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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.

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.

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.

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.

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

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.

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.

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.

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

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.

Cellular Mechanisms of Hepatotoxicity

Drug Toxicity Mechanisms

The classic division of drug reactions is into at least two major groups

Drugs that directly affect the liver and
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).

Phases of Metabolism of Drugs

Drug Toxicity Mechanisms

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).

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.

Metabolism of Drugs

Drug Toxicity Mechanisms

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

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

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.

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.

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.

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.

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.

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:

Aminotransferases are elevated much more than alkaline phosphatase levels (ALP)
Serum bilirubin may be elevated
Test of synthetic function abnormal

Cholestatic injury:

ALP elevated more so than aminotransferases
Serum bilirubin may be elevated
Test of synthetic function abnormal

Mixed injury

Mechanism of hepatotoxicity

Predictable
Idiosyncratic

Histologic findings (liver biopsy usually not necessary)

Hepatitis
Cholestasis
Steatosis

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

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

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

Symptoms of Acute DILI

Malaise
Low-grade fever
Anorexia
Nausea and Vomitin
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

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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%.

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.

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.

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.

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.

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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