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HISTORY

The original hist-pathologic. description of NAFLD ascribed to a group of obese patients. The term NASH was introduced by Ludwig and his colleagues in 1958.

 

CHARACTERISTICS

NAFLD characterized by macrovesicular  steatosis of liver, Progression to NASH to fibrosis, and advanced cirrhosis.

 

EPIDEMIOLOGY/PREVALENCE

Increasing prevalence in the world.

• US.- 10-46%

• Global: 20%

• India: 9-32%

• Hispanics-45%, Caucasians- 33%, African-Americans-31%, Asians-31%

Insulin resistance is the prevalent pathophysiological abnormality.

• Prevalence at BMI <25 is 16%. BMI>30-75%

Non-vegetarian food, fried foods, spicy food and tea linked to NAFLD

 

CAUSES

• Obesity, glucose intolerance, hypertension, hypertriglyceridemia, and low HDL cholesterol.

• Secondary to drug usage:  Corticosteroids, Tamoxifen Diltiazem, Aspirin, HAART, Valproic Acid, Amiodarone, Methotrexate, and total parenteral nutrition.

• Viruses: Hepatitis C, HIV.

• Metabolic: Hyperproteinemia, lipodystrophy, hypopituitarism, Weber Christian syndrome, and Reyes syndrome etc

• Toxins: organic solvents, mushroom toxins.

• Nutritional: Rapid weight loss, intestinal bypass surgery, and starvation.

 

PATHOGENESIS

• Hepatic Steatosis:  increased lipolysis, increased lipogenesis, decreased apoB-100, decreased leptin, and increased TNF-alpha

• Progression to NASH:  increase in reactive oxygen species, lipid peroxidation, depletion of natural antioxidant pool, intestinal microbes, , pro-inflammatory cytokines, endotoxin and apoptosis.

• The Stellate cell stimulation  leads to collagen-secreting myelofibroblast like cells and eventual hepatic fibrosis.

 

HISTOLOGIC FEATURES

Mixed inflammatory infiltrates, hepatocyte necrosis, ballooning, mallory’s hyaline, glycjogenated nuclei, and fibrosis.

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NATURAL HISTORY OF NAFLD

• Major concern: progression to cirrhosis and hepatic cellular carcinoma.

• The risk of disease progression is not clear.

• Those with simple steatosis on biopsy are at low risk for a progression while those with steatohepatitis are at higher risk.

• Some patients with fibrosis can show regression.

 

RISK FACTORS FOR PROGRESSION

• Older age

• Diabetes Mellitus

• Elevated AST and ALT

• Presence of Ballooning degeneration plus fibrosis on biopsy

• BMI > 28

• Higher visceral adiposity

• Coffee consumption associated with lower progression. Tea drinking with higher progression.

• Risk of HCC to develop in cirrhosis is 12% over 3 years.

 

CLINICAL FEATURES OF NAFLD

• Asymptomatic: 55-60%

• Malaise, & fatigue

• RUQ abdominal discomfort

• Obesity and features of metabolic syndrome

• Abnormal sleep patterns

• Hepatomegaly.

 

ALCOHOLIC STEATOHEPATITIS VERSUS NASH

• Alcoholic steatohepatitis

• Alcohol consumption history

• Jaundice present

• AST to ALT ratio >2

• Glycogen nuclei-rare

• Cholestasis often present

• Inflammation, Mallory Bodies present

• Central vein lesions seen.

 

NASH

• Alcohol history absent

• Jaundice absent

• AST to ALT ratio- <1

• Common Glycogen nuclei

• Cholestasis rare

• Patchy inflammation, with few mallory bodies.

• Central vein lesions rare.

 

LABORATORY ABNORMALITIES

• Modest ALT level raise. Rarely over 300 IUL

• AST to ALT  ratio typically <1

• Elevated Alkaline Phosphtase may be only abnormality in some cases.

• Elevated blood glucose, hypertriglyceridemia, and/or low HDL cholesterol.

• Elevated Ferritin level: 40-58%;

 

IMAGING MODALITIES

• Ultrasound- Hyperechoic, sensitivity- 85-95%, Specificity-62%

• CT Scan: Non-contrast sensitivity- 33%. Specificity- 100%

• MRI; Quantification- sensitivity-88%. Specificity 63%.

• MR Elastography and Fibroscan promising outcomes

 

LIVER BIOPSY

Most accurate for Diagnosis

 

TREATMEMENT

Weight Loss and increased physical activity:  Lead to sustained improvement in liver enzyme activity, histology, insulin levels and improved life quality.

Targets:

Weight loss of a pound a week. Exercise target of 30-60 minutes daily burning 300-400 kcal.

 

Bariatric Surgery: Shows improvement correcting metabolic syndrome features.

 

PHARMACOLOGIC THERAPIES

Vitamin E and Insulin sensitizers most common being studied.

Currently about 50 drugs being studied.

Other pharmacologic options include:

 

• ORLISTAT

Reversible inhibitor of gastric and pancreatic lipase, with 5-10% decrease in body weight in 6-12 months. Improved LFTs and histologic changes in 9 months post treatment. Well tolerated in 80% of patients

 

• STATINS

80% of NAFLD patients have dyslipidemia, but no significant changes in biochemistry or histology in NAFLD patients withy long term use.

 

• OMEGA 3 FATTY ACIDS

Associated with improved steatosis and inflammation, used especially for hypertriglyceridemia.

 

• ACE/ARB

Shown to be antifibrogenic, withnixproved insulin resistance, BP and serum biochemistry.

 

• OBETICHOIC ACID

A synthetic variant of bile acid promotes insulin sensitivity and decreased triglycerides. May improve histology. In phase 3 trials.

 

• Multiple other chemical pathways are being studied.

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Summarized by:

Dr. Parvin D. Syal