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
 Iron overload small intestines
 Medications  TPN

 Rapid weight loss  Acute fatty liver of pregnancy

 Starvation/refeeding  HELLP syndrome

syndrome  Hispanic ethnicity
 Reye’s syndrome  Hereditary
 NAFLD = Hepatic Manifestation of
Metabolic Syndrome

Risk Factors of ATP III Criteria of

NAFLD: Metabolic Syndrome:

1. (Central) Obesity 1. Waist Ø: M >90 cm; F>80

2. Type-2 DM cm
3. Dyslipidemia 2. Serum TG ≥ 250 mg/dL
3. Serum HDL: M < 40 mg/dL;
4. Hypertension
F < 50 mg/dL
5. Insulin Resistance 4. Blood press. ≥ 130/85
mmHg
5. Fasting gluc. ≥ 110 mg/dL
 Risk factors: Emerging association

 Polycystic ovary syndrome

 Hypothyroidism
 Obstructive sleep apnea
 Hypopituitarism
 Hypogonadism
 Pancreatic-duodenal resection
 Risk factor: Medications
 Amiodarone
 Methotrexate
 Tamoxifen
 Corticosteroids
 Diltiazem
 Valproic acid
 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

 Incidental finding 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 rec’s

 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
– light intake (<1/day) may have benefits**, may not***

* Promrat, et al. Hepatology 2010

** 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 Sensitizer Antioxidants
Anti-hyperlipidemics Cytoprotectants

First Hit Second Hit

Normal Steatosis NASH
Insulin resistance Lipid
 Fatty acids peroxidation

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 placebo Pio vs placebo

43% improvement vs 34% improvement vs
19%: significant 19%: not significant
(Steatosis, lobular
inflammation,
hepatocellular
ballooning and
fibrosis)

Sanyal et al, New England J of Medicine 2010

 Secondary outcome
 Vitamin E vs placebo  Pio vs placebo
– Also reduction in – 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 there’s 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-α inhibitor, and
angiotensin receptor blockers are under investigation, but so
far none has proved effective