Non Alcoholic Fatty

Liver Disease
Sigit Widyatmoko
Fakultas Kedokteran
Universitas Muhammadiyah Surakarta

Fatty liver

Normal liver

Pendahuluan
NAFLD merupakan masalah kesehatan penting

di Asia tenggara dengan prevalensi 5%-30%

NAFLD merupakan suatu spektrum penyakit
mulai dari simple steatosis sampai NASH (non
alcoholic steatohepatitis) yang agresif dan
berlanjut menjadi sirosis
Sejalan dengan epidemi obesitas dan diabetes
komplikasi NASH akan terus meningkat

By 2020

Diagnosis
NAFLD adalah infiltrasi lemak hepatik pada

> 5 % hepatosit sebagaimana dinilai dari

biopsi hati atau MR spectroscopi tanpa ada
riw asupan alkohol yang berlebihan yaitu 2
gelas standar (20 g etanol) sehari untuk
laki-laki dan 1 gelas standar (10 g etanol)
untuk perempuan
Gold standar: px jaringan biopsi hati

A clinico-pathologic syndrome encompassing a wide

range of fatty liver disease in the absence of
significant alcohol intake and other common causes
of Steatosis.
The following are the stages.
Non Alcoholic Fatty Liver Disease NAFLD
Non Alcoholic Steato Hepatitis NASH
Non Alcoholic Cirrhosis (> 60% of cryptogenic)
6

Natural History of FLD

fatty liver
steatohepatitis
steatohepatitis + fibrosis
steatohepatitis + cirrhosis

 NAFLD is a diagnosis of exclusion

-Alcoholic Hepatitis
-Drug induced Hepatitis (tamoxifen,
amiodarone)
-Viral Hepatitis
-Autoimmune Hepatitis
-Metabolic (Wilson and Hemochromatosis)

 The most challenging DDX is

alcoholic hepatitis
The histologic picture of both
conditions is similar
Consumption of alcohol less than 10
g/d in women and 20 g/d in men

 NAFLD is considered the hepatic

manifestation of insulin resistance
(metabolic) syndrome
Might be discovered incidentally in a check
up
laboratory investigations alone have
limitations for the diagnosis of NAFLD
Combination of imaging studies is
necessary for the estimation of liver

The Two HIT Concept

d Accumulation

1st
HIT

2nd
HIT

Konsep ini kini dipertanyakan. Akumulasi TG di hati akan

melindungi hepatosit dengan buffering toksisitas
11
akumulasi asam lemak bebas

NAFLD terjadi ketika ambilan dan sintesis

asam lemak bebas melebihi oksidasi dan

resekresinya ke dalam darah
Steatosis dipicu oleh aliran lemak bebas dari
jaringan adiposa dan dari diet yang berlebihan
ke dalam hati, lipogenesis hepatik de novo,
gangguan eliminasi asam lemak bebas
hepatik

Laboratory
Investigations
~ 80%
in normal range
None of the currently used tests are
specific for the diagnosis of NAFLD
Aminotransferase elevation (< 4 times ULN)
It does not correlate with the severity of
steatosis or fibrosis

 AST/ALT ratio (AAR) > 1 suggesting

cirrhosis
Higher AST , ALT levels and AAR are
associated with NASH
The pattern of aminotrasferase
elevation do not provide a distinction
between simple fatty liver and NASH.

 The differentiation between these

conditions can be made by a
histological approach.
The amount of liver fat can not be
assessed using liver function tests
The degree of fat infiltration might be
diagnosed using a variety of imaging
modalities

 Hyperbilirubinemia, hypoalbominemia and

abnormal prothrombin time are present in
cirrhosis
Hyperglycemia, hypertriglyceridemia,
hypercholestrolemia are related to
metabolic syndrome
HOMA (FIL X FPG / 22.5) is an estimate of
insulin resistance
A correlation between HOMA and hepatic
steatosis is demonstrated
Decreased apolipoprotein B is a rare cause
of familial NAFLD (with normal LDL and
HDL)

Signs and symptoms

Asymptomatic in majority of cases
Fatigue (not correlated with liver injury severity)
RUQ pain or discomfort
Hepatomegaly (50%)
Cirrhosis and portal hypertension

Obesity
Hypertension
Cardiovascular or cerebrovascular diseases
Lipodystrophy (in non obese)

Imaging studies
Ultrasonography
- Safe, easy to perform, and acceptable
- First line imaging
- Hyperechogenic liver parenchyma in
contrast to kidney or spleen
- Hepato-renal index
- Spleen longitudinal diameter (might
differentiate between NASH and simple fatty liver)

Doppler ultrasonography
Associated with hepatic parenchyma
perfusion abnormality
Hepatic vein Doppler pattern
Doppler perfusion index (DPI): a ratio
between hepatic arterial blood flow
and total liver blood flow

Normal appearance of the liver at US.

The
echogenicity of the liver is equal to or
slightly

Diffuse fat accumulation in the liver at US.

The echogenicity of the liver is greater than that of the
renal cortex (rc). Intrahepatic vessels are not well depicted.
The ultrasound beam is attenuated posteriorly,
and the diaphragm is poorly delineated.

NAFLD: risk factors

Middle age
Female gender
Over-weight or obese
Viral hepatitis
Iron overload
Medications
Rapid weight loss
Starvation/refeeding
syndrome
Reyes syndrome

Auto-immune disease
Malnutrition
Abetalipoproteinemia
Overgrowth of bacteria in
small intestines
TPN
Acute fatty liver of
pregnancy
HELLP syndrome
Hispanic ethnicity
Hereditary

Risk factors: Established

association

Obesity
Type 2 DM: insulin resistance (IR)
Dyslipidemia
Metabolic syndrome (MS)

The New Definition of MS

Waist Circum

90 (M), 80 (F)
Triglycerides
HDL

2 of 5

>150 mg
<40 (M) < 50 (F)

Dysglycemia

FPG >100 or DM

Hypertension

>130 or 85

Rx. for any of the above conditions24

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Management: Lifestyle
Interventions

Weight loss by lower caloric intake and

increased physical exercise * led to
improvement in biopsy.
9.3% weight loss: improvement in
steatosis, necrosis, and inflammation;
not fibrosis
3-5% weight loss improves steatosis
but more is needed to improve
inflammation
Alcohol consumption:
heavy intake should be avoided
light intake (<1/day) may have benefits**, may not***

Insulin sensitizing agents

Metformin *
reduction in IR and enzymes,
no improvement in histology

Thiazolidinediones
Rosiglitazone**: improved enzymes and
steatosis, but not inflammation
Pioglitazone:***+weight gain, but improvement
in hepatocellular injury
2004

*Uygun, et al Aliment Pharm Ther

*Nair, et al Aliment Pharm Ther 2004

**Ratziu, et al Gastroenterology 2008
***Sanyal, et al NE J Med 2010

PIVEN Conclusions
Vitamin E was superior to placebo in
adults with NASH and without DM
Pioglitazone may have a role in
treating patients with biopsy-proven
NASH, however long term safety and
efficacy has not been established

Sanyal et al, New EnglJ of Med 2010

Other meds for NASH

Ursodeoxycholic acid*
no histologic benefit

Omega-3 fatty acids**

Effective in treating hypertriglyceridemia in
pts with NAFLD
Evidence for treatment of NASH
inconclusive to date
Large multi-center trial on-going now
*Lindor, et al. Hepatology 2004
**Capanni, et al. Alimen Pharm Ther
2006

Statins
CVD common cause of death for
NAFLD and NASH
Stratify risks and treat accordingly
Several studies show NAFLD and
NASH pts are not at increased risk of
liver injury over general population*
No RCTs with histological end points
using statins to treat NASH
*Chalasani, et al. Am J Gastro 2012

AASLD Recommendation on
Statins
Given lack of evidence that patients
with NAFLD and NASH are at
increased risk for serious druginduced liver injury from statins, they
can be used to treat dyslipidemia in
patients with NAFLD and NASH.

Alhamdulillahi Robbil
Alamiin