Severe Hepatotoxicity in a Patient Receiving Both Acetaminophen and Zidovudine KIMBERLYSHRINER,M.D., MATTHEWBIDWELLGOETZ,M.D., LosAngeles, California
We report the development of severe hepatotoxicity in a patient on xidovudine therapy who received 3.3 g of acetaminophen in less than 36 hours. Three days later, the patient’s serum aspartate aminotransferase level was 6,724 U/L, alanine aminotransferase was 3,124 U/L, lactate dehydrogenase was 12,675 U/L, alhaline phosphatase was 34 U/L, and total bilirubiu was 20 pmol/Le These values substantially improved over the ensuing 4 days Serologic results for hepatitis B, hepatitis A, aud cytomegalovirus were all negative. The pattern and time sequence of tranaaminase elevation in this patient are consistent with acute acetaminophen hepatotoxicity, especially since xidovudine-induced hepatotoxicity is described as producing cholestasis rather than acute hepatitis. We hypothesixe that our patient’s susceptibility to acetaminophen-dependent hepatotoxicity may have been augmented by competitive utilization of glucuronidation by other drugs such as xidovudine and/or trimethoprim-sulfamethoxaxole with subsequent increased cytochrome PMdependent metabolism of acetamiuophen. Additionally, due to malnutrition and/or to human immunodeficiency virus infection per se, our patient may have had decreased hepatic reserves of glutathione with which to conjugate the toxic acetaminophen product of the Pa system. Although severe acetaminophen-associated hepatotoxicity has not previously been reported in patients receiving xidovudine, we suggest that clinicians be aware of this potential interaction and counsel malnourished patients, especially those with concomitant hepatic disease, to exercise caution when talcing both these medications.
From the Infectious Diseases Section, Department of Medicine, UCLA/ San Fernando Valley Program, Los Angeles County/Olive View Medical Center, Sylmar, California; Sepulveda Veterans Administration Medical Center, Sepulveda, California; and UCLA School of Medicine, Los Angeles, California. Requests for reprints should be addressed to Matthew Bidwell Goetz. M.D., Infectious Diseases Section (111-D), Sepulveda VAMC, Sepulveda, California 91343. Manuscript submitted May 14. 1991, and accepted in revised form September 21,199l.
94
July 1992 The American Journal of Medicine
Volume 93
A
lthough both zidovudine (ZDV) and acetaminophen are metabolized by hepatic glucuronidation [1,2], acetaminophen does not affect ZDV pharmacokinetics [3]. In contrast, the effect of ZDV on acetaminophen metabolism has received little attention. Herein we describe a patient who while receiving ZDV developed severe, acute hepatitis after taking less than 3.5 g of acetaminophen over 36 hours. We hypothesize that competition for hepatic glucuronidation, in combination with nutritional and innate human immunodeficiency virus (HIV)related depletion of hepatic glutathione stores [4,5], may have augmented the formation and activity of hepatotoxic metabolites of acetaminophen.
CASE REPORT A 31-year-old man with the acquired immunodeficiency syndrome presented with three days of fever, epigastric pain, nausea and vomiting, and a pruritic rash. His past medical history was significant for a remote history of Pneumocystis carinii pneumonia, previous alcohol abuse, and chronic recurrent pancreatitis. Two days prior to the onset of symptoms, the patient had been discharged from the hospital after a recurrence of pancreatitis; that hospitalization was complicated by phlebitis at the site of a intravenous catheter. During the 24 hours prior to rehospitalization, he took a total of four 500-mg tablets of acetaminophen to relieve discomfort at the catheter site. Other medications included ZDV 200 mg twice daily and trimethoprim-sulfamethoxazole (160 mg and 800 mg, respectively) once daily, both of which he had been taking for 6 months prior to admission without adverse consequences. He denied any recent alcohol or recreational drug use. On admission, the patient’s temperature was 38.9”C, pulse 110 beats/min, respirations 2O/min, and blood pressure 102/78 mm Hg. Physical examination was significant for cachexia, a diffuse erythematous rash, cellulitis at the previous catheter site, and modest epigastric tenderness. A room air arterial blood gas showed a pH of 7.36, PaCOz (arterial carbon dioxide pressure) of 37 torr, and Pa02 (arterial pressure of oxygen) of 51 torr. Serum electrolyte levels were normal. The initial serum amylase was 56 U/L (normal: 30 to 110 U/L), lipase was 341 U/L (normal: 23 to 208 U/L), aspar-
HEPATOTOXICITY
tate aminotransferase was 55 U/L (normal: 5 to 35 U/L), alanine aminotransferase was 29 U/L (normal: 7 to 56 U/L), alkaline phosphatase was 118 U/L (normal: 38 to 126 U/L), total bilirubin was 22.2 pmol/L (normal: 3.4 to 22.2 rmol/L), and serum albumin was 27 g/L. The prothrombin time was 13.2 seconds (control: 12.3 seconds), and the partial thromboplastin time was 22 seconds (control: 35 seconds). Results of both a flat plate radiograph of the abdomen and abdominal ultrasound examination were unremarkable. The patient was given intravenous cephalothin to treat the cellulitis and two 650-mg acetaminophen suppositories within 12 hours of his admission. Two days later, the serum aspartate aminotransferase level was 5,724 U/L, alanine aminotransferase was 3,124 U/L, lactate dehydrogenase was 12,675 U/L (normal less than 571 U/L), amylase was 400 U/L, lipase was 332 U/L, creatinine phosphokinase was 778 U/L, alkaline phosphatase was 84 U/L, and total bilirubin was 20 pmol/L. The lactate dehydrogenase was predominantly of hepatic origin. The prothrombin time was 18.1 seconds, and the partial thromboplastin time was 22 seconds. A computed tomographic scan of the abdomen showed moderate edema of the pancreas and a normal hepatobiliary system. Serologic results for hepatitis B, hepatitis A, and cytomegalovirus, monospot and Coombs’ tests, serum cryptococcal antigen, and VDRL were negative. His serum acetaminophen level was less than 5 pg/mL on the third day of this hospitalization. The patient’s fever, abdominal pain, and rash improved on the fourth hospital day. The serum aspartate aminotransferase was 3,697 U/L, alanine aminotransferase was 3,073 U/L, and lactate dehydrogenase was 1,096 U/L. Seven days after admission, his serum aspartate aminotransferase was 191 U/L and alanine aminotransferase 1,215 U/L. The prothrombin time was 13.1 seconds, amylase was 32 U/L, and lipase was 127 U/L. All cultures of blood, sputum, stool, and urine remained negative. The patient did not experience hemodynamic compromise at any time during the hospitalization.
COMMENTS The character and timing of this patient’s abnormal liver function tests are consistent with acute acetaminophen-induced hepatotoxicity (Figure 1) [6]. In contrast, common infectious causes of hepatitis were ruled out. Although hepatitis C serologies were not obtained, the degree of transaminase elevation is inconsistent with this viral entity [7]. Severe sulfonamide-related hepatotoxicity is rare and is more commonly associated with higher doses of drug than was given to this patient [8]. Previous use
AFTER ACETAMINOPHEN
AND ZIDOVUDINE
/ SHRINER
AND GOETZ
6000.
sooo4000. 3000.
Flgure 1. Temporal relation of abnormal to administration of acetaminophen.
liver
function
tests
of trimethoprim-sulfamethoxazole without adverse results in this patient also speaks against sulfonamide-induced hepatotoxicity. ZDV-induced hepatotoxicity is described as producing cholestasis rather than acute hepatitis [9]. Cephalosporin-associated hepatitis is rare and usually produces only mild transaminase elevation [lo]. Acetaminophen is normally eliminated by conjugation to sulfate or glucuronic acid; less than 5% is metabolized to a hepatotoxic intermediary by the cytochrome P450 system and then detoxified by conjugation to glutathione [ 111. Acute hepatotoxicity generally follows the ingestion of greater than 7.5 g [6]. Although severe hepatotoxicity has been reported after the ingestion of 2.5 to 5 g of acetaminophen per day [4,11], our patient, who received 3.3 g of acetaminophen over 24 to 36 hours, differs in that he was not actively consuming alcohol. We postulate that several factors may have contributed to the development of profound hepatotoxicity in our patient. Co-administration of ZDV may have impaired his ability to glucuronidate acetaminophen [2] and thus promoted acetaminophen metabolism via the Pdm system. Furthermore, detoxification of these metabolites by glutathione conjugation may have been impaired due to depletion of intra-hepatic glutathione. Such impoverishment has been observed in malnourished alcoholics [4,11] and may potentially accompany HIV infection per se [5]; indeed, ingestion of 0.5 to 3.0 g of acetaminophen reduces hepatic glutathione in normal patients [2]. Finally, although sulfonamide-related severe hepatotoxicity is unusual [8], trimethoprim/sulfamethoxazole may have aggravated our patient’s course since Pdm metabolism of sulfonamides also yields a metabolite that is conjugated by glutathione [12]. In summary, although serious acetaminophenassociated hepatotoxicity has not previously been reported among patients receivng ZDV, we suggest July
1992
The American
Journal
of Medlclne
Volume
93
95
HEPATOTOXICITV
that and with tion
AFTER ACETAMINOPHEN
AND ZIDOVUDINE
/ SHRINER
clinicians be aware of this potential interaction counsel malnourished patients, especially those concomitant hepatic disease, to exercise cauwhen taking both these medications.
REFERENCES 1. Blum R, Liao S, Good S. et al. Pharmacokinetics and bioavailabilii of zidovudine in humans. Am J Med 1988; 85 Suppl 2A: 189-94. 2 Slattery JT, Wilson JM, Kalhorn TF, Nelson SD. Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione depletion in humans. Clin Pharmacol Ther 1987; 41: 413-8. 3. Sattler FR, Ko R, Antoniskis D. et a/. Acetaminophen does not impair* clearance of zidovudine. Ann Intern Med 1991; 114: 937-40. 4. Lauterburg B, Velez M. Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut 1988; 29: 1153-7.
96
July
1992
The American
Journal
of Medicine
Volume
93
AND GOEn
5. Buhl R, Jaffe HA, Holroyd KJ, et al. Systemic glutathione deficiency in symp tom-free HIV-seropositive individuals. Lancet 1989; 2: 1294-7. 6. Rumack BH, Peterson RC. Koch GG, Amara IA. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med
1981; 141: 380-5. 7. Dienstag Jules L. Non-A, non-B hepatitis. I. Recognition, epidemiology, and clinical features. Gastroenterology 1983: 85: 439-62. 6. Sotolongo RP. Neefe LI, Rudzki C, lshak KG. Hypersensitivity reaction to suifasalazine with severe hepatotoxicity. Gastroenterology 1978; 75: 95-9. 9. Dubin G. Braffman M. Zidovudine-induced hepatotoxicity. Ann Intern Med
1989: 110: 85-6. 10. Norrby SR. Side effects of cephalosporins.
Drugs 1987; 34 Suppl2: 10520. 11. Seeff LB, Cuccherini BA, Zimmerman HJ. Adler E, Benjamin SB. Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern Med
1986; 104: 399-404. 12. Shear NH. Spielberg SP, Grant DM, Tang BK. Kalow W. Differences olism of sulfonamides
1986; 105: 179-84.
predisposing
to idiosyncratic
toxicity.
in metab Ann Intern Med
We report the development of severe hepatotoxicity in a patient on xidovudine therapy who received 3.3 g of acetaminophen in less than 36 hours. Three days later, the patient’s serum aspartate aminotransferase level was 6,724 U/L, alanine aminotransferase was 3,124 U/L, lactate dehydrogenase was 12,675 U/L, alhaline phosphatase was 34 U/L, and total bilirubiu was 20 pmol/Le These values substantially improved over the ensuing 4 days Serologic results for hepatitis B, hepatitis A, aud cytomegalovirus were all negative. The pattern and time sequence of tranaaminase elevation in this patient are consistent with acute acetaminophen hepatotoxicity, especially since xidovudine-induced hepatotoxicity is described as producing cholestasis rather than acute hepatitis. We hypothesixe that our patient’s susceptibility to acetaminophen-dependent hepatotoxicity may have been augmented by competitive utilization of glucuronidation by other drugs such as xidovudine and/or trimethoprim-sulfamethoxaxole with subsequent increased cytochrome PMdependent metabolism of acetamiuophen. Additionally, due to malnutrition and/or to human immunodeficiency virus infection per se, our patient may have had decreased hepatic reserves of glutathione with which to conjugate the toxic acetaminophen product of the Pa system. Although severe acetaminophen-associated hepatotoxicity has not previously been reported in patients receiving xidovudine, we suggest that clinicians be aware of this potential interaction and counsel malnourished patients, especially those with concomitant hepatic disease, to exercise caution when talcing both these medications.
From the Infectious Diseases Section, Department of Medicine, UCLA/ San Fernando Valley Program, Los Angeles County/Olive View Medical Center, Sylmar, California; Sepulveda Veterans Administration Medical Center, Sepulveda, California; and UCLA School of Medicine, Los Angeles, California. Requests for reprints should be addressed to Matthew Bidwell Goetz. M.D., Infectious Diseases Section (111-D), Sepulveda VAMC, Sepulveda, California 91343. Manuscript submitted May 14. 1991, and accepted in revised form September 21,199l.
94
July 1992 The American Journal of Medicine
Volume 93
A
lthough both zidovudine (ZDV) and acetaminophen are metabolized by hepatic glucuronidation [1,2], acetaminophen does not affect ZDV pharmacokinetics [3]. In contrast, the effect of ZDV on acetaminophen metabolism has received little attention. Herein we describe a patient who while receiving ZDV developed severe, acute hepatitis after taking less than 3.5 g of acetaminophen over 36 hours. We hypothesize that competition for hepatic glucuronidation, in combination with nutritional and innate human immunodeficiency virus (HIV)related depletion of hepatic glutathione stores [4,5], may have augmented the formation and activity of hepatotoxic metabolites of acetaminophen.
CASE REPORT A 31-year-old man with the acquired immunodeficiency syndrome presented with three days of fever, epigastric pain, nausea and vomiting, and a pruritic rash. His past medical history was significant for a remote history of Pneumocystis carinii pneumonia, previous alcohol abuse, and chronic recurrent pancreatitis. Two days prior to the onset of symptoms, the patient had been discharged from the hospital after a recurrence of pancreatitis; that hospitalization was complicated by phlebitis at the site of a intravenous catheter. During the 24 hours prior to rehospitalization, he took a total of four 500-mg tablets of acetaminophen to relieve discomfort at the catheter site. Other medications included ZDV 200 mg twice daily and trimethoprim-sulfamethoxazole (160 mg and 800 mg, respectively) once daily, both of which he had been taking for 6 months prior to admission without adverse consequences. He denied any recent alcohol or recreational drug use. On admission, the patient’s temperature was 38.9”C, pulse 110 beats/min, respirations 2O/min, and blood pressure 102/78 mm Hg. Physical examination was significant for cachexia, a diffuse erythematous rash, cellulitis at the previous catheter site, and modest epigastric tenderness. A room air arterial blood gas showed a pH of 7.36, PaCOz (arterial carbon dioxide pressure) of 37 torr, and Pa02 (arterial pressure of oxygen) of 51 torr. Serum electrolyte levels were normal. The initial serum amylase was 56 U/L (normal: 30 to 110 U/L), lipase was 341 U/L (normal: 23 to 208 U/L), aspar-
HEPATOTOXICITY
tate aminotransferase was 55 U/L (normal: 5 to 35 U/L), alanine aminotransferase was 29 U/L (normal: 7 to 56 U/L), alkaline phosphatase was 118 U/L (normal: 38 to 126 U/L), total bilirubin was 22.2 pmol/L (normal: 3.4 to 22.2 rmol/L), and serum albumin was 27 g/L. The prothrombin time was 13.2 seconds (control: 12.3 seconds), and the partial thromboplastin time was 22 seconds (control: 35 seconds). Results of both a flat plate radiograph of the abdomen and abdominal ultrasound examination were unremarkable. The patient was given intravenous cephalothin to treat the cellulitis and two 650-mg acetaminophen suppositories within 12 hours of his admission. Two days later, the serum aspartate aminotransferase level was 5,724 U/L, alanine aminotransferase was 3,124 U/L, lactate dehydrogenase was 12,675 U/L (normal less than 571 U/L), amylase was 400 U/L, lipase was 332 U/L, creatinine phosphokinase was 778 U/L, alkaline phosphatase was 84 U/L, and total bilirubin was 20 pmol/L. The lactate dehydrogenase was predominantly of hepatic origin. The prothrombin time was 18.1 seconds, and the partial thromboplastin time was 22 seconds. A computed tomographic scan of the abdomen showed moderate edema of the pancreas and a normal hepatobiliary system. Serologic results for hepatitis B, hepatitis A, and cytomegalovirus, monospot and Coombs’ tests, serum cryptococcal antigen, and VDRL were negative. His serum acetaminophen level was less than 5 pg/mL on the third day of this hospitalization. The patient’s fever, abdominal pain, and rash improved on the fourth hospital day. The serum aspartate aminotransferase was 3,697 U/L, alanine aminotransferase was 3,073 U/L, and lactate dehydrogenase was 1,096 U/L. Seven days after admission, his serum aspartate aminotransferase was 191 U/L and alanine aminotransferase 1,215 U/L. The prothrombin time was 13.1 seconds, amylase was 32 U/L, and lipase was 127 U/L. All cultures of blood, sputum, stool, and urine remained negative. The patient did not experience hemodynamic compromise at any time during the hospitalization.
COMMENTS The character and timing of this patient’s abnormal liver function tests are consistent with acute acetaminophen-induced hepatotoxicity (Figure 1) [6]. In contrast, common infectious causes of hepatitis were ruled out. Although hepatitis C serologies were not obtained, the degree of transaminase elevation is inconsistent with this viral entity [7]. Severe sulfonamide-related hepatotoxicity is rare and is more commonly associated with higher doses of drug than was given to this patient [8]. Previous use
AFTER ACETAMINOPHEN
AND ZIDOVUDINE
/ SHRINER
AND GOETZ
6000.
sooo4000. 3000.
Flgure 1. Temporal relation of abnormal to administration of acetaminophen.
liver
function
tests
of trimethoprim-sulfamethoxazole without adverse results in this patient also speaks against sulfonamide-induced hepatotoxicity. ZDV-induced hepatotoxicity is described as producing cholestasis rather than acute hepatitis [9]. Cephalosporin-associated hepatitis is rare and usually produces only mild transaminase elevation [lo]. Acetaminophen is normally eliminated by conjugation to sulfate or glucuronic acid; less than 5% is metabolized to a hepatotoxic intermediary by the cytochrome P450 system and then detoxified by conjugation to glutathione [ 111. Acute hepatotoxicity generally follows the ingestion of greater than 7.5 g [6]. Although severe hepatotoxicity has been reported after the ingestion of 2.5 to 5 g of acetaminophen per day [4,11], our patient, who received 3.3 g of acetaminophen over 24 to 36 hours, differs in that he was not actively consuming alcohol. We postulate that several factors may have contributed to the development of profound hepatotoxicity in our patient. Co-administration of ZDV may have impaired his ability to glucuronidate acetaminophen [2] and thus promoted acetaminophen metabolism via the Pdm system. Furthermore, detoxification of these metabolites by glutathione conjugation may have been impaired due to depletion of intra-hepatic glutathione. Such impoverishment has been observed in malnourished alcoholics [4,11] and may potentially accompany HIV infection per se [5]; indeed, ingestion of 0.5 to 3.0 g of acetaminophen reduces hepatic glutathione in normal patients [2]. Finally, although sulfonamide-related severe hepatotoxicity is unusual [8], trimethoprim/sulfamethoxazole may have aggravated our patient’s course since Pdm metabolism of sulfonamides also yields a metabolite that is conjugated by glutathione [12]. In summary, although serious acetaminophenassociated hepatotoxicity has not previously been reported among patients receivng ZDV, we suggest July
1992
The American
Journal
of Medlclne
Volume
93
95
HEPATOTOXICITV
that and with tion
AFTER ACETAMINOPHEN
AND ZIDOVUDINE
/ SHRINER
clinicians be aware of this potential interaction counsel malnourished patients, especially those concomitant hepatic disease, to exercise cauwhen taking both these medications.
REFERENCES 1. Blum R, Liao S, Good S. et al. Pharmacokinetics and bioavailabilii of zidovudine in humans. Am J Med 1988; 85 Suppl 2A: 189-94. 2 Slattery JT, Wilson JM, Kalhorn TF, Nelson SD. Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione depletion in humans. Clin Pharmacol Ther 1987; 41: 413-8. 3. Sattler FR, Ko R, Antoniskis D. et a/. Acetaminophen does not impair* clearance of zidovudine. Ann Intern Med 1991; 114: 937-40. 4. Lauterburg B, Velez M. Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut 1988; 29: 1153-7.
96
July
1992
The American
Journal
of Medicine
Volume
93
AND GOEn
5. Buhl R, Jaffe HA, Holroyd KJ, et al. Systemic glutathione deficiency in symp tom-free HIV-seropositive individuals. Lancet 1989; 2: 1294-7. 6. Rumack BH, Peterson RC. Koch GG, Amara IA. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med
1981; 141: 380-5. 7. Dienstag Jules L. Non-A, non-B hepatitis. I. Recognition, epidemiology, and clinical features. Gastroenterology 1983: 85: 439-62. 6. Sotolongo RP. Neefe LI, Rudzki C, lshak KG. Hypersensitivity reaction to suifasalazine with severe hepatotoxicity. Gastroenterology 1978; 75: 95-9. 9. Dubin G. Braffman M. Zidovudine-induced hepatotoxicity. Ann Intern Med
1989: 110: 85-6. 10. Norrby SR. Side effects of cephalosporins.
Drugs 1987; 34 Suppl2: 10520. 11. Seeff LB, Cuccherini BA, Zimmerman HJ. Adler E, Benjamin SB. Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern Med
1986; 104: 399-404. 12. Shear NH. Spielberg SP, Grant DM, Tang BK. Kalow W. Differences olism of sulfonamides
1986; 105: 179-84.
predisposing
to idiosyncratic
toxicity.
in metab Ann Intern Med
