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

cryptogenic 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 steatosis
 The Two HIT Concept

Lipid Accumulation 1st HIT

Oxidative Stress
2nd HIT
Cytokine Activation

Konsep ini kini dipertanyakan. Akumulasi TG di hati akan

melindungi hepatosit dengan buffering toksisitas akumulasi asam
11
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
Greater than that of the renal cortex (rc).
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 • Auto-immune disease
• Female gender • Malnutrition
• Over-weight or obese • Abetalipoproteinemia
• Viral hepatitis • Overgrowth of bacteria in small
• Iron overload intestines
• Medications • TPN
• Rapid weight loss • Acute fatty liver of pregnancy
• Starvation/refeeding • HELLP syndrome
syndrome • Hispanic ethnicity
• Reye’s syndrome • 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 >150 mg

HDL <40 (M) < 50 (F)

2 of 5 Dysglycemia FPG >100 or DM

Hypertension >130 or 85

24
Rx. for any of the above conditions 24
 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
*Uygun, et al Aliment Pharm Ther 2004
*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 drug-induced liver injury from
statins, they can be used to treat
dyslipidemia in patients with NAFLD and
NASH.”
Alhamdulillahi Robbil
Alamiin