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
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
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
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
Predisposing factors for progression of
NAFLD
1)
Obesity – Pt undergoing Bariatric surgery (90% steatosis, 30% NASH,
10% advanced fibrosis / cirrhosis)
2)
Metabolic conditions
–
Type 2 DM – 66% will have US evidence of NAFLD
–
Polycystic ovarian syndrome – 50%
3)
Age (may reflect longer standing undiagnosed NAFLD)
4)
Gender
M>F (?protective effect of oestrogen)
5)
Ethnicity
–
Hispanics > Other white > African Americans
6)
Genetics
–
PNPLA3 gene (Others include NCAN, GCKR, LYPLAL1)
7)
Other (HCV/HIV)
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
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
Dowman JK, Tomlinson JW, Newsome PN (2011). Systematic review: the diagnosis and staging of NAFLD and NASH. Alimentary
Pharmacology and Therapeutics 33: 525-540
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)
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
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
When to refer abnormal LFTs
• Refer?
– 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.)