Non Alcoholic Fatty

Liver Disease
(NAFLD)
Arifa Toor, MD

Non-Alcoholic
Fatty Liver
Disease (NAFLD)
Non-Alcoholic Fatty Liver Disease (NAFLD)

Objectives

Prevalance
Terminology
Pathophysiology
Diagnosis
Treatment

5 million years

50 years

Obesity Trends* Among U.S. Adults

BRFSS, 1990, 1995, 2005
(*BMI 30, or about 30 lbs overweight for 54 person)
1995

1990

2005

No Data

<10%

10%14%

15%19%

20%24%

25%29%

ource: Behavioral Risk Factor Surveillance System, CDC

30%

Obesity Trends* Among U.S. Adults

BRFSS, 2010
(*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

No Data

<10%

10%14%

15%19%

20%24%

25%29%

30%

NAFLD Prevalence: General US Adult Population

NAFLD Prevalence
General US Adult Population
Dallas Heart Study (2,200
(2,200 adults)
adults)
Assessed
Assessed NAFLD
NAFLD with
with liver
liver imaging
imaging
General
General prevalence
prevalence of
of fatty
fatty liver
liver 31%
31%
(range
(range 24%
24% - 45%)

NAFLD Prevalence
5.5-31%

Most
Most individuals
individuals (79%)
(79%) with
with fatty liver do not
exhibit
exhibit aminotransferase elevations

NHANES III (15, 700 adults)

Assessed
Assessed NAFLD
NAFLD with
with aminotransferases
aminotransferases
General
General prevalence
prevalence of
of NAFLD
NAFLD 5.5%
5.5%

3-10 x more
prevalent than
Hepatitis C

NHANES III

NHANES III
Normal
AST, ALT

5.5%Unexplained Hepatitis
BMI
Waist circumference
Triglycerides
Elevated Insulin levels
HDL cholesterol

Metabolic Syndrome
Clark,
Clark, Brancati,
Brancati, Diehl.
Diehl. Am
Am JJ Gastro
Gastro 2003;
2003; 98:960
98:960

Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-Alcoholic Fatty
Liver Disease
(NAFLD)
Alcohol-like liver disease in individuals who

Terminology
Terminology

do not consume excessive alcohol

Histologic spectrum of liver damage

NAFL fatty liver (steatosis)
NASH fatty liver + increased hepatocyte

death (steatohepatitis)
Cirrhosis regenerative nodules + fibrosis

Diagnosis of exclusion

Blood tests and imaging - insensitive, non-specific

Fatty Liver is associated

with the Metabolic
Syndrome

Central Obesity
Impaired fasting glucose
Elevated Triglycerides
Low HDL
HTN

% of NAFLD patients have the full metabolic syndro

% of NAFLD patients have at least one feature

Metabolic Syndrome

Metabolic Syndrome
Abnormal production of hormones &
cytokines that regulate inflammatory
responses

ANTIinflammatory
PROinflammatory

Fat-Derived Factors Regulate Hepatic Inflammatory Response

Fat-Derived Factors
Regulate Hepatic Inflammatory Response

Hormones

Fat

Leptin
Resistin
Adiponectin

Cytokines

Liver

TNF
TNF

TNF alpha
PAI-1

Neurotransmitters

Adiponectin
Adiponectin

NAFL/NASH + Insulin resistance

Norepinephrine
Angiotensinogen

Metabolic Syndrome - Cytokine Imbalance

Metabolic Syndrome
Cytokine Imbalance

TNF
Pro-inflammatory

Pro-apoptotic
Recruits WBCs
Promotes insulin
resistance

Adiponectin
Anti-inflammatory
Anti-inflammatory

Inhibits FA uptake
Stimulates FA oxidation
& lipid export
Enhances insulin sensitivity

Steatosis (NAFL) +
cell death + inflammation (NASH) &
insulin resistance

Metabolic Syndrome - Cytokine Imbalance

Metabolic Syndrome
Cytokine Imbalance

TNF
Pro-inflammatory

Pro-apoptotic
Recruits WBCs
Promotes insulin
resistance

Adiponectin
Anti-inflammatory
Anti-inflammatory

Inhibits FA uptake
Stimulates FA oxidation
& lipid export
Enhances insulin sensitivity

Steatosis (NAFL) +
cell death + inflammation (NASH) &
insulin resistance

NAFLD: Spectrum of Hepatic Pathology

NAFLD

Spectrum of Hepatic Pathology

Steatohepatitis
Steatohepatitis

Steatosis
Steatosis

Cirrhosis
Hepatocellular
Hepatocellular
carcinoma
carcinoma

Prognostic Implications of NASH + Fibrosis

Prognostic Implications of
NASH + Fibrosis
More consistent and rapid
progression to cirrhosis than NAFL
NAFL
NASH +
fibrosis

> 10 years

5-10 years

Cirrhosis
3%

Cirrhosis
30%

Matteoni
Matteoni et
et al.
al. Gastroenterology
Gastroenterology 1999;
1999; 116:1413
116:1413

Risk Factors for Cirrhosis

Risk Factors for Cirrhosis

Age > 45-50 years
Obesity
Diabetes
66% prevalence of bridging fibrosis
if age > 50 years and patient obese
or diabetic

Diagnosis Goals

Diagnostic
Goals in Fatty Liver Disease
Confirm etiology of liver disease
Establish clinical severity

Diagnosing Fatty Liver

Disease

No one test can diagnose this

condition
Its usually asymptomatic
Liver tests may or may not be
abnormal
AST/ALT usually <5X normal
Steatosis is usually seen on
ultrasound (but this does not
exclude concomitant diseases)

Diagnosing Fatty Liver

Disease

What to look for in the history:

Presence of features of metabolic

syndrome
Alcohol use- <1 drink/day , <2
drinks/day
Medications that can cause liver injury
Medications that can cause fatty liveramiodorone, MTX, tamoxifen, steroids,
valproic acid, HIV meds
Family history of liver disease

Exam

Diagnosing Fatty Liver

Disease
Labs

Fasting glucose, lipids, hgbA1C

Exclude other causes of liver disease
in those with elevated
transaminases:
Viral hepatitis (hep B, C)
Hemochromatosis (iron/TIBC/Ferritin)
Celiac disease (TTG/IgA)
Autoimmune disease (ANA, ASMA, IgG,
AMA)
Wilsons (age<45- ceruloplasmin)

Diagnosing Fatty Liver

Disease
Imaging

Ultrasound- first line test

Picks up steatosis when >33% of

hepatocytes are affected

CT/MRI can also be used, but not

routinely
MR spectroscopy- not widely
available, but it is the most accurate
non invasive measure of steatosis

Diagnostic Goal #3 Establish Severity

Diagnostic Goal #2 Establish

Severity
General Message
Clinical prognosis depends on histology
Steatosis generally benign
Steatohepatitis increases risk for cirrhosis
Cirrhosis is associated with significant
morbidity
and mortality

Diagnostic Goal #3 Establish Severity

Establishing Severity
Blood Tests
Aminotransferase level not useful
Can be normal in advanced disease

AST/ALT ratio may help

High in cirrhotic NAFLD

Thrombocytopenia suggests cirrhosis

bili, albumin appear late

Diagnostic Goal #3 Establish Severity

Establishing Severity
Imaging Tests
Cant distinguish fatty liver from
steatohepatitis or early cirrhosis
Stigmata of portal HTN or nodular
liver contour suggest cirrhosis
May detect unsuspected HCC

Diagnostic Goal #3 Establish Severity

Establishing Severity
Composite Indices

Clinical/lab parameters
e.g., age >45-50 + obesity or DM suggest
bridging fibrosis

Fibrosis markers
Simple scoring systems using AST/ALT/plt,
etc
Commercial tests- Fibrotest, etc

Establishing Severity
Simple Non Invasive
Simple
Non Invasive
Commercial Fibrosis
Tests
Tests

BARD score

BMI, AST/ALT ratio, +/DM

NAFLD Fibrosis score

Tests

age, glucose intol, BMI,

platelet count, albumin,
AST/ALT ratio

FIB-4 score

age, AST, ALT, platelets

ELF (Enhanced Liver

Fibrosis test)
Fibrotest
Fibrosure

FIB-4 Score

http://gihep.com/calculators/hepatology/fibrosis-4score/

INPUT: AGE, AST, ALT, Platelets

Formula: ( Age x AST ) / ( Platelets x
( sqr ( ALT ) )

Explanation of Result :
For NASH :Fib4 score < 1.30 = F0F1
Fib4 score > 2.67 = F3-F4
For HCV with or without
HIV :Fib4 score < 1.45 = F0F1Fib4 score > 3.25 = F3-F4

Diagnostic Goal #3 Establish Severity

Establishing Severity
Liver Biopsy =
Gold standard
Limitations
Sampling error
Risk
Expense

AASLD Guidelines re
Liver Biopsy in NAFLD

Liver biopsy should be considered in

patients with NAFLD who are at
increased risk to have NASH and
advanced fibrosis.
The presence of metabolic syndrome
and the NAFLD fibrosis score may
be used for identifying these
patients.
Liver biopsy should be considered in
patients with suspected co-existing

Establishing Severity
Fibroscan

Effective non-invasive tool to

measure liver stiffness which
correlates with severity of fibrosis
Sensitivity/Specificity

>90% for F3/F4

Allows risk stratification of

patients
Predictive tool for complications
of cirrhosis
Used complimentary to liver
biopsy

Our Approach
to Establishing Severity

Review imaging, basic labs for any

signs of cirrhosis
Perform fibroscan
If result appears consistent with
clinical picture no biopsy
If fibroscan non diagnostic or
inconsistent with clinical picture perform liver biopsy to assess
severity
If concomitant liver disease

Treatment

At present, there is no one standard

recommendation for the treatment of
NAFLD/NASH
There is evidence to support:
Lifestyle modifications to lose weight
(all patients)
Vitamin E (non diabetic, non cirrhotic
patients)
Treat the metabolic syndrome (obesity,
diabetes, dysplipidemia) in all NASH
patients

Management strategies in non-alcoholic fatty liver disease

(NAFLD).

J K Dyson et al. Frontline Gastroenterol

doi:10.1136/flgastro-2013-100404
Copyright BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Lifestyle Modification
Diet/Exercise

10% weight loss is associated with

histologic improvement
Avoid trans fats and fructose which
in mice are associated with
progressive fibrosis
Mediterranean diet (high in
monounsaturated fatty acids)
compared with low fat high carb diet
reduces steatosis and improves
insulin sensitivity Ryan MC J Hepatol 2013

Individualizing Therapy
Diet

Avoid high fructose

corn syrup
(sugared soft
drinks)
Avoid trans-fatty
acids (partially
hydrogenated oils)
Coffee may be
beneficial
Hepatology 2012;55(2):429-436

Bariatric Surgery

Several series show regression of

steatosis and necroinflammatory
changes after surgery (Gastroenterology
2006;130:1848-1852)

A meta-analysis of 15 studies (766

paired liver biopsies) showed that
steatosis, steatohepatitis, and
fibrosis improve or completely
resolve in the majority of patients
after bariatric surgery induced
weight loss. (Clinical Gastroenterology and

Treating the Metabolic

Syndrome

Diabetes

Metformin first line treatment after diet

Pioglitazone second line
Insulin/sulfonylureas last choice

Hypertension

ACEI and ARBs may improve hepatic

fibrosis and transaminases

Hyperlipidemia

Statins are generally safe

Liver Directed
Medications

Consider in patients with biopsy

proven NASH who have failed
lifestyle modification
Pioglitazone has shown resolution of
steatohepatitis compared to placebo
Sanyal NEJM 2010, Boettcher Aliment Pharmacol Ther 2012

?long term safety- CHF, bladder Ca

Optimum duration unknown

Vitamin E- antioxidant. Shown

improve steatohepatitis at 800IU/day

Potential downsides all cause

mortality, stroke, prostate ca

NAFLD: Therapeutic Approach

NAFLD: Therapeutic Approach

Overt Metabolic Syndrome (MS)
Yes
Treat MS
Wt loss

No

Treat NAFLD
Steatosis

Steatohepatitis

Cirrhosis

Rx
Rx DM
DM
Anti-HTN
Anti-HTN
consider
Reduced kcals
consider
Rx
Lower
Rx portal
portal HTN
HTN
Lower lipids
lipids Reduced
Exercise
Vit
Exercise
Vit E/Pioglitazone
E/Pioglitazone Screen
Screen for
for HCC
Consider
Consider liver tx

Monitor for NAFLD Progression

Physical
Physical exams
exams (portal
(portal HTN)
HTN)
Blood
Blood tests (platelets, AST/ALT)
AST/ALT)
Fibroscan
Fibroscan

Weight Loss through Lifestyle Modification Significantly

Reduces Features of Non Alcoholic Steatohepatitis

Worsened
Stabilized
Regressed

Worsened

(A) Presence of baseline

fibrosis,
(B) absence of baseline
fibrosis.
293 patients
52 weeks
Diet- 750kcal less than daily
energy need
Exercise 200min/week by
walking

Regressed

Gastroenterology, Volume 149, Issue 2, 2015, 367378.e5

Bariatric Surgery in Patients with

Non Alcoholic Steatohepatitis

109 patients
Avg BMI 4937
ALT 5225
NASH resolved in 85%

Distribution of fibrosis stage before and 1 year after surgery:

Metavir score. (fibrosis staged with Metavir score)
(n = 80/82) with paired liver biopsies before and 1 year after surgery
Gastroenterology, Volume 149, Issue 2, 2015, 379388