Fatty Liver Disease

Anggreini Susanti
 Objectives
Identify risk factors for
fatty liver disease

Order appropriate
screening tests

Diagnose and treat

fatty liver disease

Initiate appropriate
referrals
 Terminology
ALD: Alcoholic Liver Disease
Significant alcohol consumption*
> 21 drinks/week for males
> 14 drinks/weeks for females
NAFLD: Non-Alcoholic Fatty Liver Disease
steatosis without hepatocyte
injury
NASH: Non-Alcoholic Steatohepatitis
steatosis with inflammation,
hepatocyte injury
with or without fibrosis
*Sanyal, et al Hepatology 2011
Fatty liver Normal
liver
 Statistics
Alcoholic liver disease
15 million people abuse/overuse ETOH in
USA
90% of those will develop fatty livers
Moderate use with another risk factor
Non-alcoholic liver disease
Most common chronic liver disease in USA
4th most common reason for liver transplant
Projected to be the most common in 10-20yrs
Up to 20-40% adults
6 million children
By 2020
 Natural History of FLD

fatty liver

steatohepatitis

steatohepatitis + fibrosis

steatohepatitis + cirrhosis

cryptogenic cirrhosis
 NAFLD
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 hepatic manifestation of Metabolic
Syndrome
Strongly associated with metabolic
determinants (obesity, T2DM,
hypertriglyceridemia, insulin resistance)
 NAFLD dan NASH Prevalence
in Western Countries

NAFLD NASH
General Population 10 24 % 3%
(non-obese)

Obesity 57 74% 19%

Severe Obesity > 80% 50%

Angulo. Ann. Hepatol, 2002.

 NAFLD Prevalence in Asia
China : 5 24%
India : 5 28%
Indonesia : ~ 30% (2001, Jakarta)
Japan : 9 30%
Malaysia : 15 17%

(Hashimoto E. 17th APASL Conference; Kyoto, Japan, 2007)

NAFLD prevalence in Indonesia
National data not available

A. Hospital-based data since 1991:

# 10 - 20% of CLD pts not associated with HBV or HCV
# Case reports of unexplained AST or ALT elevation
later on proved of NAFLD as the responsible cause
# Hepatology Div. Cipto M Hospital (2007): ~18% out of
1427 US examination were diagnosed as NAFLD
B. Population-based study in 2001 in Jakarta (Hasan et al):

NAFLD prevalence ~30%

NAFLD is probably the 3rd CLD cause after HBV and HCV
 NAFLD: risk factors
Middle age Auto-immune disease
Female gender Malnutrition
Over-weight or obese Abetalipoproteinemia
Viral hepatitis Overgrowth of bacteria in
small intestines
Iron overload
TPN
Medications Acute fatty liver of
Rapid weight loss pregnancy
Starvation/refeeding HELLP syndrome
syndrome Hispanic ethnicity
Reyes syndrome Hereditary
NAFLD = Hepatic Manifestation of
Metabolic Syndrome

Risk Factors of ATP III Criteria of

NAFLD: Metabolic Syndrome:

1. Waist : M >90 cm; F>80

1. (Central) Obesity cm
2. Type-2 DM 2. Serum TG 250 mg/dL
3. Dyslipidemia 3. Serum HDL: M < 40 mg/dL;
F < 50 mg/dL
4. Hypertension 4. Blood press. 130/85
mmHg
5. Insulin Resistance 5. Fasting gluc. 110 mg/dL
 Risk factors: Emerging
association
Polycysticovary syndrome
Hypothyroidism
Obstructive sleep apnea
Hypopituitarism
Hypogonadism
Pancreatic-duodenal resection
 Risk factor: Medications
Amiodarone
Methotrexate
Tamoxifen
Corticosteroids
Diltiazem
Valproicacid
Highly active antiretroviral therapy
 How were NAFLD recognized?

o Mostly by ultrasound (US): bright liver

o US can only detect moderate to severe degree
of steatosis
o Patients with mild degree steatosis can not be
detected by US/CT/MRI
o US-defined NAFLD prevalence were most likely
underestimate calculation
NAFLD: Ultrasound
 Further work-up indicated

Incidentalfinding on imaging for

some other reason
Abnormal liver enzymes
Symptoms of liver disease
Rule out other causes: alcohol,
medications, hepatitis, etc.
NAFLD fibrosis score
Age Albumin
BMI AST
Hyperglycemia ALT
Platelet count

http://nafldscore.com
 NAFLD fibrosis score

< -1.455: predictor of absence of

significant fibrosis (F0-F2 fibrosis)

-1.455 to 0.675: indeterminate

score

> 0.675: predictor of presence of

significant fibrosis (F3-F4 fibrosis)
 Algorithm for evaluating
NAFLD*
*taken from AGA position paper 2002
Accidental discovery Screen those with risk factors

AST or AST
Symptomatic liver disease
elevated normal

r/o other causes of liver disease

monitor
ongoing alcohol

yes no

Abstain Imaging study

Echogenic US or fat on CT
May need biopsy
 Liver biopsy
AASLD recs

Incidental finding on imagery with

normal enzymes: no biopsy indicated,
monitor.
Presence of metabolic syndrome and
persistently elevated biochemistries
may benefit from liver biopsy
Patients with biopsy proven NASH
cirrhosis should be screened routinely
for esophageal varices and HCC
 Assessment
Symptoms
Malaise, fatigue, RUQ discomfort
Snores, disturbed sleep, wakes up tired
Chronic pain disorders, achy muscles
Physical exam
Abdominal obesity
Enlarged liver
RUQ tenderness on palpation
Labs
Consistent with metabolic syndrome
Elevated bilirubin, AST, ALT, AP, GGT
 Weight gain in the area of and above the
waist (apple type) is more dangerous than
weight gained around the hips and flank are
(pear type). Fat cells in the upper
body have different qualities than those
found in hips and thighs
NAFLD Treatment

Main goals:
to reduce / reverse fibrosis progression
to prevent hepatic cirrhosis

Limitation:
Lack of positive large scale RCT
Most studies were open-label / pilot
 Management:
Lifestyle Interventions
 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
* Promrat, et al. Hepatology 2010
light intake (<1/day) may have benefits**, may not***
** Dunn, et al. Hepatology 2008
** Gunji. et al. Am J Gastro 2009
** Moriya, et al. Alim Pharm Ther 2011
***Ruhl , et al. Clin Gastro Hepatol 2005
 NAFLD Treatment
Insulin Antioxidants
Sensitizer Cytoprotectants
Anti-
hyperlipidemic
s

First Hit Second Hit

Normal Steatosis NASH
Insulin resistance Lipid
peroxidation
Fatty acids

Weight Loss Multi-hit process

Diet / Exercise
Management
Medications
 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
 PIVENS Study
Pioglitazone , Vitamin E, placebo
96 weeks
Adults
with NASH
without DM, cirrhosis, Hep C, heart failure
limited alcohol intake over previous 5 years
Randomized trial
Pio group: 80
Vit E group: 84
Placebo: 83
Sanyal et al, New England J of Medicine 2010
 Primary outcome

Vitamin E vs Pio vs placebo

placebo 34% improvement vs
43% improvement 19%: not significant
vs 19%: significant
(Steatosis, lobular
inflammation,
hepatocellular
ballooning and
fibrosis)
Sanyal et al, New England J of Medicine
2010
 Secondary outcome
Vitamin E vs Pio vs placebo
placebo Reduction in
Also reduction in SGOT/SGPT
SGOT/SGPT Reduction in steatosis,
lobular inflammation
Improvement in IR
Increase in weight that
did not resolve after
discontinuance of Pio

Sanyal et al, New EngJ of 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

 AASLD recommendations:
Pio can be used to treat certain patients
with biopsy-proven NASH who do not
have DM but long term safety and
efficacy has not been established
Vitamin E 800 IU/day improves liver
histology in NASH pts
Not recommended to treat NASH in those
with other chronic liver diseases, diabetics,
those with NASH cirrhosis or cryptogenic
cirrhosis, NAFLD without biopsy
 Vitamin E: other concerns
Meta-analysis* including 136,000
participants found taking Vitamin E
supplements > 400 IU/day had a
higher risk of all cause mortality
Vitamin E** > 400 IU/day increases
risk of prostate cancer in relatively
healthy men
*Miller et al Annals of Internal Medicine 2005

** Klein, et al, JAMA 2011

 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
 GREACE study*

Concluded statins significantly

improve liver biochemistries and
CV outcomes in pts with elevated
enzymes likely due to NASH

Athyros et al Lancet 2010

 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.
 SUMMARY
Insulin resistance and cellular damage involving oxidative
stress, apoptotic pathways, and adipocytokines are the key
pathogenetic mechanisms of NAFLD (Multi-hit hypothesis)
So far theres no standard medical treatment specifically for
NAFLD / NASH
Sustained gradual weight loss by diet with/without exercise
(lifestyle modification) remain hallmarks of NAFLD therapy, so
are treatment for other metabolic determinants
Insulin sensitizers, cytoprotectants, antioxidants, probiotics,
anti-apoptotic, ACE-inhibitor, TNF- inhibitor, and angiotensin
receptor blockers are under investigation, but so far none has
proved effective