Fatty Liver Disease Consulting : Abbvie, Gilead, Merck Speaking : - - PDF document

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Fatty Liver Disease

Jordan Feld MD MPH Toronto Western Hospital Liver Centre McLaughlin-Rotman Centre for Global Health

Disclosures

• Dr. Feld

 Research: Abbott, Abbvie, Gilead, Janssen, Merck  Consulting: Abbvie, Gilead, Merck  Speaking: None

Dr Shah

 Relationships with commercial interests: None  Speakers Bureau/Honoraria: None  Consulting Fees: Abbvie, Gilead, Merck, Intercept, Lupin  Other: None

Learning Objectives

• 1. Understand the burden of disease caused

by fatty liver disease

• 2. Recognize the difference between simple

steatosis and steatohepatitis

• 3. Develop an approach to management

including pharmacological interventions

Obesity Epidemic We’re not much better…

19 25 31 28 23 22 29 25 26 34 Canadian Community Health Survey; Stats Canada

Epidemiology

General population studies

 Ultrasound ~22%

 Lean 16%  Obese 76%

 Liver tests

 NHANES III 3-23%  11% liver tests >1.5 x ULN

 NAFLD 46% in pop’n study in US! Farrell, Hepatology 2006, Williams Gastroenterology 2011

NAFLD is the commonest cause of elevated ALT in N. America

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Summary of NAFLD Prevalence

 AASLD estimates:

NAFLD

Global prevalence 6.3-33% Median 20%

NASH

3-5%

NASH Cirrhosis

Unknown Chalasani et al Gastro 2012

What about high risk groups?

 DM

 62% NAFLD by US  87% confirmed by bx

 Hyperlipidemia clinic

 NAFLD 50%

 Bariatric surgery

 Up to 90% NAFLD  5% unsuspected cirrhosis!

Clinical Features

• Mainly asymptomatic

(48-100%)

• Uncommonly:
• RUQ discomfort
• Fatigue
• Malaise
• Hepatomegaly (75%)
• Splenomegaly

(if cirrhosis)

• Uncommonly:
• Palmar erythema
• Spider naevi
• Ascites

Diagnosis of Exclusion

 Labs

 ALT>AST (usually AST:ALT<1, never>2)  May have GGT elevation, ALP elevation 1/3  Ferritin often high – (50-62%) – more suggestive of

NASH

 Exclude: Viral hepatitis (HBV/HCV)

Autoimmune hepatitis (IgG, ANA, SMA) Wilson’s** - (ceruloplasmin, Ur Cu) Drug

Associated Conditions

 Obesity  HTN  DM  Hyperlipidemia  Weight gain or LOSS

 Common with anorexia!

 TPN

Metabolic Syndrome

Spectrum of NAFLD

Macrovesicular Hepatic Steatosis NonAlcoholic Fatty Liver Disease

Steatosis Cirrhosis Steatohepatitis (NASH) Steatosis +

Inflammation

Alcoholic Liver Disease

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Diagnosis

 US, CT, MRI can detect steatosis

 US is cheaper but less sensitive

 Liver biopsy is gold standard

 If diagnostic uncertainty  R/O advanced fibrosis

 Fibroscan / Fibrotest

 Must exclude ETOH (>20 g/day)

Without biopsy – CANNOT distinguish Steatosis from NASH

Are there alternatives to biopsy?

 NAFLD Fibrosis Score

 Age  BMI  Hyperglycemia  Platelet count  Albumin  AST/ALT ratio

http://nafldscore.com

Angulo Hepatology 2007

Performance

 Meta-analysis of 13 studies, 3,064 patients Exclude advanced fibrosis Sens 90% Spec 60% Detect advanced fibrosis Sens 67% Spec 97%

• 1.455

0.676

Gambino Annals of Med 2011 Angulo Hepatology 2007

Histology – More than Fat

Fat=Steatosis Cirrhosis Fibrosis Neutrophils Mallory Hyaline Inflammation=Hepatitis

The Hallmark of NASH

Ballooning Hepatocytes – necessary to dx NASH

NASH vs Steatosis… Does it matter?

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Natural History

Type 1 Fat alone Type 2 Fat + Inflammation Type 3 Fat + ballooning degeneration Type 4 Fat + fibrosis and/or Mallory bodies

P<0.001

Ten year follow up of 132 patients with biopsy proven NAFLD by type. Matteoni et al. Gastroenterology 1999

Patients with NASH have a significantly higher liver related mortality than patients with simple steatosis.

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Natural History – it’s not all liver!

NAFLD vs Gen pop’n

 Causes of death  Liver - 3rd vs 13th  Over 7 years  5% cirrhosis  2% liver-related

mortality

 1 required LT  2 HCC Adams, Gastroenterology 2005

NAFLD & Mortality

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Individuals with NAFLD increased mortality vs. general population

2.

Most common cause of death with NAFL or NASH is CARDIAC

3.

Patients with NASH, but not NAFL, have increased liver-related mortality

Chalasani et al Gastro 2012

NAFLD = hepatic manifestation of the metabolic syndrome

NAFLD Obesity Diabetes HTN Syndrome X DM & obesity risk factors for progressive fibrosis DM is a risk factor for death

74% NAFLD 22% NASH

Harrison Gastro 2011

What does NAFLD really mean?

You will get diabetes!!

So what can we do? Start with lifestyle

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Can we make this happen? Principles of Lifestyle Management

 Weight loss

 Diet and exercise

 Control of metabolic risk factors

 DM  BP  Cholesterol

 Limit alcohol

How much weight do they need to lose?

5-10% weight loss adequate to improve ALT and histology

Harrison Hepatology 2009 Promrat Hepatology 2010

Weight Loss Approaches

 Any diet that achieves weight loss is effective  Options:

 Low carbohydrate (less injera!)  Low fat (replace saturated with unsaturated), <30% total  Low caloric  Mediterranean  Others…

 Add exercise

 Aim 20 minutes of aerobic exercise 3 x per week  Simple things like walking…  Attending internal medicine rounds on the 8th floor!

How strict do we have to be? Some alcohol may actually be helpful…

• Multiple studies showing that 1-2 drinks per day may reduce

progression of NASH

• If significant fibrosis  complete abstinence

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What about drugs?

Lipid Lowering Agents

Adams & Angulo, Postgrad Med J 2006 Chalasani Gastro 2012

• Statins are SAFE in NAFLD
• Association with ALT/AST elevation but not fibrosis
• Hyperlipidemia is a bigger issue
• May even improve NASH

Therapies Study Design – PIVENS trial

 247 non-DM patients with biopsy proven NASH  Randomized – placebo

Vitamin E – 800 IU/day Pioglitazone 30 mg od

 2 years of treatment – f/u liver biopsy  Primary endpoint:

 Improved histology – decreased ballooning score,

with no worsening of fibrosis, NASH score down

Sanyal et al NEJM 2010

ALT improved

Sanyal et al NEJM 2010

Pioglitazone worked…

Sanyal et al NEJM 2010

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Histology

* * * * * * * * * * p<0.05 vs plac Sanyal et al NEJM 2010

Weight Gain????

Sanyal et al NEJM 2010

But before we put Vit E in the drinking water…

Is vitamin E safe? Other therapies?

 If BMI>35 + end-organ damage

• r BMI>40  consider surgery

 Seems to benefit NASH  Reduced inflammation &

fibrosis at 1 & 5 yrs post surgery

 Benefits beyond NASH

 Improved mortality!

Mathurin Gastro 2009

My Practice

 Exclude other causes  Non-invasive assessment of fibrosis (labs,

fibrotest/NAFLD Fibrosis score, Fibroscan)

 If suggestive of fibrosis or other etiology – consider biopsy  If not – lifestyle changes x 6-12 mo

 No improvement  biopsy!

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Action based on biopsy

 Biopsy with steatosis only – no action

 Monitor for metabolic complications  Reassess in 3-5 years

 Biopsy with NASH

 No fibrosis – lifestyle changes  follow  Fibrosis – if lean, pioglitazone

• if obese, vit E – 400 or 800 IU/d

Summary

 NAFLD is increasing  everywhere  Feature of the metabolic syndrome  Spectrum from steatosis to NASH  Steatosis  very good prognosis – worry about the

heart, not the liver

 NASH – worry about the liver too!  Lifestyle first – 5-10% weight loss with diet/exercise  Modest alcohol probably okay, coffee helpful  Treatment options: Vitamin E, pioglitazone, surgery