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Non-Alcoholic Fatty Liver Disease

David W. Morris, DO, FACOIGastroenterology Specialists Inc.

This Date in History

Jan. 27, 1825

U.S. Congress approves Indian Territory leading to

governmental forced relocation of Native Americans by the

Indian Relocation Act (1830) and the Trail of Tears during which thousands of Native Americans lost their lives.

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• Where was Non-Alcoholic Fatty Liver Disease (NAFL) in the 1990’s?

• Does NAFL “progress” to Non-Alcoholic Steatohepatitis (NASH)?

• Are there risks for NAFL vs NASH?

• How is NAFL/NASH diagnosed?

• Should all cases of NAFL/NASH be treated?

• Why the sudden interest in NAFL/NASH?

Number of global SCI articles varies with time. Fitting equation during 2004–2013 is: Y = 99.279X − 198812, R2 = 0.9945. In the equation, Y is the number of accumulation articles and X is ... Zhang et al. 2015

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Definition

• Non-Alcoholic Fatty Liver Disease(NAFLD): Excess accumulation of triglycerides in the liver

• NAFL - steatosis of >5% of liver parenchyma without hepatocyte injury or fibrosis

• NASH - necroinflammatory process with hepatocyte injury (ballooning degeneration) in a background of steatosis

This Date in HistoryJan. 27, 1880

Thomas Edison patented the

incandescent lamp.

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Epidemiology

• NAFLD : 20-30% in Western countries, 5-81% in Asia.

• Prevalence is increasing worldwide (dietary, sedentary lifestyle)

• Linear rise with Diabetes and Metabolic Syndrome

• 10% higher incidence in overweight persons compared to lean persons in one U.S. study.

• Projected to be the major cause of liver related morbidity/mortality and leading indication for OLT in next 20 yrs.

• Lazo, Sem Liv Dz 2010

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Risk Factors

• Metabolic syndrome

• Increasing rate of development in Hispanic population with increased development of NASH and cirrhosis (PNPLA3 polymorphism)

• Asian population (some w/normal BMI)

• Lower incidence of steatosis in African Americans with decreased chance of developing liver failure

Risk Factors (cont.)

• PCOS

• Hyperlipidemia

• Type 2 DM

• Sedentary lifestyle, cigarette smoking

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Pathogenesis

• Excess free fatty acids/triglycerides in liver

• Insulin resistance plays a key role

• Increased hepatic lipogenesis

• Inflammatory cytokines, ROS, ER stress, mitochondrial dysfunction and hepatic insulin resistance

• Gut microbiota/pro-inflammatory cytokines

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Differential Diagnosis

• Alcoholic liver disease

• Drug-induced steatosis: MTX, amiodarone,tetracyclin, steroids, tamoxifen, chemotx, nucleoside analogs.

• HIV/HAART, viral hepatitis, A1AT, AIH, Wilson’s

Prognosis and Progression

• Mortality is directly associated with fibrosis

• Cardiovascular disease is the major cause of death in NAFLD

• Liver related mortality only accounts for 5% of deaths in NAFLD patients

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• Steatosis without inflammation tends to be stable

• Steatosis with inflammation and/or fibrosis may or may not have a benign course

• NASH = hepatocyte ballooning, steatosis and inflammation and is progressive

• Progressive fibrosis in NASH is 2x that of NAFL

• HCC risk higher in NASH than NAFL

This Date in History

Jan. 27, 1910

English Plumber, Thomas Crapper, was

instrumental in the development of indoor restrooms, died at 73

of bowel cancer.

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Screening

• Essential to identify NAFLD early - most cases identified incidentally (elevated liver tests), imaging study with fatty liver or present with cirrhosis

• Factors associated with metabolic syndrome

• Obesity, visceral adiposity

• Insulin resistance

Therapeutic Strategies

• Lifestyle intervention

• Antioxidants/FXR ligand

• Insulin resistance

• New therapeutic agents.

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Lifestyle Intervention

• Diet and physical activity - most important

• Bariatric surgery

• Achieves histological improvement in some patients

Lifestyle Intervention

• 5-10% reduction in weight

• Reduction in liver fat, NAS and inflammation, reduction in liver tests

• Impact on fibrosis unclear

• Often unable to maintain weight loss

• Consider bariatric surgery in otherwise appropriate patients

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Antioxidants/FXR ligand

• Vitamin E 800 IU daily improves steatosis, hepatic inflammation, ballooning, improves liver tests, resolves steatohepatitis but no effect on fibrosis. Use in non-diabetics.

• Increase in all cause mortality? and prostate cancer in men

• FXR ligand obeticholic acid (Ocaliva) CRT with improvement in NAS and improvement in fibrosis. Pruritus main side effect.

Targeting Hepatic Fat Accumulation

• Metformin - TONIC trial. Improved insulin resistance and ALT, not fibrosis

• Pioglitazone - PIVENS trial. Improved steatosis, inflammation, ALT, not fibrosis. Weight gain. (Conducted in non-diabetics)

• AASLD guidelines allow use in biopsy proven NASH (*Long term safety in diabetics is unknown)

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By Vi Nguyen, Jiawei Li, Dr Jude Oben31 August 2015

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