Q J Med 2000; 93: 341-349
© 2000 Association of Physicians
Paracetamol hepatotoxicity and alcohol consumption in deliberate and accidental overdose
1 From the Institute of Liver Studies, King's College Hospital, London, and 2 Institute of Hepatology, University College London and University College London Hospitals, London, UK
Received 21 December 2000 and in revised form 10 April 2000
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Summary |
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We studied the relationship between alcohol consumption and hepatotoxicity related to paracetamol ingestion both in cases of overdose with suicidal intent and in cases where paracetamol was apparently taken for therapeutic reasons. In a retrospective study of 553 patients admitted to a specialist liver unit between January 1987 and December 1993 with paracetamol-induced hepatotoxicity, there was no difference in the severity of the hepatotoxicity following either a deliberate or an inadvertent overdose. Heavy alcohol consumption was more common in males than females and more commonly associated with deliberate overdoses of >15 g. There was no correlation between alcohol consumption and severity of hepatotoxicity (mean INR and the serum creatinine levels over the first 7 days after the overdose). The significantly lower platelet count in heavy drinkers was probably the consequence of direct alcohol toxicity to the marrow. Overall there was a greater incidence of heavy alcohol consumption amongst therapeutic misadventure compared to deliberate overdose cases, but there was no difference between the two groups when amounts of <10 g/day were involved. Eleven (29%) patients in the therapeutic misadventure group were depressed, 10 of whom had previously attempted suicide. In conclusion, we were unable to demonstrate that heavy drinkers develop more severe hepatotoxicity following paracetamol overdose than non-drinkers, and from the material reported in this study, accidental overdose is a better defining term than therapeutic misadventure.
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Introduction |
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TopSummaryIntroductionMethodsStatistical analysisResultsDeliberate overdose‘Therapeutic...Severity of illness in...DiscussionReferences |
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Paracetamol overdose is a common problem presenting to Accident and Emergency departments in both the USA and Europe. In the UK, deliberate self-poisoning, particularly with paracetamol, is increasing, with rates for males approaching those of females.1,2 A rise in numbers of both non-fatal and fatal overdoses, especially in individuals under the age of 30, has also been reported from France and in that country correlates strongly with increased paracetamol sales.3 Despite similar trends in the increases of both fatal and non-fatal overdoses, the fatality rate in France is a quarter that of the UK, which has been attributed to the fact that in France, there is a restriction in the amount of paracetamol that can be purchased on a single occasion.3
In the USA, where overdoses of paracetamol taken with suicidal intent are also increasing, there have been warnings that the incidence of acute liver failure from that cause may approach that currently observed in the UK within 5 years.4 Much public concern has been generated by the suggestion that in alcoholics or binge drinkers, smaller doses of paracetamol can lead to severe hepatotoxicity.5 Indeed there have been calls in the USA for the recommended daily therapeutic dose of paracetamol to be limited to 2 g/day in heavy drinkers.6 A number of case reports dating back to 1973 and usually of single patients or a few cases only, mostly from the USA, have described instances of hepatotoxicity in patients who have taken therapeutic or near-therapeutic doses of paracetamol, often on a background of chronic alcohol consumption,7–33 although in the majority of these reports the amount drunk is poorly documented and substantiated. Zimmerman and Maddrey in proposing the term ‘therapeutic misadventure’ for such cases, reported that in 40% of their series and in 23% of the literature cases at that time, which included many of the case reports referred to above, hepatotoxicity had developed following ingestion of a therapeutic dose of paracetamol (<4 g daily). In a further 20% (27% in the literature) doses of 4–6.1 g/day were implicated.6 The paracetamol had often been taken over several days at or near the recommended daily dose, rather than at a single time point.7–33 The mechanism is thought to be a combination of an enhanced production of the toxic metabolite of paracetamol, N-acetyl-p-benzoquinoneimine (NAPQI), as a result of ethanol-induced activation of the cytochrome P450 system, and a reduced ability to detoxify this metabolite consequent on glutathione depletion, the latter being the result of chronic malnutrition, either alone or in association with alcoholism.6,23,34–38 In a retrospective study of 21 patients who had ingested paracetamol for therapeutic purposes—albeit in doses of 4 to 10 g/day—Whitcomb and Block found that hepatotoxicity was more likely to be associated with recent fasting than alcohol use.38
In the UK, the association of alcohol with paracetamol hepatotoxicity appears to be in the context of large overdoses of paracetamol taken with suicidal intent at a single time point.39,40 In the present report we have further analysed data from a large series of cases presenting to a single centre with severe paracetamol hepatotoxicity,40 examining specifically the relationship between level of alcohol consumption, the amount of paracetamol ingested within broad categories, and the severity of hepatotoxicity, both in the single overdose situation and in a smaller group of cases classified as ‘therapeutic misadventure’.
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Methods |
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During the 7-year period January 1987 to December 1993, 560 patients with paracetamol-induced severe hepatotoxicity were treated in the Liver Failure Unit of King's College Hospital (KCH). All the patients, when transferred to KCH, had a significant coagulopathy (an International Normalized Ratio (INR) of >5 at any time post overdose or an INR >2 at 24 h, >4 at 48 h or >6 at 72 h post overdose with or without evidence of a metabolic acidosis, renal failure and encephalopathy.
For the present analysis, information from the case notes was abstracted using a standardized collection form. Once the complete data set had been collected, it was analysed by a non-clinical statistician who was blinded to the aetiological relationships and hypotheses being tested. These methods have been subsequently described and validated by Gilbert et al..41 Seven cases were excluded from analysis because either the history and/or the documentation with respect to alcohol consumption was considered to be unreliable, leaving 553 (99%) of the complete series in the present analysis.
In 515 of the 553 cases, the overdose was taken at a single time point with suicidal intent—311 (60%) impulsive in response to an adverse life event, and 183 (36%) consequent on depression (patient either receiving treatment for depression or specifically described as being depressed by their next of kin or family practitioner). In 21 (4%) cases the motive for the overdose was unclear. The remaining 38 (7%) cases were classified as ‘therapeutic misadventure’, with the patients apparently having taken the paracetamol—32 over a period of time and six as a single dose—apparently for pain relief: 38% abdominal, 24% musculoskeletal, 19% head and 19% dental.
Both groups were treated routinely with an intensive liver care regimen,40 which in 265/515 overdose cases included N-acetyl cysteine (NAC): 201 within 24 h and 64 after 24 h of the overdose. This was continued until recovery in liver function or until demise of the patient. None of the therapeutic misadventure cases—with the variability in duration of paracetamol administration to the clinical course—were given NAC.
Patients were categorized into four groups according to levels of alcohol consumption as used by Zimmerman and Maddrey:6 1, non-drinkers; 2, light drinkers (males <30 g/day, females <20 g/day); 3, moderate drinkers (males <60 g/day, females <40 g/day); 4, heavy drinkers (males >60 g/day, females >40 g/day). The information on alcohol consumption was obtained by direct questioning of the patient, or if the patient was unable to provide such a history, by contact with the referring hospital and the next of kin. As such information was regarded as an important part of the clinical history, every effort was made to check the veracity of the data. The amount of paracetamol said to have been ingested by the patient was similarly substantiated wherever possible by reference to relatives or close contacts and to the referring hospital or general practitioner. To facilitate comparison, we used similar ranges to those of Zimmerman and Maddrey, i.e. <4 g/day, 4–6 g/day, 6–10 g/day, 10–15 g/day, >15 g/day28 and included an additional one of >30 g. The results of plasma paracetamol measurements provided a further check on the validity of the estimated overdose. The few patients in the overdose group (20) and the sole patient in the therapeutic misadventure group who had previously received hepatic enzyme drugs were also examined in relation to alcohol consumption.
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Statistical analysis |
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All data were expressed as medians with ranges. Comparison between groups was made by Wilcoxon rank sum test and
2 as appropriate. |
Results |
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Overall 385 (69%) of the 553 patients did not consume significant quantities of alcohol: 247 (45%) were non-drinkers and 138 (25%) were light drinkers. Of the remaining 168 patients, 47 (8%) had a moderate alcohol intake and 121 (22%) were heavy drinkers (Table 1
). Just over half (54%) of the patients were aged <30 years; 37% were between 30 and 50 years old and 9% were over 50 years old. There were no significant differences in the age distribution of the suicide and therapeutic misadventure groups (Table 1). Overall the ratio of male to female admissions was significantly greater for the deliberate overdose than the therapeutic misadventure group (1 : 1.3 and 1 : 0.6 respectively, p<0.01) although in the heavy drinking category over 90% in the therapeutic misadventure group were male (p<0.01) compared with 66% of the deliberate overdose cases (Table 1).
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Deliberate overdose |
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Analysis of the recorded data showed that the amount of paracetamol taken as a single dose was 4–6 g in two cases, 6–10 g in 16 (3%) and 10–15 g in a further 43 (8%). Of the very much larger number of patients (454, 89%) who had taken >15 g at a single time, 199 (39%) had ingested amounts of 15–30 g and 255 (49%) >30 g. When the ranges of paracetamol ingested were considered in relation to the categorized level of alcohol consumption, it was apparent that the heavy drinking group had taken significantly larger quantities of paracetamol (mean 49 g) than any of the other groups, p<0.01 (Table 1
). This group included nine cases of proven alcohol dependence, who had consumed considerably more paracetamol than the group as a whole (means of 54 g vs. 40 g) and had a higher overall mortality (63% vs. 43%). The two cases who claimed to have only taken 4–6 g were light drinkers, and of the 16 cases who had ingested 6–10 g, only four (25%) were heavy drinkers, and the remaining 12 (75%) were either light or non-drinkers. A similar pattern of alcohol consumption was seen in the 10–15 g group: nine (21%) heavy and two (5%) moderate drinkers with 32 (74%) either light or non-drinkers. Thus, of the 61 patients who had taken a single overdose of <15 g, only 13 (21%) were in the heavy drinking category. In the 15–30 g overdose group, 125 (63%) were either light or non-drinkers, 19 (10%) were moderate drinkers and 55 (27%) were heavy drinkers. The breakdown was similar for those taking >30 g of paracetamol: 165 (65%) were light or non-drinkers, 23 (9%) moderate drinkers and 67 (26%) heavy drinkers. Patients in the moderate or light drinking category were more likely to take an overdose on impulse than heavy drinkers (43% and 41% respectively, p<0.01), and overdoses occurring on a background of depression were more prevalent amongst non-drinkers than in any of the drinking categories (48% vs. 29% light, 28% moderate and 39% heavy, p<0.001). The incidence of previous suicidal behaviour did not differ between non-drinkers, light and moderate drinkers (30–36% of each group), but a significantly higher proportion (44%, 60/135) of the heavy drinkers had documented evidence of previous suicidal behaviour (p<0.01).
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‘Therapeutic misadventure’ |
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All 38 patients in this category had ingested a total cumulative dose of >4 g. One case had taken 4–6 g, one 6–10 g, four 10–15 g, nineteen 15–30 g and thirteen in excess of 30 g of paracetamol. Expressed as a daily amount, two (5%) had ingested a therapeutic or near therapeutic dose of 4–6 g over 24 h. One of these was a heavy drinker who had taken substantial quantities of other OTC analgesic preparations, as well as paracetamol. In the other case, a moderate drinker, the serum paracetamol level was above the standard treatment line at 20 h post ingestion and a greater quantity of paracetamol than was recorded may have been taken. The time over which ingestion occurred varied considerably: four cases (10%) up to 12 h, nine (24%) 12–24 h, 13 (34%) 24–48 h, three (8%) 48–72 h, and three (8%) >100 h. The remaining six (16%) took a single dose. Despite the alleged use of the drug solely for pain relief, eight (21%) of the 38 cases were under medical treatment for depression at the time of overdose, and three (8%) others were described as depressed (two by family practitioners, one by family members). In 10 of these 11 cases there had been a previous documented suicide attempt (five moderate/heavy and five light/non-drinkers).
The heavy drinking category of cases had taken larger total cumulative doses of paracetamol for pain relief than any of the other subgroups (p<0.01, Table 1). This relationship to alcohol intake also held up when the daily amount of paracetamol ingested (g/day) was examined. Only one (14%) of the seven patients who ingested 6–10 g/day was a heavy drinker, compared with five (50%) of the 10 who ingested 10–15 g/day and 7/19 (37%) where the dose ingested was >15 g. Comparison of the deliberate and therapeutic misadventure groups showed no significant differences in either age distribution or the total dose of paracetamol ingested, even when adjusted for level of alcohol consumption. The incidence of excessive (moderate or heavy) alcohol consumption was significantly higher in therapeutic misadventure cases compared to overdose cases (58% vs. 28%, p<0.01). In the therapeutic misadventure group, 71% of males and 41% of females were moderate or heavy drinkers, compared to 42% and 17% respectively in those taking a deliberate overdose (p<0.01). When cases taking <10 g and <10 g/day from either therapeutic misadventure and deliberate overdose were compared, there was no difference in the incidence of excessive alcohol consumption.
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Severity of illness in relation to alcohol consumption |
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Survival was 63% following a deliberate overdose and 58% after therapeutic misadventure. For both groups, survival was independent of the level of alcohol consumption and the amount of paracetamol taken (Table 2
). Renal dialysis was required by 54% (278/515) of the deliberate overdose cases and 56% (21/38) of the therapeutic misadventure group, and there was no correlation with heavy alcohol consumption in either of the groups (Table 2). The need for inotropic support and the percentage of cases that fulfilled transplant criteria were similar in both groups, and also independent of the level of alcohol consumption (Table 2). Relatively few of those fulfilling transplant criteria had a transplant carried out: 37 in all (31 overdose, six therapeutic misadventure), and significant differences between the categories of alcohol consumption were not observed. There was no significant difference in the percentage of patients that developed grade III:IV encephalopathy (58% and 55% for therapeutic misadventure and deliberate overdose respectively) and there was no association with alcohol consumption (Table 2). Overall, there was no difference in the incidence of complications post deliberate overdose between drinkers and non-drinkers, and the pattern of these complications was similar following both deliberate overdose and therapeutic misadventure.
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The mean serum creatinine and the mean INR in the deliberate overdose group did not differ significantly between light, moderate or heavy alcohol consumption categories on any of the first 7 days post overdose (Figure 1
and 2). Over this period, none of the cases required FFP or plasma infusion (which is not part of the intensive care protocol) or dialysis, which could have influenced these values. There was also no correlation between alcohol consumption and mean arterial pH over the same time period. The mean white blood cell count (WBC) was significantly lower in heavy drinkers on day 3 post overdose (12.1±0.7) than in non-drinkers (14.4±0.74, p<0.05), or light drinkers (16.6±0.83, p<0.05), but otherwise showed no correlation with the category of alcohol consumption. Mean platelet count was the one laboratory investigation that correlated strongly with alcohol consumption. For the first 5 days post overdose, the platelet count of the heavy drinkers was significantly lower than in the cases in any of the other categories of alcohol consumption (Figure 3). Graphical presentation and statistical analysis of the serum transaminase data was not possible, as they were invariably recorded as >5000 IU/l or >10 000 IU/l, rather than as exact values, in cases where levels were substantially elevated.
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The longer duration of ingestion in the therapeutic misadventure cases did not allow direct comparison of serial biochemical and haematological data with those in the deliberate overdose group. Figures for peak mean INR and creatinine (8.9±3.0 and 414±83.8 µmol/l, respectively) and minimum mean platelet count (85±17 109/l) were similar to those in the deliberate overdose group (INR 8.9 vs. 10.2, creatinine 414 vs. 442 µmol/l) but the minimum platelet count was lower in the latter group (52 vs. 85x109/l).
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Discussion |
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The incidences of multiple organ failure and overall survival were independent of the level of alcohol consumption and were similar for both groups of patients. There was no difference in the apparent severity of hepatotoxicity or outcome following therapeutic misadventure or a deliberate overdose, and there was no evidence that heavy drinkers from either group developed more severe hepatotoxicity. The high mortality of 40% for the complete series, including both deliberate overdose and therapeutic misadventure cases is an indication of referral bias and the more severely affected cases being sent on to a specialist liver centre. Both groups of patients were treated by the same intensive liver care regimen. In the overdose cases, no correlation could be detected between use and time of starting NAC and the various categories of alcohol consumption. The number who had received enzyme-inducing drugs previously was very small in relation to the size of the series, and no relationship to alcohol consumption could be discovered.
After a deliberate overdose, haematological and biochemical disturbances appeared to be unaffected by the level of alcohol consumption, with the exception of the platelet count which was significantly lower in heavy drinkers. This was expected, as acute alcohol ingestion causes thrombocytopaenia by inhibiting platelet release and chronic alcohol use is known to inhibit directly both marrow platelet production and circulating platelet function.42 The biochemical and haematological disturbances occurring as a consequence of a therapeutic misadventure were no less severe than in the deliberate overdose cases.
A high prevalence of heavy alcohol consumption in the deliberate overdose group is a consistent finding in studies of suicidal behaviour and deliberate self-harm. The reported suicide rate amongst excessive drinkers is up to 80 times that of the general population, and alcohol is implicated in up to 80% of all completed suicides.43–51 In the year after an initial suicide attempt, heavy drinkers have a 51-fold increased risk of a successful suicide as compared with the general population.51 Consequently, previous suicidal behaviour is more likely in heavy drinkers,47 and is a common feature of self-poisoning cases.52 The prevalence of heavy alcohol consumption in the therapeutic misadventure group was even higher than in the series as a whole: 60% overall and 75% of males. These figures were similar to those reported in the series of patients similarly categorized by both Whitcomb and Block (66% overall, 83% of males) and Zimmerman and Maddrey (64% overall).6,38
The deliberate overdose group was predominantly female, except for a subgroup of heavy alcohol consumers, whereas the majority of therapeutic misadventure cases were male. A male predominance in both their own and literature cases of therapeutic misadventure was also reported by Zimmerman and Maddrey, although in Whitcomb and Block's series, females outnumbered males almost 3 : 1.6,38
According to Prescott, hepatotoxicity occurs following ingestion of a single dose of paracetamol only when a dose >125 mg/kg (7.5 g in a 60 kg individual) is absorbed, and the likelihood of toxicity increases substantially as the absorbed dose exceeds 250 mg/kg (15 g in a 60 kg individual).53 In keeping with this and with our findings in the present series, Whitcomb and Block could find no cases of hepatotoxicity following ingestion of a therapeutic dose of paracetamol.38 In the present series, 25% of therapeutic misadventure cases had ingested <10 g/day. In only a quarter of these cases could heavy drinking be implicated as a potentiating factor and in common with Whitcomb and Block, we similarly found that heavy alcohol intake was more commonly associated with doses in excess of 10 g/day.38 Thus, the present study provides no evidence that heavy alcohol consumption enhances the toxicity of paracetamol to such an extent that severe liver damage occurs following the ingestion of therapeutic or near therapeutic doses. This finding is in agreement with earlier studies in large series of unselected patients reported by Rumack54 and Read et al.,55 as well as in the recent paper of Schiodt et al..56
According to Zimmerman and Maddrey, a disproportionate number of cases of therapeutic misadventure have taken paracetamol over a period of days with a background of chronic alcoholism.6,23 In the present series, the proportion of our cases ingesting the drug for 24 h or more was considerably lower than in the series of Zimmerman and Maddrey, and we had no cases where ingestion was continued beyond 5 days.6 Although Whitcomb and Block described cases with a paracetamol intake over more than 7 days, this was in the context of daily ingestion of <10 g, and was observed predominantly in non-drinkers.38 When amounts in excess of 10 g/day were taken, the ingestion period was always less than 4 days, presumably because of the rapid development of hepatotoxicity in this group.38 In well over half of the literature cases, included those reported by Zimmerman and Maddrey, the ingested dose was above the recommended daily maximum,8–12,14–24,26–32 and in this context accidental overdose is a more accurate description. The term ‘therapeutic misadventure’ in our view is better restricted to those cases where hepatotoxicity has clearly followed a daily paracetamol use for pain or other symptom relief of 4 g or less.
The evidence from animal models that chronic alcohol consumption increases susceptibility to paracetamol toxicity is often described as convincing. However, an enhanced production of NAPQI in either chronic alcoholics or heavy drinkers has not been demonstrated following ingestion of therapeutic doses of paracetamol.51,58 Skinner et al. concluded that in alcoholics, microsomal enzyme induction was unlikely to be an important mechanism after finding that a 2-week period of abstinence had no effect on the production of the toxic metabolites of paracetamol.59 Furthermore, animal data suggests that alcohol induces cytochrome P450 IIE1 only when used for a short period (3 days) and not after more prolonged use.60 There is also some evidence that alcohol when ingested acutely may be hepatoprotective and that the degree of protection is proportional to the dose of alcohol used.61–65 Both in man and in animal models, the protective action of alcohol can persist beyond its half-life, and is found even against a background of chronic alcohol consumption.61,66 However, in a recent clinical series from the US, there was no difference in outcome or clinical course of those drinking at time of overdose compared with those who had previously drunk heavily.67
Depletion of glutathione in the context of excess NPAQI production is central to the development of paracetamol-induced hepatotoxicity. In rats, chronic alcohol consumption depletes hepatic glutathione as a result of increasing cellular turnover and hepatic efflux of glutathione, whereas induced vitamin B deficiency directly impairs glutathione synthesis.68,69 In man, chronic alcoholism is often associated with poor nutrition70 and a reduced level of glutathione synthesis.58 These factors may only increase the risk of hepatic injury when increased quantities of NAPQI are produced which, on the basis of the human data recorded, is dependent on the ingestion of a substantial amount of paracetamol.58,70,71 Furthermore, the metabolism of paracetamol in the rat—the most widely used species in experimental toxicity studies—differs significantly from that of man, which renders extrapolation of data from such studies to the clinical situation questionable.72
The fact that almost one third of the ‘accidental’ cases in this study were depressed and 10 of these 11 had taken previous overdoses raises the question of a more deliberate suicidal intent. Suicidal intent is notoriously difficult to exclude, as up to half of all such attempts (of all types) are either concealed or denied.73,74 This pattern of behaviour is apparently more common in heavy, invariably male, drinkers in whom attempted suicide is an integral aspect of problem drinking that is often not appreciated by non-psychiatrists.51 Finally, it is to be stressed that the phenomenon of ‘accidental’ overdosage is not unique to paracetamol overdose, as it is observed following other drug ingestions in heavy drinkers where a metabolic interaction with alcohol is not a factor.50,51
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Notes |
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Address correspondence to Professor R. Williams, Institute of Hepatology, University College London, 69–75 Chenies Mews, London WC1E 6HX. e-mail: roger.williams{at}ucl.ac.uk
Current address: Department of Gastroenterology, Manchester Royal Infirmary, Manchester M13 9WL
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References |
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