Update on Non-Alcoholic Fatty Liver Disease

<strong>Update</strong> on Non-Alcoholic Fatty
Liver Disease
Kathleen E Corey, MD, MPH
Gastrointestinal Unit, MGH

Outline
What are steatosis and NASH
Why should you care about NASH
How is NASH diagnosed
Treating NASH

Case Presentation
• AM is a 63M with obesity and hyperlipidemia
who presents for evaluation of abnormal LFTs.
• AST 57, ALT 52, AP 80, TB 0.4
• No history of alcohol use, no risk factors for viral
hepatitis

Case Presentation
• Viral serologies, iron studies, AIAT, celiac
studies, TSH normal
• ANA positive at 1:40, ASMA positive at
1:80
• US shows fatty infiltration, no ascites,
splenomegaly or abdominal varices

Case Presentation: What is
the diagnosis
• Autoimmune hepatitis
• Viral hepatitis
• NAFLD
• Celiac disease

What is the next step
• Weight loss and exercise
• Watchful waiting – repeat LFTs in 1 year
• Start Vitamin E
• Liver Biopsy

Case Presentation
• Liver biopsy
– 33-66% steatosis
– Diffuse lobular
inflammation with
glycogenated nuclei
– Hepatocyte ballooning
– Fibrosis stage 4 of 4
c/w cirrhosis

NAFLD
Spectrum of Hepatic Pathology
Steatohepatitis
Steatosis
Cirrhosis
Hepatocellula
r carcinoma

Non-Alcoholic Fatty Liver (NAFL)
Steatosis
Fatty hepatocytes
Intracellular
fat deposition

Non-Alcoholic SteatoHepatitis
(NASH)
Intracellular
fat deposition
Necrosis
Fibrosis
Fat deposits
Inflammation
Fibrosis with necrosis

Cirrhosis
Regenerati
ve nodule
Fibrosis
Nodules
surrounded by
fibrosis

How Many Americans Have
NAFLD
• 10%
• 25%
• 40%
• 60%
• 75%

Impact of NAFLD
Wanless IR Hepatology 1990
Thursz. EASL Berlin 2011

NAFLD Prevalence Dallas
Heart Study
(~1100 African Americans, 700 Caucasians, 400 Hispanics)
No risk factors
(n = 375)
Assess risk factors
for fatty liver
H 1 -NMR spectroscopy
Define normal
liver fat content
Assess prevalence of increased liver fat (steatosis)
in entire population & ethnic subgroups

Dallas Heart Study Results
Liver fat
< 5.5%
Liver fat
> 5.5%
Steatosis = 31%
Liver enzymes NORMAL in most (79%) with steatosis

Prevalence of Hepatic Steatosis: Varies with Ethnicity
Prevalence of Hepatic Steatosis
Varies with Ethnicity
Fatty liver
45%
33%
24%
Hispanics Whites Blacks

NAFLD in High-Risk Populations: Type 2 Diabetes Mellitus
NAFLD in High-Risk Populations
Type 2 Diabetes Mellitus
• 50% prevalence on ultrasound
•NASH unusually common
• Steatosis: 12%
• NASH: 87%
•Fibrosis or cirrhosis documented in 20%
Gupter et al. J Gastro Hepatol 2004;19:854-859
Tolman et al. Ann Intern Med 2004; 141:946-956

What percentage of NASH
patients have cirrhosis
• 1.5%
• 3%
• 20%
• 33%
• 55%

Neuschwander-Tetri Hepatology 2010
Impact of NAFLD
• Cirrhosis complicates 1% of patients with
steatosis, up to 33% of NASH
• NASH is associated with increased risk of
HCC
• NASH cirrhosis will be the leading
indication for OLT by 2020
Dam-Larsen Gut 2007

Prognostic Implications
of NASH + Fibrosis
• More consistent and rapid progression
to cirrhosis than NASH alone
NASH
> 10 years
Cirrhosis
3%
NASH +
fibrosis
5-10 years
Cirrhosis
35%
Matteoni Gastroenterology 1999

Impact of NAFLD
• NAFLD is associated with an increased all
cause mortality
• NAFLD is associated with increased risk of
cardiovascular disease in diabetic and
non-diabetic patients
Tarher Diabetes Care 2007
Ekstedt M Hepatolgy 2006

Diagnostic Goals
• Goal #1: Determine the etiology of liver
disease as NAFLD
• Goal #2: Determine the type of NAFLD
• Goal #3: Determine the severity of
NAFLD

Goal #1: Determine the
Etiology
• Who might have NAFLD
– Anyone with an elevated AST or ALT
– Anyone with the Metabolic Syndrome
– Anyone with fatty liver on imaging
– Anyone with cryptogenic cirrhosis

Goal #1: Determine the
Etiology
• Exclude other causes of abnormal LFTs
– Alcohol use
– Viral hepatitis
– Autoimmune liver disease (PBC, PSC, AIH)
– Celiac disease
– Thyroid disease
– Iron deposition disease
• Evaluate for presence of metabolic
syndrome

Goal #1: Determine the
Etiology
• AST and ALT

Goal #1Determine the
Etiology
• Imaging for NAFLD
– US, MRI and CT can
assess for fat
– Other liver disease
can cause steatosis
– Absence of fat does
not exclude NAFLD
especially in setting of
advanced fibrosis

Goal #1: Determine the
Etiology
• Distinguish Alcoholic Liver Disease from
NAFLD
– NAFLD Implies no EtOH or “safe” EtOH levels
– 2 drink or less per day for women, 3 drinks or
less per day for men
– This is a recent increase in allowable alcohol
use from the AASLD
Chalasani et al Hepatology 2012

Secondary Causes of
NAFLD
• Hepatitis C
• Wilsons Disease
• Disorders of lipid
metabolism
– Abetalipoproteinemia
– Hypobetalipoproteinemia
– Andersen’s disease
– Weber-Christian syndrome
• Total parenteral nutrition
• Severe weight loss
• Celiac disease
• Medications
– Amiodarone
– Diltiazem
– Tamoxifen
– Steroids
– Highly active antiretroviral
therapy

Goal #2: Determine the
Type of NAFLD
• Liver function tests are insufficient to distinguish
steatosis and NASH
• In a cohort of diabetics 86% of both steatosis and NASH had normal
LFTs
• ALT is not a reliable marker to differentiate steatosis from NASH
Tarher Diabetes Care 2007

Goal #2: Determine the Type
of NAFLD
• Metabolic syndrome is associated with increased risk of
NASH
• Elevated Ferritin level suggests increased risk for NASH
• Biopsy is the only definitive way to differentiate steatosis
and NASH
Tarher Diabetes Care 2007

Goal #3: Determine the
Severity of Disease
• Goal is to identify patients with advanced
fibrosis or cirrhosis
• The absence of signs of cirrhosis of
physical exam, labs suggesting synthetic
dysfunction or PHTN or imaging
suggesting cirrhosis are not sufficient to
exclude cirrhosis
• Liver biopsy is needed

Goal #3: Determine the Severity
of Disease
• Risk Factors for Cirrhosis
• Age > 45-50 years
• Obesity
• Diabetes
• 66% prevalence of bridging fibrosis if
age > 50 years and patient obese or
diabetic
• NAFLD fibrosis score

Liver Biopsy
Liver Biopsy

Risks of Liver Biopsy
• Post-procedure RUQ pain
• Bleeding
• Organ perforation
• Bile peritonitis

• NASH
– Fat
Is there NASH on Liver
– Lobular
inflammation
– Ballooning
degeneration
• Fibrosis
– Stage 3 or 4 (out of
4) is advanced
fibrosis = cirrhosis
Biopsy

Weight Loss & Exercise are
Cornerstones of Therapy
• Weight loss
– 3-5% weight loss improves steatosis
– 7-10 % weight loss has been associated with a significant
reduction in NAS
• Weight loss surgery
– 69% had complete resolution of NASH
– 65% had partial or complete improvement in fibrosis
• Exercise in absence of weight loss decreases steatosis
Ekstedt J of Hepatology 2007 (statin)
Mummadi CGH 2008
Pomrat Hepatology 2010 (7%)

Pioglitazone Improves
Inflammation in NASH
• Pioglitazone 30- 45mg daily for 48-96
weeks
• Necroinflammation and steatosis improved
considerable in pioglitazone group
• No improvement in fibrosis seen
Belfort NEJM 2006
Sanyal NEJM 2010

Vitamin E Improves
Steatosis & Inflammation
• RTC of 247 patients with biopsy proven NASH
without DM
• Vitamin E 800 units daily
• Vitamin E lobular inflammation and steatosis
• No change in fibrosis was seen
Sanyal NEJM 2010

Vitamin E and Prostate
Cancer
• 35 533 men randomized to selenium, vitamin E or both
agents, or both matched placebos for 7- 12 years.
• Compared with placebo, the absolute increase in risk of
prostate cancer per 1000 person- years was 1.6 for
vitamin E, 0.8 for selenium, and 0.4 for the combination.
• Use vitamin E with caution in men with NASH
EA Klein et al., JAMA 2011

Pharmacotherapy Under
Investigation
• Alpha lipoic acid
• Linagliptin
• PUFA
• ARB/ACEi
• Metformin
• OKT3
• HMG CoA reductase
inhibitors
• Ezetimibe
Basu AASLD 2011 #1658
Takeshita AASLD 2011 #1599

Advanced Fibrosis - Refer
to Hepatology
• Advanced fibrosis = cirrhosis
• Patients need
– EGD for variceal screening
– Q6months US or MRI for HCC screening
– MELD labs (INR, Cr, total bilirubin)
– Monitoring for the complications of advanced liver
disease

Take Home Messages
NASH is the form of NAFLD that can progress
NASH leads to cirrhosis and HCC
Biopsy is needed for
NASH Diagnosis
Weight loss and
pharmacotherapy