Features of Patients With Severe Hepatitis Due to Mushroom Poisoning and Factors Associated With Outcome

Accepted Manuscript Features of Patients With Severe Hepatitis Due to Mushroom Poisoning and Factors Associated with Outcome Maurizio Bonacini, Katerina Shetler, Ira Yu, Robert C. Osorio, Robert W. Osorio

PII: DOI: Reference:

S1542-3565(17)30145-3 10.1016/j.cgh.2016.11.039 YJCGH 55099

To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 27 November 2016 Please cite this article as: Bonacini M, Shetler K, Yu I, Osorio RC, Osorio RW, Features of Patients With Severe Hepatitis Due to Mushroom Poisoning and Factors Associated with Outcome, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2016.11.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Features of Patients With Severe Hepatitis Due to Mushroom Poisoning and Factors Associated with Outcome Short title: Mushroom induced hepatitis

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Maurizio Bonacini, *, Katerina Shetler , Ira Yu , Robert C Osorio , Robert W. Osorio, ,

Department of Gastroenterology and Hepatology, California Pacific Medical Center, San Francisco,

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Stanford University, Stanford Medical Center, Palo Alto, CA

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Washington University, St Louis, MO

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National Kidney and Transplant Institute, Manila, Philippines

Department of Transplantation California Pacific Medical Center, San Francisco, CA

*Address reprint requests to: Maurizio Bonacini, M.D., Mission Gastroenterology and Hepatology,

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1580 Valencia St, Suite 208, San Francisco, CA 94110. E-mail: [email protected];

tel: +1-

415-641-5430; fax: +1-415-641-6201.

The authors did not receive financial support for this manuscript and report no conflict of interest.

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Data collection: MB, KS, IY, RO, RWO

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Statistics: MB, KS

Writing and proofreading manuscript: MB, KS, IY, RO, RWO Word count: 1717

Keywords: Amanita phalloides, Amanita ocreata, mushroom poisoning, mycetismus, hepatotoxicity, liver failure, liver transplantation Abbreviations

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OLT, orthotopic liver transplantation Background & Aims: Acute liver failure following ingestion of toxic mushrooms is a significant medical problem. Most exposures to toxic mushrooms produce no symptoms or only mild gastroenteritis, but some lead to severe hepatic necrosis and fulminant hepatic failure requiring liver transplantation. We

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aimed to assess mortality from mushroom poisoning and identify variables associated with survival and liver transplantation.

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Methods: We collected information from 27 patients (13 male; median age, 47 years) admitted to the emergency department within 24 hrs of ingesting wild mushrooms. They developed severe liver injury (serum levels of transaminases above 400 IU/L) and were treated with activated charcoal and N-

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acetylcysteine at a tertiary medical center in San Francisco, California, from January 1997 through December 2014. Viral hepatitis, autoimmune liver disease, acetaminophen, salicylate toxicity, and chronic liver diseases were ruled out for all patients. We analyzed patient demographics, type and amount of mushroom ingested, time since ingestion, presenting symptoms, laboratory values, and therapies administered. A good outcome was defined as a survival without need for liver transplant. A poor outcome was defined as death or liver transplant. Positive predictive values were calculated, and 2 test was used to analyze dichotomous variables.

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Results: Liver injury was attributed to ingestion of Amanita phalloides in 24 patients and Amanita ocreata in 3 patients. Twenty-four of the patients ingested mushrooms with meals, 3 patients for

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hallucinogenic purpose. At 24–48 hrs after ingestion, all patients had serum levels of alanine aminotransferase ranging from 554 to 4546 IU/L (median, 2185 IU/L). Acute renal impairment developed in 5 patients. Twenty-three patients survived without liver transplantation and 4 patients had

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poor outcomes (1 woman underwent liver transplantation on day 20 after mushroom ingestion and 3 women died from hepatic failure). Of the 23 patients with peak levels of total bilirubin level of 2 mg/dL or more during hospitalization, only 4 had a poor outcome. No men but 4 women had a poor outcome. Peak serum level of aspartate aminotransferase below 4000 IU/L, peak international normalized ratio below 2, and a value of serum factor V above 30% identified patients with good outcomes with a 100% positive predictive value; if these peak values were used as a cutoff, 10/27 patients (37%), 7/27 patients (26%), and 6/12 (50%), respectively, could have avoided transfer to a transplant center.

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Conclusion: In an analysis of 27 patients with hepatocellular damage due to mushroom (Amanita) poisoning and peak levels total bilirubin above 2 mg/dL, the probability of liver transplantation or death is 17%, fulfilling Hy’s law. Patients with peak levels of aspartate aminotransferase below 4000 IU/L can be monitored in a local hospital, whereas patients with higher levels should be transferred to liver

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KEY WORDS: risk factor, liver transplantation, prognosis, ALT, AST

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transplant centers. Women and older patients were more likely to have a poor outcome than men and

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Introduction Acute liver failure following toxic mushroom ingestion is a significant problem worldwide and in the United States.[1-4] Although the majority of toxic mushroom

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exposures cause no or only mild symptoms [4, 5], in some cases, they lead to severe hepatic necrosis and fulminant hepatic failure necessitating orthotopic liver transplantation (OLT).[1, 3, 6]

Several variables associated with prognosis have been studied. However, none has

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been recommended to triage patients with good prognosis who could be safely

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treated in a local hospital, rather than transferred to a transplant center [7]. Our goals were two-fold: to assess mortality due to mushroom poisoning and to identify variables associated with survival without OLT.

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Patients and Methods Study Design

This study is a prospective/retrospective chart review of 27 patients with a history of

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wild mushroom ingestion associated with severe liver injury managed by our Institution between January 1997 and December 2014. Eight patients were located by review of discharge and admission diagnosis codes in our medical record system

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before 2003; thereafter, data from 19 patients were collected prospectively. Inclusion criteria were evidence of mushroom ingestion and transaminase levels 10 times over the upper limit of normal (>400 IU/L). Eight of these patients were described in a previous article. [8]

Demographics, ingestion data, presenting symptoms, laboratory values, and therapies administered were abstracted from the medical records.

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“Good outcome” was defined as a survival without need for liver transplant. A poor outcome was defined as death or OLT. The California Pacific Medical Center (CPMC) Institutional Review Board gave

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permission to review patients’ charts, waiving written consent. Statistics

Laboratory data were represented as the median peak value and ranges. Timing was

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determined by using the best estimation of ingestion time as the starting point. Initial and follow-up values for transaminases, international normalized ratio (INR), bilirubin,

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and factor V activity (as percent) were recorded to establish their respective predictive values. Positive predictive values were calculated using the formula TP/TP+FP, where TP are true-positive results and FP false-positive results. The chisquare test was used to establish the P value between 2 groups for dichotomous variables.

Admission Data

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Results

From January 1997 until December 2014, 27 patients, 13 men and 14 women, were

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admitted with symptoms attributable to acute mushroom poisoning. The median age was 47 years (range, 15-82 years). All patients presented to the emergency

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department within 24 hours of ingesting wild mushrooms. All presented with nausea, vomiting, abdominal cramps or pain, and diarrhea. Table 1 summarizes demographic and laboratory data. A. phalloides was recognized by emergency department personnel as the specific culprit in 11 patients (41%); A. ocreata was documented in 3 patients (11%). Twenty-three patients were transferred to CPMC for the management of severe acute liver injury. Viral hepatitis, autoimmune liver disease, acetaminophen and salicylate toxicity were ruled out in all patients on admission using serology and toxicology screen.

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Abdominal ultrasound was negative for biliary diseases. No patient had evidence of chronic liver disease. Twenty-four patients (89%) ingested mushrooms with meals and 24/27 (89%) were

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foreign-born, from Armenia, China, Jordan, Mexico, and Russia. Three (11%) of the patients ate mushrooms for hallucinogenic purposes. One of these 3 patients had a positive screening result for amphetamines and barbiturates.

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Clinical Course

Gastrointestinal symptoms led all our patients to seek medical attention. At 24 to 48

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hours after ingestion, all patients had transaminase elevation with alanine aminotransferase (ALT) ranging from 554 to 4546 IU/L (median, 2185 IU/L). Peak ALT and aspartate aminotransferase (AST) levels are illustrated in Table 1. Acute renal impairment developed in 5 patients (19%), 4 of whom (15%) required continuous venovenous hemofiltration. Hepatic encephalopathy, ranging from grade I

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to IV, developed in 9 patients (33%). Prognosis

Twenty-three patients (85%) survived without liver transplantation. Four patients

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(15%) were defined as having a poor outcome. One 33-year-old woman received an OLT on day 20 after mushroom ingestion. Three other women, aged 31, 70, and 83

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years died as a result of hepatic failure. Of the 23 patients in whom a peak total bilirubin ≥2 mg/dL developed during their hospitalization, 4/23 (17%) had a poor outcome. No men had a poor outcome (0%) compared to women (29%, P=0.04). Forty percent of patients ≥65 years old (2/5) had a poor outcome versus 10% in younger patients (2/22, P=0.15). Predictive Value of Laboratory Parameters

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The peak of AST and ALT levels occurred earlier (days 2-3) than peak INR (days 3-4), whereas the peak bilirubin occurred at day 5. The median peak AST was 5480 IU/L, whereas the median peak ALT was 6282 IU/L. Serum AST activity declined rapidly (Fig. 1). The median peak INR was 3.0. Ten patients received fresh-frozen plasma

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infusions to keep INR <3.5 per intensive care unit protocol.

To estimate positive predictive values for survival without OLT, we evaluated different peak laboratory cutoff values. We found that peak serum AST level <4000 IU/L, peak

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INR <2, and nadir factor V ≥30% had 100% positive predictive value for a good

outcome. Using those peak values as a cutoff, 10/27 patients (37%), 7/27 patients

a transplant center.

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(26%), and 6/12 (50%) respectively would have been potentially spared a transfer to

The nadir factor V value was available in 3 of 4 patients who had a poor outcome; values were 9%, 13%, and 15%. The 3 surviving patients aged >65 years had nadir factor V values of 20%, 28%, and 32%. The median nadir serum phosphorus level

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was not predictive of outcome. Therapy

The mainstay of therapy consisted of activated charcoal (average, 6 doses per

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patient) and N-acetylcysteine. Twenty percent N-acetylcysteine was administered enterally to all patients with a single loading dose of 140 mg/kg followed by additional

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doses of 70 mg/kg every 4 hours.. Penicillin G was administered intravenously to 19 patients; 2 patients had a penicillin allergy. A silymarin preparation was given to 14 patients; 6 received it initially as an intravenous preparation, the remainder as an oral preparation. Of the patients who received silymarin, 3/14 (21%) had a poor outcome. Of those who did not receive it, 1 of 13 (8%) died. Penicillin G and N-acetylcysteine were discontinued when the prothrombin time INR was <2 and the ALT level had decreased to <50% of its peak value.

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Discussion

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The genus Amanita accounts for >90% of fatal mushroom poisonings.[5] The wide disparity in reported outcomes in patients with Amanita ingestion reflects different degrees of disease severity at the time of referral. [4,9] For example, a survey from Florida [4] found that mushroom exposure is frequent in children but results in only 1% (13/1346) reporting life-threatening effects. The U.S. Acute Liver Failure Study

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Group (ALFSG) recently reported a 46% OLT free survival in 18 patients with acute liver injury from mushroom poisoning [9]. These patients represented 0.8% of the

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enrolled cohort [9].

The rule colloquially known as “Hy’s law” states that in cases of drug-induced hepatocellular jaundice, the case fatality rate ranges from 10% to 50%.”[10] In the present case series, mortality or OLT rate was 17% in patients who developed a peak bilirubin ≥2 mg/dL, thus consistent with Hy’s law. However, this mortality appears

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significantly higher than DILI, where 70% of patients evaluated within the NIHsupported DILI Network had jaundice, and mortality was <10%. [11] The majority of our patients did well despite the severe initial presentation and in

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retrospect did not need to be evaluated in a transplant center. In an era of increasing emphasis on cost-containment and optimization of resources, it would be important to identify clinical or laboratory variables that may reliably identify patients will do well

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with conservative medical management. This test or variable would have the following characteristics: •

100% predictive value for survival

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Easily available in any setting

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Measurable early in the course of the disease

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Not dependent on administration of plasma, albumin, or fluids.

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Two large cohorts specifically including patients with amatoxin intoxication have identified ALT [12] or AST.[13], peak INR [13], bilirubin and creatinine [12] as predictors of mortality. The latter is, however, predictive later in the clinical course, hence not useful for early triage. Serum factor V activity, expressed as percentage of

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normal, has been used as a prognostic indicator in cases of fulminant liver failure, including Amanita toxicity.[14] Unfortunately this assay is not always immediately available. A new index, which includes encephalopathy grade, INR, bilirubin,

phosphorus, and log(10) M30 value at study entry has identified ALF patients with a

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poor outcome with 86% sensitivity and 65% specificity. However, levels of M30, a cleavage product of cytokeratin-18 caspase,[16] are currently research tools.

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The main prognostic variables identified in the available literature (AST, INR and factor V) significantly improved in our cohort between days 3 and 5 post-ingestion (Fig. 1). A peak AST <4000 IU/L had a 100% positive predictive value for OLT-free survival and would have saved 10 patients from a transfer to our tertiary center. In contrast, a peak INR and nadir factor V with cutoff values of <2 and ≥30%, respectively, would have avoided a transfer in 7 and 6 patients. A recent Belgian

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article also shows that all 3 survivors had peak AST < 4000 [7]. We also found that female gender and advanced age were associated with a poor outcome. This was also noted in recent reports where 63% and 75% of fatalities (or OLT) respectively,

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occurred in women. [3,9] Because INR is affected by the frequent administration of fresh-frozen plasma and factor V is not widely available, AST clearly emerged as the best marker for survival. The corollary is that patients who have total bilirubin > 2

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mg% at presentation or AST>4000 should be transferred to a transplant center. The others may be followed locally and triaged according to evolving AST levels. In summary, we described 27 cases of mushroom (Amanita) poisoning that presented with severe hepatocellular damage. The probability of OLT or death due to Amanita hepatotoxicity is 17% in patients who have a peak total bilirubin >2 mg/dL, thus fulfilling Hy’s law. Peak AST levels <4000 IU/L identify patients who can be safely monitored in a local hospital. Patients who have bilirubin > 2 mg/dL, or

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AST>4000 at presentation or during follow-up should be transferred to a liver

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transplant center.

Acknowledgment

We thank Dr. Mariana Lotersztain and all the clinicians who helped treat the patients

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described in this article.

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References

1. Centers for Disease Control and Prevention. Amanita phalloides mushroom poisoning- Northern California, January 1997. JAMA 1997;278:16-17. 2. Grabhorn E, Nielsen D, Hillebrand G, Brinkert, F Herden U, Fischer L, Ganschow R. Successful outcome of severe Amanita phalloides poisoning in children. Pediatr

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Transplant 2013;17(6):550-555.

3. Roberts DM, Hall MJ, Falkland M, Strasser SI, Buckley NA. Amanita phalloides poisoning and treatment with silibinin in the Australian Capital Territory and New

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South Wales. Med J Aust 2013;198(1):43-47.

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4. Kintziger KW, Mulay P, Watkins S et al. Wild mushroom exposure in Florida, 20032007. Publ Health Rep 2011;126:844-852. 5. Mas A. Mushrooms, amatoxins, and the liver. J Hepatol 2005;42:166-169. 6. Kroncke KD, Fricker G, Meier PJ, Gerok W, Wieland T, Kurz G. Alfa – amanitin uptake into hepatocytes. J Biol Chem 1986;261(27):12562-12567. 7. Vanooteghem S, Arts J, Decock S et al. Four patients with Amanita Phalloides poisoning. Acta Gastroenterol Belg 2014;77:353-356

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8. Rengstorff DS, Osorio RW, Bonacini M. Recovery from severe hepatitis caused by mushroom poisoning without liver transplantation. Clin Gastroenterol Hepatol 2003;1:392-396.

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9. Karvellas CJ, Tillman H, Leung AA et al. Acute liver injury and acute liver failure from mushroom poisoning in North America. Liver Int. 2016;36(7):1043-50.

10. Zimmerman H. The Adverse Effects of Drugs. 2nd ed. Philadelphia: Lippincott;

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1999.

11. Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899

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patients with Drug-induced liver injury: the DILIN prospective study. Gastroenterology 2015;148:1340-52.

12. Ganzert M, Felgenhauer N, Zilker T. Indication of liver transplantation following amatoxin intoxication. J Hepatol 2005;42:202-209.

13. Trabulus S, Altiparmak MR. Clinical features and outcome of patients with

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amatoxin-containing mushroom poisoning Clin Toxicol 2011;49:303-310. 14. Ferreira R, Romãozinho JM, Amaro P, Ferreira M. Assessment of emergency liver transplantation criteria in acute liver failure due to Amanita phalloides. Eur J

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Gastroenterol Hepatol 2011;23(12):1226-1232. 15. Enjalbert F, Rapior S, Nouguier-Soule J, Guillion S, Amouroux N, Cabot C.

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Treatment of Amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol 2002:40(6):715-757. 16. Rutherford A, King LY, Hynan LS, Vedvyas C, Lin W, Lee WM, Chung RT; ALF Study Group. Development of an accurate index for predicting outcomes of patients with acute liver failure. Gastroenterology 2012;143(5):1237-1243.

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Figure 1. AST levels and factor V activity: course over time in patients with toxic

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mushroom poisoning. AST, aspartate aminotransferase

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