WHS PR Symposium - Non-Alcoholic Fatty Liver Disease
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Women's Health SocietyWHS PR Symposium - Non-Alcoholic Fatty Liver Disease
Uploaded by
Women's Health SocietyBarretts
BarrettsEsophagus
Esophagus
Non-Alcoholic Fatty Liver Disease
Federico Rodrguez-Prez
Gastroenterologist and Hepatologist
I have no disclosures regarding
this topic
Objectives
To understand the epidemiology and
natural history of NAFLD
Recognize the clinical presentation of
NAFLD
Understand the strategies for the
diagnosis and treatment of NAFLD
Non-Alcoholic
Non-AlcoholicFatty
FattyLiver
LiverDisease
Disease(NAFLD)
(NAFLD)
Non-Alcoholic Fatty Liver Disease
(NAFLD)
What is it?
Why care?
Whom to treat?
NAFLD
What is it?
Evidence of hepatic steatosis either by
imaging or histology
No other causes for secondary hepatic fat
accumulation
Significant alcohol consumption
> 3 drinks on any day (> 30gm/day) or > 14
drinks per week in men
> 2 drinks on any day (20gm/day) or > 7 drinks
per week in women
Use of steatogenic medication
Hereditary disorders
NAFLD
NAFLD is the most common cause of
CLD
Strongly associated with metabolic
risk factors: obesity, diabetes
mellitus, and dyslipidemia
Histologically categorized into
steatosis and steatohepatitis
NAFLD: A Global Challenge
>2/3 American
adults are
overweight or
obese
In US, 30 million
adults may have
NAFLD
8.6 million may have
NASH !!
Prevalence of
NAFLD in the US
is 20 -51%
Prevalence of Hepatic Steatosis
Varies with Ethnicity
Prevalence of
metabolic
syndrome in PR >
30%
58.3
58.3
44.1%
44.1%
Fatty liver
M
35.1%
35.1%
24%
24%
Hispanics
Whites
Blacks
Torres DM. Clinic Gastro Hep 2012
NAFLD: Disease Spectrum
NAFLD: Nonalcoholic fatty liver disease
NAFL: nonalcoholic fatty liver
NASH: nonalcoholic steatohepatitis
NAFLD
NAFL
Steatosis
(Macrovesicular)
NASH
Steatosis
Inflammation
Ballooning
Cirrhosis
Fibrosis
Inflammation
Non-Alcoholic
Non-AlcoholicFatty
FattyLiver
LiverDisease
Disease(NAFLD)
(NAFLD)
Non-Alcoholic Fatty Liver Disease
(NAFLD)
What is it?
Why care?
Who to treat?
Non-Alcoholic
Non-AlcoholicFatty
FattyLiver
LiverDisease
DiseaseClinical
ClinicalImplications
Implications
Non-Alcoholic Fatty Liver Disease
Clinical Implications
Steatosis
Few symptoms / signs of
liver disease
Benign course?
<10% go to cirrhosis
Risk factor for cirrhosis in
HCV & AFLD
1.7% liver related mortality
Non-Alcoholic
Non-AlcoholicFatty
FattyLiver
LiverDisease
DiseaseClinical
ClinicalImplications
Implications
Non-Alcoholic Fatty Liver Disease
Clinical Implications
Steatohepatitis
Mallory
Mallory body
ballooned
ballooned
More severe metabolic
syndrome
~ 30% advanced fibrosis
May promote HCC
dead
dead
8.6% liver related
mortality
Non-Alcoholic
Non-AlcoholicFatty
FattyLiver
LiverDisease
DiseaseClinical
ClinicalImplications
Implications
Non-Alcoholic Fatty Liver Disease
Clinical Implications
Cirrhosis (F4)
Morbidity / mortality
significant
liver-related
co-morbidities
12.1 % liver related
mortality
HCC risk high
NAFLD
Spectrum of Hepatic Pathology
Steatohepatitis
Steatohepatitis
Steatosis
Cirrhosis
Cirrhosis
Hepatocellular
carcinoma
NASH and HCC
Patients with NASH cirrhosis have
increased risk of liver cancer and
screening should be performed
Yearly cumulative incidence is 2.6 %
compared to 4% in HCV cirrhotic
patients
Diabetes, older age, obesity, alcohol
consumption, hepatic iron
deposition are risk factors for the
development of HCC
Ascha, Hepatology 2010
Starley, Hepatology 2010
Bhala et al, Hepatology 2011
Conclusion: Why care?
Long-term outcomes of patients with
NAFLD and NASH:
Patients with NAFLD have increase
overall mortality
Most common cause of death in
patients with NAFLD and NASH is
cardiovascular disease.
Patients with NASH have an increased
risk of liver-related mortality including
HCC
Diagnosis & Evaluation
Clinical Features: NAFLD
Most are asymptomatic (77%)
Diagnosed on routine laboratory testing
or abdominal imaging
Symptoms: fatigue, malaise, vague RUQ
abdominal pain
Hepatomegaly (up to 75%), splenomegaly
(up to 25%)
53-80% are overweight
> 1/3 have the metabolic syndrome
Bacon B., et al. Gastroenterology. 1994
Powell EE., et al.Hepatology. 1990
Okolo PI., et al. Sleisenger and Fortrans, 6th Ed. 1998
Evaluation of Incidentally Discovered
Hepatic Steatosis
Patients with unsuspected hepatic steatosis
detected on imaging:
No symptoms and normal liver biochemistries
rule out significant alcohol consumption or
medications and assess for metabolic risk
factors
Those who have symptoms /signs/abnormal liver
biochemistries evaluate as if they have
suspected NAFLD and work-up accordingly.
NAFLD Practice guidelines:Hepatology, Vol. 55, No. 6, 2012
Diagnosis & Evaluation
#1 Identify risk factors associated
with NAFLD (Table 1)
Table 1: Risk factors associated with NAFLD
Vuppalanchi R. Hepatology 2009
Diagnostic
DiagnosticGoal
Goal#1
#1Determine
DetermineEtiology
EtiologyisisFLD
FLD
Who might have NASH?
The Metabolic Syndrome
WC >102 cm M and 88cm W
>130/85mmhg
>250mg/dl
<40 M and <50 W
Fasting plasma glucose level
>110mg/dl
High prevalence in
patients with
Cryptogenic
cirrhosis
Strong predictor
for NASH
** MAY IDENTIFY
PATIENTS WITH
ABNORMAL LIVER
TESTS WHO WILL
BENEFIT FROM A
LIVER BIOPSY**
Risk of NASH105 pts lap sx for obesity & liver bx
80
70
60
50
40
% of Pts with NASH
30
20
10
0
Not DM or HTN
Dixon JB, Gastro 2001
HTN
DM
DM + HTN
Components of the metabolic syndrome
Red Flags for NASH
Age
Gender
Hispanic
HTN
Obesity
Diabetes
ALT and AST level
AST/ALT
Insulin level
No lab test or imaging study
will be able to predict with
100% accuracy
The more risk factors the
more likely the patient has
NASH
#2 Exclude significant alcohol
consumption and competing etiologies
for hepatic steatosis (Table 2)
NAFLD Practice guidelines:Hepatology, Vol. 55, No. 6, 2012
#3 Exclude coexistent causes for
CLD
Initial Evaluation
Negative viral / autoimmune / genetic markers
Patients with NAFLD can present with mild elevation of
ferritin.
But patients with persistent increased ferritin level and
increase iron saturation in the context of homozygous or
heterozygous C282Y HFE mutations liver biopsy.
21% of patients with NAFLD can present with mild
elevations of autoantibodies level (ANA 1:160; ASMA 1:40)
High serum titers of autoantibodies with other
features of autoimmune liver disease complete
workup
Diagnostic Tools
Diagnostic evaluation: Liver
Profile
ALT and/or AST are only mildly-moderately
elevated
25-30% with enzymes may have fibrosis or
cirrhosis
Normal liver biochemistry results do not
exclude advance fibrosis
AST/ALT ratio < 1 but this ratio increases as
fibrosis advances
+/- increase in alkaline phosphatase and GGT
Non-Invasive Markers of
Fibrosis
NAFLD Fibrosis Score
(http:nafldscore.com)
Age, BMI, hyperglycemia, platelet count,
albumin, AST/ALT ratio
< -1.455 had 90% sensitivity and 60%
specificity to exclude advanced
fibrosis
> 0.676 had 67% sensitivity and 97%
specificity to identify the presence of
advanced fibrosis
Imaging Techniques
US, CT, and MRI can
identify steatosis
Insensitive and not
specific
Can suggest the
presence of cirrhosis
when manifestations
of portal
hypertension are
evident
Cannot distinguish simple steatosis from
steatohepatitis with fibrosis
Transient Elastography
Liver stiffness is proportional to shear
wave velocity
Formula (Youngs Modulus): E=pv22
V=velocity
P=density of tissue
Stiffness is measured in kilopascals
Goals of Liver biopsy
Identify NASH (ballooning, inflammation, etc)
Establish diagnosis
Clinical trials
Stage fibrosis
Rule out concomitant liver disease (iron
loading, etc)
Prognosis
Conclusions
Ask yourself what it is that you want to know
If NASH vs not NASH
Consider liver biopsy
The more the risk factors, the greater the likelihood the
patient has NASH
If mild fibrosis vs advanced fibrosis
Consider Fibroscan
Management of NAFLD
NAFNAFLD Practice guidelines:HepatologyVol. 55, No. 6, 2012
NAFLD Practice guidelines:Hepatology, Vol. 55, No. 6, 2012
Lifestyle Modifications
Dieting vs Healthy Eating
Sugarstacks.com
Harvard Healthy Eating Plates and
Helathy Eating Pyramid website
Weight watchers
Lifestyle Modifications
Exercise
Metabolic benefit vs weight loss
Gym
Trainer
Dancing
Walking: 3 times to 5 times per week
Other Management Advices
Check Hepatitis A/B
Identify Vit D deficiency
Treat sleep apnea
Limit acetaminophen intake: not
more than 2000 mg per day
Allow statin use if necessary to
control elevated cholesterol
Cardiovascular disease in NAFLD
Cardiovascular disease is the leading cause
of death
Patients w NAFLD should be risk stratified for
CV dz and managed accordingly
Statins can be used safely to treat
dyslipidemia since there is no evidence that
patients with CLD are at higher risk for
serious liver injury than those w/o liver dz
(2012 AASLD guidelines)
Bariatric Surgery
Foregut bariatric surgery can be
effective in improving hepatic
histology in selected patients
(severely obese) without liver failure
or portal HTN
Not contraindicated in obese
patients with NAFLD w/o cirrhosis
but type, safety, and efficacy not
established in cirrhotics
Mummadi et al. 2008, 2012 AASLD guideline
Management of NASH
Pharmacotherapy for NASH
No drugs have been approved
Pharmacotherapy is based on trial
data
PIVENS Study
Further analysis showed that best
results were seen in patients who
took Vitamin E and also achieved
weight loss
Vitamin E may increase
cardiovascular risk and prostate
cancer
Farnesoid X (nuclear) Receptor
(FXR)
Activation:
Inhibits hepatic de novo lipogenesis
Increases insulin sensitivity
Protects hepatocytes against bile acid
induced cytotoxicity
Agonists may be useful in NASH
Obeticholic Acid (OCA)
Semi-synthetic derivative of the
primary human bile acid
chenodeoxycholic acid
Natural agonist of FXR
FLINT Clinical Trial
NIH funded trial in 283 patients
Obeticholic acid 25 mg po qd vs
placebo for 72 weeks
Non-cirrhotics
Improvement in NAFLD Activity
Score:
(46% in OCA vs 21% in placebo)
Side effects: severe pruritus 3%
Gut Permeability and
Microbial/Gut Toxin translocation
in NASH
Elevated endotoxin levels observed
in NASH
Derived from:
1) Gram negative bacterial overgrowth
(Actinobacteria and Proteobacteria)
2) Increased intestinal permeability:
high fat diet
3) Impaired hepatic clearance of
endotoxin
High Fructose Diet
Induces alterations in gut-barrier
function and endotoxemia
Upregulation of all hepatic Toll-like
receptors
Dietary Modifications that May Act
on the Gut Barrier
Avoid alcohol
Avoid Fructose diets
Use of Probiotics (lactobacillus)
Use of Prebiotics (lactulose)
Symbiotics: Probiotics + Prebiotics
Summary and Conclusions
NAFLD is a common disorder, its more severe form
NASH has a potential to progress to cirrhosis
Most common cause of death in patients with NAFLD is
cardiovascular disease; therefore, statins can be used safely
to treat dyslipidemia
Patients with NASH have an increased risk of liverrelated mortality including HCC
Liver biopsy is the gold standard for histologic
stratification but Fibroscan can rule out fibrosis/cirrhosis
non-invasively
Summary and Conclusions
Drug therapy of NASH must only be provided in those
with documented and established NASH
Vitamin E may be used in selected patients
Obeticholic Acid may be considered in the future
Dietary modifications and exercise play an important
role in management of patients with NAFLD
