Alcoholic Liver Disease

Front 1

What is the percentage of liver disease in Native Americans?

What percent of all deaths from chronic liver disease in Native Americans?

Back 1

41%

65%

Front 2

Back 2

Front 3

What percent of chronic liver disease is alcoholic liver disease?

What percent of deaths from cirrhosis?

Back 3

Front 4

What is the number one and number two cause of chronic liver disease in the US?

Back 4

Front 5

Back 5

Front 6

Back 6

Front 7

Back 7

Front 8

Back 8

Front 9

Back 9

Front 10

What age for alcoholic hepatitis?

How much alcohol is required and for how many years?

Rapid onset of what clinical sign?

Other symptoms?

What will be enlarged and tender on physical exam?

Compare the AST and ALT ratios.

Back 10

Front 11

Alcoholic hepatitis:

Will you see leukocytosis?

Elevated INR?

Back 11

Front 12

Back 12

Front 13

Is there a well understood pathogenesis of alcoholic hepatitis?

Back 13

Not really.

Front 14

What gene was associated with increased susceptibility of to ALD in East Asians?

What is the polymorphism in caucasians?

Back 14

Front 15

What two chemicals cause intestinal injury and increased permeability resulting in endotoxemia? What does endotoxemia result in an inflammatory response by?

Back 15

Front 16

Back 16

Front 17

Two hit theory:

1st Hit: _______ liver
Oxidative stress
↑_______ ratio
Obesity and DM: genetics/diet
______ sensitizes liver to 2nd hits
2nd Hit:
______ and necrosis
Oxidative stress/______/immunological reaction

Back 17

1st Hit: Fatty liver
Oxidative stress
↑NADH/NAD ratio
Obesity and DM: genetics/diet
Fat sensitizes liver to 2nd hits
2nd Hit:
Inflammation and necrosis
Oxidative stress/hypoxia/immunological reaction

Front 18

What are these all used for in alcoholic hepatitis?

Back 18

Predictors of survival

Front 19

Back 19

Front 20

Identify the numbers for the Glasgow Alcoholic Hepatitis Score (1, 2, 3)

Age

WBC

BUN

INR

Bilirubin

Back 20

Front 21

Back 21

KNOW WHAT MELD IS FOR THE EXAM! DON'T KNOW FORMULA, JUST KNOW WHAT IT DEPENDS ON

Front 22

Back 22

Front 23

What are three advanced liver diseases in alcoholics?

Back 23

Front 24

Back 24

Front 25

Back 25

Front 26

What is the condition?

What percent of patients with this condition had ethanol abuse? What was its effect on cirrhosis and survival compared to those without ethanol abuse?

Back 26

Front 27

Patients with which mutation had more advanced fibrosis and cirrhosis?

Heterozygosity of which gene likely plays a role in increasing iron loading and liver injury?

Back 27

Front 28

Alcoholic cirrhotic patients with which mutations had increased hepatic iron scores and higher rates of HCC?

Back 28

Front 29

What is shown here?

Back 29

a1AT deficiency

Front 30

What is phenotype MZ?

Back 30

Front 31

In patients with alpha one antitrypsin deficiency, what percent had chronic hepatitis associated with alcohol? What percent had alcoholic cirrhosis?

Back 31

Front 32

What are the three most important environmental factors determining ALD risk?

Back 32

Ethanal patterns

Obesity and associated hyperglycemia

Front 33

Obviously, you want to avoid alcohol and optimize nutrition, but what are two drug therapies for treatment of ALD?

Back 33

Pentoxifylline

Immunsuppression with corticosteroids

Front 34

Back 34

Front 35

Back 35

Front 36

Therapy = nutrition and abstinence

Back 36

Front 37

Draw the pathogenic pathways of alcoholic liver disease interrelationships.

Back 37

Front 38

What do all changes in alcoholic liver disease begin in? What can accumulate even after moderate intake of alcohol?

What is the gross appearance of the liver in someone with chronic alcoholism and fatty liver.

Is fatty change reversible?

Back 38

Front 39

“Alcohol causes steatosis, dysfunction of ___ and cellular membranes, ___, and oxidative stress.

At millimolar concentrations, alcohol directly affects ___ and mitochondrial function and membrane fluidity.

Hepatocellular steatosis results from
(1) shunting of normal substrates away from catabolism and toward lipid biosynthesis, as a result of increased generation of reduced ___ by the two major enzymes of alcohol metabolism, ___ dehydro­genase and acetaldehyde dehydrogenase;

(2) impaired assembly and secretion of ___; and

(3) increased peripheral catabolism of __, thus releasing free fatty acids into the circulation.”

Back 39

“Alcohol causes steatosis, dysfunction of mitochondrial and cellular membranes, hypoxia, and oxidative stress.

At millimolar concentrations, alcohol directly affects microtubular and mitochondrial function and membrane fluidity.

Hepatocellular steatosis results from
(1) shunting of normal substrates away from catabolism and toward lipid biosynthesis, as a result of increased generation of reduced nicotinamide adenine dinucleotide (NADH) by the two major enzymes of alcohol metabolism, alcohol dehydro­genase and acetaldehyde dehydrogenase;

(2) impaired assembly and secretion of lipoproteins; and

(3) increased peripheral catabolism of fat, thus releasing free fatty acids into the circulation.”

Front 40

What three major things is alcoholic hepatitis characterized by? (histology)

What is the major difference between alcoholic hepatitis and viral/autoimmune hepatitis?

Back 40

Front 41

What condition is shown on the slide here? Identify neutrophils and Mallory Denk bodies.

Back 41

Front 42

What are the arrows pointing to?

How long can they persist after exposure to alcohol has ended?

Back 42

Mallory-Denk bodies

Front 43

Alcoholic Liver Disease: Hepatitis

“____ (the major intermediate metabolite of alcohol) induces lipid peroxidation and acetaldehyde-protein adduct formation, disrupting cytoskeletal and membrane function.

Alcohol impairs hepatic metabolism of ____, which decreases glutathione levels, thereby sensitizing the liver to _____ injury. The induction of cytochrome P-450 enzymes in the liver by alcohol increases alcohol catabolism in the ____ and enhances the conversion of other drugs (e.g., acetaminophen) to toxic metabolites.

Alcohol stimulates the release of ____ from sinusoidal endothelial cells, causing vasoconstriction and contraction of activated, myofibroblastic stellate cells, leading to a decrease in hepatic sinu­soidal _____.

Alcohol causes the release of bacterial ____ from the gut into the portal circulation, inducing inflammatory responses in the liver, due to the activation of NF-κB, and release of ___, ___, and ___.”

Back 43

“Acetaldehyde (the major intermediate metabolite of alcohol) induces lipid peroxidation and acetaldehyde-protein adduct formation, disrupting cytoskeletal and membrane function.

Alcohol impairs hepatic metabolism of methionine, which decreases glutathione levels, thereby sensitizing the liver to oxidative injury. The induction of cytochrome P-450 enzymes in the liver by alcohol increases alcohol catabolism in the endoplasmic reticulum and enhances the conversion of other drugs (e.g., acetaminophen) to toxic metabolites.

Alcohol stimulates the release of endothelins from sinusoidal endothelial cells, causing vasoconstriction and contraction of activated, myofibroblastic stellate cells, leading to a decrease in hepatic sinu­soidal perfusion.

Alcohol causes the release of bacterial endotoxin from the gut into the portal circulation, inducing inflammatory responses in the liver, due to the activation of NF-κB, and release of TNF, IL-6, and TGF-α.”

Front 44

What is the ear lies pattern of hepatic fibrosis in alcoholic liver disease?

What does fibrosis begin with?

Back 44

Front 45

What does fibrosis start and spread to?

What is the process of capillarization?

Back 45

Front 46

Pericellular fibrosis.

What is the characteristic pattern?

Back 46

Front 47

When alcohol use continues without interruption over the long term, nodules of regenerating hepatocytes (regenerative nodules) come to be separated by broad bands of _____ tissue. The continual subdivision of established nodules by new webs of perisinusoidal scarring leads to a classic _____ (Laennec) cirrhosis first described for end-stage alcoholic liver disease.

Back 47

Front 48

What is the condition?

Back 48

Cirrhosis

Front 49

Cirrhosis with ongoing necrosis of hepatocytes is called what?

Back 49

Active cirrhosis

Front 50

Is cirrhosis reversible?

Back 50

Yes

Early stages of scarring can regress with cessation of alcohol use, but the farther along toward cirrhosis the liver gets, the more vascular derangements prevent a full restoration of normal. Complete regression of alcoholic cirrhosis, while reported, is rare:

Front 51

What percent of alcoholics develop cirrhosis?

Men or women more susceptible? Why?

Which race is more susceptible?

Which enzyme found in 50% of Asians has a very low activity?

Back 51

Front 52

What can cause hepatomegaly with mild elevations of serum bilirubin and alkaline phosphatase levels? Is severe hepatic dysfunction unusual?

Back 52

Hepatic steatosis

Front 53

Alcoholic hepatitis tends to appear _____, usually following a bout of heavy drinking. Symptoms and laboratory manifestations may range from minimal to acute liver failure. Between these two extremes are the nonspecific symptoms of malaise, _____, weight loss, upper abdominal discomfort, and tender _____, and the laboratory findings of hyperbilirubinemia, elevated serum aminotransferases and alkaline phosphatase, and often a neutrophilic leukocytosis.

In contrast to other chronic liver diseases where serum ALT tends to be higher than serum AST, serum ___ levels tend to be higher than serum ___ levels in a 2:1 ratio or higher in alcoholic liver disease. This can sometimes be helpful in the differential diagnosis of chronic liver injury.

An acute cholestatic syndrome may appear, resembling large bile duct obstruction.

The outlook is unpredictable; each bout of hepatitis incurs about a 10% to 20% risk of death.

Back 53

Alcoholic hepatitis tends to appear acutely, usually following a bout of heavy drinking. Symptoms and laboratory manifestations may range from minimal to acute liver failure. Between these two extremes are the nonspecific symptoms of malaise, anorexia, weight loss, upper abdominal discomfort, and tender hepatomegaly, and the laboratory findings of hyperbilirubinemia, elevated serum aminotransferases and alkaline phosphatase, and often a neutrophilic leukocytosis.

In contrast to other chronic liver diseases where serum ALT tends to be higher than serum AST, serum AST levels tend to be higher than serum ALT levels in a 2:1 ratio or higher in alcoholic liver disease. This can sometimes be helpful in the differential diagnosis of chronic liver injury.

An acute cholestatic syndrome may appear, resembling large bile duct obstruction.

The outlook is unpredictable; each bout of hepatitis incurs about a 10% to 20% risk of death.

Front 54

What is the five-year survival in alcoholic liver disease? What does it drop to in those who continue to imbibe, and lower yet in many who continue drinking to great excess.

What are the five proximate causes of death in end-stage alcoholic liver disease?

Back 54

Front 55

What are some components of Mallory-Denk bodies

Back 55

Cytokeratin 8 and 18 => ubiquitin normally recycles but gets stuck to them due to toxicity of alcohol

NOT SPECIFIC FOR ALCOHOLIC LIVER DISEASE

Rounder, more oblong than a1AT (more rounded)