Lecture 35: Fatty Liver Disease

Question 1

What are the two causes of fatty liver disease?

Answer 1

1. alcoholic liver disease
2. nonalcoholic fatty liver disease
   These two look the EXACT SAME histologically

Question 2

How is alcohol metabolized?

Answer 2

1. Alcohol  (alcohol dehydrogenase)  acetaldehyde
2. Acetaldehyde  (Aldehyde dehydrogenase)  Acetate
   Alcohol is metabolized by being metabolized to a carboxylic acid
   Both reactions lead to a NADH byproduct

Question 3

What is the pathophysiology of alcoholic liver disease?

Answer 3

Increased NADH leads to increased fatty acid synthesis
Decreased mitochondrial beta-oxidation fatty acids
Fatty acids accumulate in hepatic cytoplasm
Esterification
Stored as triglycerides
Fatty liver

Question 4

How does alcohol cause liver damage?

Answer 4

1. oxidative stress
2. lipid peroxidation
3. kupffer cell activation

Question 5

How does alcohol cause fibrosis?

Answer 5

Stellate cells (primary collagen producing cells of the liver)
Normally quiescent (play a role in vitamin A metabolism)
Number of compounds produced during EtOH metabolism can activate stellate cells
-acetaldehyde
-oxygen radicals
-products of lipid peroxidation
-TGF-beta (kupffer cell activation)

Question 6

What is the pathogenesis of fatty liver disease by alcohol?

Answer 6

A. Excess production of NADH during metabolism of alcohol leads to excess synthesis and decreased breakdown as FFAs
B. These fatty acids are stored as triglycerides in the hepatocytes leading to steatosis
C. Production of free radicals and activation of Kupffer (liver macrophage) and Stellate Cells lead to necroinflammatory and fibrotic changes in the liver

Question 7

What is the prognosis of fatty liver due to alcohol?

Answer 7

Entirely reversible if you discontinue EtOH

May progress to hepatitis/cirrhosis if they continue to drink heavily

Question 8

What are the laboratory study values for alcoholic hepatitis?

Answer 8

AST > ALT is 2:1

A scotch and tonic is greater than ALT (mnemonic)

Question 9

What are the histological features of alcoholic hepatitis?

Answer 9

1. macrovesicular steatosis
2. poly infiltrates
3. centrilobular hepatocyte swelling
4. ballooning degeneration
5. Mallory bodies

Question 10

What are the signs and symptoms of alcoholic hepatitis?

Answer 10

1. Asterixis (inability to extend at the wrist)
2. jaundice
3. ascites
4. PALMAR ERYTHEMA

Question 11

What is NAFLD?

Answer 11

Entity with histology that resembles alcohol-induced liver injury but by definition occurs with little/no history of alcohol
Spectrum of disease that encompasses:
i. steatosis
ii. NASH (SteatoHepatitis = fat + inflammation)
iii. Cirrhosis

Question 12

What is NASH?

Answer 12

Nonalcoholic Steatohepatitis

Most likely to die from a heart attack

Question 13

Once you have cirrhosis, can you reverse it?

Answer 13

No it is irreversible

Question 14

What does nondrinker mean?

Answer 14

< than 2 standard drinks/day in men

< than 1 standard drinks/day in women

Question 15

How many obese children are affected by fatty liver?

Answer 15

Up to 77%

Question 16

What is metabolic syndrome?

Answer 16

Insulin Resistance Syndrome or syndrome X
Defined by at least 3 of these 5 criteria
i. abdominal obesity
ii. elevated triglycerides
iii. low HDL cholesterol
iv. elevated BP
v. elevated fasting plasma glucose

Question 17

What is the pathophysiology of NAFLD?

Answer 17

Exact mechanisms still not understood
Hypotheses suggest combination of two factors:
i. insulin resistance
AND
ii. Oxidative stress on hepatocytes

Question 18

How may insulin resistance lead to NAFLD?

Answer 18

No insulin signal = increased lipolysis (because no inhibition of lipolysis in adipocytes)
Increased lipolysis = increased FFA in blood
Increased FFA = increased FFA within hepatocytes = mitochondrial B-oxidation overload = accumulation of FFAs within hepatocytes
FFAs can also induce cytochrome p450 microsomal lipoxygenase = cytochrome p450 produce free oxygen radicals = induce lipid peroxidation of hepatocyte membranes

Question 19

How do you treat NFLD?

Answer 19

Weight reduction and correction of central obesity

Limited evidence for drug therapy

Question 20

Why use vitamin E for NAFLD?

Answer 20

Because it is an antioxidant and helps with at least one of the hypothesized etiologies

Question 21

What are other etiologies of fatty liver disease?

Answer 21

Medications like steroids
Wilson’s disease
TPN
Disorders of lipid metabolism like Weber-Christina Disease

Question 22

What is the gold standard of treatment for NAFLD?

Answer 22

I. The gold standard treatment for NAFLD is weight reduction of central obesity and treatment of other proponents of metabolic syndrome