DRUG-INDUCED LIVER DISEASE

PREPARED BY:
RODD OCLARINO
MECHANISMS OF DRUG-
INDUCED LIVER DISEASE
 STIMULATION OF AUTOIMMUNITY

AUTOIMMUNE INJURIES
 involve antibody mediated cytotoxicity or direct cellular toxicity
 happens when enzyme-drug adducts migrate to the cell surface
and form neoantigens, these antigens serve as targets for cytolytic
attack by T cells.
 are associated with:
o HALOTHANE
o SULFAMETHOXAZOLE
o CARBAMAZEPINE
o NEVIRAPINE
 STIMULATION OF AUTOIMMUNITY

CHRONIC ACTIVE HEPATITIS

 a type of autoimmune-mediated disease associated with
dantrolene, isoniazid, phenytoin, nitrofurantoin, and trazodone.
 these drugs appear to form antiorganelle antibodies.
 progressive disease with a high mortality rate
 more common in females than males.
 diagnosis of chronic active hepatitis requires multiple episodes
that occur long after exposure to the offending agent to identify
the causative agent.
 IDIOSYNCRATIC REACTION
IDIOSYNCRATIC DRUG-RELATED HEPATOTOXICITY
 rare and usually occurs in a small proportion of individuals.
 may be classified as allergic reaction or nonallergic reaction.
 ALLERGIC REACTION
 are characterized by fever, rash, and eosinophilia.
 allergic reactions are usually dose-related and have a short
latency period which is less than one month.
 these allergy reactions may be caused by:
• MINOCYCLINE
• NITROFURANTOIN
• PHENYTOIN
upon reexposure to the offending agent, the patient will
experience
 IDIOSYNCRATIC REACTION
IDIOSYNCRATIC DRUG-RELATED HEPATOTOXICITY
 NONALLERGIC REACTION
 devoid of the hypersensitivity features and usually have a
long
latency period (several months).
 these patients often have normal liver function tests for 6
months or
longer and then suddenly develop hepatotoxicity.
 it is either be independent of the dose or dose-related.
 drugs that are associated with nonallergic drug-related
hepatitis are:
• AMIODARONE
• ISONIAZID
 DISRUPTION OF CALCIUM
HOMEOSTASIS AND CELL MEMBRANE
INJURY
 Drug-induced damage to the cellular proteins that are involved with
calcium homeostasis can lead to:
• influx of intracellular calcium that causes a decline in adenosine
triphosphate levels
• disruption of the actin fibril assembly
 The resulting impact on the cell is blebbing of the cell membrane,
rupture, and cell lysis.
 Drugs that impair calcium homeostasis include:
• LOVASTATIN
• VENLAFAXINE
• PHALLOIDIN  active component of mushrooms
 METABOLIC ACTIVATION OF THE
CYTOCHROME P450 ENZYMES
 most hepatocellular injuries involve the production of high-energy reactive metabolites
by the cyp450 system.
 Covalent bonds are formed by these metabolites with enzymes and nucleic acids that
lead to adduct formation.
 In the case of acute toxicity, the enzyme-drug adduct can cause cell injury or cell lysis.
 NEOPLASIA is one long term consequence of adducts that form with DNA.
 patients with a single nucleotide polymorphism (SNP) that codes for slow-reacting
variants of CYP450 will react differently from those with a SNP that codes for very fast-
reacting variants.
 makes individual genetic differences a significant factor of this disease
 examples of drugs that cause this mechanical injury include:
 ACETAMINOPHEN
 FUROSEMIDE
 DICLOFENAC
 STIMULATION OF APOPTOSIS
APOPTOSIS
 represents a distinct pattern of cell lysis that is characterized by:
• cell shrinkage
• fragmentation of nuclear chromatin
 the pathways occur by interactions between death ligands and death
receptors.
• DEATH LIGANDS  tumor necrosis factor and fas ligand.
• DEATH RECEPTORS  tumor necrosis factor 1 and fas.
 these interactions activate caspases which cleave cellular proteins
and eventually lead to cell death. cumulative doses of
acetaminophen cause apoptosis.
 MITOCHONDRIAL INJURY
 drugs that impair mitochondrial structure, function, or dna synthesis can
disrupt by:
• β-OXIDATION OF LIPIDS
• OXIDATIVE ENERGY PRODUCTION WITHIN THE HEPATOCYTE
 prolonged interruption of β-oxidation leads to:
o MICROVESICULAR STEATOSIS  acute diseases
o MACROVESICULAR DISEASE  chronic diseases
o HEPATIC FAILURE AND DEATH  severe mitochondrial damage
 mitochondrial injury by inhibiting β-oxidation can be caused by:
 ASPIRIN
 VALPROIC ACID
 LIVER NEOPLASTIC DISEASE

 Both carcinoma- and sarcoma-like lesions have been identified.

 Hepatic tumors associated with drug therapy are usually benign and
remit when drug therapy is discontinued.
 The model for drug-induced hepatic cancer is polyvinyl chloride
exposure.
 Used in the production of many types of plastic products, polyvinyl
chloride induces angiosarcoma in exposed workers after as few as 3
years of exposure.
ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE
 ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE

 Knowing the patient’s history is the best and important method for
assessing and monitoring drug-induced liver disease.
 This includes questioning the patients drug use and a
thorough review of systems are essential.
 Protocols can be used to accurately assess a patient for
hepatoxicity such as proposed by DANAN and BENICHOU.
 ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE

Recreational drugs or drugs of abuse may be a possible cause of

hepatoxicity. COCAINE has been directly linked to liver disease.
ECSTASY(methylenedioxymethamphetamine) has induced
fulminant hepatitis.
CONCOMITANT INJECTION OR INGESTION OF ADULTERANTS
have a big
impact on the incidence of hepatic disease under street drugs.
* Many of these adulterants are either directly toxic or
serve to
enhance the toxicity of the drug.
 ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE

 When assessing hepatoxicity, it is also important to determine nondrug

hepatic disease risk.
 ARSENIC
• it is known to induce both acute and chronic hepatic
reactions.
• in low concentrations is found in insect lumber.
 Even if exposure to an environmental toxin in and of itself does not
produce a hepatic reaction, it may predispose a patient to a hepatic
reaction when a drug is added.
 ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE
COMMON HEPATIC TOXINS FOUND IN OCCUPATIONAL OR
ENVIRONMENTAL EXPOSURES THAT CAN ADD TO A PATIENT’S RISK
FOR DEVELOPING A HEPATIC LESION INCLUDE:
 ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE
 Many herbal remedies were once wisely abandoned because of their
common adverse reactions.
 The use of alternative medicines must be monitored and solicited for
example:
 COMFREY TEA: Common cause of hepatocellular damage
 CHINESE REMEDY JIN BU HUAN: elegantly presented chaparral
capsules containing grease wood leaves, the end of
therapy with these types of agents is occasionally
severe disability or death from fulminant hepatic
failure.
 PENNYROYAL OIL: dose-related hepatotoxicity
 MARGOSA OIL: dose-related hepatotoxicity
 CLOVE OIL: dose-related hepatotoxicity
 ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE

 Nutritional status of a patient may play an important role in the

development of a drug-induced liver disease.
 low serum levels of vitamins E and C, along with lutein and the
α- and
β-carotenes are associated with asymptomatic elevations in
transaminases.
 high serum levels iron, transferrin, and selenium are also
associated with asymptomatic elevations of transaminases.
 Patients who are malnourished because of illness or long-term alcohol
abuse make up the most susceptible group.
 ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE
 All potential drug reactions should be judged as:
• timing of the reaction versus drug administration
• pharmacokinetic considerations
• information in the literature records about previous reactions
• inclusion of alternative nondrug causes
• close clinical observation when the drug in question is stopped
 It is also important to keep in mind that most elevations in liver enzymes will not be
associated with a drug.
 In a study of all patients admitted to a hospital in the United Kingdom with elevated liver
aminotransferases
 only 9% of cases involved a drug other than alcohol as the possible cause.
 In all cases, titers of serum antibodies to hepatitis A, B, and C should be drawn.
 Even in cases in which the drug is absolutely targeted as the cause, viral hepatitis
may be a complication.
 ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE

 When determining the exact type of hepatic lesion there is no good

clinical test available except for liver biopsy.
 The specificity of any serum enzyme depends on the distribution of that
enzyme in the body.
 After an acute hepatic lesion is established, it may take weeks for these
concentrations to return to normal.
ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE
 ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE

KEYPOINTS
ALKALINE found in the bile duct epithelium, bone, and intestinal and
PHOSPHATASE kidney cells.
more specific for hepatic disease than alkaline phosphatase,
5'-NUCLEOTIDASE because most of the body’s store of 5'-nucleotidase is in
the liver.
GLUTAMATE good indicator of centrolobular necrosis because it is found
DEHYDROGENASE primarily in centrolobular mitochondria.
sensitive indicators of necrotic lesions within the liver.
commonly measured in serum because of their high
AST AND ALT
concentrations and easy liberation from the hepatocyte
cytoplasm.
 ASSESSMENT OF DRUG-INDUCED
LIVER DISEASE
 SERUM BILIRUBIN CONCENTRATION
• another sensitive indicator of most hepatic lesions
• has a significant prognostic value.
• high peak bilirubin concentrations are associated with poor survival.
 Other important findings that indicate poor survival are:
• a peak prothrombin time greater than 40 seconds
• elevated serum creatinine
• low arterial pH.
 The presence of encephalopathy or prolonged jaundice are not good
signs for the survival of the patient and are strong indicators for
transplantation.
MEASUREMENT OF
LIVER FUNCTION
 MEASUREMENT OF LIVER FUNCTION

 A GOOD COMPOUND FOR A LIVER FUNCTION TEST WOULD

THEORETICALLY BE:
• Nontoxic and lacking any pharmacologic effect;
• Either rapidly and completely absorbed orally or easily
administered via a peripheral vein;
• Eliminated only by the liver;
• Easily measured (drug and its metabolite) in blood, saliva, or
urine.
 MEASUREMENT OF LIVER FUNCTION

 Several tests are used in research settings and in liver transplant

patients to indicate liver function and they measure qualities of
hepatic clearance:
• SULFOBROMOPHTHALEIN
• INDOCYANINE GREEN
• SORBITOL
 Advantage of sorbitol over indocyanine green is a much
lower incidence of allergic reactions
 It is partially cleared by the kidney, and urine levels must also
be determined during the test
 MEASUREMENT OF LIVER FUNCTION

 A good estimate of hepatic clearance can be obtained by serial

blood levels of a variety of hepatically eliminated drugs if an assay is
locally available.
 Ultrasound and computed tomographic imaging can be used on a
periodic basis to monitor for the development of fibrosis or vascular
lesions in the liver and for hepatocellular carcinomas.
 MEASUREMENT OF LIVER FUNCTION

 Injury of liver should be classified by the histologic findings when

liver biopsy is performed.
 In cases in which there is no biopsy, the pattern of liver
enzyme
elevation can estimate the type of injury.
 Hepatocellular injuries are marked by elevations in
transaminase that
are at least two times normal.
 If the alkaline phosphatase is also elevated, a hepatocellular
lesion is
still suspected when the elevation of ALT is notably higher
than the
 MEASUREMENT OF LIVER FUNCTION

 A liver injury is ACUTE

 lasts less than 3 months
 it is considered chronic after 3 months of consistent
symptoms or
enzyme elevation.
 If an acute liver injury progresses from normal to severe in a
matter
of a few days or weeks, it is considered fulminant
 A liver injury is SEVERE
 marked jaundice
 prothrombin time does not improve by more than 50%
after the
MONITORING
 MONITORING

AST and ALT

 are the most commonly used transaminases in the clinical
setting.
 Concentrations of these enzymes should be obtained
approximately every 4 weeks, depending on the reported
characteristics of the reaction in question.
 METHOTREXATE should be monitored every 4 weeks, because
toxicity usually develops over a period of several weeks to
months.
 In addition, some recommend that SULFOBROMOPHTHALEIN
or INDOCYANINE-GREEN excretion studies be performed on a
regular basis and that patients treated for very long periods of
GENERAL GUIDELINES THAT CAN
HELP IN DETERMINING A
MONITORING SCHEDULE FOR
DRUGS WHERE NO PRIOR
RECOMMENDATIONS ARE
PUBLISHED INCLUDE:
THANK YOU PO