Medicolegal Issues

Liver Risks Abound


Drug-induced liver injury (DILI) or hepatotoxicity accounts for more than 50% of all cases of acute liver failure. DILI, often life-threatening, is the leading cause of patient referral for liver transplantation.1,2

DILI is an important diagnostic challenge for the treating clinician because of its presentation, which is often a diagnosis of exclusion. Determination of all potential causes of hepatic injury need to be assessed through onset of symptoms and a careful drug history (including prescription and over-the-counter medication, dietary supplements, and complementary and alternative therapies).3

DILI has brought an increase in Food and Drug Administration (FDA) “black box” warnings. Among the drugs affected are ketoconazole, pemoline, tolcapone, valproate sodium, and zalcitabine.4

A number of drugs have been withdrawn from the U.S. market after DILI or interactions with those that are hepatically metabolized, such as:

Off the Market

Trasylol (aprotinin, Bayer) will no longer be marketed to control bleeding during cardiac surgery. Preliminary data suggesting increased risk of death when compared with two other antifibrinolytic drugs in a recently concluded Canadian study. In 2006, the FDA revised the labeling for aprotinin to strengthen its safety warning and limit its approved usage to patients at an increased risk for blood loss and blood transfusion during coronary bypass graft surgery. In certain cases where physicians identify that the benefits outweigh the risks of aprotinin use, the FDA will try to facilitate limited access to it.—MK

  • Astemizole (cardiotoxicity);
  • Bromfenac sodium, cisapride (cardiotoxicity);
  • Felbamate, mibefradil (cardiotoxicity);
  • Temafloxacin (abnormal liver function tests, as well as renal failure and other serious adverse events);
  • Terfenadine (cardiotoxicity);
  • Troglitazone; and
  • Trovafloxacin mesylate.

One of the most common causes of DILI is intentional or unintentional overdose with acetaminophen.

DILI has been classified into two major types: cholestatic and hepatocellular, or cytolytic injury. In cholestatic liver injury, the serum alkaline phosphatase (ALP) is elevated; total bilirubin level (TBL) and the alanine aminotransferase (ALT) may also be elevated. In hepatocellular injury, initial elevation is noted in the ALT.

There may also be overlap in the pattern of injury (mixed-pattern injury) whereby ALP and ALT are elevated. These patterns of injury may be defined further by the degree of enzyme elevation, such as an ALT level of three or more times the upper limit of normal (ULN), an ALP level two or more times ULN, and TBL two or more times ULN if associated with an elevation of ALP or ALT.

Hepatotoxicity is often predictable—but not always. When predictable, the reaction is usually dose-dependent, such as in the case of acetaminophen. These reactions usually occur shortly after a threshold for toxicity has been reached. Unpredictable reactions can occur days or months after exposure, usually without warning. Hypersensitivity reactions are often delayed and occur upon repeated exposure to the agent. Symptoms of immunologic injury may include rash, fever, or eosinophilia. More severe forms include Stevens-Johnson syndrome, toxic epidermal necrolysis, or cytopenias. Reactions are more severe upon repeat exposure or rechallenge of the offending agent.

New Drugs

The anticonvulsant oxcarbazepine (generic Trileptal) is now available as a first-time generic. It has been FDA approved as monotherapy or in combinations with other drugs for the treatment of partial seizures in patients age 4 or older. Generic availability includes 150, 300, and 600 mg tablets. Serious dermatologic reactions have been reported with use of the brand, and common side effects include lethargy and vertigo

Reclast Injection (zoledronic acid) has been FDA approved for the treatment for post-menopausal osteoporosis. It is administered as a once-yearly, 15-minute intravenous (IV) infusion. In a study of more than 7,700 women, zoledronic acid reduced the risk of hip fractures by 41% and spine fractures by 70%. Bone-mineral density significantly increased at both of these sites compared with placebo. Spine fracture reduction was sustained over three years.

Risedronate will soon be available because the brand drug’s (Actonel) patent has expired. Risedronate has received tentative FDA approval for the treatment of glucocorticoid-induced osteoporosis, Paget’s disease, and for the treatment and prevention of postmenopausal osteoporosis. The manufacturer has 180-day marketing exclusivity on this product once litigation has been completed.


New Indications, Dosage

A 250 mg carisoprodol tablet (Soma 250 mg) was approved by the FDA on Sept. 13. It is being marketed as a new and improved carisoprodol product with comparable efficacy to the 350 mg strength. However, because this is a new strength, there is no generic equivalent. Originally approved in 1959, carisoprodol is indicated for short-term use (two to three weeks) in musculoskeletal discomfort. Additionally, the Soma 250 mg capsule has been discontinued. Use caution when prescribing carisoprodol to potential patients, bearing in mind that only Soma 350 mg has generic equivalents.—MK


Patients usually present with vague symptoms that may include nausea, anorexia, fatigue, right upper-quadrant discomfort, jaundice, or dark urine. Patients with cholestatic liver disease may also present with pruritus.

Any of these along with laboratory evidence of liver injury should indicate further investigation into possible DILI. Impaired hepatic function such as increased prothrombin time and encephalopathy (signs of acute liver failure) indicate severe hepatic injury.

The Agents

Common causes of hepatocellular injury include: acetaminophen, fluoxetine, highly active antiretroviral therapies, kava kava (other herbal products), non-steroidal anti-inflammatory drugs, paroxetine, rifampin, risperidone, statins, trazodone, and troglitazone.

Common causes of cholestatic injury include: ampicillin-clavulanic acid, anabolic steroids, chlorpromazine, clopidogrel, estrogens, mirtazapine, terbinafine, and tricyclics.

Common causes of mixed-pattern injury include: amitriptyline, azathioprine, captopril, carbamazepine, enalapril, erythromycins, flutamide, phenytoin, sulfonamides, trazodone, and trimethoprim-sulfamethoxazole.

Most cases of non-fulminant hepatitis will improve upon cessation of offending or potentially offending agent(s). Assess hepatic injury immediately via continuously obtained biochemical tests.

Consult a hepatologist or gastroenterologist immediately if jaundice, impaired hepatic function or clinical signs of acute hepatic failure (e.g., encephalopathy) are evident.

Report all cases of potential DILI to the FDA’s adverse events reporting program, Medwatch, at medwatch or by calling (800) 332-1088. For patients receiving potentially hepatotoxic agents, liver function test monitoring is recommended following a baseline assessment. Some agents require monthly rather than periodic monitoring. For a list of some agents that require hepatic monitoring and the recommended frequency, visit TH

Michele B. Kaufman is a freelance medical writer based in New York City.


  1. Nathwani RA, Kaplowitz N. Drug hepatotoxicity. Clin Liver Dis. 2006;10:207-217.
  2. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731-739.
  3. Hepatic Toxicity Possibly Associated with Kava-Containing Products—United States, Germany, and Switzerland, 1999-2002. MMWR Weekly, Nov. 29, 2002/51(47):1065-1067. Available at: Last accessed Nov. 5, 2007.
  4. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002;287:17:2215-2220.
  5. Tice SA, Parr D. Medications that require hepatic monitoring. Hospital Pharmacy 2004;39(6):595-606.

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