Liver Path 3 - SRS Flashcards
Autoimmune hepatitis involves injury to normal hepatocytes by infiltrating T cells and plasma cells leading to fibrosis/cirrhosis. Lab tests for what characteristic antibodies are useful?
In addition to the antibodies, what else can you look for?
- Anti-nuclear antibodies
- Anti-smooth (actin) muscle antibodies
Also, look for high levels of polyclonal IgG
Autoimmune hepatitis is a chronic disease but is typicaly highly responsive to what two drugs?
Immunosuppression by prednisone and azathioprine
Are antimitochondrial antibodies found in autoimmune hepatitis?
Not usually.
These are more often seen in primary biliary cirrhosis.
In what patients is autoimmune hepatitis most common?
Is there a genetic association?
Young women.
Yes, HLA-DR in caucasians
What are the two types of autoimmune hepatitis?
Type 1
Type 2
What is the typical population affected by type 1 autoimmune hepatitis?
What antibodies are associated with type 1?
- Middle-aged women
- Antibodies include
- Antinuclear (ANA)
- Anti-smooth muscle (actin) antibodies (ASMA)
- pANCA
What is the typical population affected by type 2 autoimmune hepatitis?
What antibodies are associated with type 2?
–children or teenagers (mostly female)
–associated with anti-liver kidney microsomal antibodies (anti-LKM1)
Autoimmune hepatitis shares patterns of injury with acute or viral chronic hepatitis.
What are the features considered typical of autoimmune hepatitis?
–Extensive interface hepatitis
–Plasma cell predominance in the mononuclear inflammatory infiltrates
What do you see here in this sample?
What is going on with this patient?
Autoimmune hepatitis
Active interface hepatitis with numerous plasma cells in the portal inflammatory infiltrate and extending into the adjacent hepatic parenchyma are shown.
In both types of autoimmune hepatitis either an indolent or aggressive course may occur. What is the likely outcome in untreated?
Liver fails
What is a major component of the inflammatory infiltrate seen in autoimmune hepatitis?
plasma cells
What is the most common cause of acute liver failure in the US?
Tylenol
What are some examples of drug induced liver injuries?
- Bile duct injury
- Steatosis and steatohepatitis
- Vascular injury/veno-occlusive disease
- Neoplasms
What are three mechanisms by which drugs/chemicals can cause hepatic injury?
- Direct toxicity
- Hepatic conversion to a toxic form
- Immune mechanisms - agent acts as hapten
What are two common patterns of drug/toxin mediated hepatic injury?
Periportal region
pericentral region
If the periportal region is damaged, what processes are impaired?
Gluconeogenesis
Cholesterol synthesis
Urea synthesis
If the pericentral region is damaged, what are processes suffer as a result? 5
- Glycolysis
- bile acid synthesis
- glutamine synthesis
- drug metabolism
- p450-dependent bioactivation
What zone is the periportal zone?
Zone 1
What else is zone 3 called?
Perivenular region
What zone is the most common for zonal necrosis to occur?
Identify the toxins that are associated with this.
Zone 3
Acetaminophen
Bromobenzene
CCL4
CHCL3
copper salts
pyrrolizidine alkaloids
tannic acid
amanita phalloides toxins
What are some agents that characteristically produce periportal necrosis?
phosphorous
ferrous sulfate
Concentrated acetic acid
proteus vulgaris endotoxin
halothane
Except in rare cases of drug induced chronic hepatitis, the liver injury subsides and disappears after what?
Cessation of exposure/treatment to/with offending drug
What drug is particularly associated with hepatocellular injury?
Acetaminophen
What drug is associated with autoimmune hepatocellular injury?
halothane hepatitis
What drug is associated with cholestatic liver injury?
Estrogen
Acetaminophen is now the most common cause of acute liver failure necessitating transplantation in the United States.
What is the toxicity from?
What greatly enhances the toxicity?
Metabolic by-product (NAPQI)
Concurrent ETOH consumption
What is the antidote to acetaminophen induced acute liver failure and when must you give it?
What is the median acute dose that causes liver failure?
- Antidote is N-acetyl cysteine; must give within 8-12 hours; restores glutathione
- The median acute dose causing liver failure is 24 g (48 extra-strength tablets)
Apart from Ethanol, what are two other drugs to keep in mind that are inducers of CYP2E1 and increase actaminophen toxicity?
- •Isoniazid (INH)
- •Phenobarbital
Reye syndrome is associated with aspirin (though causality is not proven), and is a rare, potentially fatal syndrome typically seen in children.
What is the dysfunction?
What is seen on histology?
- Mitochondrial dysfunction, primarily liver and brain
- Extensive accumulation of fat droplets (microvesicular steatosis)
Most drugs/toxins affecting the liver can be classified as what?
Predictable
Unpredictable
How do predictable hepatotoxins act?
In a dose-dependent manner, and occur in most individuals.
Describe the action of unpredictable/idiosyncratic hepatotoxins.
Happen in rare individuals and are often independent of dose.
What is the most common hepatotoxin causing chronic liver failure?
Alcohol
What develops in all ETOH drinkers after moderate intake?
Is it permanent?
What will LFTs look like?
Fatty liver
Reversible until fibrosis develops
LFTs midly elevated
What is seen on microscopy of a patients liver with alcoholic hepatitis?
- Ballooning (swelling) and necrosis of hepatocytes
- formation of Mallory bodies
- Acute inflammation around degenerating cells
- centrilobular fibrosis
What percent of patients with alcoholic hepatitis die in the acute phase?
What percent develop cirrhosis?
10% mortality in acute phase
70% develop Cirrhosis
Alcohol is a hepatotoxin that inferes with what in hepatocytes?
This leads to what?
Mitochondrial and microsomal function leading to an accumulation of lipid.
Alcoholic Cirrhosis may be partially reversible, and includes what features in the background of the histo?
Steatosis and alcoholic hepatitis
What do you see in this picture?
Alcoholic foamy degeneration in which both macrovesicular and microvesicular steatosis is present in the perivenular and mid-zones.
What is the arrow pointing to in this slide from an alcoholic with steatohepatitis?
Neutrophilic infiltration
What is this?
What is this image recognize to be a precursor for?
Steatohepatitis
The development of cirrhosis
When you see the attached findings what jumps out at you?
What should you be thinking?
- Mallory Hyaline
- Think acute alcoholic hepatitis
What are these?
What do they represent?
- Mallory Bodies
- Represent tangles of intermediate keratin filaments complexed with proteins like ubiquitin.
What do you see here?
Fatty liver disease with pericentral vein fibrosis
What anatomical/histological area is the fibrosis here impacting?
The space of Disse
The pathophysiology of alcoholic fatty liver disease and NAFLD both begin with large globules of triglyceride in hepatocytes.
The steatotic liver is vulnerable to injury. What are causes of hepatocellular injury and fibrosis common to both settings?
Oxidative stress
proinflammatory activity of cytokines and friends (similar agents)
Beyond the ox stress and cytokines, what additional insults must occur to cause continued progressive damage to hepatocytes and promote inflammation and fibrosis. What does this likely involve?
–Inflammatory effects of gut-derived endotoxin
–Oxidative stress/lipid peroxidation
–Genetic polymorphisms
What is the threshold daily etoh intake required to produce pathologic changes of alcoholic hepatitis?
40 g (although on the very next slide he says 80g… so yeah)
(4 beers/day)
Which is more harmful to the liver, steady daily drinking or binge drinking?
Appears to be steady daily drinking.
How many years of drinking before development of cirrhosis?
What proportion of alcoholics develop liver disease?
10 - 15 years, and only occurs in a small proportion of alcoholics
NAFLD and •Hepatic steatosis (fatty liver) in individuals who do not consume alcohol or do so in very small quantities is associated with what conditions?
metabolic syndrome
- Obesity
- insulin resistance
- diabetes
- hyperlipidemia
- hypertension
Asymptomatic NAFLD patients have elevated Aminotransferase levels (<250 IU/L) and metabolic risk factors. What manner of testing usually identifies this condition?
•Liver imaging (ultrasound, computed tomography, or magnetic resonance imaging) obtained for another reason shows fatty infiltration
What does this MRI of a non-acoholic patient show?
NAFLD - arrow indicate fat infiltration
What are the two patterns of disease in non-alcoholic fatty liver disease?
Isolated Fatty liver
non-alcoholic steatohepatitis
Describe what is seen as far as fatty change, necrosis and inflammation in NAFLD.
•Fatty liver (NAFLD): > 5% fatty change but no necroinflammatory change
Describe the findings common to NASH. 4
- ballooning degeneration,
- necrosis,
- lobular inflammation,
- ± fibrosis
What is the most likely outcome of NAFLD?
80% isolated fatty liver, with no increased mortality vs. general population
What happens to the other 20% that don’t end up with isolated fatty liver?
NASH
What two things can NASH progress to?
NASH cirrhosis - 11%
HCC
What can NASH cirrhosis progress to (if it does, which is uncommon)?
Decompensation
HCC
What are four risk factors associated with alcoholic liver disease?
- Amount and duration of alcohol consumption
- Female gender
- Genetic factors
- Protein-calorie malnutrition
What are four risk factors associated with NAFLD?
- Obesity
- Type 2 diabetes
- Dyslipidemia
- Metabolic syndrome
What are the leading causes of liver cirrhosis in the USA? top 3
- •Chronic alcoholism is the leading cause of cirrhosis in the United States
- •Chronic hepatitis C is the second leading cause of cirrhosis in the United States
- •Nonalcoholic steatohepatitis (NASH)
Identify the stages of fibrosis in chronic hepatitis shown in the image.
- Top left: Portal
- Top Right: Periportal
- Bottom left: septal
- Bottom Right: cirrhosis
