Lecture 35: Fatty Liver Disease Flashcards
What are the two causes of fatty liver disease?
- alcoholic liver disease
- nonalcoholic fatty liver disease
These two look the EXACT SAME histologically
How is alcohol metabolized?
- Alcohol (alcohol dehydrogenase) acetaldehyde
- Acetaldehyde (Aldehyde dehydrogenase) Acetate
Alcohol is metabolized by being metabolized to a carboxylic acid
Both reactions lead to a NADH byproduct
What is the pathophysiology of alcoholic liver disease?
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
How does alcohol cause liver damage?
- oxidative stress
- lipid peroxidation
- kupffer cell activation
How does alcohol cause fibrosis?
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)
What is the pathogenesis of fatty liver disease by alcohol?
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
What is the prognosis of fatty liver due to alcohol?
Entirely reversible if you discontinue EtOH
May progress to hepatitis/cirrhosis if they continue to drink heavily
What are the laboratory study values for alcoholic hepatitis?
AST > ALT is 2:1
A scotch and tonic is greater than ALT (mnemonic)
What are the histological features of alcoholic hepatitis?
- macrovesicular steatosis
- poly infiltrates
- centrilobular hepatocyte swelling
- ballooning degeneration
- Mallory bodies
What are the signs and symptoms of alcoholic hepatitis?
- Asterixis (inability to extend at the wrist)
- jaundice
- ascites
- PALMAR ERYTHEMA
What is NAFLD?
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
What is NASH?
Nonalcoholic Steatohepatitis
Most likely to die from a heart attack
Once you have cirrhosis, can you reverse it?
No it is irreversible
What does nondrinker mean?
< than 2 standard drinks/day in men
< than 1 standard drinks/day in women
How many obese children are affected by fatty liver?
Up to 77%
What is metabolic syndrome?
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
What is the pathophysiology of NAFLD?
Exact mechanisms still not understood Hypotheses suggest combination of two factors: i. insulin resistance AND ii. Oxidative stress on hepatocytes
How may insulin resistance lead to NAFLD?
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
How do you treat NFLD?
Weight reduction and correction of central obesity
Limited evidence for drug therapy
Why use vitamin E for NAFLD?
Because it is an antioxidant and helps with at least one of the hypothesized etiologies
What are other etiologies of fatty liver disease?
Medications like steroids
Wilson’s disease
TPN
Disorders of lipid metabolism like Weber-Christina Disease
What is the gold standard of treatment for NAFLD?
I. The gold standard treatment for NAFLD is weight reduction of central obesity and treatment of other proponents of metabolic syndrome
