Correspondence

Drug-Related Hepatotoxicity

N Engl J Med 2006; 354:2191-2193May 18, 2006

Article

To the Editor:

In the excellent review of drug-related hepatotoxicity by Navarro and Senior (Feb. 16 issue),1 antithyroid agents were not included in the authors' list of medications that cause injury to the liver. Both classes of antithyroid agents, propylthiouracil and methimazole, are known rarely to cause liver dysfunction, which is among the small number of their idiosyncratic toxic effects. The antithyroid drugs have distinct patterns of injury: propylthiouracil has hepatocellular toxic effects and methimazole induces cholestasis.2 The severity of these toxic effects ranges from elevated levels of enzymes without permanent injury to fulminant hepatic failure leading to liver transplantation.3 Although the mechanism of the cholestatic picture seen with methimazole is unclear, propylthiouracil may induce vasculitides related to antineutrophil cytoplasmic antibodies, suggesting an immunologic mechanism underlying hepatocellular injury due to propylthiouracil.

As the authors suggest with regard to other drugs, we do not routinely monitor liver enzymes in patients receiving antithyroid medications, since mild elevations of aminotransferase levels are common when 300 mg or more of propylthiouracil is prescribed daily, independent of baseline levels of liver enzymes in patients with thyrotoxicosis.4

Marie E. McDonnell, M.D.
Lewis E. Braverman, M.D.
Boston Medical Center, Boston, MA 02118
marie.mcdonnell@bmc.org

4 References

1
Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006;354:731-739
Full Text | Web of Science | Medline

2
Braverman LE, Utiger RD, eds. Werner and Ingbar's the thyroid: a fundamental and clinical text. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:670-1.

3
Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 2004;10:1018-1023
CrossRef | Web of Science | Medline

4
Liaw Y-F, Huang M-J, Fan K-D, Li KL, Wu SS, Chen TJ. Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism: a cohort study. Ann Intern Med 1993;116:424-428

To the Editor:

Navarro and Senior mention that the most common cause of acute liver failure in the United States is acetaminophen overdose and describe prevention strategies for hepatotoxicity but not the effect of controlling the public supply of this medication. In the United Kingdom, changes in legislation in 1998 limited the number of tablets in a packet of acetaminophen sold by pharmacies to 32 (16 g) and by other outlets to 16 (8 g). This limitation has resulted in a significant change in the incidence of acetaminophen overdoses.1 The rates of admission to liver units have dropped by 30 percent since this legislation came into force, with a commensurate drop in the number of patients listed for liver transplantation. Approximately 39 deaths appear to have been avoided per year.1

Kinesh P. Patel, M.B., B.S.
Hammersmith Hospital, London W12 0HS, United Kingdom
kinesh_patel@yahoo.co.uk

1 References

1
Hawton K, Simkin S, Deeks J, et al. UK legislation on analgesic packs: before and after study of long term effect on poisonings. BMJ 2004;329:1076-1076[Erratum, BMJ 2004;329:1159.]
CrossRef | Web of Science | Medline

To the Editor:

The list of common medications known to cause hepatotoxic effects in the report by Navarro and Senior does not include the endothelin-receptor antagonists used to treat pulmonary hypertension. These oral medications are now the cornerstone of therapy for this condition.1

In the Bosentan Randomized Trial of Endothelin Antagonist Therapy (BREATHE-1) study, hepatitis developed in 3 percent of the patients receiving bosentan after 16 weeks, as compared with no cases of hepatitis in the placebo group.2 In this study cohort, 14.9 percent of patients had hepatic aminotransaminase levels elevated more than three times the upper limit of normal, including 4.2 percent of patients with levels more than eight times the upper limit of normal.3 The effects were seen as late as 26 weeks into therapy, thus necessitating serial monitoring of liver enzymes.3 This hepatotoxicity appears to be a class effect.4 Physicians who are not familiar with these medications need to be aware of potential complications. Awareness is important because these agents have proved to be effective therapy in patients with pulmonary hypertension.

Kieran McIntyre, M.D.
University of Toronto, Toronto, ON M5P 1K5, Canada

4 References

1
Liu C, Cheng J. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Syst Rev 2005;1:CD004434-CD004434
Medline

2
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903[Erratum, N Engl J Med 2002;346:1258.]
Full Text | Web of Science | Medline

3
McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005;25:244-249[Erratum, Eur Respir J 2005;25:942.]
CrossRef | Web of Science | Medline

4
Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;169:441-447
CrossRef | Web of Science | Medline

To the Editor:

When considering drug-induced hepatotoxicity, niacin should be kept in mind. Niacin is used both as a prescription medication for the treatment of hyperlipidemia and as an over-the-counter vitamin supplement. Although cholestasis may occur in association with niacin use,1 the liver injury is most commonly hepatocellular in nature.2 It is unclear whether niacin or one of its metabolites is the cause of the toxic effects.3 Both the crystalline and sustained-release formulations of niacin can induce hepatotoxic effects, but the sustained-release form causes more cases and with greater severity.4 Toxic effects can occur with the sustained-release form even at low doses taken for a short time.5

Miguel G. Madariaga, M.D.
University of Nebraska Medical Center, Omaha, NE 68118
mmadariaga@unmc.edu

5 References

1
Patel SD, Taylor HC. Intrahepatic cholestasis during nicotinic acid therapy. Cleve Clin J Med 1994;61:70-75
Web of Science | Medline

2
Hodis HN. Acute hepatic failure associated with the use of low-dose sustained-release niacin. JAMA 1990;264:181-181
CrossRef | Web of Science | Medline

3
Malloy MJ, Frost PH, Kane JP. Niacin -- the long and the short of it. West J Med 1991;155:424-426
Medline

4
Dalton TA, Berry RS. Hepatotoxicity associated with sustained-release niacin. Am J Med 1992;93:102-104
CrossRef | Web of Science | Medline

5
Etchason JA, Miller TD, Squires RW, et al. Niacin-induced hepatitis: a potential side effect with low-dose time-release niacin. Mayo Clin Proc 1991;66:23-28
Web of Science | Medline

To the Editor:

We wonder whether Navarro and Senior should take into consideration the potential complications arising from the use of various illicit drugs such as 3,4-methylenedioxymethamphetamine (“ecstasy”), cocaine,1 and cannabis.2

Nicola Mumoli, M.D.
Marco Cei, M.D.
Alessandro Cosimi, M.D.
Ospedale Civile Livorno, 57100 Livorno, Italy
nimumoli@tiscali.it

2 References

1
Selim K, Kaplowitz N. Hepatotoxicity of psychotropic drugs. Hepatology 1999;29:1347-1351
CrossRef | Web of Science | Medline

2
Kew MC, Bersohn I, Siew S. Possible hepatotoxicity of cannabis. Lancet 1969;1:578-579
CrossRef | Web of Science | Medline

Author/Editor Response

As Drs. McDonnell and Braverman point out, we did not include antithyroid agents in our list of drugs that may cause injury to the liver. Drs. McIntyre and Madariaga note that we also did not list or discuss niacin, especially in the sustained-release formulation, or bosentan, the endothelin-receptor antagonist that has become the treatment of choice for pulmonary hypertension. All these agents are worthy of inclusion and deserve discussion because of the important lessons they provide, but space simply did not permit a comprehensive list or discussion of all the drugs that may cause liver injury in some people. The best source for more complete information remains the 1999 book Hepatotoxicity by the late Dr. Hyman Zimmerman,1 even more than six years after his death.

A review of hepatic injury resulting from the use of illicit substances was beyond the scope of our article. Nevertheless, as Mumoli and colleagues point out, such substances are common potential hepatotoxins. The clinical evaluation of a patient with suspected hepatotoxicity due to illicit-drug use would not differ from that of a patient with injury from a prescribed pharmaceutical agent. Their comments underscore the importance of obtaining a complete history of ingested, injected, or inhaled substances, including over-the-counter medications, so-called dietary supplements, special diets, environmental chemicals, and alcohol, as well as illicit or recreational agents. The liver has to cope with them all, often in combination.

In the United Kingdom, unlike the United States, access to acetaminophen is regulated, and the incidence of overdoses, especially of the intentional variety, has thereby decreased, as Dr. Patel points out. U.S. law is different, and the authority of the U.S. Food and Drug Administration is limited. This agency is not empowered to regulate the practice of medicine, nor does it currently limit acetaminophen purchases or package size (including number of tablets). Warnings and advice to pharmacists, consumer organizations, and others have been issued,2 but such counsel may or may not be heeded. Alternative measures may be considered if current attempts to decrease acetaminophen hepatotoxicity are unsuccessful.3

Finally, we want to call attention to the active research into the incidence and mechanisms of drug-induced liver injury summarized recently at a conference sponsored by the American Association for the Study of Liver Diseases4 and the ongoing cooperative study by governmental, industrial, and academic investigators in the Hepatotoxicity Steering Group.5

Victor J. Navarro, M.D.
Jefferson Medical College, Philadelphia, PA 19107
victor.navarro@jefferson.edu

John R. Senior, M.D.
Food and Drug Administration, Silver Spring, MD 20907

Since publication of the article, Dr. Navarro reports having been retained as a drug safety consultant for Ono Pharma USA.

5 References

1
Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 1999.

2
Food and Drug Administration. Letter to state boards of pharmacy: acetaminophen hepatotoxicity and nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal and renal toxicity. January 22, 2004. (Accessed May 1, 2006, at http://www.fda.gov/cder/drug/analgesics/letter.htm.)

3
Galson S. Acetaminophen hepatotoxicity. Hepatology 2004;40:1021-1022
CrossRef | Web of Science

4
Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology 2006;43:618-631
CrossRef | Web of Science | Medline

5
Hepatotoxicity Steering Group. Drug-induced liver toxicity: fifth annual meeting, January 25–26, 2006. (Accessed May 1, 2006, at http://www.fda.gov/cder/livertox/.)

Citing Articles (2)

Citing Articles

1
Aaron J. Pugh, Ashutosh J. Barve, Keith Falkner, Mihir Patel, Craig J. McClain. (2009) Drug-Induced Hepatotoxicity or Drug-Induced Liver Injury. Clinics in Liver Disease 13:2, 277-294
CrossRef
2
(2006) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 15:11, i-xii
CrossRef