Drug Induced Liver Injury

Introduction
The liver is the second largest organ in the body (after the skin), and is essential in keeping
the body functioning properly. The liver is located in the upper right-hand side of the
abdomen. It performs many functions in the body, including processing the body's nutrients,
manufacturing bile to help digest fats, synthesizing many important proteins, regulating blood
clotting, and breaking down potentially toxic substances into harmless ones that the body
can use or excrete. Inflammation of the liver may, in severe cases, interfere with these
processes and allow potentially toxic substances to accumulate. Inflammation can occur
while the liver is performing its functions, such as metabolizing drugs.
The liver is able to regenerate or repair up to two-thirds of injured tissue, including
hepatocytes, biliary epithelial cells, and endothelial cells. Healthy cells take over the function
of damaged cells, either indefinitely or until the damage is repaired.
Drugs are an important cause of liver injury. Drug-induced hepatotoxicity poses a significant
problem in drug development and public health. Drug induced liver injury (DILI) is a rare
event. More than 900 drugs, toxins, and herbs have been reported to cause liver injury, and
drugs account for 20-40% of all instances of fulminant hepatic failure.
In the United States, drug-induced liver injury (DILI) is the most common cause of acute liver
failure. It can occur due to ingestion of any therapeutic drug, herbal product, or xenobiotic.
Further complicating matters is the fact that it has an unpredictable and heterogeneous
course, ranging from an asymptomatic rise in liver enzymes to acute liver failure.
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Introduction
Approximately 75% of the idiosyncratic drug reactions result in liver transplantation or death.
Drug-induced hepatic injury is the most common reason cited for withdrawal of an approved
drug.
The common drugs causing DILI appear geographical. Although antimicrobials are the
commonest cause of drugs worldwide, the class of antimicrobials varies geographically, with
amoxicillin and flucloxacillin common in the Europe in contrast to antituberculosis drugs in
India.
DILI is a leading cause of acute liver failure (ALF) in the Western world, with paracetamol
being the commonest drug followed by antimicrobials. In India antituberculosis drugs are the
commonest cause of drug-induced ALF in adults and children, contributing to 5.7–22% of all
cases of ALF. Paradoxically, many could be preventable, as empirical treatment for
tuberculosis in 43–60% drives most of the reasons for antituberculous ALF.
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Morbidity / Mortality
In the United States, approximately 2000 cases of acute liver failure occur annually and
drugs account for over 50% of them (39% are due to acetaminophen, 13% are
idiosyncratic reactions due to other medications). Drugs account for 2-5% of cases of
patients hospitalized with jaundice and approximately 10% of all cases of acute hepatitis.
Drug-induced hepatitis is vastly unrecognized and underreported, such that the true
incidence is unknown. Reported estimates range from 1:10,000 cases to 1:100,000 cases.
In reality, this could be more common given that in large areas of the world, the number of
people taking drugs which includes complementary or over the counter medicines cannot
be estimated. Depending upon the setting, in which it is sought, the incidence of DILI
varies.
Healthcare providers must be vigilant in identifying drug-related liver injury because early
detection can decrease the severity of hepatotoxicity if the drug is discontinued. The
manifestations of drug-induced hepatotoxicity are highly variable, ranging from
asymptomatic elevation of liver enzymes to fulminant hepatic failure. Knowledge of the
commonly implicated agents and a high index of suspicion are essential in diagnosis.
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Drugs Known to Damage The Liver
Drugs that can damage the Liver: There are certain drugs and drug classes that have a
higher likelihood of damaging the liver. These substances include
Antibiotics:
Erythromycin.
Amoxicillin-clavulanate.
Tetracyclines (doxycycline,
minocycline, tetracycline).
Antipsychotic drugs:
Risperidone.
Chlorpromazine.
Statins (treats high cholesterol).
Antifungal drugs:
Terbinafine.
Ketaconazole.
Antihypertensives:
Lisinopril.
Captopril.
Methyldopa.
Halothane (anesthetic).
Birth control pills.
Antidepressants:
Setraline.
Fluoxetine.
Bupropion.
Anticonvulsants:
Phenobarbital.
Carbamazepine.
Phenytoin.
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Drugs Known to Damage The Liver
Other Drugs
Supplements and herbs
Comfrey tea.
Chaparral.
Skullcap.
Kava.
Excess vitamin A and iron.
Pyrrolizidine alkaloids.
Camellia sinensis (in black and green
tea).
Pennyroyal oil (used in production of
teas).
Over the counter pain-relievers:
Acetaminophen.
Nonsteroidal anti-inflammatory drugs:
Naproxen.
Ibuprofen.
Anabolic steroids.
Recreational and illicit drugs:
Heroin
Inhalants
Cocaine
MDMA or Ecstasy.
Methamphetamine
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Risk Factors for DILI
Risk factors for DILI can be classified in two main categories:
• Drug related (e.g., dose, concomitant medications, polypharmacy)
• Host related (e.g., age, gender, alcohol intake, concomitant infections).
Drug-related factors:
Hundreds of agents can lead to liver injury. In fact, the US National Library of Medicine and
the National Institute of Diabetes and Digestive and Kidney Diseases have created
LiverTox (http://www.livertox.nih.gov/), an online database that provides detailed
information on more than 600 such agents. Antibiotics are the most common cause of DILI,
followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives,
analgesics, antineoplastic drugs, and lipid-lowering agents.
Among antibiotics, the specific medication most often responsible for DILI varies by
geographical region. Amoxicillin/clavulanic acid is the most common causative antibiotic in
the United States, whereas anti-tuberculosis agents such as isoniazid, rifampin, and
pyrazinamide are the most common causative drugs in developing countries such as India,
where the prevalence of tuberculosis is still high. Herbal and dietary supplements are
emerging as an important cause of DILI.
The use of multiple drugs further increases the risk of developing DILI. Drugs with a
recommended daily dose of <50 mg are rarely associated with DILI.
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Host Factors:
Race: Some drugs appear to have different toxicities based on race. For example, blacks
and Hispanics may be more susceptible to isoniazid (INH) toxicity. The rate of metabolism
is under the control of P-450 enzymes and can vary from individual to individual.
Age: Apart from accidental exposure, hepatic drug reactions are rare in children. Elderly
persons are at increased risk of hepatic injury because of decreased clearance, drug-to-
drug interactions, reduced hepatic blood flow, variation in drug binding, and lower hepatic
volume. In addition, poor diet, infections, and multiple hospitalizations are important
reasons for drug-induced hepatotoxicity.
Sex: Although the reasons are unknown, hepatic drug reactions are more common in
females.
Alcohol ingestion: Alcoholic persons are susceptible to drug toxicity because alcohol
induces liver injury and cirrhotic changes that alter drug metabolism. Alcohol causes
depletion of glutathione (hepatoprotective) stores that make the person more susceptible to
toxicity by drugs.
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Liver disease: Preexisting liver disease has not been thought to make patients more
susceptible to drug-induced liver injury, but it may be that a diminished liver reserve or the
ability to recover could make the consequences of injury worse. Although the total
cytochrome P-450 is reduced in chronic liver disease, some may be affected more than
others. The modification of doses in persons with liver disease should be based on the
knowledge of the specific enzyme involved in the metabolism. Patients with HIV infection
who are co-infected with hepatitis B or C virus are at increased risk for hepatotoxic effects
when treated with antiretroviral therapy. Similarly, patients with cirrhosis are at increased
risk of decompensation by toxic drugs.
Genetic factors: A unique gene encodes each P-450 protein. Genetic differences in the P-
450 enzymes can result in abnormal reactions to drugs, including idiosyncratic reactions.
Debrisoquine is an antiarrhythmic drug that undergoes poor metabolism because of
abnormal expression of P-450-II-D6. This can be identified by polymerase chain reaction
amplification of mutant genes. This has led to the possibility of future detection of persons
who can have abnormal reactions to a drug.
Other comorbidities: Persons with AIDS, persons who are malnourished, and persons
who are fasting may be susceptible to drug reactions because of low glutathione stores.
Drug formulation: Long-acting drugs may cause more injury than shorter-acting drugs.
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Host factors: Factors that may enhance susceptibility to drugs, possibly inducing liver
disease, are as follows:
• Female - Halothane, nitrofurantoin, sulindac
• Male - Amoxicillin-clavulanic acid (Augmentin)
• Old age - Acetaminophen, halothane, INH, amoxicillin-clavulanic acid
• Young age - Salicylates, valproic acid
• Fasting or malnutrition - Acetaminophen
• Large body mass index/obesity - Halothane
• Diabetes mellitus - Methotrexate, niacin
• Renal failure - Tetracycline, allopurinol
• AIDS - Dapsone, trimethoprim-sulfamethoxazole
• Hepatitis C - Ibuprofen, ritonavir, flutamide
• Preexisting liver disease - Niacin, tetracycline, methotrexate
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Pathophysiology and Mechanisms of DILI
Hepatocellular and Extracellular Mechanisms:
Disruption of the hepatocyte: Covalent binding of the drug to intracellular proteins can
cause a decrease in ATP levels, leading to actin disruption. Disassembly of actin fibrils at the
surface of the hepatocyte causes blebs and rupture of the membrane.
Disruption of the transport proteins: Drugs that affect transport proteins at the canalicular
membrane can interrupt bile flow. Loss of villous processes and interruption of transport
pumps such as multidrug resistance–associated protein 3 prevent the excretion of bilirubin,
causing cholestasis.
Cytolytic T-cell activation: Covalent binding of a drug to the P-450 enzyme acts as an
immunogen, activating T cells and cytokines and stimulating a multifaceted immune
response.
Apoptosis of hepatocytes: Activation of the apoptotic pathways by the tumor necrosis
factor-alpha receptor of Fas may trigger the cascade of intercellular caspases, which results
in programmed cell death.
Mitochondrial disruption: Certain drugs inhibit mitochondrial function by a dual effect on
both beta-oxidation energy production by inhibiting the synthesis of nicotinamide adenine
dinucleotide and flavin adenine dinucleotide, resulting in decreased ATP production.
Bile duct injury: Toxic metabolites excreted in bile may cause injury to the bile duct
epithelium.
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Cellular Mechanisms of Hepatotoxicity
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Drug Toxicity Mechanisms
The classic division of drug reactions is into at least two major groups
1. Drugs that directly affect the liver and
2. Drugs that mediate an immune response, as follows:
Intrinsic or predictable drug reactions: Drugs that fall into this category cause
reproducible injuries in animals, and the injury is dose related. The injury can be due to the
drug itself or to a metabolite. Acetaminophen is a classic example of a known intrinsic or
predictable hepatotoxin at supertherapeutic doses. Another classic example is carbon
tetrachloride.
Idiosyncratic drug reactions: Idiosyncratic drug reactions can be subdivided into those that
are classified as hypersensitivity or immuno-allergic and those that are metabolic-
idiosyncratic. Regarding hypersensitivity reactions, phenytoin is a classic, if not common,
cause of hypersensitivity reactions. The response is characterized by fever, rash, and
eosinophilia and is an immune-related response with a typical short latency period of 1-4
weeks. A metabolic-idiosyncratic reaction occurs through an indirect metabolite of the
offending drug. Unlike intrinsic hepatotoxins, the response rate is variable and can occur
within a week or up to one year later. It occurs in a minority of patients taking the drug, and
no clinical manifestations of hypersensitivity are noted. INH toxicity is considered to fall into
this class. Not all drugs fall neatly into one of these categories, and overlapping mechanisms
may occur with some drugs (e.g., halothane).
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Phases of Metabolism of Drugs
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The liver metabolizes virtually every drug or toxin introduced in the body. Most drugs are
lipophilic (fat soluble), enabling easy absorption across cell membranes. In the body, they
are rendered hydrophilic (water soluble) by biochemical processes in the hepatocyte to
enable inactivation and easy excretion.
Metabolism of drugs occurs in 2 phases: Phase 1 reaction: The drug is made polar by
oxidation or hydroxylation. All drugs may not undergo this step, and some may directly
undergo the phase 2 reaction.
Phase 1 reaction (The cytochrome P-450 enzymes catalyze): Most of these intermediate
products are transient and highly reactive. These reactions may result in the formation of
metabolites that are far more toxic than the parent substrate and may result in liver injury. As
an example, the metabolite of acetaminophen is N -acetyl-p-benzoquinone-imine (NAPQI)
and is produced with ingestion of high doses. NAPQI is responsible for the liver injury in
cases of toxicity. Cytochrome P-450 enzymes are hemoproteins located in the smooth
endoplasmic reticulum of the liver. At least 50 enzymes have been identified, and based on
structure, they are categorized into 10 groups, with groups 1, 2, and 3 being the most
important in drug metabolism. Each P-450 enzyme can metabolize many drugs. Drugs that
share the same P-450 specificity for biotransformation may competitively inhibit each other,
resulting in drug interactions. Several drugs can induce and inhibit the P-450 enzyme (see
below).
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Phase 2 reactions may occur within or outside the liver. They involve conjugation with a
moiety (i.e., acetate, amino acid, sulfate, glutathione, glucuronic acid) that further increases
solubility. Subsequently, drugs with high molecular weight may be excreted in bile, while the
kidneys excrete the smaller molecules.
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Drugs that induce the P-450 enzymes are as follows:
• Phenobarbital
• Phenytoin
• Carbamazepine
• Primidone
• Ethanol
• Glucocorticoids
• Rifampin
• Griseofulvin
• Quinine
• Omeprazole - Induces P-450 1A2
Drugs that inhibit the P-450 enzymes are as follows:
• Amiodarone
• Cimetidine
• Erythromycin
• Grape fruit
• Isoniazid
• Ketoconazole
• Metronidazole
• Sulfonamides
• Quinidine
• Omeprazole - Inhibits P-450 2C8
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Factors influencing Drug Metabolism
Genetics: Genetic alterations may contribute to diminished metabolism, lack of metabolism,
or excessive metabolism of a drug.
• Polymorphisms of CYP2C9 - affects the metabolism of S-warfarin, omeprazole,
tolbutamide
• Polymorphism of CYP2C19 - affects the metabolism of S-mephenytoin
• Polymorphism of glutathione s-transferase can affect metabolism of acetaminophen
• HLA (human leukocyte antigen)- association between certain HLA haplotypes and the
development of DILI from fluclox-, augmentin
Nutrition: A person’s nutritional status influences the expression of certain CYPs, both in
health and with underlying liver disease. Expression of CYP2E1 is increased by obesity, high
fat intake, and fasting
• Fasting/malnutrition - may increase risk of DILI from acetaminophen; this is thought to be
due to its affect on detoxifying cofactors such as glutathione
• Obesity - methotrexate, halothane
• Grapefruit juice - inhibits CYP3A, primarily acting on intestinal form of the enzyme;
affecting levels of absorption of several drugs including immunosuppressive meds-
cyclosporine and tacrolimus
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Multi-drug effect: A drug may either inhibit or enhance (inducer) another drugs metabolism.
Competitive inhibition of CYP can lead to clinically important drug interactions when there
are no alternative pathway for the metabolism of a toxic drug or its metabolite.
• Competition for phase 2 reactions such as glucuronidation and sulfation, for example, by
phenytoin, may lower the dose threshold for acetaminophen-induced hepatotoxicity.
• Phase 3 transporters have also been reported to be inhibited (e.g., atorvastatin,
carvedilol, clarithromycin, and sertraline) and induced (e.g., amiodarone, diltiazem,
erythromycin, and St John’s Wart); significantly altering the secretion activity of this group.
Age and sex: During adult life, the expression of some CYPs declines by up to 10% with
advancing age. Expression of CYP 3A4 and 2E1 seem to be different among men and
women, which may explain the enhanced metabolism of certain drugs, however it’s still
unclear whether this increases the risk of hepatic drug reactions.
Dose: Severe DILI rarely occurs from drugs taken at doses less than 10mg; drugs
administered at >/= 50mg are more likely to cause DILI.
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Disease-related changes - expression of CYP
• DM
• Hypothyroidism
Underlying liver disease
• Decreased P450: Cirrhosis is associated with decreased levels of total cytochrome P450
and also reduced hepatic perfusion; results in decreased clearance of such as
propranolol, which is usually metabolized rapidly by the liver.
• Decreased hepatic clearance.
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Stages of Liver Toxicity
Fatty liver and inflammation: Fatty liver, also known as steatorrhoeic hepatosis, is the
build-up of excess fat in the liver cells. It is normal for the liver to contain some fat. But, if fat
accounts for more than 10% of the liver's weight, the individual has fatty liver. In countries
where obesity is becoming a serious health issue, fatty liver is predicted to affect
approximately 25% of the general population. Fatty liver occurs before inflammation is
present.
Sometimes, inflammation from a fatty liver is linked to alcohol abuse, known as alcoholic
steatohepatitis. Otherwise the condition is called nonalcoholic steatohepatitis, or NASH.
NASH is very common in overweight persons over the age of 30. The liver is invaded by an
excessive amount of fat and a normal healthy liver tissue is partially replaced with areas of
unhealthy fats. In such a liver, the liver cells and the spaces in the liver are filled with fat so
that the liver becomes slightly enlarged and heavier.
Hepatitis is an inflammation of the liver that can be caused by viruses, chemicals, drugs,
alcohol, inherited diseases, or the individual's own immune system. This inflammation can be
acute (short-term), flaring up and then resolving within a few weeks to months, or chronic
(long-term), lasting many years. Chronic hepatitis may begin to damage the liver for 20 years
or more before causing significant symptoms related to progressive liver damage such as
cirrhosis (scarring and loss of function), liver cancer, or death.
In the early stage of any liver disease, the liver may become inflamed, tender, and enlarged.
However, an inflamed liver may cause no discomfort at all.
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Fibrosis: If left untreated, the inflamed liver will start to scar. As excess scar tissue (a type of
fibrous tissue) grows, it replaces healthy liver tissue. This process is called fibrosis. Scar
tissue cannot function as healthy liver tissue can. Scar tissue may keep blood from flowing
through the liver. The healthy part of the liver now has to work harder. The liver can
regenerate, however, and may heal itself from fibrosis.
Cirrhosis: If left untreated, the liver may become so seriously scarred that it can no longer
heal itself. This stage, when the damage cannot be reversed, is called cirrhosis. Cirrhosis
can lead to a number of complications, including liver cancer. In some individuals, the
symptoms of cirrhosis may be the first signs of liver disease. Symptoms of cirrhosis include:
easy bruising; fluid buildup in the legs and/or abdomen; the skin and eyes may take on a
yellow color, a condition called jaundice; the skin may itch intensely; blood may back up in
vessels leading to the liver because of blockage and may burst; increased sensitivity to
medications and their side effects; developing insulin resistance and type-2 diabetes; or
buildup of toxins in the brain, causing problems with concentration, memory, sleeping, or
other mental functions.
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Liver failure: Liver failure means that the liver is losing or has lost all of its function. It is a
life-threatening condition that demands urgent medical care. The first symptoms of liver
failure are often nausea, loss of appetite, fatigue, and diarrhea. Because these symptoms
can have any number of causes, it may be hard to tell that the liver is failing.
As liver failure progresses, the symptoms become more serious. The individual may become
confused and disoriented, and extremely sleepy. There is a risk of coma and death.
Immediate treatment is needed. The medical team will try to save whatever part of the liver
that still works. If this is not possible, the only option may be a liver transplant.
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Clinical Presentation
Clinical Presentation: Type of injury is reflected by the pattern of liver test abnormalities.
LFTs abnormal for less than 3 months; Chronic DILI- abnormal for more than 3 months
Hepatocelluar (cytotoxic) injury:
1. Aminotransferases are elevated much more than alkaline phosphatase levels (ALP)
2. Serum bilirubin may be elevated
3. Test of synthetic function abnormal
Cholestatic injury:
1. ALP elevated more so than aminotransferases
2. Serum bilirubin may be elevated
3. Test of synthetic function abnormal
Mixed injury
Mechanism of hepatotoxicity
Predictable
Idiosyncratic
Histologic findings (liver biopsy usually not necessary)
Hepatitis
Cholestasis
Steatosis
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Predictable - intrinsic hepatotoxins
• Predictably cause dose-dependent hepatocellular necrosis
• Latent period- brief (hours to a few days)
• Fairly consistent from person to person and among animal models
• Serum aminotransferases 8 to 500 times normal; ALP less elevated
• Often removed from clinical use
• Some still in use due to known dose-related toxicity
 Hepatotoxic in large doses (i.e. acetaminophen, iron sulfate)
 Known dose-effect (i.e. ethanol, IV tetracycline, L-asparaginase)
Idiosyncratic
• Unpredictable
• Species-specific, often cannot be reproduced in animal models
• Latent period- variable, generally 1 to 3 months
• Doses >50mg/day more likely to cause DILI compared to dosing <10mg
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Hepatocellular
- ALT/ALP ratio > 5
- ~ 50% of DILI is hepatocellular
- AST >> ALT- think muscle injury or alcoholic hepatitis
- Neither above 400
Cholestatic
- ALP > 2x ULN
- ALT/ALP ratio < 2
Mixed
- 5 > ALT/ALP ratio > 2
Hy’s law- serum bilirubin >2x ULN, aminotransferases >3x ULN
- Associated with worse prognosis
- Mortality as high as 14 percent
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• Acute DILI
– Mild asymptomatic liver test abnormalities - Asymptomatic abnormal liver
chemistries- 1/100 to 1/100,000 ; most resolve with drug cessation
– Cholestasis with pruritis
– Acute illness with jaundice- resembles viral hepatitis - 10 to 14% mortality due to
liver failure
– Acute liver failure
• Chronic DILI- may resemble
– AIH (Autoimmune Hepatitis)
– PBC (Primary Biliary Cirrhosis)
– Sclerosing cholangitis
– Alcoholic liver disease
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• Symptoms of Acute DILI
– Malaise
– Low-grade fever
– Anorexia
– Nausea and Vomiting
– RUQ pain
– Jaundice
– Acholic stools
– Dark urine
• Symptoms of Chronic DILI
– May present with signs of cirrhosis
– Jaundice
– Spider Angioma
– Palmer erythema
– Gynecomastia
– Ascites
– Encephalopathy
– Asterixis
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Diagnosis
Physical examination:
History: If an acetaminophen over dosage has occurred, it is important to determine the
time and amount of acetaminophen taken. It is important to know what medications the
individual has ingested and how much. Having access to all medication bottles that the
person may have taken will help to determine the maximum amount taken.
Physical: Look for signs and symptoms of liver toxicity. These signs may include jaundice
(yellow skin), abdominal pain, vomiting, and ascites (fluid in the abdomen). On physical
examination, look for liver tenderness and enlargement using palpation.
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Diagnosis
Blood Tests:
Albumin: Serum albumin levels measures the main protein made by the liver and tells how
well the liver is making this protein. Low levels of albumin may indicate liver damage.
Ammonia: An ammonia test measures the amount of ammonia in the blood. Most ammonia
in the body forms when protein is broken down by bacteria in the intestines. The liver
normally converts ammonia into urea, which is then eliminated in urine. Ammonia levels in
the blood rise when the liver is not able to convert ammonia to urea. This may be caused by
cirrhosis or severe hepatitis.
Alpha-fetoprotein (AFP) test: Alpha-fetoprotein (AFP) is a type of protein produced in the
developing embryo and fetus. In humans, AFP levels decrease gradually after birth, reaching
adult levels by 8-12 months. If an individual has high levels of alpha-fetoprotein in the blood,
it may be a sign of liver cancer. Healthy adult males and non-pregnant females typically have
less than 40 micrograms of alpha-fetoprotein per liter of blood.
Bilirubin: Bilirubin is a waste product made from old blood cells; it is a yellow compound that
causes jaundice and dark urine when present in increased amounts. Tests for bilirubin levels
help determine if the liver is functioning appropriately.
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Diagnosis
Blood Tests:
INR: International normalized ratio (INR) is a blood-clotting test. It is used to measure how
quickly blood forms a clot, compared with normal clotting time. The liver produces certain
proteins (clotting factors) that help in blood clotting. If there is liver disease and cirrhosis, the
liver may not produce the normal amount of proteins and then the blood is not able to clot
normally. When a doctor is evaluating the function of the liver, a high INR usually means that
the liver is not working as well as it could because it is not making the blood clot normally.
Liver biopsy: A liver biopsy may be performed to determine the extent of liver damage and
to determine the best treatment option for the patient. During the procedure, a needle is
inserted into the liver and a small tissue sample is removed. The tissue is then analyzed
under a microscope in a laboratory.
Liver enzymes: Another blood test may be performed to check for elevated levels of liver
enzymes, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
These enzymes leak into the bloodstream when liver cells are injured. Also, alkaline
phosphatase (ALP) levels may be checked. ALP is an enzyme related to the bile ducts. ALP
levels are often increased when they are blocked. Liver enzymes help catalyze or start
chemical reactions in the liver cells. These enzymes are released into the bloodstream when
the liver is damaged.
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Diagnosis
Blood Tests:
Transferrin saturation test: The transferrin saturation test reveals how much iron is bound
to the protein that carries iron in the blood. Transferrin saturation tests are used in
determining if hemochromatosis exists. Transferrin saturation values higher than 45% are
considered too high. The total iron binding capacity test measures how well the blood can
transport iron, and the serum ferritin test shows the level of iron in the liver. If either of these
tests shows higher than normal levels of iron in the body, THEN doctors can order a special
blood test to detect the genetic mutation for hemochromatosis, which will confirm the
diagnosis. If the mutation is not present, hereditary hemochromatosis is not the reason for
the iron buildup and the doctor will look for other causes.
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Diagnosis
Diagnostic Tests:
In diagnosing liver toxicity, the doctor may use images of the liver obtained by an ultrasound
test, a computerized tomography (CT) scan, or a magnetic resonance imaging (MRI) scan.
These diagnostic tests can determine if the presence of liver damage exists. Evidence of
fatty liver or liver damage can be viewed by the doctor as dark spots or abnormal images.
A liver scan is a diagnostic procedure to evaluate the liver for suspected disease. A harmless
amount of a radioactive substance that concentrates in the liver is injected intravenously (IV
or into the veins) and the image of its distribution in the liver is analyzed to diagnose
abnormalities. Women who are pregnant or breastfeeding should not have this test.
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Differential Diagnosis
Differential diagnoses are as follows:
• Acute viral hepatitis
• Autoimmune hepatitis
• Nonalcoholic steatohepatitis (NASH)
• Shock liver/cardiovascular causes, especially right-sided heart failure
• Cholecystitis
• Cholangitis
• Budd-Chiari syndrome
• Alcoholic liver disease
• Cholestatic liver disease
• Pregnancy-related conditions of liver
• Malignancy
• Wilson disease
• Hemochromatosis
• Coagulation disorders
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Diagnosis
Laboratory studies
In general, an increase of serum alanine transaminase (ALT) to greater than 3 times the
upper limits of normal should be followed by repeat testing (hepatic function panel) within 72
hours to confirm the abnormalities and to determine if they are increasing or decreasing.
There also should be inquiry made about symptoms. Serum ALT may rise and fall quite
rapidly, and waiting a week or two before obtaining confirmation of elevations may lead to a
false conclusion that the initially observed abnormality was spurious. Of greater concern,
delay in retesting may allow progression to severe worsening if the initial abnormality was
the herald of a severe reaction to follow. The need for prompt repeat testing is especially
great if the ALT is much greater than 3 times the upper limits of normal and/or total bilirubin
level is greater than 2 times the upper limit of normal.
Initial testing should include complete blood cell count, basic metabolic profile, hepatic
function panel and urinalysis. Patients with a hepatocellular process generally have a
disproportionate elevation in serum aminotransferase levels compared with alkaline
phosphatase levels, while those with cholestasis have the opposite findings. Hepatitis B
serology (hepatitis B surface antigen, anti–hepatitis B surface antibody, anti–hepatitis B core
antibody, hepatitis C serology) and hepatitis A serology (anti–hepatitis A virus antibody)
should be performed to exclude an infectious etiology.
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Diagnosis
Laboratory studies
ANA testing may help in cases of possible autoimmune hepatitis. Positive ANA and ASMA
findings may add to the diagnostic evaluation but are usually confusing and hence not used.
The presence of antibodies to specific forms of CYP has been associated with
hypersensitivity to some drugs. For example, some antibodies and the associated drugs
involved are as follows: CYP 1A2, dihydralazine; CYP 3A1, anticonvulsants; and CPY 2E1,
halothane. Their role in pathophysiology is uncertain but may help in diagnosis. Lymphocyte
transformation to test drugs may be observed for drugs acting through immunologic
reactions, but this is not commonly used.
Imaging studies
Ultrasonography is inexpensive compared with CT scanning and MRI and is performed in
only a few minutes. Ultrasonography is effective to evaluate the gall bladder, bile ducts, and
hepatic tumors.
CT scanning can help detect focal hepatic lesions 1 cm or larger and some diffuse
conditions. It can also be used to visualize adjacent structures in the abdomen.
MRI provides excellent contrast resolution. It can be used to detect cysts, hemangiomas,
and primary and secondary tumors. The portal vein, hepatic veins, and biliary tract can be
visualized without contrast injections.
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Treatment
General: Therapies for liver toxicity focus on reducing the complications of the disease.
Individuals who knowingly have been exposed to the hepatitis B virus (HBV) should consult
their healthcare providers as soon as possible. Patients who receive an injection of hepatitis
B immune globulin within 24 hours of exposure to the virus may not develop HBV infection.
Patients should also receive the first of three injections of the hepatitis B vaccine.
Diuretics: Diuretics, or fluid tablets, are used in the treatment of fluid retention in the legs
(edema) or abdomen (ascites).
Laxatives: Laxatives, such as lactulose (Chronulac®), are used to prevent constipation and
to reduce the chances of the poisonous substances, such as ammonia, from the bowel
bypassing the liver and reaching the brain, causing drowsiness, confusion, and coma
(hepatic encephalopathy).
Weight loss and exercise: If the individual's body mass index (BMI) is above 25, a diet and
exercise program may reduce the amount of accumulated fat in the liver. BMI measures the
amount of fat the body contains. The most effective diet is rich in fiber and low in calories
and saturated fat, with total fat accounting for no more than 30% of total calories.
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Treatment
Diabetes control: Strict management of diabetes with diet, medications, or insulin lowers
blood sugar, which may prevent further liver damage. Blood sugar control may also reduce
the amount of accumulated fat in the liver.
Cholesterol control: Controlling elevated levels of cholesterol and triglycerides with diet,
exercise, and cholesterol-lowering medications may help stabilize or reverse nonalcoholic
fatty liver disease.
Avoidance of toxic substances: If an individual has nonalcoholic fatty liver disease,
especially nonalcoholic steatohepatitis (NASH), alcohol should not be consumed.
Medications and other substances that can cause liver damage should also be avoided,
such as acetaminophen (Tylenol®).
Ursodiol (Actigall®): Ursodiol (Actigall®) is a prescription medication most commonly used
to treat gallstones. Ursodiol decreases production of bile acids, which may in theory help
lower elevated levels of liver enzymes in individuals with liver disease.
Beta-blockers: For portal hypertension, the doctor may prescribe a beta blocker, such as
propranolol (Inderal®). These drugs are normally used in hypertension or high blood
pressure. Side effects include fatigue and loss of sexual desire.
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Treatment
N-acetyl cysteine (NAC): The antidote to acetaminophen overdose is N-acetylcysteine
(NAC). NAC is most effective when given within eight hours of ingesting acetaminophen.
Indeed, NAC can prevent liver failure if given early enough. For this reason, it is absolutely
necessary that acetaminophen poisoning be recognized, diagnosed, and treated as early as
possible. NAC can be purchase over-the-counter (OTC) as a dietary supplement, but when
used for acetaminophen toxicity, NAC is a concentrated solution that is prescribed by a
doctor and mixed appropriately by a pharmacist.
Other medications: Researchers are studying the effects of several medications on insulin
resistance and nonalcoholic fatty liver disease in individuals with and without diabetes.
These include metformin (Glucophage®, Glucophage XR®), pioglitazone (Actos®),
rosiglitazone (Avandia®), and betaine (Cystadane®). Another drug being investigated is
orlistat (Xenical®), a medication that blocks the absorption of some of the fat from food.
Early results indicate that orlistat may reduce the amount of fat in the liver.
Interferon: Interferons are natural proteins produced by the cells of the immune system in
response to challenges by foreign agents such as viruses, bacteria, parasites, and tumor
cells. Administering additional synthetic interferon may stimulate the body's immune
response to hepatitis B virus (HBV) and help prevent the virus from spreading. Two
interferon medications are available: interferon alfa-2b (Intron A®) and peginterferon alfa-2a
(Pegasys®). Intron A® is administered by injection several times a week. Pegasys® is given
by injection once a week.
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Treatment
Not everyone is a candidate for interferon treatment. In a few cases, interferon has
successfully eliminated the virus completely. However, the infection can return in the future.
Several side effects are associated with interferon, including depression, fatigue, muscle
pain, body aches, fever, and nausea. Interferon may also cause a decreased production of
red blood cells. Symptoms are usually worse during the first two weeks of treatment and in
the first four to six hours after receiving an injection of interferon.
Lamivudine (Epivir-HBV®): Lamivudine (Epivir-HBV®) is an antiviral medication that helps
prevent HBV from replicating in the body's cells. The medication is usually taken in tablet
form once daily. Side effects during treatment are generally mild, but some patients may
experience a severe worsening of symptoms when they stop taking the medication. Patients
should tell their healthcare providers if they have had any kidney problems or history of
pancreatitis before starting this medication. Patients should call their healthcare providers
immediately if they experience a worsening of jaundice (yellowing of the skin and eyes) or if
they experience any unusual bruising, bleeding, or fatigue while taking the medication.
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Treatment
Adefovir dipivoxil (Hepsera®): Adefovir dipivoxil (Hepsera®) is a tablet taken orally once a
day to help prevent HBV from replicating inside the body's cells. This drug is effective in
patients who are resistant to lamivudine. Like lamivudine, side effects are generally mild, but
symptoms may worsen when treatment is stopped. Hepsera® may cause kidney toxicity in
patients with underlying kidney disease. A change in the amount of urine produced or blood
in the urine may indicate kidney toxicity. Other side effects may include weakness,
headache, fever, increased cough, nausea, vomiting, diarrhea, or gas.
Entecavir (Baraclude®): Entecavir (Baraclude®) is an antiviral medication that was
approved by the U.S. Food and Drug Administration (FDA) in March 2005 for HPV (human
papilloma virus). HPV infection is a sexually transmitted disease that may lead to cervical
cancer in women. This medication is taken orally once a day. Studies comparing entecavir to
lamivudine in hepatitis treatment found that entecavir was more effective. Baraclude® may
cause symptoms of hepatitis to worsen once medication is discontinued.
Liver transplant: When the liver has been severely damaged, a liver transplant may be the
only treatment option. Liver transplants are increasingly successful. However, there are not
enough donor organs available for every patient who needs a transplant, and not all patients
are suitable transplant candidates. It is estimated that more than 10,000 living donor
transplants have been performed worldwide, and that the donor recipient death rate ranges
from 0.1-0.3%.
41 of 52

Prevention / Patient Education
Reducing alcohol and drug consumption: Drink alcohol in moderation, if at all. Over many
years, more than one drink a day for women and more than two drinks a day for men may be
enough to lead to cirrhosis. Use of certain drugs, including some illegal drugs (such as
cocaine, heroin, and methamphetamine), may also cause liver disease. If fatty liver or
hepatitis exists, no alcohol should be consumed.
Only use prescription and nonprescription drugs when needed and take only the
recommended doses. Acetaminophen (Tylenol®) dosages should be followed specifically as
stated by the manufacturer or by a healthcare provider. The manufacturer has set a
maximum dose of 4 grams of acetaminophen (the equivalent of eight extra-strength tablets
or capsules, 500 milligrams each) per day. However, healthcare professionals recommend
that individuals who take prescription medications or drink alcohol daily should only take a
maximum of 2-3 grams per 24 hours. Many over-the-counter (OTC) products may also
contain acetaminophen (Tylenol®). It is important not to exceed the total daily dosage of four
grams acetaminophen. Acetaminophen should only be used for the short-term (no more than
two weeks) treatment of conditions such as minor aches and pains. Particular caution is
need in dosing infants with acetaminophen to ensure that the correct dose is given.
Do not mix other drugs with alcohol. Acetaminophen (Tylenol®) can be toxic to the liver even
if individuals drink in moderation.
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Hepatitis vaccination: If an individual is at increased risk of contracting hepatitis or if they
already been infected with any form of the hepatitis virus, a doctor will recommend the
hepatitis B vaccine. A vaccine is also available for hepatitis A.
Dietary supplements: Herbal supplements that can be toxic to the liver may include kava
(Piper methysticum), chaparral (Larrea taridentata), comfrey (Symphytum officinale),
germander (Teucrium chamaedrys), kombucha tea, mistletoe (Viscum album), pennyroyal
(Mentha pulegium), and skullcap (Scutellaria laterifolia). Also, avoid high doses of fat soluble
vitamins, including vitamins A, D, E, and K, as they can also be potentially toxic to the liver.
Avoiding contact with blood and body fluids from others: Hepatitis viruses can be
spread by accidental needle sticks, improper cleanup of blood or body fluids, and sharing
intravenous needles. It is also possible to become infected by sharing razor blades or
toothbrushes or by having unsafe sex.
Avoiding chemical toxins: When using toxic chemicals such as cleaners, ventilating the
room or wearing a mask is important. Take similar protective measures when spraying
insecticides, fungicides, paint, and other toxic chemicals. When using insecticides and other
toxic chemicals, covering the skin with gloves, long sleeves, a hat, and a mask is
recommended by healthcare professionals. Chemical toxins may damage liver cells and
cause liver dysfunction.
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Given the idiosyncratic nature of most drugs, it is difficult to predict who and when during the
course of treatment will develop hepatotoxicity. Rational drug prescribing is central to
minimizing DILI particularly in patients with risk factors such as old age, comorbid diseases,
HIV status, daily dose of drug >50 mg, or poly pharmacy.
Caution should be exercised in the empirical treatment for tuberculosis given the high
incidence of severe DILI including acute liver failure. Knowledge of drug–drug interaction and
drug–disease interaction is also important. Except for few drugs such as methotrexate,
clinically significant DILI is usually accompanied by symptoms, such that vigilance for
symptoms is the key in the detection of early onset DILI.
Patients and caregivers should be educated about the development of new symptoms such
as nausea, vomiting, anorexia, dark urine or jaundice. The suspected drug or drugs should
be stopped at the slightest suspicion of DILI, in order to prevent progressive liver damage.
Debate continues about the need and the timing of liver function tests particularly in those
who need to be on medications for a long duration. There is no clear evidence that such a
practice influences much in the detection or prevention of clinically significant liver injury.
Additional constraints include the costs and inconvenience of the tests, physician ambiguity
and varying guidelines with regard to timing of the tests.
44 of 52

Patients and caregivers should be educated about the development of new symptoms such
as nausea, vomiting, anorexia, dark urine or jaundice. The suspected drug or drugs should
be stopped at the slightest suspicion of DILI, in order to prevent progressive liver damage.
Debate continues about the need and the timing of liver function tests particularly in those
who need to be on medications for a long duration. There is no clear evidence that such a
practice influences much in the detection or prevention of clinically significant liver injury.
Additional constraints include the costs and inconvenience of the tests, physician ambiguity
and varying guidelines with regard to timing of the tests.
45 of 52

Summary
The number of cases of DILI is expected to rise because of the increased availability of
prescription medications resulting from changes in insurance coverage and the burgeoning
HDS market. Pharmacists can play an integral role in helping prevent DILI and in identifying
DILI when it does occur so that the offending agent can be discontinued, if possible. In order
to best protect their patients, pharmacists must be knowledgeable about the drugs
associated with DILI, as well as their clinical features and the disease course. It is essential
to perform a thorough medication history in a patient suspected of experiencing DILI. Once
DILI is confirmed, patients should be followed for a minimum of 6 months to assess for the
development of chronic injury. Medication therapy management is one tool pharmacists can
use to help identify patients who have DILI or are at risk for it.
46 of 52

Active Learning
Drug-induced liver injury (DILI) is an important clinical problem, which has received more
attention in recent decades. It can be induced by small chemical molecules, biological
agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP),
and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI
clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-
cholestatic mixed injury, and vascular injury based on the types of injured target cells. The
CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical
manifestation and gives 16 evidence-based recommendations on diagnosis, differential
diagnosis, treatment, and prevention of DILI.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419998/
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