Non alcoholic fatty liver disease

(NAFLD)

George Therapondos

MBChB, FRCP (Edin), MPH

Hepatology

Ochsner Multiorgan Transplant

Institute

Disclosures

• Investigator for Conatus

Pharmaceuticals

•Consulting for Grifols and Medtronic

• Speaker for Grifols and Medtronic

Disclosures

• I have no financial interest/arrangement

of affiliation with one or more

organizations that could be perceived

as a real or apparent conflict of interest

in the context of the subject of this

program and/or presentation.

• All presentations have been peer

reviewed to eliminate any commercial

bias

Objectives

NAFLD:

• Epidemiology and natural history

• Diagnosis

• Treatment options

• Emerging/potential treatments

NAFLD Definitions

Entire spectrum of fatty liver disease

• Hepatic Steatosis

• Fatty infiltration

• No inflammation, hepatocellular injury or

fibrosis

• Nonalcoholic steatohepatitis (NASH)

• Inflammation (steatohepatitis) with or without

fibrosis

Diagnosing NAFLD

• Evidence of hepatic steatosis

– Imaging

– Histology (liver biopsy)

• No causes for secondary hepatic fat

accumulation

– Significant alcohol intake

– Use of steatogenic medications

Natural History of NAFLD

Fig. 1.

The disease spectrum of nonalcoholic fatty liver disease. ( A) Schematic of progression of

NAFLD. The accumulation of TG within lipid droplets in hepatocytes causes steatosis.

Steatosis associated with inflammation, cell death, and fibrosis is referred to as NASH,

which can progress to cirrhosis. Individuals with cirrhosis have an increased risk of

hepatocellular carcinoma. (B) Histological sections illustrating normal liver, steatosis,

NASH, and cirrhosis. Collagen fibers are stained blue with Masson’s trichrome stain. The

portal triad (PT), which consists of the hepatic artery, portal vein, and bile duct, and the

central vein (CV) are shown.

Cohen et al. Page 9

Science. Author manuscript; available in PMC 2011 December 2.

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Cohen JC, Horton JD, Hobbs HH (2011). Human fatty liver disease: old questions and new insights. Science 332(6037):1519-1523

● Strongly associated with insulin resistance and considered the

hepatic manifestation of the metabolic syndrome.

Global prevalence of NAFLD

• Data from 22 countries and 8,515,431 subjects

• Global prevalence of NAFLD by imaging was

25.24% with highest prevalence in the Middle

East and S America

• Prevalence based on ICD coding or blood

testing is lower suggesting underestimation

• NASH in general population estimated between

1.5-6.45% Younossi ZM et al. Hepatology 2016

NAFLD: Epidemiology

• Overlooked or underestimated in the past, and not well

known at present

• Highest prevalence is in adults aged 40-60 yrs, but

NAFLD occurs in children & adolescents

• High prevalence in industrialized countries

• NASH appears to be overtaking chronic hepatitis C as

the next “epidemic” in liver disease

Mittal A. Clinical Gastro and Hepatology 2015

Cardiovascular implications of

NAFLD

Cardiac arrhythmias

• Atrial fibrillation

• Prolonged QTc

• Premature ventricular

complexes and VT

CVS diseases

• Increased prevalence

• Independently of

traditional risk factors

• Genetic polymorphisms

may play a role

Cardiovascular diseases are the

commonest cause of death in patients

with NAFLD

Diagnosis

Symptoms of NAFLD

•No symptoms

• Fatigue, malaise (rarely)

• RUQ pain/discomfort

Liver Enzymes

– Normal range for ALT/AST < 20 women

– Normal range for ALT/AST < 30 men

• Alkaline phosphatase can be slightly elevated in

some (1/3)

• Bilirubin is usually normal

• Ferritin elevated in approx 50%

• Significant liver disease can be seen in those

with NAFLD and normal liver enzymes

Who to Evaluate?

• Persistently abnormal enzymes

• unexplained hepatomegaly or liver imaging

suggestive of NAFLD

• Other lab abnormalities associated with liver

disease eg high ferritin

• NO CLEAR CONCENSUS RE FORMAL

EVALUATION

Treatment

Management strategies in non-alcoholic fatty liver disease (NAFLD).

Dyson J K et al. Frontline Gastroenterol

doi:10.1136/flgastro-2013-100404

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Other factors

Avoid excessive

alcohol

• < 1 drink/day for

women

• < 2 drinks/day for

men

Bariatric surgery

Bariatric surgery- conclusions

• Reduces weight

• Improves diabetes

• Reduces necroinflammation

• Reduces fibrosis progression

• ? Who should benefit from this

• ?patient selection

• ?cirrhosis

Medications

• Vitamin E 400-800 IU/day

–Only can be recommended in biopsy

proven NASH without cirrhosis

–Should not be used in diabetic pts or pts

with cardiovascular disease

The therapeutic landscape of non‐alcoholic steatohepatitis

Perazzo and Dufour. Liver International Nov 2016

Multiple ongoing drug trials

- usually oral, well tolerated

• Variety of targets

•Metabolic homeostasis

• Inflammation

•Oxidative stress

• fibrosis

• Pioglitazone trials- Sanyal (PIVENS) 2010 and Cusi

(2016)

- Histologic improvement in NASH but with weight gain

and concerns about bone fractures/bladder ca and

cardiovascular risk

• FXR agonist- OCA- 2 trials (Mudaliar et al. 2013 +

Neuschwander et al. FLINT trial 2015) - some

encouraging results but pruritus was a significant AE

(23%)

• PPAR α/δ agonist—elafibranor. Ratziu et al. 2016.

GOLDEN-505)-no histologic difference between drug

and placebo.

- AE issues with reversible creatinine elevations

• Armstrong et al. 2016- LEAN trial- Liraglutide- NASH

reversal (39% vs 9%)

• Safadi et al. 2014- Aramchol- some metabolic changes

Clinical approach to patient with NAFLD

• Rule out other causes of abnormal LFTs or fatty

liver first!

• Non-invasive liver assessment/biopsy to stage

the disease

• Lifestyle modification- weight loss/exercise

• Treat diabetes/BP/lipids

• Vitamin E (?)

• Pioglitazone (??)

Conclusions

1. LFTs are unreliable

2. Lifestyle modification works but difficult

3. Most patients will have an excellent LIVER outcome but few will progress to cirrhosis

4. Significant cardiovascular morbidity and mortality

5. Multiple agents under investigation + bariatric surgery