- Email: [email protected]
Influence of acetaminophen at therapeutic doses on surrogate markers of severity of acute viral hepatitis
© Masson, Paris, 2006.
25,*,1$/ $57,&/(
Gastroenterol Clin Biol 2006;30:763-768
Influence of acetaminophen at therapeutic doses on surrogate markers of severity of acute viral hepatitis
César YAGHI, Khalil HONEIN, Joseph BOUJAOUDE, Rita SLIM, Rami MOUCARI, Raymond SAYEGH Division of Gastroenterology, Hôtel-Dieu de France University Hospital, Beirut, Lebanon.
SUMMARY
RÉSUMÉ
Objectives — Data on the influence of acetaminophen intake on acute viral hepatitis is scarce, but it could play a role in the worsening of this disease. The aim of this study was to determine whether the intake of acetaminophen at therapeutic doses affects the severity of acute viral hepatitis.
Influence de la prise d’acétaminophène à doses thérapeutiques sur les marqueurs de sévérité des hépatites virales aiguës César YAGHI, Khalil HONEIN, Joseph BOUJAOUDE, Rita SLIM, Rami MOUCARI, Raymond SAYEGH (Gastroenterol Clin Biol 2006;30:763-768)
Methods — This was a prospective study concerning 37 consecutive patients hospitalized for acute viral hepatitis. Acetaminophen consumption and time since last intake were assessed by a questionnaire. Parameters of severity were studied in comparison to time related serum concentrations of acetaminophen.
Objectifs — Les données concernant l’influence de la prise d’acétaminophène sur les hépatites virales sont rares, mais cette prise pourrait avoir un rôle dans leur aggravation. Notre objectif était d’établir si la prise d’acétaminophène avait une influence sur la sévérité des hépatites aiguës virales.
Results — Patients hospitalized for acute viral hepatitis (18 male, 19 female patients) had a mean age of 29.2 ± 11.5 years. The causal virus was HAV (n = 23), HBV (n = 7) and other viruses (n = 8). The mean cumulated dose of acetaminophen was 7.7 ± 5.65 g. The daily dose did not exceed the therapeutic dosage and the mean was 1.95 ± 0.81 g (1-3 g). Patients who received 7.5 g of acetaminophen or more had a lower prothrombin index 52.4 ± 30.3% vs 74.2 ± 17.2% (P = 0.039), and a lower factor V 54.7 ± 33.2% vs 83.3 ± 19.6% (P = 0.033). Prothrombin index and bilirubinemia were negatively correlated with time related plasma acetaminophen concentrations.
Malades et méthodes — Il s’agit d’une étude prospective concernant 37 malades consécutifs hospitalisés pour hépatite virale aiguë. La quantité d’acétaminophène et l’intervalle de temps depuis la dernière prise étaient évalués par un questionnaire. Les paramètres de sévérité de l’hépatite étaient étudiés par la concentration plasmatique d’acétaminophène en fonction du temps écoulé depuis la dernière prise. Résultats — Les malades hospitalisés pour hépatite aiguë virale (18 hommes, 19 femmes) d’âge moyen 29,2 r 11,5 ans présentaient une hépatite aiguë A, B, ou autre chez respectivement 23, 7, et 8 malades. La dose cumulée moyenne d’acétaminophène par malade était de 7,7 r 5,65 g. La posologie quotidienne moyenne était de 1,95 r 0,81 g (1-3 g). Les malades qui avaient reçu une dose cumulée d’acétaminophène t 7,5 g avaient un taux de prothrombine plus bas (52,4 r 30,3 % vs 74,2 r 17,2 %) (P = 0,039), ainsi qu’un taux plus faible du facteur V (54,7 r 33,2 % vs 83,3 r 19,6 %) (P = 0,033). Le taux de prothrombine et la bilirubinémie étaient corrélés négativement avec la concentration plasmatique d’acétaminophène.
Conclusions — The use of acetaminophen at therapeutic doses was associated with greater alterations of surrogate markers of the severity of acute viral hepatitis especially hepatitis A. This was related to cumulated dosages and correlated to the time related acetaminophen plasma concentrations. Acetaminophen use should be interrupted when acute hepatitis is suspected.
Conclusion — L’utilisation d’acétaminophène à posologie thérapeutique était associée par une altération des marqueurs biologiques de sévérité des hépatites virales en particulier les hépatites A. Cette altération était liée à la prise cumulée d’acétaminophène, et corrélée avec la concentration plasmatique d’acétaminophène en fonction du temps écoulé depuis la dernière prise. La prise d’acétaminophène devrait être arrêtée quand le diagnostic d’hépatite aiguë est posé.
Acetaminophen is used to treat symptoms such as pain and fever. Therapeutic plasma levels range from 10 to 30 μg/mL. Peak levels after therapeutic doses do not exceed 20 μg/mL and they do not accumulate with multiple daily dosing [1]. However, patients who develop severe liver injury and continue to ingest multiple doses of acetaminophen may accumulate the drug due to prolongation of the half life of acetaminophen [2]. In the clini-
cal setting, therapeutic dosages should take into account several factors, including history of ethanol abuse as well as the underlying hepatic illness. Several cases of severe liver toxicity have been reported even when the drug was taken at normal doses in alcoholic patients [3-6]. Furthermore, acetaminophen overdose, either intentional or unintentional, plays a major role in the etiology of acute liver failure. During the prodromal period of viral infections, there is a down regulation of the gene expression of major cytochrome P-450 enzymes through proinflammatory cytokines, such as
Reprints: C. YAGHI, Division of Gastroenterology, Hôtel-Dieu de France Adib Ishac Street, Achrafieh, Beirut, Lebanon. E-mail : cesar.yaghi @usj.edu.lb
Part of the content of this paper was presented at the “Journées Francophones de Pathologie Digestive” on Paris in March 2004 and at the poster session of the UEGW 2004 held in Prague on September 2004.
Introduction
763
C. Yaghi et al.
interleukins, transforming growth factor beta1, human hepatocyte growth factor, and lymphocytotoxin. The resulting effect varies according to the involved cytokines and the specific cytochrome P-450, eventually leading to either metabolite-mediated adverse drug reactions or alteration of the metabolism of the drug [7]. Thus, acetaminophen metabolism is altered during acute viral hepatitis, and this alteration persists during the convalescence phase and disappears only after complete recovery from hepatitis. The elimination phase of acetaminophen is protracted, whereas the peak plasmatic concentration following a single dose is not affected [8]. The evolution of plasma acetaminophen concentrations after multiple dosages has not been studied in this setting. In patients with liver failure and portal hypertension, the absorption of acetaminophen is faster especially in the presence of esophageal varices [9]. Patients with cirrhosis have a higher area under curve and lower clearance of acetaminophen [9]. Increased absorption may be related to portal hypertension whereas protracted elimination is mainly due to liver failure [9]. Data on the role of acetaminophen in the course of acute viral hepatitis is scarce, but it seems to contribute to liver injury. Many questions remain unanswered [2]. In a recent paper it was shownthat fulminant hepatitis A was associated with female gender, the rapid elimination of HAV detected by PCR, genotype other than genotype 1A, and acetaminophen intake [10]. However, in multivariate analysis, the only two independent prognostic variables were increased bilirubin levels and low or undetectable viremia. Acetaminophen is currently used for fever especially during the prodromal period before acute viral hepatitis is suspected. Data from the Acute Liver Failure Study Group showed that acetaminophen was detected in the serum of 20% of patients with acute viral hepatitis. In these patients median alanine aminotransferase levels were higher than in patients who did not take acetaminophen [11]. In a recent review, it was suggested that the 24 hour intake of acetaminophen in patients with acute or chronic liver disease should be restricted to around 2 g/day, which is half the suggested maximal dose of 4 g/day [12].
hepatitis. All patients had an abdominal ultrasound rule out chronic liver disease. All patients had liver enzyme tests as well as bilirubin, prothrombin index and factor V dosages. The severity of hepatitis and fulminant liver failure were defined in accordance with the Beaujon criteria [13]. Alcohol consumption was classified into 4 groups: (0) no alcohol, (1) less than 20 g per week, (3) 20 to 60 g per week, and (4) more than 60 g per week.
Statistical analysis Numeric data are expressed as mean ± standard deviation. Comparisons were made using the Chi square test and Fisher exact test for categorical data. Comparison of continuous variables was performed using the Student’s unpaired t-test and non parametric tests, as indicated. A two tailed probability P value of less than 0.05 was considered significant. Linear regression was used to assess the influence of acetaminophen concentrations on the prothrombin index while taking into account the interval since the last intake of acetaminophen.
Results Clinical characteristics Thirty seven consecutive patients (18 males and 19 females) were included in our study. Mean age was 29.3 ± 11.5 years and age ranged from 15 to 69 years. Fever was found in 33 (89.2%) patients. None of our patients had a chronic liver disease. Prolonged fasting was found in only one patient and was related to repeated vomiting and oral intolerance. Alcohol consumption was less than 60 g/week (n = 19, 51.4%) or absent (n = 18, 48.6%) in all our patients. None of our patients had chronic alcohol abuse or recurrent binges.
Etiology Twenty two patients had an acute hepatitis A, 7 an acute hepatitis B, and among 8, hepatitis was related to either EBV or CMV. Out of the patients presenting with hepatitis B, 4 were severe, of whom, 3 had a fulminant liver failure, with 2 deaths related to liver disease (table I). Eight patients had a severe hepatitis in the HAV group. With respect to EBV related hepatitis a single patient had an increased prothrombin index (table I).
The aim of our study was to assess whether the intake of acetaminophen at usual therapeutic levels is associated with increased severity in the course of acute viral hepatitis.
Patients and methods
Acetaminophen intake in patients with acute viral hepatitis
Study population
Thirty two patients (86.5%) had taken acetaminophen. The quantity of acetaminophen and the interval since the last Intake could be precisely established in 25 patients. Total consumption, the mean number of days of acetaminophen intake and the daily dose of acetaminophen was equivalent in all groups. Interval since the last intake was longest in patients with acute hepatitis B (table I). All patients received acetaminophen prior to hospitalization and/or to the diagnosis of acute hepatitis and did not receive any further dose once the diagnosis was established. The mean cumulated dose of acetaminophen was 7.7 ± 5.7 g ranging from 1.5 g to 28 g taken over a mean period of 4.2 ± 3.2 days ranging from 1 to 14 days. The mean daily dose was 1.9 ± 0.8 g and extreme doses ranged from 1 g/day to 3 g/day. There were novoluntary or involuntary acetaminophen overdoses in our population. Mean plasma acetaminophen concentrations were 32.3 ± 15.7 mg/L. Mean interval since the last intake was 33.5 ± 23.7 hours. When the interval was ≥ 24 hours, the mean plasma acetaminophen concentration was 34.8 mg/L, whereas when the delay was < 24 hours, the mean plasma concentration was 27.9 mg/L. This difference was not statistically significant. On the other hand, all patients (11/25) with a prothrombin index < 60% had acetaminophen detectable in plasma after a delay ≥ 24 hours. None of the patients with severe acute hepatitis had an interval of < 24 hours since” the last intake. For
This was a prospective study of 37 consecutive patients hospitalized for acute viral hepatitis of various etiologies between December 2002 and February 2004. The causes for hospitalization were either acute liver failure or oral intolerance. A standardized questionnaire evaluating the quantity of ingested acetaminophen since the beginning of the symptoms, the interval since the last intake, as well as the search for factors associated with increased acetaminophen toxicity, (alcohol use, prolonged fasting, and underlying liver disease). Prolonged fasting was defined as the absence of food intake for more than 24 hours. An underlying liver disease was ruled out by taking into account clinical, biological and serology parameters particularly in patients with hepatitis B. Acetaminophen concentrations were assessed upon admission. A quantitative colorimetric method in the serum at 430 nm was used, with a precision ranging from 1 to 1.07 (Sigma Diagnostics, Acetaminophen). Acute hepatitis was diagnosed by Anti HAV IgM for acute hepatitis A, Anti HBc IgM along with the absence of Anti HBc IgG, for acute hepatitis B, IgM Anti viral capsid antibodies (Anti VCA) for EBV associated hepatitis, and IgM Anti CMV and pp65 antigen for CMV associated
ABBREVIATIONS : HAV HBV CMV EBV
: Hepatitis A virus : Hepatitis B virus : Cytomegalovirus : Epstein-Barr virus 764
Acetaminophen and acute viral hepatitis
Table I. – Characteristics of patients with regards to biological parameters, acetaminophen consumption, and etiology of viral hepatitis. Caractéristiques des malades en fonction des paramètres biologiques, de la consommation d’acétaminophène, et de l’étiologie de l’hépatite. HAV
HBV
Other viruses
N = 23
N=7
N=8
Age
24.9 ± 5.7*†
43.2 ± 20†
36± 14.5*
AST (IU/mL)
2061 ± 1655*
1839 ± 2018
511 ± 389*
ALT (IU/mL)
2796 ± 2060*
2668 ± 3028
683 ± 420*
GGT (IU/mL)
259 ± 104
172 ± 84
223 ± 178
Alk. Phosphatase
203 ± 92
157 ± 65
150 ± 46
Bilirubin μmol/L (IU/mL)
91.2 ± 80.6†
195.3 ± 166.9*†
40.8 ± 47.8*
Prothrombin index (%)
66.6 ± 21.5†
34.2 ± 20.5*†
78 ± 15.8*
Factor V (%)
77.5 ± 26.8†
47.8 ± 41.3*†
83.8 ± 21.6*
Severe or (Fulminant hepatitis)
8 (0)
4 (3)
1 (0)
Hepatic encephalopathy (death)
0 (0)
3 (2)
0 (0)
20 (16)
3 (3)
8 (6)
Quantity of ingested acetaminophen (g)
5.0 ± 3.6
5.1 ± 5.9
8.4 ± 9.6
Number of days of intake
3.3 ± 1.4
8 ± 5.3
5.2 ± 4.5
Daily dosage (g)
1.8 ± 0.9
1.5 ± 0.5
2.2 ± 0.4
Interval since last intake (hours)
33.5 ± 22.8†
64 ± 25*†
18.3 ± 8.9*
Serum concentration of acetaminophen (mg/L)
33.4 ± 16.9
37.9 ± 21.7
25.4 ± 4.6
Acetaminophen intake (data with known time elapsed since last intake)
* = HAV versus other virus, P < 0.05. † = HAV versus HBV, P < 0.05. ‡ = HBV versus other virus, P < 0.05.
patients with prothrombin index ≥ 60%, 9 patients were detected within 24 hours, and 5 after 24 hours. When the interval was ≥ 24 hours, 68.7% had severe hepatitis whereas 31.3% had non severe hepatitis (P < 0.001).
in aminotransferase levels, AST or ALT for the cumulated dose of acetaminophen (table III). Two patients died from fulminant liver failure related to HBV infection. Both had a cumulated acetaminophen consumption of more than 7.5 g, and these patients had the highestproduct of the serum concentration of acetaminophen times the interval elapsed since the last intake in our studied population, with respectively 90.0 and 129.7. This product was respectively 41.0 ± 21.2 and 109.9 ± 28.1 for spontaneous recovery and for death (table II).
Prothrombin index in relation to acetaminophen concentrations The Log (Ln) of the plasma concentration of acetaminophen and the time interval since the last intake were negatively correlated with the prothrombin index. This correlation was found in patients with acute hepatitis A. There was no statistically significant correlation in either of the groups of patients with acute hepatitis B nor EBV or CMV related hepatitis (figure 2).
Bilirubin relation to acetaminophen concentrations Patients who received 7.5 g of acetaminophen or more, had a tendency to have higher bilirubin levels but this was not statistically significance. The product of the mean serum concentrations ofacetaminophen times the interval since the last intake was 61.2 when the bilirubin level was above 60 μmol/L versus 33.3 when the bilirubin level was below 60 μmol/L (P = 0.01). This difference was also significant in the group with acute hepatitis A (54.0 vs 29.1, P = 0.02), but not in patients with acute hepatitis B in whom the difference was not statistically significant (109.9 vs. 64.3, P > 0.05). Patients who had bilirubin above 60 μmol/L and a prothrombin index below 60% had the highest product (81.7 ± 26.5), whereas the lowest product was found in patients with neither (23.5 ± 10.8). In patients with a bilirubin > 60 μmol/L or prothrombin activity < 60%, the value was intermediate (39.9 ± 22.3 and 49 ± 13.3 respectively for bilirubin and prothrombin index) (figure 1) (table II).
On the other hand, the product of the mean serum concentration of acetaminophen times the time interval since the last intake was 66.8 when the prothrombin index was less than 60% versus 30.9 when the prothrombin index was above 60% (P = 0.001) (table II). This difference was found in the acute hepatitis A group and could not be analyzed in the hepatitis B group since all the patients had a prothrombin index < 60% in this subgroup. There was no significant difference in patients with CMV or EBV related hepatitis. The cumulated dose of acetaminophen in our population was 7.7 ± 5.7 g. Patients who received 7.5 g of acetaminophen or more had a lower prothrombin index, and a lower factor V activity. It should be noted that none of the patients exceeded the recommended dose of acetaminophen. There was no difference 765
C. Yaghi et al.
Table II. – Impact of the product of the Log serum concentration of acetaminophen by the time interval elapsed since the last intake with respect to markers of severity of acute hepatitis and mortality rate. Influence du produit Log de la concentration plasmatique d’acétaminophène x le temps écoulé depuis la dernière prise en fonction des marqueurs de sévérité des hépatites aiguës et du taux de mortalité. Product < 50
Product ≥ 50
N = 14 (%)
N = 11 (%)
HAV
9
8
HBV
0
3
Other
5
0
5 (35.7)
8 (72.7)
0.066
0 (0)
2 (18.2)
0.096
Bilirubin > 60 μmol/L (N = 12)
4 (28.6)
8 (72.7)
0.028
TP < 60%, (N = 12)
3 (21.4)
9 (81.8)
0.003
0 (0)
6 (54.5)
0.001
Cause of Hepatitis
Cumulated acetaminophen > 7.5g Death
Bilirubin > 60 μmol/L and TP < 60%
P
0.02
TP: prothrombin index.
Table III. – Influence of cumulated dose of acetaminophen on the severity parameters of acute viral hepatitis. Note that none of the patients exceeded the recommended daily dosage. Influence de la dose cumulée d’acétaminophène sur la sévérité de l’hépatite virale aiguë. Il est à noter qu’aucun malade n’a consommé au-delà des doses recommandées. Acetaminophen cumulated dose ≥ 7.5g
< 7.5g
n = 13
n = 12
P
138.3 ± 154.3
62.9 ± 33.7
0.11
TP (%)
52.4 ± 30.3
74.2 ± 17.2
0.039
Factor V (%)
54.7 ± 33.2
83.3 ± 19.6
0.033
ALT (IU/mL)
2287 ± 2504
2470 ± 1869
NS
AST (IU/mL)
1641 ± 1967
1977 ± 1478
NS
Bilirubin level (μmol/L)
TP: prothrombin index.
Linear regression analysis showed a relation between plasma bilirubin concentrations with the time related concentration of acetaminophen. Statistical significance could not be reached for subgroups of viral hepatitis (figure 2).
potential for hepatotoxicity after acute overdose is best predicted from the Rumack-Matthew nomogram [14]. In certain settings and in particular in alcoholic patients, severe hepatotoxicity may occur after ingestion of as little as 4 g in 24 hours. Recent severe fasting wasalso considered a predisposing factor in patients with acetaminophen hepatotoxicity who had taken only 4 to 10 g in 24 hours [15]. The role of acetaminophen in increasing the severity of acute viral hepatitis was shown in patients with fulminant hepatitis A where the consumption of acetaminophen was a poor prognostic factor [10]. The dose that aggravates liver function tests has never been described, and in our series, the cut-off point of the cumulated dose was 7.5 g. AST and ALT levels were identical regardless of the ingested amount of acetaminophen. The prothrombin index and factor V were more altered in the group of patients who had taken more than 7.5 g. It is noteworthy that 85% of our patients consumed acetaminophen prior to hospitalization, making the comparison with a non-acetaminophen group difficult since the number of patients in this group is very low. Furthermore, in our experience, almost all patients with severe acute hepatitis or fulminant liver failure had consumed acetaminophen at some moment during the prodromal phase.
Time related acetaminophen concentration with relation to evolution In patients with hepatitis B, the mean Ln of the plasma concentration of acetaminophen and the interval of time since the last intake were respectively 64.3 and 109.8 in patients with a favorable outcome or death related to acute liver failure (P < 0.05). The mean product was respectively 42.8 and 30.3 in patients with acute hepatitis A and hepatitis of other etiologies. No deaths occurred in these two groups.
Discussion Acetaminophen is a well-recognized cause of acute liver failure when taken in doses above 150 mg/kg/day (> 10 g). The 766
Acetaminophen and acute viral hepatitis
There is controversial evidence on the efficiency of acetylcysteine treatment for non-acetaminophen-induced acute liver failure [16]. Some of the controversy might be explained by a susceptibility to low dose acetaminophen in some patients, and its role in aggravating liver failure. Acetylcysteine could be beneficial in this subset of patients. Criteria for the severity of acute viral hepatitis include INR or prothrombin ratio, serum bilirubin and prothrombin index. The prothrombin index INR may be affected by multiple factors including liver failure, chronic cholestasis, acetaminophen, N-acetyl-cysteine [17-19]. Acetaminophen may decrease the prothrombin index in patients with acetaminophen poisoning without hepatic injury. This effect is proportional to the ingested dose and to the nomogram-based risk [18]. It is due to a decrease in the function of factor VII but not to the amount of antigenic factor VII in exposed patients [18]. In our patients, the ingested amount of acetaminophen was within therapeutic range and the mean cumulated dose was 7.7 g, which is low in comparison to described doses affecting the prothrombin index. Furthermore, the plasma concentration of acetaminophen was lower than concentrations seen in acetaminophen intoxications, and it is not known if such concentrations affect the prothrombin index. Finally, the drop in the prothrombin index was correlated with a decrease in factor V suggesting that the latter was probably mainly related to the severity of hepatitis. N-acetylcysteine treatment was reported to decrease the prothrombin index in all patients [17]. In our patients, all plasma acetaminophen dosages were performed prior to the start of N-acetylcysteine perfusion. In a recent study, the detection of plasmatic acetaminophen-containing protein adducts showed that unrecognized acetaminophen
110 100 Mean Ln acetaminophen × time
90 80 70 60 50 40 30
>=60% <60, <60, < 60%
20
>=60,
>=60, < 60%
10 A
B
C
D
Fig. 1 – Line Chart representing mean Log acetaminophen plasma concentration x time interval since the last intake in relation to Prothrombin index and bilirubin in all patients. A = bilirubin < 60 μmol/L and prothrombin index > 60%, B = bilirubin ≥ 60 μmol/L and prothrombin index ≥ 60%, C = bilirubin < 60 μmol/L and prothrombin index < 60%, D = bilirubin ≥ 60 μmol/L and prothrombin activity < 60%. Differences were statistically significant (P < 0.05) excepted for B versus C (P = 0.09). Représentation graphique du Log de la concentration plasmatique d’acétaminophène x le temps écoulé depuis la dernière prise en fonction du taux de prothrombine et de la bilirubine plasmatique. A = bilirubine < 60 Pmol/L et TP > 60 %, B = bilirubine t 60 Pmol/L et TP t 60 %, C = bilirubine < 60 Pmol/L et TP < 60 %, D = bilirubine t 60 Pmol/L et TP < 60 %. Les différences étaient statistiquement significatives sauf pour B versus C (P = 0,09).
Overall population
100
100
75
Prothrombin index
Prothrombin index
120
R2 = 0.523, P< 0.001 50
25
HAV
75
50
25
R2= 0.30, P= 0.024
0
20
40
60
80
100
120
140
0
Time X Ln plasma acetaminophen
400
400
300
300
200
R2 = 0.404, P= 0.001
100
0
0 20
40
60
80
100
120
60
80
100
120
140
140
HAV
200
100
0
40
500
Overall population
Bilirubin
Bilirubin
500
20
Time X Ln plasma acetaminophen
R2= 0.124, P= 0.166
0
Time X Ln plasma acetaminophen
20
40
60
80
100
120
140
Time X Ln plasma acetaminophen
Fig. 2 – Graphic representation of the regression curves of Log (Ln) plasma acetaminophen concentration with respect to severity parameters of acute hepatitis showing overall population and HAV patients with respect to prothrombin index and bilirubin. Représentation graphique des courbes de régression du produit du Log de la concentration plasmatique d’acétaminophène x le temps écoulé depuis la dernière prise en fonction du taux de prothrombine et de la bilirubine dans la population globale et chez les malades atteints d’hépatite aiguë A. 767
C. Yaghi et al.
poisoning might account for 20% of acute liver failure of unknown etiologies [19, 20]. This technique might be interesting for detecting the influence of acetaminophen in acute viral hepatitis. The increase in serum bilirubin observed in viral hepatitis is also a marker of severity. However, increased serum bilirubin can interfere with the enzymatic and chromogenic reactions involved in the acetaminophen dosing methods. Acetaminophen was detected in specimens from hyperbilirubinemic patients without a history of recent acetaminophen exposure. Dilution of hyperbilirubinemic specimens produces a correction of apparent acetaminophen concentrations. The threshold for interference of bilirubin with acetaminophen dosage is < 85 μmol/L [21]. In conclusion, Acetaminophen might be toxic even when used at therapeutic dosages in the patients with acute viral hepatitis, in particular acute hepatitis A. In our patients, time related plasma concentrations of acetaminophen was correlated to bilirubin levels and the prothrombin index which are surrogate markers for the severity of acute viral hepatitis. Acetaminophen should be discontinued and avoided once the diagnosis of acute hepatitis is established.
acetaminophen used in genetically predisposed persons. Am J Ther 2002;9:149-56.
8. Jorup-Ronstrom C, Beermann B, Wahlin-Boll E, Melander A, Britton S. Reduction of acetaminophen and aspirin metabolism during viral hepatitis. Clin Pharmacokinet 1986;11:250-6.
9. Zapater P, Lasso De La Vega MC, Horga JF, Such J, Frances R, Esteban A, et al. Pharmacokinetic variations of acetaminophen according to liver dysfunction and portal hypertension status. Aliment Pharmacol Ther 2004;20:29-36.
10. Rezende G, Roque-Afonso AM, Samuel D, Gigou M, Nicand E, Ferre V, et al. Viral and clinical factors associated with the fulminant course of hepatitis A infection. Hepatology 2003;38:613-18.
11. Polson J, Ocama P, Larson AM, Hynan L, Lalani E, Harrison M, et al. Role of acetaminophen in acute liver failure due to viral hepatitis (abstract). Hepatology 2003;34:544A.
12. Lee W. Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the Risks of Hepatic Failure. Hepatology 2004;40:6-9.
13. Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis 1986;6:97-106.
14. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol 2002;40:3-20.
15. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxi-
REFERENCES
city with fasting and ethanol use. JAMA 1994;272:1845-50.
1. Rumack BH. Acetaminophen misconceptions. Hepatology 2004;
16. Sklar GE, Subramaniam M. Acetylcysteine treatment for non-
40:10-5.
2. Kaplowitz N. Acetaminophen Hepatoxicity: What Do We Know, What
acetaminophen-induced acute liver failure. Ann Pharmacother 2004; 38:498-500.
Don’t We Know, and What Do We Do Next? Hepatology 2004;40:23-6.
17. Schmidt LE, Knudsen TT, Dalhoff K, Bendtsen F. Effect of acetylcys-
3. Mofredj A, Cadranel JF, Darchy B, Barbare JC, Cazier A, Pras V,
teine on prothrombin index in paracetamol poisoning without hepatocellular injury. Lancet 2002;360:1151-2.
et al. Hepatotoxicity caused by therapeutic doses of paracetamol in alcoholics. Report of 2 cases of fatal hepatitis in cirrhosis. Ann Med Interne, Paris 1999;150:507-11.
18. Whyte IM, Buckley NA, Reith DM, Goodhew I, Seldon M, Dawson AH. Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII. Ther Drug Monit 2000;22:742-8.
4. Andreu V, Gomez-Angelats E, Bruguera M, Rodes J. Severe hepatitis from therapeutic doses of paracetamol in an alcoholic patient. Gastroenterol Hepatol 1999;22:235-7.
19. Muldrew KL, James LP, Coop L, McCullough SS, Hendrickson HP,
5. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB.
Hinson JA, et al. Determination of acetaminophen-protein adducts in mouse liver and serum and human serum after hepatotoxic doses of acetaminophen using high-performance liquid chromatography with electrochemical detection. Drug Metab Dispos 2002;30:446-51.
Acetaminophen hepatotoxicity in alcoholics: a therapeutic misadventure. Ann Intern Med 1986;104:399-404.
6. Schmidt LE, Dalhoff K, Poulsen HE. Acute versus chronic alcohol
20. Davern TJ, James L, Larson A, Fontana R, Polson J, Lalani E, et al.
consumption in acetaminophen-induced hepatotoxicity. Hepatology 2002;35:876-82.
Serum acetaminophen adducts identify patients with severe acetaminophen toxicity (abstract). Hepatology 2003;34:539A.
7. Prandota J Important role of prodromal viral infections responsible for
21. Bertholf RL, Johannsen LM, Bazooband A, Mansouri V. False-positive
inhibition of xenobiotic metabolizing enzymes in the pathomechanism of idiopathic Reye’s syndrome, Stevens-Johnson syndrome, autoimmune hepatitis, and hepatotoxicity of the therapeutic doses of
acetaminophen results in a hyperbilirubinemic patient. Clin Chem 2003;49:695-8.
768
25,*,1$/ $57,&/(
Gastroenterol Clin Biol 2006;30:763-768
Influence of acetaminophen at therapeutic doses on surrogate markers of severity of acute viral hepatitis
César YAGHI, Khalil HONEIN, Joseph BOUJAOUDE, Rita SLIM, Rami MOUCARI, Raymond SAYEGH Division of Gastroenterology, Hôtel-Dieu de France University Hospital, Beirut, Lebanon.
SUMMARY
RÉSUMÉ
Objectives — Data on the influence of acetaminophen intake on acute viral hepatitis is scarce, but it could play a role in the worsening of this disease. The aim of this study was to determine whether the intake of acetaminophen at therapeutic doses affects the severity of acute viral hepatitis.
Influence de la prise d’acétaminophène à doses thérapeutiques sur les marqueurs de sévérité des hépatites virales aiguës César YAGHI, Khalil HONEIN, Joseph BOUJAOUDE, Rita SLIM, Rami MOUCARI, Raymond SAYEGH (Gastroenterol Clin Biol 2006;30:763-768)
Methods — This was a prospective study concerning 37 consecutive patients hospitalized for acute viral hepatitis. Acetaminophen consumption and time since last intake were assessed by a questionnaire. Parameters of severity were studied in comparison to time related serum concentrations of acetaminophen.
Objectifs — Les données concernant l’influence de la prise d’acétaminophène sur les hépatites virales sont rares, mais cette prise pourrait avoir un rôle dans leur aggravation. Notre objectif était d’établir si la prise d’acétaminophène avait une influence sur la sévérité des hépatites aiguës virales.
Results — Patients hospitalized for acute viral hepatitis (18 male, 19 female patients) had a mean age of 29.2 ± 11.5 years. The causal virus was HAV (n = 23), HBV (n = 7) and other viruses (n = 8). The mean cumulated dose of acetaminophen was 7.7 ± 5.65 g. The daily dose did not exceed the therapeutic dosage and the mean was 1.95 ± 0.81 g (1-3 g). Patients who received 7.5 g of acetaminophen or more had a lower prothrombin index 52.4 ± 30.3% vs 74.2 ± 17.2% (P = 0.039), and a lower factor V 54.7 ± 33.2% vs 83.3 ± 19.6% (P = 0.033). Prothrombin index and bilirubinemia were negatively correlated with time related plasma acetaminophen concentrations.
Malades et méthodes — Il s’agit d’une étude prospective concernant 37 malades consécutifs hospitalisés pour hépatite virale aiguë. La quantité d’acétaminophène et l’intervalle de temps depuis la dernière prise étaient évalués par un questionnaire. Les paramètres de sévérité de l’hépatite étaient étudiés par la concentration plasmatique d’acétaminophène en fonction du temps écoulé depuis la dernière prise. Résultats — Les malades hospitalisés pour hépatite aiguë virale (18 hommes, 19 femmes) d’âge moyen 29,2 r 11,5 ans présentaient une hépatite aiguë A, B, ou autre chez respectivement 23, 7, et 8 malades. La dose cumulée moyenne d’acétaminophène par malade était de 7,7 r 5,65 g. La posologie quotidienne moyenne était de 1,95 r 0,81 g (1-3 g). Les malades qui avaient reçu une dose cumulée d’acétaminophène t 7,5 g avaient un taux de prothrombine plus bas (52,4 r 30,3 % vs 74,2 r 17,2 %) (P = 0,039), ainsi qu’un taux plus faible du facteur V (54,7 r 33,2 % vs 83,3 r 19,6 %) (P = 0,033). Le taux de prothrombine et la bilirubinémie étaient corrélés négativement avec la concentration plasmatique d’acétaminophène.
Conclusions — The use of acetaminophen at therapeutic doses was associated with greater alterations of surrogate markers of the severity of acute viral hepatitis especially hepatitis A. This was related to cumulated dosages and correlated to the time related acetaminophen plasma concentrations. Acetaminophen use should be interrupted when acute hepatitis is suspected.
Conclusion — L’utilisation d’acétaminophène à posologie thérapeutique était associée par une altération des marqueurs biologiques de sévérité des hépatites virales en particulier les hépatites A. Cette altération était liée à la prise cumulée d’acétaminophène, et corrélée avec la concentration plasmatique d’acétaminophène en fonction du temps écoulé depuis la dernière prise. La prise d’acétaminophène devrait être arrêtée quand le diagnostic d’hépatite aiguë est posé.
Acetaminophen is used to treat symptoms such as pain and fever. Therapeutic plasma levels range from 10 to 30 μg/mL. Peak levels after therapeutic doses do not exceed 20 μg/mL and they do not accumulate with multiple daily dosing [1]. However, patients who develop severe liver injury and continue to ingest multiple doses of acetaminophen may accumulate the drug due to prolongation of the half life of acetaminophen [2]. In the clini-
cal setting, therapeutic dosages should take into account several factors, including history of ethanol abuse as well as the underlying hepatic illness. Several cases of severe liver toxicity have been reported even when the drug was taken at normal doses in alcoholic patients [3-6]. Furthermore, acetaminophen overdose, either intentional or unintentional, plays a major role in the etiology of acute liver failure. During the prodromal period of viral infections, there is a down regulation of the gene expression of major cytochrome P-450 enzymes through proinflammatory cytokines, such as
Reprints: C. YAGHI, Division of Gastroenterology, Hôtel-Dieu de France Adib Ishac Street, Achrafieh, Beirut, Lebanon. E-mail : cesar.yaghi @usj.edu.lb
Part of the content of this paper was presented at the “Journées Francophones de Pathologie Digestive” on Paris in March 2004 and at the poster session of the UEGW 2004 held in Prague on September 2004.
Introduction
763
C. Yaghi et al.
interleukins, transforming growth factor beta1, human hepatocyte growth factor, and lymphocytotoxin. The resulting effect varies according to the involved cytokines and the specific cytochrome P-450, eventually leading to either metabolite-mediated adverse drug reactions or alteration of the metabolism of the drug [7]. Thus, acetaminophen metabolism is altered during acute viral hepatitis, and this alteration persists during the convalescence phase and disappears only after complete recovery from hepatitis. The elimination phase of acetaminophen is protracted, whereas the peak plasmatic concentration following a single dose is not affected [8]. The evolution of plasma acetaminophen concentrations after multiple dosages has not been studied in this setting. In patients with liver failure and portal hypertension, the absorption of acetaminophen is faster especially in the presence of esophageal varices [9]. Patients with cirrhosis have a higher area under curve and lower clearance of acetaminophen [9]. Increased absorption may be related to portal hypertension whereas protracted elimination is mainly due to liver failure [9]. Data on the role of acetaminophen in the course of acute viral hepatitis is scarce, but it seems to contribute to liver injury. Many questions remain unanswered [2]. In a recent paper it was shownthat fulminant hepatitis A was associated with female gender, the rapid elimination of HAV detected by PCR, genotype other than genotype 1A, and acetaminophen intake [10]. However, in multivariate analysis, the only two independent prognostic variables were increased bilirubin levels and low or undetectable viremia. Acetaminophen is currently used for fever especially during the prodromal period before acute viral hepatitis is suspected. Data from the Acute Liver Failure Study Group showed that acetaminophen was detected in the serum of 20% of patients with acute viral hepatitis. In these patients median alanine aminotransferase levels were higher than in patients who did not take acetaminophen [11]. In a recent review, it was suggested that the 24 hour intake of acetaminophen in patients with acute or chronic liver disease should be restricted to around 2 g/day, which is half the suggested maximal dose of 4 g/day [12].
hepatitis. All patients had an abdominal ultrasound rule out chronic liver disease. All patients had liver enzyme tests as well as bilirubin, prothrombin index and factor V dosages. The severity of hepatitis and fulminant liver failure were defined in accordance with the Beaujon criteria [13]. Alcohol consumption was classified into 4 groups: (0) no alcohol, (1) less than 20 g per week, (3) 20 to 60 g per week, and (4) more than 60 g per week.
Statistical analysis Numeric data are expressed as mean ± standard deviation. Comparisons were made using the Chi square test and Fisher exact test for categorical data. Comparison of continuous variables was performed using the Student’s unpaired t-test and non parametric tests, as indicated. A two tailed probability P value of less than 0.05 was considered significant. Linear regression was used to assess the influence of acetaminophen concentrations on the prothrombin index while taking into account the interval since the last intake of acetaminophen.
Results Clinical characteristics Thirty seven consecutive patients (18 males and 19 females) were included in our study. Mean age was 29.3 ± 11.5 years and age ranged from 15 to 69 years. Fever was found in 33 (89.2%) patients. None of our patients had a chronic liver disease. Prolonged fasting was found in only one patient and was related to repeated vomiting and oral intolerance. Alcohol consumption was less than 60 g/week (n = 19, 51.4%) or absent (n = 18, 48.6%) in all our patients. None of our patients had chronic alcohol abuse or recurrent binges.
Etiology Twenty two patients had an acute hepatitis A, 7 an acute hepatitis B, and among 8, hepatitis was related to either EBV or CMV. Out of the patients presenting with hepatitis B, 4 were severe, of whom, 3 had a fulminant liver failure, with 2 deaths related to liver disease (table I). Eight patients had a severe hepatitis in the HAV group. With respect to EBV related hepatitis a single patient had an increased prothrombin index (table I).
The aim of our study was to assess whether the intake of acetaminophen at usual therapeutic levels is associated with increased severity in the course of acute viral hepatitis.
Patients and methods
Acetaminophen intake in patients with acute viral hepatitis
Study population
Thirty two patients (86.5%) had taken acetaminophen. The quantity of acetaminophen and the interval since the last Intake could be precisely established in 25 patients. Total consumption, the mean number of days of acetaminophen intake and the daily dose of acetaminophen was equivalent in all groups. Interval since the last intake was longest in patients with acute hepatitis B (table I). All patients received acetaminophen prior to hospitalization and/or to the diagnosis of acute hepatitis and did not receive any further dose once the diagnosis was established. The mean cumulated dose of acetaminophen was 7.7 ± 5.7 g ranging from 1.5 g to 28 g taken over a mean period of 4.2 ± 3.2 days ranging from 1 to 14 days. The mean daily dose was 1.9 ± 0.8 g and extreme doses ranged from 1 g/day to 3 g/day. There were novoluntary or involuntary acetaminophen overdoses in our population. Mean plasma acetaminophen concentrations were 32.3 ± 15.7 mg/L. Mean interval since the last intake was 33.5 ± 23.7 hours. When the interval was ≥ 24 hours, the mean plasma acetaminophen concentration was 34.8 mg/L, whereas when the delay was < 24 hours, the mean plasma concentration was 27.9 mg/L. This difference was not statistically significant. On the other hand, all patients (11/25) with a prothrombin index < 60% had acetaminophen detectable in plasma after a delay ≥ 24 hours. None of the patients with severe acute hepatitis had an interval of < 24 hours since” the last intake. For
This was a prospective study of 37 consecutive patients hospitalized for acute viral hepatitis of various etiologies between December 2002 and February 2004. The causes for hospitalization were either acute liver failure or oral intolerance. A standardized questionnaire evaluating the quantity of ingested acetaminophen since the beginning of the symptoms, the interval since the last intake, as well as the search for factors associated with increased acetaminophen toxicity, (alcohol use, prolonged fasting, and underlying liver disease). Prolonged fasting was defined as the absence of food intake for more than 24 hours. An underlying liver disease was ruled out by taking into account clinical, biological and serology parameters particularly in patients with hepatitis B. Acetaminophen concentrations were assessed upon admission. A quantitative colorimetric method in the serum at 430 nm was used, with a precision ranging from 1 to 1.07 (Sigma Diagnostics, Acetaminophen). Acute hepatitis was diagnosed by Anti HAV IgM for acute hepatitis A, Anti HBc IgM along with the absence of Anti HBc IgG, for acute hepatitis B, IgM Anti viral capsid antibodies (Anti VCA) for EBV associated hepatitis, and IgM Anti CMV and pp65 antigen for CMV associated
ABBREVIATIONS : HAV HBV CMV EBV
: Hepatitis A virus : Hepatitis B virus : Cytomegalovirus : Epstein-Barr virus 764
Acetaminophen and acute viral hepatitis
Table I. – Characteristics of patients with regards to biological parameters, acetaminophen consumption, and etiology of viral hepatitis. Caractéristiques des malades en fonction des paramètres biologiques, de la consommation d’acétaminophène, et de l’étiologie de l’hépatite. HAV
HBV
Other viruses
N = 23
N=7
N=8
Age
24.9 ± 5.7*†
43.2 ± 20†
36± 14.5*
AST (IU/mL)
2061 ± 1655*
1839 ± 2018
511 ± 389*
ALT (IU/mL)
2796 ± 2060*
2668 ± 3028
683 ± 420*
GGT (IU/mL)
259 ± 104
172 ± 84
223 ± 178
Alk. Phosphatase
203 ± 92
157 ± 65
150 ± 46
Bilirubin μmol/L (IU/mL)
91.2 ± 80.6†
195.3 ± 166.9*†
40.8 ± 47.8*
Prothrombin index (%)
66.6 ± 21.5†
34.2 ± 20.5*†
78 ± 15.8*
Factor V (%)
77.5 ± 26.8†
47.8 ± 41.3*†
83.8 ± 21.6*
Severe or (Fulminant hepatitis)
8 (0)
4 (3)
1 (0)
Hepatic encephalopathy (death)
0 (0)
3 (2)
0 (0)
20 (16)
3 (3)
8 (6)
Quantity of ingested acetaminophen (g)
5.0 ± 3.6
5.1 ± 5.9
8.4 ± 9.6
Number of days of intake
3.3 ± 1.4
8 ± 5.3
5.2 ± 4.5
Daily dosage (g)
1.8 ± 0.9
1.5 ± 0.5
2.2 ± 0.4
Interval since last intake (hours)
33.5 ± 22.8†
64 ± 25*†
18.3 ± 8.9*
Serum concentration of acetaminophen (mg/L)
33.4 ± 16.9
37.9 ± 21.7
25.4 ± 4.6
Acetaminophen intake (data with known time elapsed since last intake)
* = HAV versus other virus, P < 0.05. † = HAV versus HBV, P < 0.05. ‡ = HBV versus other virus, P < 0.05.
patients with prothrombin index ≥ 60%, 9 patients were detected within 24 hours, and 5 after 24 hours. When the interval was ≥ 24 hours, 68.7% had severe hepatitis whereas 31.3% had non severe hepatitis (P < 0.001).
in aminotransferase levels, AST or ALT for the cumulated dose of acetaminophen (table III). Two patients died from fulminant liver failure related to HBV infection. Both had a cumulated acetaminophen consumption of more than 7.5 g, and these patients had the highestproduct of the serum concentration of acetaminophen times the interval elapsed since the last intake in our studied population, with respectively 90.0 and 129.7. This product was respectively 41.0 ± 21.2 and 109.9 ± 28.1 for spontaneous recovery and for death (table II).
Prothrombin index in relation to acetaminophen concentrations The Log (Ln) of the plasma concentration of acetaminophen and the time interval since the last intake were negatively correlated with the prothrombin index. This correlation was found in patients with acute hepatitis A. There was no statistically significant correlation in either of the groups of patients with acute hepatitis B nor EBV or CMV related hepatitis (figure 2).
Bilirubin relation to acetaminophen concentrations Patients who received 7.5 g of acetaminophen or more, had a tendency to have higher bilirubin levels but this was not statistically significance. The product of the mean serum concentrations ofacetaminophen times the interval since the last intake was 61.2 when the bilirubin level was above 60 μmol/L versus 33.3 when the bilirubin level was below 60 μmol/L (P = 0.01). This difference was also significant in the group with acute hepatitis A (54.0 vs 29.1, P = 0.02), but not in patients with acute hepatitis B in whom the difference was not statistically significant (109.9 vs. 64.3, P > 0.05). Patients who had bilirubin above 60 μmol/L and a prothrombin index below 60% had the highest product (81.7 ± 26.5), whereas the lowest product was found in patients with neither (23.5 ± 10.8). In patients with a bilirubin > 60 μmol/L or prothrombin activity < 60%, the value was intermediate (39.9 ± 22.3 and 49 ± 13.3 respectively for bilirubin and prothrombin index) (figure 1) (table II).
On the other hand, the product of the mean serum concentration of acetaminophen times the time interval since the last intake was 66.8 when the prothrombin index was less than 60% versus 30.9 when the prothrombin index was above 60% (P = 0.001) (table II). This difference was found in the acute hepatitis A group and could not be analyzed in the hepatitis B group since all the patients had a prothrombin index < 60% in this subgroup. There was no significant difference in patients with CMV or EBV related hepatitis. The cumulated dose of acetaminophen in our population was 7.7 ± 5.7 g. Patients who received 7.5 g of acetaminophen or more had a lower prothrombin index, and a lower factor V activity. It should be noted that none of the patients exceeded the recommended dose of acetaminophen. There was no difference 765
C. Yaghi et al.
Table II. – Impact of the product of the Log serum concentration of acetaminophen by the time interval elapsed since the last intake with respect to markers of severity of acute hepatitis and mortality rate. Influence du produit Log de la concentration plasmatique d’acétaminophène x le temps écoulé depuis la dernière prise en fonction des marqueurs de sévérité des hépatites aiguës et du taux de mortalité. Product < 50
Product ≥ 50
N = 14 (%)
N = 11 (%)
HAV
9
8
HBV
0
3
Other
5
0
5 (35.7)
8 (72.7)
0.066
0 (0)
2 (18.2)
0.096
Bilirubin > 60 μmol/L (N = 12)
4 (28.6)
8 (72.7)
0.028
TP < 60%, (N = 12)
3 (21.4)
9 (81.8)
0.003
0 (0)
6 (54.5)
0.001
Cause of Hepatitis
Cumulated acetaminophen > 7.5g Death
Bilirubin > 60 μmol/L and TP < 60%
P
0.02
TP: prothrombin index.
Table III. – Influence of cumulated dose of acetaminophen on the severity parameters of acute viral hepatitis. Note that none of the patients exceeded the recommended daily dosage. Influence de la dose cumulée d’acétaminophène sur la sévérité de l’hépatite virale aiguë. Il est à noter qu’aucun malade n’a consommé au-delà des doses recommandées. Acetaminophen cumulated dose ≥ 7.5g
< 7.5g
n = 13
n = 12
P
138.3 ± 154.3
62.9 ± 33.7
0.11
TP (%)
52.4 ± 30.3
74.2 ± 17.2
0.039
Factor V (%)
54.7 ± 33.2
83.3 ± 19.6
0.033
ALT (IU/mL)
2287 ± 2504
2470 ± 1869
NS
AST (IU/mL)
1641 ± 1967
1977 ± 1478
NS
Bilirubin level (μmol/L)
TP: prothrombin index.
Linear regression analysis showed a relation between plasma bilirubin concentrations with the time related concentration of acetaminophen. Statistical significance could not be reached for subgroups of viral hepatitis (figure 2).
potential for hepatotoxicity after acute overdose is best predicted from the Rumack-Matthew nomogram [14]. In certain settings and in particular in alcoholic patients, severe hepatotoxicity may occur after ingestion of as little as 4 g in 24 hours. Recent severe fasting wasalso considered a predisposing factor in patients with acetaminophen hepatotoxicity who had taken only 4 to 10 g in 24 hours [15]. The role of acetaminophen in increasing the severity of acute viral hepatitis was shown in patients with fulminant hepatitis A where the consumption of acetaminophen was a poor prognostic factor [10]. The dose that aggravates liver function tests has never been described, and in our series, the cut-off point of the cumulated dose was 7.5 g. AST and ALT levels were identical regardless of the ingested amount of acetaminophen. The prothrombin index and factor V were more altered in the group of patients who had taken more than 7.5 g. It is noteworthy that 85% of our patients consumed acetaminophen prior to hospitalization, making the comparison with a non-acetaminophen group difficult since the number of patients in this group is very low. Furthermore, in our experience, almost all patients with severe acute hepatitis or fulminant liver failure had consumed acetaminophen at some moment during the prodromal phase.
Time related acetaminophen concentration with relation to evolution In patients with hepatitis B, the mean Ln of the plasma concentration of acetaminophen and the interval of time since the last intake were respectively 64.3 and 109.8 in patients with a favorable outcome or death related to acute liver failure (P < 0.05). The mean product was respectively 42.8 and 30.3 in patients with acute hepatitis A and hepatitis of other etiologies. No deaths occurred in these two groups.
Discussion Acetaminophen is a well-recognized cause of acute liver failure when taken in doses above 150 mg/kg/day (> 10 g). The 766
Acetaminophen and acute viral hepatitis
There is controversial evidence on the efficiency of acetylcysteine treatment for non-acetaminophen-induced acute liver failure [16]. Some of the controversy might be explained by a susceptibility to low dose acetaminophen in some patients, and its role in aggravating liver failure. Acetylcysteine could be beneficial in this subset of patients. Criteria for the severity of acute viral hepatitis include INR or prothrombin ratio, serum bilirubin and prothrombin index. The prothrombin index INR may be affected by multiple factors including liver failure, chronic cholestasis, acetaminophen, N-acetyl-cysteine [17-19]. Acetaminophen may decrease the prothrombin index in patients with acetaminophen poisoning without hepatic injury. This effect is proportional to the ingested dose and to the nomogram-based risk [18]. It is due to a decrease in the function of factor VII but not to the amount of antigenic factor VII in exposed patients [18]. In our patients, the ingested amount of acetaminophen was within therapeutic range and the mean cumulated dose was 7.7 g, which is low in comparison to described doses affecting the prothrombin index. Furthermore, the plasma concentration of acetaminophen was lower than concentrations seen in acetaminophen intoxications, and it is not known if such concentrations affect the prothrombin index. Finally, the drop in the prothrombin index was correlated with a decrease in factor V suggesting that the latter was probably mainly related to the severity of hepatitis. N-acetylcysteine treatment was reported to decrease the prothrombin index in all patients [17]. In our patients, all plasma acetaminophen dosages were performed prior to the start of N-acetylcysteine perfusion. In a recent study, the detection of plasmatic acetaminophen-containing protein adducts showed that unrecognized acetaminophen
110 100 Mean Ln acetaminophen × time
90 80 70 60 50 40 30
>=60% <60, <60, < 60%
20
>=60,
>=60, < 60%
10 A
B
C
D
Fig. 1 – Line Chart representing mean Log acetaminophen plasma concentration x time interval since the last intake in relation to Prothrombin index and bilirubin in all patients. A = bilirubin < 60 μmol/L and prothrombin index > 60%, B = bilirubin ≥ 60 μmol/L and prothrombin index ≥ 60%, C = bilirubin < 60 μmol/L and prothrombin index < 60%, D = bilirubin ≥ 60 μmol/L and prothrombin activity < 60%. Differences were statistically significant (P < 0.05) excepted for B versus C (P = 0.09). Représentation graphique du Log de la concentration plasmatique d’acétaminophène x le temps écoulé depuis la dernière prise en fonction du taux de prothrombine et de la bilirubine plasmatique. A = bilirubine < 60 Pmol/L et TP > 60 %, B = bilirubine t 60 Pmol/L et TP t 60 %, C = bilirubine < 60 Pmol/L et TP < 60 %, D = bilirubine t 60 Pmol/L et TP < 60 %. Les différences étaient statistiquement significatives sauf pour B versus C (P = 0,09).
Overall population
100
100
75
Prothrombin index
Prothrombin index
120
R2 = 0.523, P< 0.001 50
25
HAV
75
50
25
R2= 0.30, P= 0.024
0
20
40
60
80
100
120
140
0
Time X Ln plasma acetaminophen
400
400
300
300
200
R2 = 0.404, P= 0.001
100
0
0 20
40
60
80
100
120
60
80
100
120
140
140
HAV
200
100
0
40
500
Overall population
Bilirubin
Bilirubin
500
20
Time X Ln plasma acetaminophen
R2= 0.124, P= 0.166
0
Time X Ln plasma acetaminophen
20
40
60
80
100
120
140
Time X Ln plasma acetaminophen
Fig. 2 – Graphic representation of the regression curves of Log (Ln) plasma acetaminophen concentration with respect to severity parameters of acute hepatitis showing overall population and HAV patients with respect to prothrombin index and bilirubin. Représentation graphique des courbes de régression du produit du Log de la concentration plasmatique d’acétaminophène x le temps écoulé depuis la dernière prise en fonction du taux de prothrombine et de la bilirubine dans la population globale et chez les malades atteints d’hépatite aiguë A. 767
C. Yaghi et al.
poisoning might account for 20% of acute liver failure of unknown etiologies [19, 20]. This technique might be interesting for detecting the influence of acetaminophen in acute viral hepatitis. The increase in serum bilirubin observed in viral hepatitis is also a marker of severity. However, increased serum bilirubin can interfere with the enzymatic and chromogenic reactions involved in the acetaminophen dosing methods. Acetaminophen was detected in specimens from hyperbilirubinemic patients without a history of recent acetaminophen exposure. Dilution of hyperbilirubinemic specimens produces a correction of apparent acetaminophen concentrations. The threshold for interference of bilirubin with acetaminophen dosage is < 85 μmol/L [21]. In conclusion, Acetaminophen might be toxic even when used at therapeutic dosages in the patients with acute viral hepatitis, in particular acute hepatitis A. In our patients, time related plasma concentrations of acetaminophen was correlated to bilirubin levels and the prothrombin index which are surrogate markers for the severity of acute viral hepatitis. Acetaminophen should be discontinued and avoided once the diagnosis of acute hepatitis is established.
acetaminophen used in genetically predisposed persons. Am J Ther 2002;9:149-56.
8. Jorup-Ronstrom C, Beermann B, Wahlin-Boll E, Melander A, Britton S. Reduction of acetaminophen and aspirin metabolism during viral hepatitis. Clin Pharmacokinet 1986;11:250-6.
9. Zapater P, Lasso De La Vega MC, Horga JF, Such J, Frances R, Esteban A, et al. Pharmacokinetic variations of acetaminophen according to liver dysfunction and portal hypertension status. Aliment Pharmacol Ther 2004;20:29-36.
10. Rezende G, Roque-Afonso AM, Samuel D, Gigou M, Nicand E, Ferre V, et al. Viral and clinical factors associated with the fulminant course of hepatitis A infection. Hepatology 2003;38:613-18.
11. Polson J, Ocama P, Larson AM, Hynan L, Lalani E, Harrison M, et al. Role of acetaminophen in acute liver failure due to viral hepatitis (abstract). Hepatology 2003;34:544A.
12. Lee W. Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the Risks of Hepatic Failure. Hepatology 2004;40:6-9.
13. Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis 1986;6:97-106.
14. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol 2002;40:3-20.
15. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxi-
REFERENCES
city with fasting and ethanol use. JAMA 1994;272:1845-50.
1. Rumack BH. Acetaminophen misconceptions. Hepatology 2004;
16. Sklar GE, Subramaniam M. Acetylcysteine treatment for non-
40:10-5.
2. Kaplowitz N. Acetaminophen Hepatoxicity: What Do We Know, What
acetaminophen-induced acute liver failure. Ann Pharmacother 2004; 38:498-500.
Don’t We Know, and What Do We Do Next? Hepatology 2004;40:23-6.
17. Schmidt LE, Knudsen TT, Dalhoff K, Bendtsen F. Effect of acetylcys-
3. Mofredj A, Cadranel JF, Darchy B, Barbare JC, Cazier A, Pras V,
teine on prothrombin index in paracetamol poisoning without hepatocellular injury. Lancet 2002;360:1151-2.
et al. Hepatotoxicity caused by therapeutic doses of paracetamol in alcoholics. Report of 2 cases of fatal hepatitis in cirrhosis. Ann Med Interne, Paris 1999;150:507-11.
18. Whyte IM, Buckley NA, Reith DM, Goodhew I, Seldon M, Dawson AH. Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII. Ther Drug Monit 2000;22:742-8.
4. Andreu V, Gomez-Angelats E, Bruguera M, Rodes J. Severe hepatitis from therapeutic doses of paracetamol in an alcoholic patient. Gastroenterol Hepatol 1999;22:235-7.
19. Muldrew KL, James LP, Coop L, McCullough SS, Hendrickson HP,
5. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB.
Hinson JA, et al. Determination of acetaminophen-protein adducts in mouse liver and serum and human serum after hepatotoxic doses of acetaminophen using high-performance liquid chromatography with electrochemical detection. Drug Metab Dispos 2002;30:446-51.
Acetaminophen hepatotoxicity in alcoholics: a therapeutic misadventure. Ann Intern Med 1986;104:399-404.
6. Schmidt LE, Dalhoff K, Poulsen HE. Acute versus chronic alcohol
20. Davern TJ, James L, Larson A, Fontana R, Polson J, Lalani E, et al.
consumption in acetaminophen-induced hepatotoxicity. Hepatology 2002;35:876-82.
Serum acetaminophen adducts identify patients with severe acetaminophen toxicity (abstract). Hepatology 2003;34:539A.
7. Prandota J Important role of prodromal viral infections responsible for
21. Bertholf RL, Johannsen LM, Bazooband A, Mansouri V. False-positive
inhibition of xenobiotic metabolizing enzymes in the pathomechanism of idiopathic Reye’s syndrome, Stevens-Johnson syndrome, autoimmune hepatitis, and hepatotoxicity of the therapeutic doses of
acetaminophen results in a hyperbilirubinemic patient. Clin Chem 2003;49:695-8.
768