Chapter 18 – Drug- and Toxin-Induced Liver Disease Flashcards
What accounts for about 10% of adverse
drug reactions, and is the most common cause of fulminant hepatitis in the United States .
Drug-induced liver injury
The liver is subject to potential damage from an enormous array of pharmaceutical and
environmental chemicals. [39]
The incidence of liver injury induced by prescribed drugs is estimated to be between 14 and 40 per
100,000 patients.
What is the critical factor that influences the susceptibility to drug induced injury?
- (1) from direct toxicity to hepatocytes or biliary epithelial cells, causing necrosis, apoptosis, or disruption of cellular function;
- (2) through hepatic conversion of a xenobiotic to an active toxin; or
- (3) through immune mechanisms, usually by a drug or a metabolite acting as a hapten to convert a cellular protein into an immunogen
Drug reactions may either be what?
- predictable (intrinsic) or
- unpredictable (idiosyncratic).
What is a predictable drug reactions?
Predictable drug reactions can occur in anyone who receives a sufficient dose of an agent.
What is unpredictable drug reaction
Unpredictable reactions depend on idiosyncracies of the host, particularly the rate at which the
host metabolizes the agent, and the intensity of the immune response.
Idiosyncratic drug
reaction should be considered in any patient receiving what kind of drug?
a therapeutic drug who develops
evidence of liver damage.
Which age group is Idiosyncratic drug
reaction more susceptible?
Generally, adults are more susceptible than children, and women are
affected more than men.
Important examples include chlorpromazine, an agent that causes cholestasis in patients who are slow to metabolize it to an innocuous byproduct, and halothane, which can cause a fatal immune-mediated hepatitis in some patients who are exposed to this
anesthetic on multiple occasions.
What is the course of development in Drug- and Toxin-Induced Liver Disease?
It should be noted that the injury may be immediate or may take weeks to months to develop, presenting only after severe liver damage has developed. It may take the form of hepatocyte necrosis, cholestasis, or insidious onset of liver dysfunction.
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Pattern of
Injury
- Cholestatic
- Cholestatic hepatitis
- Hepatocellular necrosis
- Steatosis
- Steatohepatitis
- Fibrosis and cirrhosis
- Granulomas
- Vascular lesions
- Neoplasms
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Cholestatic
Morphologic Findings
Bland hepatocellular cholestasis, without inflammation
Examples of Associated Agents
- Contraceptive and anabolic steroids;
- estrogen replacement therapy
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Cholestatic
hepatitis
Morphologic Findings
- Cholestasis with lobular necroinflammatory activity;
- may show bile duct destruction
Examples of Associated Agents
- Numerous antibiotics;
- phenothiazines
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Hepatocellular
necrosis
Morphologic Findings
Spotty hepatocyte necrosis
Examples of Associated Agents
- Methyldopa,
- phenytoin
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Hepatocellular
necrosis
Morphologic Findings
- Submassive necrosis,
- zone 3
Examples of Associated Agents
- Acetaminophen,
- halothane
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Hepatocellular
necrosis
Morphologic Findings
Massive necrosis
Examples of Associated Agents
Isoniazid,
phenytoin
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Steatosis
Morphologic Findings
Macrovesicular
Examples of Associated Agents
- Ethanol,
- methotrexate,
- corticosteroids,
- total parenteral nutrition
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Steatohepatitis
Morphologic Findings
Microvesicular, Mallory bodies
Examples of Associated Agents
- Amiodarone,
- ethanol
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Fibrosis and
cirrhosis
Morphologic Findings
Periportal and pericellular fibrosis
Examples of Associated Agents
- Methotrexate,
- isoniazid,
- enalapril
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Granulomas
Morphologic Findings
Noncaseating epithelioid granulomas
Examples of Associated Agents
- Sulfonamides,
- numerous other agents
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Vascular
lesions
Morphologic Findings
- Sinusoidal obstruction syndrome (venoocclusive disease):
- obliteration of central
Examples of Associated Agents
- High-dose chemotherapy,
- bush teas
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Vascular
lesions
Morphologic Findings
Budd-Chiari syndromel
Examples of Associated Agents
Oral contraceptives
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Vascular
lesions
Morphologic Findings
Sinusoidal dilatation
Examples of Associated Agents
Oral contraceptives, numerous
other agents
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Vascular
lesions
Morphologic Findings
Peliosis hepatis: blood-filled cavities, not lined
by endothelial cells
Examples of Associated Agents
Anabolic steroids, tamoxifen
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Neoplasms
Morphologic Findings
Hepatic adenoma
Examples of Associated Agents
Oral contraceptives, anabolic
steroids
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Neoplasms
Morphologic Findings
Hepatocellular carcinoma
Examples of Associated Agents
Thorotrast
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Neoplasms
Morphologic Findings
Cholangiocarcinoma
Examples of Associated Agents
Thorotrast
TABLE 18-5 – Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury
Neoplasms
Morphologic Findings
Angiosarcoma
Examples of Associated Agents
Thorotrast, vinyl chloride
Among the agents listed in Patterns of Injury in Drug- and Toxin-Induced Hepatic Injury hepatic injury is considered predictable with overdoses
of what?
- acetaminophen,
- exposure to Amanita phalloides toxin,
- carbon tetrachloride, and,
- to a certain extent, alcohol.
What plays a major role in individual susceptibility to even “predictable” hepatotoxins?
However, individual genetic differences in the hepatic metabolism of xenobiotics through activating and detoxification pathways play a major role in individual susceptibility to even “predictable” hepatotoxins.
Many other xenobiotics, such as sulfonamides, α-methyldopa, and allopurinol, cause idiosyncratic reactions.
What is the leading cause of drug-induced acute liver failure the ?
acetaminophen
The most common prescription drugs causing idiosyncratic injury (that is, drug toxicity unrelated to drug
dosage) include what?
- antibiotics and, in particular,
- isonazid,
- nonsteroidal analgesics, and
- anti-seizure medications.
How does Idiosyncratic reactions evolve?
with a subacute course and are usually characterized by high bilirubin levels.
What can be responsible for both
predictable and idiosyncratic liver damage.
Herbal preparations
What is Reye syndrome?
Reye syndrome, a rare and potentially fatal
syndrome of mitochondrial dysfunction in liver, brain, and elsewhere, occurs predominantly in
childrenand ischaracterized morphologicallybyextensive accumulation of fat droplets within
hepatocytes (microvesicular steatosis).
How does Reye syndrome developed?
Its development has been associated with the
administration of acetylsalicylic acid (aspirin) for the relief of fever, but a causal relationship
between aspirin and Reye syndrome has not been established.
Nevertheless, aspirin should be
avoided in children with febrile illness.
What is the effect of Long-term methotrexate administration in the liver?
an effective
treatment for moderate to severe psoriasis, can cause liver injury, including hepatic steatosis
and fibrosis.
Drug-induced liver disease is usually followed by what?
recovery upon removal of the drug.
Exposure to a toxin or therapeutic agent should always be included in the differential diagnosis of liver
disease
T or F
True
What is the is the leading cause of liver disease in most Western countries?
Excessive alcohol (ethanol) consumption
In the United States, 50% of the population 18 years of age or older drink alcohol.
A subset of these individuals suffer serious health consequences associated with alcoholism (
Chapter 9 ).
Of greatest impact is alcoholic liver disease, which affects more than 2 million Americans and causes 27,000 deaths a year.
There are three distinctive, albeit overlapping,
forms of alcoholic liver disease:
- (1) hepatic steatosis (fatty liver disease) ,
- (2) alcoholic hepatitis,and
- (3) cirrhosis ( Fig. 18-22 ).
FIGURE 18-22 Alcoholic liver disease. The interrelationships among hepatic steatosis,
hepatitis, and cirrhosis are shown, depicting key morphologic features.
Hepatic Steatosis (Fatty Liver) .
After even moderate intake of alcohol, what happens?
microvesicular lipid droplets accumulate in hepatocytes.
With chronic intake of alcohol, what happens to the liver?
lipid accumulates creating large, clear macrovesicular globules that compress and displace the hepatocyte nucleus to the periphery of the cell.
What is the macroscopic appearance of the fatty liver of chronic alcoholism ?
Macroscopically,
a large (as heavy as 4 to 6 kg), soft organ that is yellow and greasy.
Although there is little or no fibrosis
at the outset, with continued alcohol intake fibrous tissue develops around the terminal hepatic veins and extends into the adjacent sinusoids.
The fatty change is completely
reversible if there is abstention from further intake of alcohol.
The fatty change is completely
reversible if there is abstention from further intake of alcohol.
T or F
True
Alcoholic Hepatitis (Alcoholic Steatohepatitis). Alcoholic hepatitis is characterized by:
- Hepatocyte swelling and necrosis
- Mallory bodies
- Neutrophilic reaction
- Fibrosis
Alcoholic Hepatitis (Alcoholic Steatohepatitis)
What is the morphoology of
Hepatocyte swelling and necrosis?
- *Single or scattered foci** of cells undergo
- *swelling (ballooning) and necrosis.**
The swelling results from the accumulation of fat
and water,as well as proteins that normally are exported.
In some cases there is cholestasis in surviving hepatocytes and mild deposition of hemosiderin (iron) in hepatocytes and Kupffer cells.
Alcoholic Hepatitis (Alcoholic Steatohepatitis)
What are Mallory bodies?
Scattered hepatocytes accumulate tangled skeins of cytokeratin intermediate filaments such as cytokeratin 8 and 18, in complex with other proteins
such as ubiquitin.
Mallory bodies are visible as eosinophilic cytoplasmic clumps in hepatocytes ( Fig. 18-23 ).
These inclusions are a characteristic but not specific
feature of alcoholic liver disease, since they also present in NAFLD, PBC, Wilson
disease, chronic cholestatic syndromes, and hepatocellular tumors.
Mallory bodies are a characteristic but not specific
feature of alcoholic liver disease, since they also present in what?
- NAFLD,
- PBC,
- Wilson disease,
- chronic cholestatic syndromes, and
- hepatocellular tumors.
In line with the characteristics of Alcoholic Hepatitis (Alcoholic Steatohepatitis)
Describe the Neutrophilic reaction.
Neutrophilic reaction:
Neutrophils permeate the hepatic lobule and accumulate
around degenerating hepatocytes, particularly thosehaving Mallory bodies.
Lymphocytes and macrophages also enter portal tracts and spill into the parenchyma.
Alcoholic hepatitis is almost always accompanied by prominent activation of
sinusoidal stellate cells and portal tract fibroblasts, giving rise to what?
fibrosis
Most frequently fibrosis is sinusoidal and perivenular, separating parenchymal cells
occasionally, periportal fibrosis may predominate, particularly with repeated bouts of heavy alcohol intake.
What is Cirrhosis?
Cirrhosis.
The final and irreversible form of alcoholic liver disease usually evolves slowly and
insidiously but may develop in 1 or 2 years in some cases.
At first what is the appearance of the cirrhotic liver?
- yellowtan,
- fatty, and enlarged,
- usually weighing over 2 kg.
Over the span of years, what is the histological appearance of Cirrhosis?
it is transformed into a brown, shrunken, nonfatty organ, sometimes less than 1 kg in weight.
Initially the developing fibrous septa are delicate and extend through sinusoids from central to portal regions as well as from portal tract to portal tract.
Regenerative activity of entrapped
parenchymal hepatocytes generates uniform micronodules.
With time the nodularity becomes
more prominent; scattered larger nodules create a “hobnail” appearance on the surface of
the liver ( Fig. 18-24A ).
As fibrous septa dissect and surround nodules, the liver becomes more fibrotic, loses fat, and shrinks progressively in size.
Parenchymal islands are engulfed by wider bands of fibrous tissue, and the liver is converted into a mixed micronodular and macronodular pattern ( Fig. 18-24B ).
Ischemic necrosis and fibrous obliteration of nodules
eventually create broad expanses of tough, pale scar tissue (“Laennec cirrhosis”).
Bile stasis
often develops; Mallory bodies are only rarely evident at this stage.
Thus, end-stage
alcoholic cirrhosis comes to resemble,bothmacroscopically and microscopically,
the cirrhosis developing from viral hepatitis and other causes.
What is Laennec cirrhosis?
Ischemic necrosis and fibrous obliteration of nodules
eventually create broad expanses of tough, pale scar tissue (“Laennec cirrhosis”).
FIGURE 18-23 Alcoholic hepatitis.
A, The cluster of inflammatory cells marks the site of a necrotic hepatocyte (arrow).
B, Eosinophilic Mallory bodies are seen in hepatocytes, which are surrounded by fibrous (Masson stain) tissue.
FIGURE 18-24 Alcoholic cirrhosis.
A, The characteristic diffuse nodularity of the surface
reflects the processes of nodular regeneration and scarring. The greenish tint of some
nodules is due to bile stasis. A hepatocellular carcinoma is present as a budding mass at
the lower edge of the right lobe (lower left) .
B, The microscopic view shows nodules of
varying sizes entrapped in blue-staining fibrous tissue. The liver capsule is at the top
(Masson trichrome).
What is the pathogenesis of ALCOHOLIC LIVER DISEASE?
Short-term ingestion of as much as 80 gm of alcohol (six beers or 8 ounces of 80-proof liquor) over one to several days generally produces mild, reversible hepatic steatosis.
Daily intake of
80 gm or more of ethanol generates significant risk for severe hepatic injury,anddaily ingestion
of 160 gm or more for 10 to 20 yearsis associatedmore consistently with severe injury.
Only
10% to 15% of alcoholics, however, develop cirrhosis. Thus, other factors must also influence
the development and severity of alcoholic liver disease. These factors include:
- Gender
- Ethnic differences
- Genetic factors
- Co-morbid conditions.
How many ounces of beer can produce mild, reversible hepatic steatos?
Short-term ingestion of as much as 80 gm of alcohol (six beers or 8 ounces of 80-proof liquor) over one to several days generally produces mild, reversible hepatic steatosis.
Daily ingestion of how many ounces can generate siginificant risk for hepatic injury?
Daily intake of
80 gm or more of ethanol generates significant risk for severe hepatic injury
How many ounces of alcohol injection is associated more consistently with severe injury?
daily ingestion of 160 gm or more for 10 to 20 years
Only
10% to 15% of alcoholics, however, develop cirrhosis. Thus, other factors must also influence
the development and severity of alcoholic liver disease. These factors include:
- Gender
- Ethnic differences
- Genetic factors
- Co-morbid conditions.
When it comes to gender, which is more susceptible to hepatic injury?
. Women seem to be more susceptible to hepatic injury than men are, although the majority of patients are men.
Why are women more susceptible in hepatic injury than men?
This difference may be related to alcohol
pharmacokinetics and metabolism, and theestrogen-dependent response to gutderived
endotoxin (LPS) in the liver. [42]
Estrogen increases gut permeability to
endotoxins, which, in turn, increase the expression of the LPS receptor CD14 in Kupffer
cells.
This predisposes to increased production of pro-inflammatory cytokines and
chemokines.
In the United States, cirrhosis rates are higher for African Americans than for white Americans.
What is the reason?
The difference cannot be explained by the amount of alcohol consumption, since there is no significant difference in consumption among the ethnic
groups.
Studies with twins suggest that there is a genetic component in alcoholinduced
liver disease. There is also a strong family association, but in these cases it is
difficult to separate genetic from environmental influences.
What are the Genetic factors associated to alcohol induced liver disease?
Current attention is being
given to genetic polymorphisms in detoxifying enzymes and some cytokine promoters.
ALDH*2, a genetic variant of aldehyde-dehydrogenase (ALDH), found in 50% of Asians,
has a very low activity ( Chapter 9 ).
Individuals who are homozygous for ALDH*2 are
unable to oxidize acetaldehyde and do not tolerate alcohol.
What are the co-morbid conditions that increase the
severity of alcoholic liver disease?
Iron overload and infections with HCV and HBV
What are the detrimental effects of alcohol and its byproducts on hepatocellular function?
Exposure to alcohol causes:
- steatosis,
- dysfunction of mitochondrial and
- cellular membranes,
- hypoxia, and
- oxidative stress.
At millimolar concentrations, alcohol directly affects
microtubular and mitochondrial functionandmembrane fluidity
Hepatocellular steatosis results from what?
- (1) shunting of normal substrates away from catabolism and toward lipid biosynthesis, as a result of generation of excess reduced nicotinamide adenine dinucleotide (NADH + H+ ) 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.
What is the major metabolite of alcohol?
Acetaldehyde
The causes of alcoholic hepatitis are uncertain but some of the factors in its pathogenesis are
discussed. What are these?
- Acetaldehyde (the major intermediate metabolite of alcohol) induces lipid peroxidation and acetaldehyde-protein adduct formation, further disrupting cytoskeletal and membrane function.
- Cytochrome P-450 metabolism produces reactive oxygen species (ROS) that react with cellular proteins, damage membranes, and alter hepatocellular function.
- In
addition, alcohol-induced impaired hepatic metabolism of methionine leads to decreased
intrahepatic glutathione levels, thereby sensitizing the liver to oxidative injury. The induction of
CYP2E1 and other 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.
Why do alcoholics result to deficiency of vitamins ( such as thiamine)
Alcohol can become a major source of calories in the diet of an alcoholic, _displacing other
nutrients and leading to malnutrition and deficiencies of vitamins (such as thiamine)._
This is
compounded by impaired digestive function, primarily related to chronic gastric and intestinal
mucosal damage, and pancreatititis.
What is the reason for the inflammatory response in the liver in relation to alcohilic hepatitis?
Alcohol causes the release of bacterial endotoxin from the gut into the portal circulation, inducing inflammatory responses in the liver, such as the activation of NF-κB, and release of
TNF, IL-6, and TGF-α.
What is the reason for Portal Hypertension in Alcoholic hepatits?
In addition, alcohol stimulates the release of endothelins from sinusoidal endothelial cells, causing vasoconstriction and the contraction of activated stellate cells (“myofibroblasts”), leading to a decrease in hepatic sinusoidal perfusion (already discussed
under “Portal Hypertension”).
In summary, alcoholic liver disease is a chronic disorder featuring steatosis, hepatitis progressive fibrosis, cirrhosis, and marked derangement of vascular perfusion. I
t can be
regarded as a maladaptive state in which cells in the liver respond in an increasingly pathologic
manner to a stimulus (alcohol) that originally was only marginally harmful.
For some unknown
reason, cirrhosis develops in only a small fraction of chronic alcoholics.
Hepatic steatosis (fatty liver) may become evident as what?
hepatomegaly, with mild elevation oserum bilirubin and alkaline phosphatase levels.
Severe hepatic dysfunction is unusual. Alcohol
withdrawal and the provision of an adequate diet are sufficient treatment. In contrast, alcoholic
hepatitis tends to appear acutely, usually following a bout of heavy drinking. Symptoms and
laboratory manifestations may range from minimal to fulminant hepatic failure. Between these
two extremes are the nonspecific symptoms of malaise, anorexia, weight loss, upper abdominal
discomfort, tender hepatomegaly, and the laboratory findings of hyperbilirubinemia, elevated
alkaline phosphatase, and often a neutrophilic leukocytosis. 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. With repeated bouts, cirrhosis appears in
about one third of patients within a few years. Alcoholic hepatitis also may be superimposed on
established cirrhosis. With proper nutrition and total cessation of alcohol consumption, the
alcoholic hepatitis may clear slowly. However, in some patients, the hepatitis persists, despite
abstinence, and progresses to cirrhosis.
Severe hepatic dysfunction is unusual in Hepatic steatosis (fatty liver)
T or F
True
What is the treatment for Hepatic steatosis (fatty liver)?
Alcohol withdrawal and the provision of an adequate diet are sufficient treatment.
What is the clinical course of Alcoholic hepatitis?
In contrast to Hepatic steatosis (fatty liver), alcoholic
hepatitistends to appear acutely,usually following a bout of heavy drinking.
What are the clinical symptoms of alcoholic hepatitis?
Symptoms and laboratory manifestations may range from minimal to fulminant hepatic failure.
Between these two extremes are the nonspecific symptoms of :
- malaise,
- anorexia,
- weight loss,
- upper abdominal discomfort,
- tender hepatomegaly, and the
- laboratory findings of hyperbilirubinemia, elevated alkaline phosphatase, and often a
- neutrophilic leukocytosis.
.
An acute cholestatic syndrome of Alcoholic hepatitis may
appear, resembling what?
large bile duct obstruction.
What is the prognosis of hepatitis?
The outlook is unpredictable; each bout of
hepatitis incurs about a 10% to 20% risk of death.
With repeated bouts, cirrhosis appears in
about one third of patients within a few years. Alcoholic hepatitis also may be superimposed on
established cirrhosis.
With proper nutrition and total cessation of alcohol consumption, the alcoholic hepatitis may clear slowly.
However, in some patients, the hepatitis persists, despite abstinence, and progresses to cirrhosis
What are the manifestations of alcoholic cirrhosis?
similar to those of other forms of cirrhosis.
What are the lab findings in Alcoholic cirrhosis?
Laboratory findings reflect the hepatic dysfunction, with elevated serum aminotransferase,
hyperbilirubinemia, variable elevation of serum alkaline phosphatase, hypoproteinemia
(globulins, albumin, and clotting factors),andanemia.
In some instances, liver biopsy may be
indicated, since in about 10% to 20% of cases of presumed alcoholic cirrhosis, another disease
process is found.
Finally, cirrhosis may be clinically silent, discovered only at autopsy or when stress such as infection or trauma tips the balance toward hepatic insufficiency.
What is the long-term outlook for alcoholics with liver disease?
variable.
- Five-year survival approaches 90% in abstainers who are free of jaundice, ascites, or hematemesis;
- it drops to 50% to 60% in those who continue to imbibe.
In the end-stage alcoholic, what is the proximate causes of death?
- (1) hepatic coma,
- (2) massive gastrointestinal hemorrhage,
- (3) intercurrent infection (to which these patients are predisposed),
- (4) hepatorenal syndrome following a bout of alcoholic hepatitis, and
- (5) hepatocellular carcinoma (the risk of developing this tumor in alcoholic cirrhosis is 1% to 6% of cases annually).
END
Drug- & Toxin-Induced Liver Disease
