Ontario College of Family
Physicians
51st Annual Scientific Assembly
Barry Lumb
Fatty Liver Disease
Faculty/Presenter Disclosure
• Faculty: Dr. Barry Lumb
• Program: 51st Annual Scientific Assembly
• Relationships with commercial interests:
– NONE
Disclosure of Commercial
Support
• This program has received NO financial support in any form
• This program has received NO in-kind support from any organization
• Potential for conflict(s) of interest:
NONE
Mitigating Potential Bias
• NONE
NAFLD: Non-alcoholic fatty liver disease
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Definitions
Epidemiology
Pathogenesis
Diagnosis
 Interpretation of liver biochemistry
Prognosis
Management options
NAFLD: Non-alcoholic liver disease
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NAFL: Simple fat accumulation, no
inflammation or fibrosis
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NASH: Fat accumulation with varying degrees
of inflammation and/or fibrosis
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NASH cirrhosis
NAFLD
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Most common liver disorder
Majority of previously diagnosed “cryptogenic
cirrhosis”
Very high prevalence depending on modality used:
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Ultrasound – >15%
MRI - >30%
Liver biopsy – 33% potential donors
Autopsy – 70% of obese, 35% of lean patients
NASH and cirrhosis in much smaller percent
NASH
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“Metabolic steatohepatitis”
Histologically indistinguishable from alcohol
induced liver disease
Various grading systems
Degree of inflammation
 Degree of fibrosis (ie. Risk of cirrhosis)
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NAFLD: Non-alcoholic fatty liver disease
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NAFL: Non-alcoholic fatty liver
NASH: Non-alcoholic steatohepatitis
NAFL
NASH
“Significant alcohol intake”
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Amounts are unclear
Balance between potential for liver disease
versus probable protective effect of moderate
alcohol
Probable higher risk in obesity, female, NAFLD
Male – 2 drinks per day
Female – maybe < 1 drink per day
NAFLD
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Predictors –
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? Female gender
Obesity
Diabetes
Age > 40
Metabolic syndrome
Obstructive sleep apnea
Hyperuricemia
Polycystic ovary syndrome
Hyperlipidemia (esp hypertriglyceridemia, low HDL
Ethnic variability (Hispanic origin)
Metabolic Syndrome
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Most predictive of NAFLD and NASH
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Central obesity - BMI or W/H ratio
Arterial hypertension
Dyslipidemia (↑TG or ↓HDL)
Glucose intolerance/insulin resistance
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NAFLD
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Obesity and other risk factors are not universal
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Rule out other secondary causes of fatty liver
Meds – amiodarone, methotrexate, tamoxifen,
steroids
 Other rare conditions – Wilson’s, Starvation,
Hepatitis C genotype 3, TPN
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Pathogenesis: “Two hit” hypothesis
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First Hit
Insulin resistance causes hyperinsulinemia
 Promotes FFA generation from adipose tissue
 Promotes de novo hepatic lipogenesis
 May activate profibrotic cytokines
 Impaired balance between influx, synthesis of
hepatic lipids versus export or oxidation
 Hepatic triglyceride accumulation in the liver
(steatosis)
 Reduced hepatic export of VLDL
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Pathogenesis: “Two hit” hypothesis
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Second hit
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Steatotic liver vulnerable to secondary injury
Inflammation
 Fibrosis
 Cirrhosis
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Pathogenesis: “Two hit” hypothesis
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Second Hit
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Other mediators/factors cause oxidative injury
 Low anti-oxidant levels
 Iron excess
 Leptins – stimulate platelet derived growth factor
 Abnormal gut microbiome
 Adiponectin – normally protective, reduced in
NAFLD
NAFLD - Diagnosis
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Usually asymptomatic – vague, non-specific
symptoms
Incidental finding
Hepatomegaly
 Liver chemistry testing
 Ultrasound, CT, MRI
 Screening in high risk individuals
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NAFLD: Liver Biochemistry
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Mild to moderate ALT elevation
AST/ALT ratio <1 (unless cirrhotic)
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Versus alcohol >2
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Very poor correlation between severity and ALT
levels
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Possibly:
↑ferritin, IgA, GGT
 SMA, ANA positive
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Hepatocellular enzymes: AST, ALT
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Sensitive indicators of hepatocellular damage
AST many sources
ALT serum half life > AST
Hepatocellular damage ALT elevation predominant
 AST:ALT ratio <1
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Hepatocellular enzymes: AST, ALT
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? Extent of investigation of ALT < 3 x normal
< 6 months duration
 Rule out Hepatitis B and C
 Elevated Ferritin, Iron saturation >45
 Drugs
 Ultrasound
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NAFLD highly probable
NAFLD: GGT
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Sensitive but non-specific indicator of biliary
disease
Clarification of source of raised AP
Induced by ethanol, phenytoin and other drugs
Strong association with
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BMI, NAFLD, alcohol, cholesterol, triglycerides,
analgesic usage
Alcohol and liver enzymes
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Prolonged intake
Depletion of hepatic AST and ALT but ALT
predominant
 AST/ALT ratio > 2
 Total AST < 400
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Frequently striking elevation of GGT
NAFL or NASH?
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Significant red flags
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Clinical stigmata of chronic liver disease
Spiders
 Splenomegaly
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Elevated MCV
 Elevated ferritin
 Low platlets (<140,000)
 Imaging – “shrunken liver”, splenomegaly, ascites
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NAFLD: ALT level
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Poor association between ALT level and
degree of fatty infiltration, inflammation
and fibrosis
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Don’t let a low ALT talk you out of
concern if other features present
NAFLD: Imaging
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Ultrasound, CT, MRI
Reliable for moderate to severe fatty infiltration
 No association with NAFLD versus NASH, fibrosis
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Associated features of cirrhosis
Fibroscan is promising for assessing degree of
fibrosis
NAFLD: Assessing severity
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Independent markers of progression to fibrosis
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Age > 50 (OR 14.1)
DM (OR 12.5) – especially poorly controlled
BMI > 28 (OR 5.7)
Triglycerides >1.7 (OR 5)
Other markers of inflammation and fibrosis?
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IgA, hyaluronic acid levels
Risk factors – DM, metabolic syndrome
NAFLD: Liver Biopsy
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Only accurate confirmation of inflammation
and/or fibrosis
Exclusion of other causes of abnormal
biochemistry
Value in absence of proven medical therapy
controversial unless features of chronic liver
disease
NAFLD: Prognosis and progression
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Risk is unclear but:
Class 1 and 2 unlikely to progress
 Class 3 and 4 (NASH)
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Progressive fibrosis 25% at 5 years
 Cirrhosis 15% at 5 years
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Mortality related to underlying disease states
 Increased incidence of hepatocellular carcinoma if
cirrhosis
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NAFLD: Management options
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Very few RCTs
Most studies are short duration
AST and Ultrasound as surrogate markers are
unreliable
Acceptable alcohol intake?
Subsets of patients with different therapies?
NAFLD: Management options
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Diet, exercise, weight loss!!??
Anti-oxidants - vitamin E 400 iU
Statins (no increased risk of hepatotoxicity)
Pioglitazone (Actos)
Ursodeoxycholic acid (Urso)
Losartan
Metformin