Non-alcoholic fatty liver disease and when to refer abnormal LFTs Dr Alexander Evans Consultant Hepatologist & Gastroenterologist Royal Berkshire Hospital

NAFLD - The Problem! Prevalence of abnormal LFTs in primary care is between 6 and 20%. Abnormal LFTs may further represent a major burden to the NHS by way of investigations The natural history of most liver diseases is many decades, and abnormal LFTs will not lead to serious liver disease in the short or medium term, and in many cases not even in the long term.

BUT! Mortality and Morbidity from liver disease is increasing Prior to the development of end stage liver disease patients are usually asymptomatic Primary care practitioners (PCPs) are thus commonly faced with the scenario of abnormal liver enzymes in patients in whom there are no clinical risks, signs or symptoms of liver disease.

Current Practice BSG commissioning report for jaundice and abnormal LFTs “The decision of whom to refer to secondary care with abnormal liver enzymes and when is often arbitrary and has no relationship to the risk of serious disease being present.” There is therefore a wide variation in thresholds for referral to secondary care Advised development of local referral protocols Commonest cause of asymptomatic abnormal LFTs is NAFLD

Natural History and terminology of NAFLD ● Strongly associated with insulin resistance and considered the hepatic manifestation of the metabolic syndrome. Cohen JC, Horton JD, Hobbs HH (2011). Human fatty liver disease: old questions and new insights. Science 332(6037):1519-1523

NAFLD - Prevalence Prevalence? Biopsy diagnostic Controversy of “normal ALT levels” NAFLD spectrum of disease seen with normal LFTs from post-mortem studies. Cryptogenic cirrhosis

Prevalence studies for NAFLD Incidence of NAFLD is underreported and subject to huge variation anywhere between 29 and 1000 cases per 100 000 patient years. Increasing in incidence as rates of obesity and DM increase Prevalence – again difficult to assess as liver biopsy is the current gold standard diagnostic test and is invasive and not without risk – cannot justify this for population studies. Biopsy studies of healthy liver donors and autopsy series’ suggest 15-50% Non-invasive modalities suggest 5-25% (but how accurate is diagnosing NAFLD on ALT/AST??? Or on USS???). The current upper limit of normal for aminotransferases has also been challenged and therefore the prevalence may be higher than previously thought - Given that females tend to have lower aminotransferases and still have NAFLD, it has been proposed that the ULN be reduced to 19U/l for women. Equally the whole spectrum of NAFLD has been seen in patients with normal enzymes. In the US, prevalence of NAFLD is assumed to be approximately 30% as one third of the population is obese, with histological NASH in about 3-5%. Globally the median prevalence is about 20%. In all children about 3% have NAFLD, and 50% of obese children have NAFLD. Vernon G, Baranova A, Younossi ZM (2011). Systematic review: the epidemiology and natural history of NAFLD and NASH in adults. Alimentary Pharmacology and Therapeutics 34:274-285 7

Prevalence studies for NAFLD Probably about 25% prevalence in the UK (and increasing reflecting increase in obesity and DM). Prevalence estimated to be at least 30% in USA 50% of obese children have NAFLD Incidence of NAFLD is underreported and subject to huge variation anywhere between 29 and 1000 cases per 100 000 patient years. Increasing in incidence as rates of obesity and DM increase Prevalence – again difficult to assess as liver biopsy is the current gold standard diagnostic test and is invasive and not without risk – cannot justify this for population studies. Biopsy studies of healthy liver donors and autopsy series’ suggest 15-50% Non-invasive modalities suggest 5-25% (but how accurate is diagnosing NAFLD on ALT/AST??? Or on USS???). The current upper limit of normal for aminotransferases has also been challenged and therefore the prevalence may be higher than previously thought - Given that females tend to have lower aminotransferases and still have NAFLD, it has been proposed that the ULN be reduced to 19U/l for women. Equally the whole spectrum of NAFLD has been seen in patients with normal enzymes. In the US, prevalence of NAFLD is assumed to be approximately 30% as one third of the population is obese, with histological NASH in about 3-5%. Globally the median prevalence is about 20%. In all children about 3% have NAFLD, and 50% of obese children have NAFLD. Vernon G, Baranova A, Younossi ZM (2011). Systematic review: the epidemiology and natural history of NAFLD and NASH in adults. Alimentary Pharmacology and Therapeutics 34:274-285 8 8

Predisposing factors for progression of NAFLD Obesity – Pt undergoing Bariatric surgery (90% steatosis, 30% NASH, 10% advanced fibrosis / cirrhosis) Metabolic conditions Type 2 DM – 66% will have US evidence of NAFLD Polycystic ovarian syndrome – 50% Age (may reflect longer standing undiagnosed NAFLD) Gender M>F (?protective effect of oestrogen) Ethnicity Hispanics > Other white > African Americans 6) Genetics PNPLA3 gene (Others include NCAN, GCKR, LYPLAL1) 7) Other (HCV/HIV) Age – increased prevalence with age and greater risk of fibrosis/cirrhosis, but does this just represent a longer duration of disease? Older people also more likely to have other comorbidities such as DM, hypertension, hyperlipidaemia etc. Gender – Probably commoner in men. Ethnicity – unclear why Genetics – NAFLD noted to cluster in families but low heritability factor of 0.27. One PNPLA3 allele variant is commonly seen in Hispanics (high rates of NAFLD). Another variant of the same gene is associated with lower liver fat content and this gene is found in higher frequencies amongst African Americans. Diabetes – About 2/3rd of patients with type 2 DM will have USS evidence of NAFLD. The liver disease may also be more progressive in this population. PCOS – considered the ovarian manifestation of the metabolic syndrome. Approx 50% of PCOS patients will have evidence of NAFLD on USS/elevated ALT compared to 20% in weight and age-matched non PCOS controls. Obesity – Relationship of obesity and NAFLD is well recognised. In terms of extent, of patients undergoing bariatric surgery, approx 75% have simple steatosis, 20-30% have NASH and 10% advanced fibrosis/cirrhosis. Other associations – HCV: appears to increase insulin resistance and exacerbate the metabolic syndrome; especially genotype 3. Relatively high prevalence also in the HIV population, those with myotonic dystrophy, or primary hyperaldosteronism. Vernon G, Baranova A, Younossi ZM (2011). Systematic review: the epidemiology and natural history of NAFLD and NASH in adults. Alimentary Pharmacology and Therapeutics 34:274-285 9

NAFLD - Prognosis Increased overall mortality compared to matched control populations. Commonest cause of death in patients with NAFLD, NAFL and NASH is cardiovascular disease. Increased liver-related mortality rate – increasingly common indication for liver transplantation (15-20%). Kawamura Y et al (2011). Large scale long term follow up study of Japanese patients with NAFLD for the onset of HCC. American Journal of Gastroenterology doi:10.1038/ajg.2011.327

Management of NAFLD in Primary Care ● History: Usually diagnosed on random blood tests performed on patients with unrelated symptoms. Higher threshold for screening at risk populations (e.g. Obesity / PCOS / Diabetics). Consider other risk factors for abnormal LFTs – Alcohol / viral hepatitis etc ● Examination: ?signs of chronic liver disease / BMI ● Investigations: FBC,U&E, LFTs, GGT, Fasting Cholesterol & Glucose, INR. Consider performing liver screen if in doubt about diagnosis: HBV,HCV serology, Immunoglobulins, AI liver screen (ANA, AMA, Anti-LKM, Anti-SmA, Ferritin, αFP) - US abdomen: usually described as showing “diffuse increase in echogenicity of liver suggestive of fatty infiltration”

Who to refer? Calculate NAFLD fibrosis score or fatty liver index! (Age, BMI, hyperglycaemia, plts, albumin, AST/ALT ratio). – AUROC 0.85 for advanced fibrosis. (There’s an app!!) www.nafldscore.com

Proposed algorithm for the workup of a patient with NAFLD. Dowman JK, Tomlinson JW, Newsome PN (2011). Systematic review: the diagnosis and staging of NAFLD and NASH. Alimentary Pharmacology and Therapeutics 33: 525-540 14

Management of NAFLD in Primary Care 1) Lifestyle changes – WEIGHT LOSS Explain diagnosis and set realistic target weight Nutritional counselling – refer to dietician Exercise – 3-4 times per week, expend 400 kcal per session Promrat et al 2010: Intensive lifestyle intervention (diet, exercise, behaviour modification) vs structured education alone. Weight loss 9.3% vs 0.2% (p = 0.003) Decrease in NAS 72% vs 30% (p=0.03) Most NAFLD patients are obese so diet and exercise form the basis for initial management. The rationale is that this decreases white adipose tissue which subsequently decreases insulin resistance. Exercise may also increase muscle insulin sensitivity. Nutritional counselling – mainly focussed on caloric restriction, but some evidence to suggest decreasing saturated fats, trans-fats, and fructose (in soft drinks) may be beneficial. Promrat study – outcome was liver histology as defined by Kleiner’s NAS score at 48 weeks. Significant increase in weight loss in intensive group which translated into a significant reduction in NASH as defined by a fall of 3 or more in Kleiner’s NAS or post-treatment of less than 2. These findings have been replicated in other studies. Younossi ZM (2008). Review article: current management of NAFLD and NASH. Alimentary Pharmacology and Therapeutics 28: 2-12 Dowman JK, Armstrong MJ, Tomlinsomn JW, Newsome PN (2011). Current therapeutic strategies in NAFLD. Diabetes, Obesity and Metabolism 13: 692-702 15

Medication for NAFLD 1) Metformin 2) Lipid-lowering agents (statins) commonest cause of death is cardiovascular. Reduced rate of HCC and improvement in LFTs Statins are safe in liver disease!! (RCTs) 3) Vitamin E PIVENS trial 2010 – Improvement in NASH: 43% vs 19%, p=0.001 Considered 1st line for pharmacotherapy of NASH (not in diabetic patients!) 4) Thiazolidinediones (pioglitazone) Improvement in liver histology whilst on drug but may relapse on stopping. Causes weight gain 5) ?role for Glucagon-like peptide 1 (GLP-1), DPP-4 inhibitors. 6) Small proof of concept studies in Angiotensin receptor blockers / pentoxyfilline. Sanyal AJ et al (2010). Pioglitazone, Vitamin E or placebo for NASH. New England Journal of Medicine 362: 1675-85

Weight loss Interventions for NAFLD? 1) Orlistat Zelber-Sagi et al 2006: Orlistat vs no orlistat 6/12 treatment resulted in improved transaminases, steatosis on USS, and weight loss Hussein et al 2007: Orlistat in NASH 6/12 treatment improves histological steatosis, fibrosis and inflammation 2) Gastric Band/Bypass Mathurin et al.Gastroenterology 2009;137:532-540 – Prospective study – clinical, metabolic and liver histology at baseline, Yr 1 and Yr 5 after bariatric surgery. (56% Gastric Band, 21% Gastric bypass, Bilio-intestinal bypass 23%) Significant Improvement in steatosis and hepatocyte ballooning, but equivocal as to whether fibrosis improves. Cost neutral at 18 months Orlistat – pancreatic and gastric lipase inhibitor which will inhibit the uptake of about 30% of dietary triglycerides. Sibutramine – Serotonin and noradrenaline reuptake inhibitor that increases satiety. 10% reduction in body weight at 6 months, decrease USS steatosis, improved AST/ALT but increased risk of non-fatal CV morbidity so currently suspended by MHRA Rimonabant – cannabinoid receptor antagonist. Induced significant weight loss and improved insulin resistance but associated with psychiatric side effects. Similar more liver-specific agents may come in the future. GLP-1 e.g. exenetide/liraglutide. Have been proven to be of benefit in type 2 diabetes: increase insulin production and decrease glucagon in a glucose-dependent manner and so improve glycaemic control. Also induce weight loss by delaying gastric emptying and centrally suppressing appetite. Some case reports suggest these may be useful in NAFLD, and there is some evidence showing a reduction in liver enzymes, steatosis and insulin resistance. DPP-4 is the enzyme which breaks down GLP-1 and is found to be increased in patients with NASH and this correlates with degree of steatosis. DPP-4 inhibitors may therefore have a role. 17

When to refer abnormal LFTs Any patient with clinical, biochemical or radiological signs of liver cirrhosis. Any patient in whom there is any doubt about the diagnosis of NAFLD. Any patient whose LFTs fail to normalise with weight loss. Any patient who despite above management options fails to lose weight, in whom a liver biopsy / Fibroscan is indicated (NAFLD fibrosis score / F.L.I.)