Liver Path 3 Flashcards
Autoimmune hepatitis
Injury to normal hepatocytes by infiltrating T cells and plasma cells leading to fibrosis/cirrhosis
Lab tests to detect immunologic abnormalities
Characteristic antibodies:
- Anti-nuclear antibodies
- Anti-smooth (actin) muscle antibodies
High level of polyclonal immunoglobulins (IgG)
Chronic disease but usually highly response to immunosuppression by prednisone and azathioprine
prevalence of autoimmune hepatitis
Most common in young women
Genetic predisposition (HLA-DR in Caucasians)
~50% of patients with AIH will have * concurrent autoimmune disorders
In Western Europe and North America, where viral hepatitis prevalence rates are relatively low, AIH accounts for roughly 20% of chronic hepatitis in the white populations
Type 1 autoimmune hepatitis:
middle-aged women
antinuclear (ANA), anti–smooth muscle (actin) antibodies* (ASMA) and pANCA
Type 2 autoimmune hepatitis:
children or teenagers (mostly female)
associated with anti-liver kidney microsomal antibodies (anti-LKM1)*
Histopathology of Autoimmune Hepatitis
Autoimmune hepatitis shares patterns of injury with acute or chronic viral hepatitis
Features considered typical of autoimmune hepatitis include:
Extensive interface hepatitis
Plasma cell predominance in the mononuclear inflammatory infiltrates
Robbins key concepts on autoimmune hepatitis
There are two primary types of autoimmune hepatitis:
- Type 1 autoimmune hepatitis is most often seen in middle-aged women and is most characteristically associated with antinuclear and anti–smooth muscle antibodies (ANA and ASMA)
- Type 2 autoimmune hepatitis is most often seen in children or teenagers and is associated with anti-liver kidney microsomal autoantibodies (anti-LKM1)
Autoimmune hepatitis may either develop with a rapidly progressive acute disease or follow a more indolent path; if untreated, both are likely to lead to liver failure.
Plasma cells are a prominent and characteristic component of the inflammatory infiltrate in biopsy specimens showing autoimmune hepatitis.
drug and toxin causes of liver injury, acute or chronic
esp. acetaminophen, ethanol
Exposure to a toxin or therapeutic agent should always be included in the differential diagnosis of any form of liver disease
Acute Hepatitis
Symptoms: nonspecific constitutional symptoms; jaundice
Liver chemistry tests: AST & ALT»_space;>Alk phos and TBili
Histologic pattern: lobular disarray with minimal portal changes and no fibrosis
Drug-Induced Liver Injury
Bile duct injury
Steatosis and steatohepatitis
Vascular injury/veno-occlusive disease
Neoplasms
Drug and Chemical induced Hepatic Injury
Drug-induced liver diseases can mimic all forms of acute and chronic hepatobiliary diseases
Hepatic injury may result from
Direct toxicity
Hepatic conversion to a toxic form
Immune mechanisms..agent acts as hapten
Patterns of Drug- and Toxin-Induced Hepatic Injury
The manifestations of drug-induced hepatotoxicity are highly variable*
- Periportal region: gluconeogenesis, cholesterol and urea synthesis; high oxygen
- Pericentral region: Glycolysis, bile acid and glutamine synthesis, drug metabolism, p450-dependent bioactivation
prognosis of drug-induced liver injury
Except in rare cases of drug-induced chronic hepatitis, the liver injury subsides and disappears after the cessation of treatment with the drug
Drug-Induced Liver Injury examples
Hepatocellular injury
- Acetaminophen
Autoimmune hepatocellular injury
- Halothane hepatitis
Cholestatic liver injury
- Estrogen (may have genetic predisposition)
Acetaminophen
now the most common cause of acute liver failure necessitating transplantation in the United States
Toxicity is from a metabolic by-product (NAPQI); Zone 3 necrosis (pericentral)
Toxicity is greatly enhanced by concurrent ETOH consumption (upregulation of cytochrome P-450 system)
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)
Drugs that Induce CYP2E1 Increase Acetaminophen Toxicity
**Ethanol
Isoniazid (INH)
Phenobarbital
Reye Syndrome
Associated with aspirin (causality not proven)
Rare, potentially fatal syndrome
Predominantly in children
Mitochondrial dysfunction, primarily liver and brain
Extensive accumulation of fat droplets (microvesicular steatosis)
* Acute liver failure without extensive necrosis
Key Concepts (Robbins) Drug- or Toxin-Induced Liver Injury
Most drugs or toxins affecting the liver may be classified as:
- Predictable hepatotoxins, acting in a dose-dependent manner and occurring in most individuals.
- Unpredictable or idiosyncratic hepatotoxins, which happen in rare individuals and which are often independent of dose
Hepatotoxins may cause harm from direct cell toxicity, through hepatic conversion of a xenobiotic to an active toxin, or by immune mechanisms, such as by the drug or a metabolite acting as a hapten to convert a cellular protein into an immunogen.
The most common hepatotoxin causing acute liver failure is
acetaminophen.
The most common hepatotoxin causing chronic liver disease is
alcohol.
Fatty Liver Diseases
Alcoholic Fatty liver:
- Alcoholic fatty liver
- Alcoholic steatohepatitis
- Alcoholic cirrhosis
Non-alcoholic fatty liver disease (NAFLD):
- Non-alcoholic fatty liver
- Non-alcoholic steatohepatitis (NASH)
- Non-alcoholic cirrhosis
Overlapping Stages of Alcoholic Liver Injury
FATTY LIVER
- Develops in all drinkers after moderate intake
- Completely reversible until there is fibrosis
- Have mild elevation of LFT’s
ALCOHOLIC HEPATITIS
- Ballooning (swelling) and necrosis of hepatocytes with formation of Mallory bodies
- Acute inflammation especially around degenerating cells
- Centrilobular fibrosis
- 10% mortality acute phase, 70% develop Cirrhosis
CIRRHOSIS
Features of steatosis and alcoholic hepatitis seen in background.
May be partially reversible
Mallory Hyaline
pink globs
They represent tangles of intermediate keratin filaments complexed with proteins like ubiquitin.
need to think about acute alcoholic hepatitis
pericellular fibrosis
seen as thin strands that are located in the perisinusoidal space of Disse and surround cords of hepatocytes.
time to stop the drug
Pathophysiology Ethanol and NAFLD
Both start with large globules of triglyceride in hepatocytes
The steatotic liver is vulnerable to injury.
Hepatocellular injury and fibrosis may develop in the presence of oxidative stress and the proinflammatory activity of cytokines and similar agents.
Fatty Liver to Steatohepatitis
Further insults must occur to cause continued progressive damage to hepatocytes and promote inflammation/fibrosis
These likely involve:
Inflammatory effects of gut-derived endotoxin
Oxidative stress/lipid peroxidation
Genetic polymorphisms
Alcoholic Liver Disease
11% of men and 6% of women are alcoholic, but only 10% of those individuals will get cirrhosis
Threshold daily alcohol intake of 40 g is necessary to produce pathologic changes of alcoholic hepatitis.
4 Beers –> Hepatic Injury
Key Concepts (Robbins) Alcoholic Liver Disease
Alcoholic liver disease is a chronic disorder that can give rise to steatosis, alcoholic hepatitis, progressive steatofibrosis and marked derangement of vascular perfusion leading eventually to cirrhosis.
Consumption of 80 gm/day of alcohol is considered to be the threshold for the development of alcoholic liver disease.
It may take 10 to 15 years of drinking for the development of cirrhosis, which occurs only in a small proportion of chronic alcoholics.
The multiple pathologic effects of alcohol include changes in lipid metabolism, decreased export of lipoproteins, and cell injury caused by reactive oxygen species and cytokines.
Non-Alcoholic Fatty Liver DiseaseNALFLD
Hepatic steatosis (fatty liver) in individuals who do not consume alcohol or do so in very small quantities
Associated with metabolic syndrome (obesity, insulin resistance or diabetes, hyperlipidemia and hypertension.
Non-Alcoholic Fatty Liver DiseasePresentation
Asymptomatic patients have elevated Aminotransferase levels (under 250 IU/L) and metabolic risk factors
Liver imaging (ultrasound, computed tomography, or magnetic resonance imaging) obtained for another reason shows fatty infiltration
Two patterns of nonalcoholic liver disease
Fatty liver (NAFLD): > 5% fatty change but no necroinflammatory change
Non-alcoholic steatohepatitis (NASH): ballooning degeneration, necrosis, lobular inflammation, ± fibrosis
RISK FACTORS FOR ALCOHOLIC LIVER DISEASE AND NONALCOHOLIC FATTY LIVER DISEASE
alcoholic: amount and duration of alcohol consumption, female, genetic factors, protein-calorie malnutrition
Non-alcoholic liver disease: obesity, type 2 diabetes, dyslipidemia, metabolic syndrome
Key Concepts (Robbins) Nonalcoholic Fatty Liver Disease
The most common metabolic disorder is nonalcoholic fatty liver disease, which is associated with the metabolic syndrome, obesity, type 2 diabetes mellitus or other impairments of insulin responsiveness, dyslipidemia, and hypertension.
Nonalcoholic fatty liver disease may show all the changes associated with alcoholic liver disease: steatosis, steatohepatitis, and steatofibrosis, even though the features of steatohepatitis (e.g., hepatocyte ballooning, Mallory-Denk bodies, and neutrophilic infiltration) are often less prominent than they are in alcohol-related injury.
Pediatric NAFLD is being increasingly recognized as the obesity epidemic spreads to pediatric age groups, although its histologic features differ somewhat from that seen in adults.
Most common Causes of Liver Cirrhosis in USA
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)
chronic hepatitis: staging fibrosis
1: portal
2: periportal
3: septal
4: cirrhosis
