol-use disorders: diagnosis and clinical management of alcohol-related physical complications’. This guideline has been written for healthcare professionals and other staff who care for people with alcohol-related physical complications. The guideline is available in a number of formats, including a quick reference guide. You may want to hand out copies of the quick reference guide at your presentation so that your audience can refer to it. See the end of the presentation for ordering details. You can add your own organisation’s logo alongside the NICE logo. We have included notes for presenters, broken down into ‘key points to raise’, which you can highlight in your presentation, and ‘additional information’ that you may want to draw on, such as a rationale or an explanation of the evidence for a recommendation. Where necessary, the recommendation will be given in full. DISCLAIMER This slide set is an implementation tool and should be used alongside the published guidance. This information does not supersede or replace the guidance itself. PROMOTING EQUALITY Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Workshop on putting NICE guidance into practice June 2010 NICE public health guidance 24

Background Alcohol is attributable for: 14,982 deaths in England (2005) 500,000 recorded crimes (England) up to 35% of attendances at hospital emergency departments (2003) 24% of adults drink a hazardous or harmful amount NOTES FOR PRESENTERS: Key points to raise: Alcohol-related harm is estimated to cost society between £17.7 billion and £25.1 billion per year (DH 2008). Between 1980 and 2008 alcohol became 75% more affordable (Information Centre 2009). It costs the NHS in England up to £2.7 billion a year to treat the chronic and acute effects of drinking (DH 2008). Additional information: This is one of three pieces of NICE guidance addressing alcohol-related problems among people aged 10 years and older. The others are: ‘Alcohol-use disorders in adults and young people: clinical management’ (publication expected May 2010). ‘Alcohol dependence and harmful use: diagnosis and management in young people and adults’ (publication expected January 2011).

AUDIT – C For people aged 16 years and over Screening AUDIT – C For people aged 16 years and over NOTES FOR PRESENTERS: Key points to raise: For the purposes of this guidance, screening involves identifying people who are not seeking treatment for alcohol problems but who may have an alcohol-use disorder. Practitioners may use any contact with clients to carry out this type of screening. The term is not used here to refer to national screening programmes such as those recommended by the UK National Screening Committee (UK NSC).  In most cases, AUDIT (alcohol use disorders identification test) should be used to assess those aged 16 and older. If time is limited, an abbreviated version should be used (such as AUDIT-C, AUDIT-PC, CRAFFT, SASQ or FAST). Screening tools should be appropriate to the setting. For instance, in an emergency department, FAST or PAT would be most appropriate. For assessing the needs of children and young people aged 10-15 years see Recommendation 6. Additional information: AUDIT is a 10 question screening tool that asks about drinking frequency and intensity. It can detect 92% of hazardous and harmful drinkers. Categories of risk can be defined by scores used in the AUDIT, these are: 1-7: low risk drinking 8-15: hazardous drinking 16-19: harmful drinking 20+: possible dependence Shorter versions of the AUDIT tool range between one and four questions (such as AUDIT-C on the slide above). Although these are useful in settings with limited time available, they are generally less accurate than the full AUDIT and do not differentiate clearly between hazardous, harmful and possibly dependent drinking. Scoring: A total of 5+ indicates increasing or higher risk drinking.

Summary Addresses recognising alcohol dependency Advice on “brief intervention” Criteria for specialist referral show signs of moderate or severe alcohol-dependence have failed to benefit from structured brief advice and an extended brief intervention and still want help show signs of severe alcohol-related impairment or have a related co-morbid condition

Alcohol-use disorders: physical complications ABOUT THIS PRESENTATION: This presentation has been written to help you raise awareness of the NICE clinical guideline on ‘Alcohol-use disorders: diagnosis and clinical management of alcohol-related physical complications’. This guideline has been written for healthcare professionals and other staff who care for people with alcohol-related physical complications. The guideline is available in a number of formats, including a quick reference guide. You may want to hand out copies of the quick reference guide at your presentation so that your audience can refer to it. See the end of the presentation for ordering details. You can add your own organisation’s logo alongside the NICE logo. We have included notes for presenters, broken down into ‘key points to raise’, which you can highlight in your presentation, and ‘additional information’ that you may want to draw on, such as a rationale or an explanation of the evidence for a recommendation. Where necessary, the recommendation will be given in full. DISCLAIMER This slide set is an implementation tool and should be used alongside the published guidance. This information does not supersede or replace the guidance itself. PROMOTING EQUALITY Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Implementing NICE guidance June 2010 NICE clinical guideline 100

Acute alcohol withdrawal: 1 For people in acute alcohol withdrawal with, or who are assessed to be at high risk of developing, alcohol withdrawal seizures or delirium tremens, offer admission to hospital for medically assisted alcohol withdrawal. NOTES FOR PRESENTERS: Key priority for implementation recommendation 1.1.1.1 in full: shown on slide Other recommendations: For young people under 16 years who are in acute alcohol withdrawal, offer admission to hospital for physical and psychosocial assessment, in addition to medically assisted alcohol withdrawal. [1.1.1.2] For certain vulnerable people who are in acute alcohol withdrawal (for example, those who are frail, have cognitive impairment or multiple comorbidities, lack social support, have learning difficulties or are 16 or 17 years), consider a lower threshold for admission to hospital for medically assisted alcohol withdrawal.[1.1.1.3] For people who are alcohol dependent but not admitted to hospital, offer advice to avoid a sudden reduction in alcohol intake (see additional information) and information about how to contact local alcohol support services. [1.1.1.4] Additional information While abstinence is the goal, a sudden reduction in alcohol intake can result in severe withdrawal in dependent drinkers.

and alcohol dependence NICE clinical guideline 115 Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence ABOUT THIS PRESENTATION: This presentation has been written to help you raise awareness of the NICE clinical guideline on Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence. This guideline has been written for health and social care professionals who have direct contact with, and make decisions concerning, the care of young people and adults with alcohol dependence or harmful alcohol use. The guideline is available in a number of formats, including a NICE version and quick reference guide. As the presenter, you should have access to the NICE version and should be familiar with its content. You may want to hand out copies of the quick reference guide at your presentation so that your audience can refer to it. See the end of the presentation for ordering details. You can add your own organisation’s logo alongside the NICE logo. We have included notes for presenters, broken down into ‘key points to raise’, which you can highlight in your presentation, and ‘additional information’ that you may want to draw on, such as a rationale or an explanation of the evidence for a recommendation. Where necessary, the recommendation will be given in full. Slide 15 presents an algorithm containing hyperlinks to allow you to show additional details of the contents of the information boxes. Use these hyperlinks during your presentation. In order to guarantee effective use of the hyperlinks you must ensure you are clicking exactly on the hyperlink (wait for the mouse arrow to turn to a hand). Once you have viewed all of the hyperlinks on slide 15, click on the screen away from the algorithm and you will be taken to the next slide where the presentation will continue as normal DISCLAIMER This slide set is an implementation tool and should be used alongside the published guidance. This information does not supersede or replace the guidance itself. PROMOTING EQUALITY Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Implementing NICE guidance February 2011 NICE clinical guideline 115

Source: General Lifestyle Survey, Office for National Statistics Epidemiology Weekly alcohol consumption of more than 50 units (men) or more than 35 units (women) by age (years) and gender – Great Britain, 2009 NOTES FOR PRESENTERS: Key points to raise: 24% of the adult population in England, including 33% of men and 16% of women, consumes alcohol in a way that is potentially or actually harmful to their health or well being (Defined as scoring 8 or more on the Alcohol Use Disorders Identification Test AUDIT) (McManus et al. 2009). 4% of adults in England are alcohol dependent (6% men; 2% women) (Defined as scoring 16 or more on the AUDIT) (Drummond et al. 2005). Alcohol related hospital admissions increased by 85% between 2002–03 and 2008–09, accounting for 945,000 admissions with a primary or secondary diagnosis wholly or partly related to alcohol in 2006–07, 7% of all hospital admissions (North West Public Health Observatory 2010). Additional information To clarify the terms used in association with alcohol consumption and its risks, the Department of Health now recommends the use of terms: lower risk, increasing risk and higher risk because these are more readily understood by the general public and reflect the level of risk incurred by drinkers as their consumption increases. These terms differ from the categories of alcohol dependence identified on the previous slide. Alcohol dependence is a type of drinking that develops in regular excessive drinkers, mainly in those drinking at higher risk levels (Department of Health’s Learning Centre. E-learning for primary care, 2009. Available at www.alcohollearningcentre.org.uk/alcoholeLearning/learning/IBA/Module1_v2/D/ALC_Session/443/tab_580.html). For more information about the terms lower risk, increasing risk and higher risk, visit the alcohol learning centre www.alcohollearningcentre.org.uk References Drummond DC, Oyefes, N, Phillips T et al. (2005) Alcohol needs assessment research project: the 2004 national alcohol needs assessment for England. Department of Health, London McManus S, Meltzer H, Brugha T et al. (2009) Adult psychiatric morbidity in England, 2007: results of a household survey. NHS Information Centre for Health and Social Care, Leeds North West Public Health Observatory (2010) Local alcohol profiles for England. www.nwph.net/alcohol/lape/ (accessed 5 October 2010) Source: General Lifestyle Survey, Office for National Statistics

Background Current practice and service provision across the country is varied Only 6% per year of people aged 16–65 years who are alcohol dependent receive treatment Comorbid mental and physical disorders are common. NOTES FOR PRESENTERS: Key points to raise: Comorbid mental disorders commonly include depression, anxiety disorders and drug misuse. Physical comorbidities, which are common, include gastrointestinal disorders and neurological and cardiovascular disease. Many people experience long-term consequences of alcohol misuse that may significantly shorten their life even when alcohol consumption has stopped or reduced. Of the 1 million people aged between 16 and 65 who are alcohol dependent in England, only about 6% per year receive treatment. Reasons for this include the often long period between developing alcohol dependence and seeking help, limited availability of specialist alcohol treatment services in some parts of England and under-identification of alcohol misuse by health and social care professionals. Diagnosis and assessment of the severity of alcohol misuse is important because it points to the treatment interventions required. Acute withdrawal from alcohol in the absence of medical management can be hazardous in people with severe alcohol dependence, as it may lead to seizures, delirium tremens and, in some instances, death. Current practice and service provision across the country is varied and access to a range of assisted withdrawal and treatment services and psychological interventions varies as a consequence. In addition, when the alcohol misuse has been effectively treated, many people continue to experience problems in accessing services for comorbid mental and physical health problems. Alcohol service structures are poorly developed, with care pathways often ill defined.

Assisted alcohol withdrawal Person who drinks > 15 units alcohol per day or scores > 20 on AUDIT Assessment Consider offering: – assessment for and delivery of a community-based assisted withdrawal, or – assessment and management in specialist alcohol services if there are safety concerns about a community-based assisted withdrawal. NOTES FOR PRESENTERS: Key points to raise: See page 15 of the quick reference guide for more information about outpatient based community withdrawal programmes and intensive community withdrawal programmes. See slide 16 and see page 16 of the quick reference guide for more information about recommended drug regimes for assisted withdrawal programmes. See slide 24 for details of the Sample chlordiazepoxide dosing regimens implementation tool which provides examples of fixed-dose and symptom-triggered regimens for chlordiazepoxide dosing in alcohol withdrawal. The evidence indicated that a community setting for assisted withdrawal is as clinically effective and safe for the majority of patients as an inpatient or residential setting and it is also likely to be more cost effective. The group of experts who developed this guideline identified that symptom-triggered assisted withdrawal was practical only in those inpatient settings that had 24-hour medical monitoring and high levels of specially trained staff. Therefore, the preferred method for assisted withdrawal was a fixed-dose regimen for community and residential settings. Community base assisted withdrawal Inpatient and residential withdrawal Intensive community programmes after assisted withdrawal for severe or mild to moderate dependence with complex needs

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