clinical features and outcome of patients with amatoxin-containing mushroom poisoning

8
POISONS CENTRES Clinical features and outcome of patients with amatoxin-containing mushroom poisoning SINAN TRABULUS 1 and MEHMET R. ALTIPARMAK 2 1 Department of Nephrology, Istanbul Research and Training Hospital, Istanbul, Turkey 2 Department of Nephrology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey Objective. We aimed to determine clinical and laboratory findings that were different between those patients who died and those who survived and to look for factors associated with the mortality in amatoxin-containing mushroom poisoning. Methods. The mushroom poisoning patients who were admitted to our clinic between 1996 and 2009 were retrospectively evaluated. The diagnosis was based on a history of mushroom ingestion, clinical picture and the presence of serum alpha-amanitin. Patients were divided into two groups as the survival group and the fatality group. Clinical and laboratory findings were compared between the two groups. Relation between variables and clinical outcome was analyzed. Results. A total of 144 amatoxin poisoning patients were included in this study. Patients who died were more likely to have demonstrated low mean arterial pressure, encephalopathy, mucosal hemorrhage, oliguria–anuria, hypoglycemia, and thrombocytopenia during the hospitalization. Low sodium values and high urea, AST, ALT, total bilirubin, LDH, prothrombin time, international normalized ratio, and activated partial thromboplastin time values were associated with increased likelihood of mortality. Nineteen patients developed acute renal failure. Fourteen patients developed acute hepatic failure. All the 14 patients who died developed acute hepatic failure. The mortality rate was 9.7%. Conclusions. The factors associated with mortality determined in this retrospective study may be helpful for clinical outcome assessment and monitoring of patients with amatoxin-containing mushroom poisoning. Keywords Kidney; Liver; Metabolic Introduction Poisoning by wild mushrooms has been described in many regions of Turkey. 1–3 Amanita phalloides and Amanita verna are responsible for severe cases of poisoning. 4 These mushrooms are most commonly found during the late summer or autumn in well-forested areas. Ingestion of amatoxin-containing mushrooms may ac- count for approximately 90% of deaths attributable to mushroom ingestion worldwide. 5,6 There are currently 10 known amatoxins with molecular weights of approximately 900 Daltons. 5,7 The major amatoxins, the alpha-, beta-, and gamma-amanitins, damage the liver and kidney via irreversible binding to RNA polymerase II. 6,8 Of these, alpha-amanitin is thought to be primarily responsible for human disease. 6 No specific amatoxin antidote is available. The optimal management of the amatoxin poisoning is still not determined. Treatment strategies are characterized as preliminary medical care and supportive measures. Treat- ment appears to be primarily intensive supportive care. Supportive therapies consist of detoxication procedures (toxin removal from the digestive, biliary, and urinary systems and extra-corporeal detoxication) and administra- tion of drugs used singly or in combination (e.g. b-lactam antibiotics, silymarin, and antioxidant drugs). 9 Liver transplantation is characterized as a last resort for progres- sive liver failure with encephalopathy. This is a retrospective review to ascertain clinical and laboratory findings that were statistically different between those patients who died and those who survived. In addition, we looked for factors associated with the mortality in amatoxin-containing mushroom poisoning. Methods The mushroom poisoning patients who were admitted to our clinic between January 1996 and December 2009 were retrospectively evaluated by examing medical records of patients. The two archive staffs collected the data, and they were blinded to provide the objectivity of the study. They were medically trained personnel. They collected data onto Received 3 September 2010; accepted 20 February 2011. Address correspondence to Dr. Sinan Trabulus, Ardiçli Evler Sitesi Go ¨ kkusagi Mah. Salkim Sok. No: 45/2 Bahçesehir, Istanbul, Turkey. E-mail: [email protected] Clinical Toxicology (2011) 49, 303–310 Ó 2011 Informa Healthcare USA, Inc. ISSN 1556-3650 print/ISSN 1556-9519 online DOI: 10.3109/15563650.2011.565772 303 Clinical Toxicology Downloaded from informahealthcare.com by University of Toronto on 08/11/14 For personal use only.

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Page 1: Clinical features and outcome of patients with amatoxin-containing mushroom poisoning

POISONS CENTRES

Clinical features and outcome of patients withamatoxin-containing mushroom poisoning

SINAN TRABULUS1 and MEHMET R. ALTIPARMAK2

1Department of Nephrology, Istanbul Research and Training Hospital, Istanbul, Turkey2Department of Nephrology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey

Objective. We aimed to determine clinical and laboratory findings that were different between those patients who died and those whosurvived and to look for factors associated with the mortality in amatoxin-containing mushroom poisoning. Methods. The mushroompoisoning patients who were admitted to our clinic between 1996 and 2009 were retrospectively evaluated. The diagnosis was based on ahistory of mushroom ingestion, clinical picture and the presence of serum alpha-amanitin. Patients were divided into two groups as thesurvival group and the fatality group. Clinical and laboratory findings were compared between the two groups. Relation between variablesand clinical outcome was analyzed. Results. A total of 144 amatoxin poisoning patients were included in this study. Patients who diedwere more likely to have demonstrated low mean arterial pressure, encephalopathy, mucosal hemorrhage, oliguria–anuria, hypoglycemia,and thrombocytopenia during the hospitalization. Low sodium values and high urea, AST, ALT, total bilirubin, LDH, prothrombin time,international normalized ratio, and activated partial thromboplastin time values were associated with increased likelihood of mortality.Nineteen patients developed acute renal failure. Fourteen patients developed acute hepatic failure. All the 14 patients who died developedacute hepatic failure. The mortality rate was 9.7%. Conclusions. The factors associated with mortality determined in this retrospectivestudy may be helpful for clinical outcome assessment and monitoring of patients with amatoxin-containing mushroom poisoning.

Keywords Kidney; Liver; Metabolic

Introduction

Poisoning by wild mushrooms has been described in manyregions of Turkey.1–3 Amanita phalloides and Amanitaverna are responsible for severe cases of poisoning.4 Thesemushrooms are most commonly found during the latesummer or autumn in well-forested areas.Ingestion of amatoxin-containing mushrooms may ac-

count for approximately 90% of deaths attributable tomushroom ingestion worldwide.5,6 There are currently 10known amatoxins with molecular weights of approximately900 Daltons.5,7 The major amatoxins, the alpha-, beta-, andgamma-amanitins, damage the liver and kidney viairreversible binding to RNA polymerase II.6,8 Of these,alpha-amanitin is thought to be primarily responsible forhuman disease.6

No specific amatoxin antidote is available. The optimalmanagement of the amatoxin poisoning is still not

determined. Treatment strategies are characterized aspreliminary medical care and supportive measures. Treat-ment appears to be primarily intensive supportive care.Supportive therapies consist of detoxication procedures(toxin removal from the digestive, biliary, and urinarysystems and extra-corporeal detoxication) and administra-tion of drugs used singly or in combination (e.g. b-lactamantibiotics, silymarin, and antioxidant drugs).9 Livertransplantation is characterized as a last resort for progres-sive liver failure with encephalopathy.This is a retrospective review to ascertain clinical and

laboratory findings that were statistically different betweenthose patients who died and those who survived. In addition,we looked for factors associated with the mortality inamatoxin-containing mushroom poisoning.

Methods

The mushroom poisoning patients who were admitted to ourclinic between January 1996 and December 2009 wereretrospectively evaluated by examing medical records ofpatients. The two archive staffs collected the data, and theywere blinded to provide the objectivity of the study. Theywere medically trained personnel. They collected data onto

Received 3 September 2010; accepted 20 February 2011.Address correspondence to Dr. Sinan Trabulus, Ardiçli EvlerSitesi Gokkusagi Mah. Salkim Sok. No: 45/2 Bahçesehir, Istanbul,Turkey. E-mail: [email protected]

Clinical Toxicology (2011) 49, 303–310� 2011 Informa Healthcare USA, Inc.ISSN 1556-3650 print/ISSN 1556-9519 onlineDOI: 10.3109/15563650.2011.565772

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forms with pre-determined variables. Patients older than 16years were enrolled in this study.The diagnosis of amatoxin-containing mushroom poison-

ing was based on a history of mushroom ingestion,characteristic clinical picture, and the presence of serumalpha-amanitin. The alpha-amanitin was analyzed in onemember of each family and in other remaining patients byhigh-performance liquid chromatography in serum sam-ples.5,6 Toxin level was measured in the family memberfirst admitted to the hospital. Alpha-amanitin level wasmeasured during the admission to hospital, and a singlemeasurement was performed. The identification of mush-rooms by an experienced mycologist could not be carriedout.Clinical findings during the hospital course such as

symptoms, time to onset of symptoms, onset of symptomsbefore or after 6 h, mean arterial pressure (MAP), ECGfindings, body temperature, jaundice, hepatic encephalo-pathy (irrespective of the grade), and mucosal hemorrhagewere obtained from hospital medical records. Late-onsettoxicity was defined as onset of symptoms after 6 h.Mucosal hemorrhage was defined as the bleeding frommucous membranes of gastrointestinal tract, oral cavity, andgenital tract.MAP was calculated using the following equation:

MAP ¼ DP þ 1/3 (SP – DP) (DP, diastolic pressure,mmHg; SP, systolic pressure, mmHg)

Hypotension was defined as MAP5 70 mmHg. Pre-mature ventricular beats occurring after normal beat wereaccepted as ventricular arrhythmia. Fever was defined asaxillary temperature more than 37.28C. Hypothermia wasdefined as rectal temperature below 35.08C. Jaundice wasdefined as a clinical finding on examination and a specificbilirubin level (a yellowish pigmentation of the skin and theconjunctival membranes caused by hyperbilirubinemia,plasma bilirubin4 1.5 mg/dL).Laboratory findings (serum alpha-amanitin, values of

serum sodium, potassium, calcium, phosphorus, albumin,initial and maximal values of serum urea, creatinine, uricacid, AST, ALT, LDH, total bilirubin, prothrombin time(PT), international normalized ratio (INR), activated partialthromboplastin time (APTT), initial and minimal values ofserum glucose, and initial and minimal platelet counts) wererecorded. Time to the first rise in AST, ALT, total bilirubin,and PT after mushroom ingestion was detected. Time to thefirst decrease in platelet count after mushroom ingestion wasdetermined. Hyponatremia was defined as a serum sodiumlevel of 5135 mEq/L.Laboratory findings such as urinary output, initial hypo-

glycemia and hypoglycemia during the hospitalization,thrombocytopenia, and microscopic hematuria were recorded.Oliguria was defined as an urine output below 400 mL/

day, and anuria was defined as an urine output below50 mL/day. Hypoglycemia was accepted as a plasmaglucose level of less than 60 mg/dL. Thrombocytopenia

was defined as a platelet count below 100,000/mL.Microscopic hematuria was accepted as the excretion ofmore than five red blood cells per high-power field in acentrifuged urine specimen.Treatment modalities, time to onset of hemoperfusion

(HP), number of HP sessions, total HP duration, clinicaloutcome (death or survival), the presence of acute hepaticfailure and/or acute renal failure, and causes of mortalitywere detected. Season of poisoning was recorded as ahistorical data.Acute hepatic failure was defined as development of

hepatic encephalopathy (confusion, stupor, and coma),decreased production of proteins (such as albumin andblood clotting proteins), and the development of coagulo-pathy, usually an INR of greater than 1.5, within 4 weeksafter the first signs (such as jaundice) in a patient withoutpreexisting cirrhosis.Acute renal failure was diagnosed on the basis of clinical

history and laboratory data (rapid time course, 548 h,absolute increase in serum creatinine of �0.3 mg/dL,percentage increase in serum creatinine of �50%, andreduction in urine output, defined as 0.5 mL/kg/hr for morethan 6 h).Patients were divided into two groups as the survival

group and the fatality group. Clinical and laboratoryfindings were compared between the two groups fordetermination of factors associated with mortality. Thecomparisons of clinical and laboratory characteristics weremade using Student’s t-test if data were normally distributedand Mann-Whitney U test otherwise. Wilcoxon signed-ranktest was used for comparison of platelet counts before andafter HP treatment. Differences in categorical variables wereevaluated with the Chi-square analysis and Fisher’s exacttest. The odds ratios (OR) and their 95% confidenceintervals (CI) were calculated to estimate the strength ofthe association between clinical characteristics, thosepatients who died, and those who survived. Relationbetween numerical variables and clinical outcome wasevaluated with Pearson correlation test. Relation betweennominal variables and clinical outcome was analyzed withSpearman’s rho correlation test. Data were expressed asmean + SD. p values5 0.05 were accepted as significant.All computations were conducted using SPSS for Windows,version 16.0, software (SPSS Inc., Chicago, IL).This study was approved by the Ethics Committee of

Istanbul University Cerrahpasa Medical Faculty.

Results

One hundred fifty-five patients with mushroom poisoningwere evaluated. There were 11 patients presumed to haveamanita poisoning but whose serum alpha-amanitin levelswere negative. Therefore, they were excluded from thestudy. A total of 144 amatoxin poisoning patients (72females and 72 males) were included in this study.A significant portion of the cases came in a group pattern,mostly as members of a family. Sixty-eight of these patients

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were the members of 27 different families. Two of thefemale patients were 6 and 7 weeks pregnant.None of the patients consumed ethanol with mushroom

ingestion. None had been treated with aspirin or acetami-nophen (which may complicate the picture in terms ofbleeding and hepatic toxicity) before coming to the hospital.The pre-existing conditions are as follows: diabetesmellitus in six patients, hypertension in nine patients,ischemic heart disease in five patients, chronic obstructivepulmonary disease in two patients, and vasculitis in twopatients.Mushroom poisonings usually occurred between June and

December. The majority of the cases came in October (59patients) and November (51 patients). A total of 137 patientspicked out wild mushrooms from forests and meadows.Seven patients purchased wild mushrooms from localbazaars. One hundred twelve patients were from Istanbuland its provinces.The most common symptoms during the hospital course

were as follows: nausea in 139 patients, vomiting in 129patients, diarrhoea in 82 patients, abdominal pain in 78patients, vertigo in 27 patients, weakness in 16 patients,mucosal hemorrhage in 12 patients, and headache in 10patients. Demographic and clinical characteristics of patientsare outlined in Table 1.On the physical and laboratory examinations, hypotension

was present in 21 patients, abdominal tenderness in 21patients, encephalopathy in 10 patients, jaundice in 9patients, fever in 8 patients, hypoglycemia in 8 patients,sinus tachycardia in 7 patients, oliguria-anuria in 5 patients,sinus bradycardia in 2 patients, ventricular arrhythmia in 2patients, and hypothermia in 1 patient. Laboratory results ofpatients are shown in Table 2.

There was not a standing protocol to treat all patients thesame way. The use of each of the following treatmentmodalities5,6,9,10 was at the discretion of the treatingphysician: 1) gastric lavage, only within 60 min afteringestion; 2) supportive therapy with correction of hypovo-lemia, hypoglycemia, electrolyte imbalances, and metabolicacidosis; 3) correction of the coagulation disordersby parenteral vitamin K (10 mg daily for three days) andfresh-frozen plasma (2 to 6 U initially); 4) activatedcharcoal as multiple doses (20–40 g every 3–4 h) for 24 hor more; 5) b-lactam antibiotics: high doses of penicillin G(300,000–1,000,000 U/kg/day IV) or ceftazidime (4.5 g IVevery 2 h); 6) N-acetylcysteine (loading dose: 150 mg/kg IVinfusion over 60 min; maintenance dose: 50–100 mg/kgover 20 h).Gastric lavage was only done in six patients presented

within 2 h from ingestion. Activated charcoal was used in 89patients. b-lactam antibiotics were the drugs mostly used.Penicillin G was used in 41 patients and ceftazidime in70 patients. Both drugs were administered to 15 patients.No major side effects were observed during the administra-tion of b-lactam antibiotics. As silymarin was not availablein Turkey during the study period, it was not given.N-acetylcysteine was given to only 11 patients.In contrast to other therapies, all patients were treated

with HP. HP was used concurrently with hemodialysis(HD).11 The HP cartridge was placed upstream of thedialyzer. HP was performed with a sorbent-containingcartridge using either activated charcoal or an AmberliteXAD-4 resin as the sorbent. Adsorba 300 C (Gambro,Sweden) and AluKart (Erika, USA) as activated charcoalwere used in 82 and 55 patients, respectively. Haemoresin(Braun, Germany) as Amberlite XAD-4 resin was used in

Table 1. Demographic and clinical characteristics of all patients, patients who died, and those who survived.

CharacteristicsAll patients(n ¼ 144)

Patients whodied (n ¼ 14)

Patients whosurvived (n ¼ 130) p* value OR (95% CI)

Age (years) 37.4+ 15.0 37.0+ 16.4 37.4+ 14.9 NSGender (female/male) 72/72 8/6 64/66 NS 0.72 (0.23–2.21)Time to onset of symptoms (h) 10.1+ 8.3 13.4+ 7.8 13.1+ 14.0 NSLate-onset toxicity (onset of

symptoms 4 6 h)112 (77.7%) 13 (92.8%) 99 (76.1%) NS{ 4.07 (0.51–32.37)

MAP (mmHg) 84.7+ 14.8 71.4+ 23.4 86.2+ 12.9 0.003Jaundice 9 (6.2%) 2 (14.2%) 7 (5.3%) NS{ 2.92 (0.54–15.70)Encephalopathy 10 (6.9%) 9 (64.2%) 1 (0.7%) 0.000{ 232.20 (24.45–2204.94)Mucosal hemorrhage 12 (8.3%) 5 (35.7%) 7 (5.3%) 0.002{ 9.76 (2.57–36.99)Oliguria-anuria 5 (3.4%) 4 (28.5%) 1 (0.7%) 0.000{ 51.60 (5.25–506.39)Initial hypoglycemia 6 (4.1%) 1 (7.1%) 5 (3.8%) NS{ 2.18 (0.23–20.37)Hypoglycemia during the

hospitalization8 (5.5%) 3 (21.4%) 5 (3.8%) 0.023{ 8.0 (1.64–38.97)

Thrombocytopenia 12 (8.3%) 6 (42.8%) 6 (4.6%) 0.000{ 15.50 (4.06–59.10)Microscopic hematuria 28 (19.4%) 5 (35.7%) 23 (17.6%) NS{ 2.58 (0.79–8.43)

Note: *p value for comparisons between patients who died and those who survived.{Fisher’s Exact Test was used.

NS, nonsignificant; OR, odds ratio; CI, confidence interval; MAP, mean arterial pressure

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seven patients. Blood flow rates were maintained at 250 to300 mL/min. Each HP treatment was applied for 3 h a day.HP treatment was continued until the clinical and biochem-ical improvement in patients.There were significant differences in MAP values and the

percentages of patients with encephalopathy, mucosalhemorrhage, oliguria-anuria, hypoglycemia during thehospitalization, and thrombocytopenia between patientswho died and patients who survived. Patients who diedwere more likely to have demonstrated low MAP,encephalopathy, mucosal hemorrhage, oliguria-anuria, hy-poglycemia during the hospitalization, and thrombocytope-nia. There were no significant differences in the otherclinical variables between the two groups (Table 1).We found that there were significant differences in

minimal glucose values, levels of initial and maximal urea,AST, ALT, and total bilirubin, levels of maximal LDH, PT,INR, and APTT, sodium values, and minimal platelet countsbetween patients who died and patients who survived. Therewere no significant differences in the other laboratoryfindings between the two groups (Table 2).

There were no significant differences in terms of time toonset of the first rise in AST, ALT, total bilirubin, and PTbetween patients who died and those who survived. Also,there was no significant difference in terms of the firstappearance time of thrombocytopenia between the twogroups (Table 3).Five patients had glucose values below 50 mg/dL at any

time. There was a significant difference in terms offrequency for hypoglycemia (550 mg/dL) between patientswho died and those who survived (3 vs. 2, respectively)(p ¼ 0.007). We found that the individuals who died weremore likely to have demonstrated hypoglycemia (OR:17.45; 95% CI: 2.63–115.79).Not all patients who had mucosal hemorrhage had an

elevated INR. Seven of 12 patients with mucosal hemor-rhage had an abnormal INR (41.2). In all patient groups,there were six patients with an INR4 5.0. Mucosalhemorrhage was determined in one of these patients. Threeof these patients died.We observed that there was no significant correlation

between serum alpha-amanitin levels and time to onset of

Table 2. Laboratory findings of all patients, patients who died, and those who survived.

Parameters All patients (n ¼ 144) Patients who died (n ¼ 14) Patients who survived (n ¼ 130) p* value

Alpha-amanitin (mg/mL){ 0.597+ 0.342 1.013+ 0.178 0.561+ 0.331 NSInitial glucose (mg/dL) 112.4+ 40.5 136.0+ 83.0 110.2+ 33.6 NSMin glucose (mg/dL) 100.5+ 28.3 75.0+ 39.3 103.0+ 25.9 0.004Initial urea (mg/dL) 38.3+ 21.9 49.4+ 18.0 37.1+ 22.1 0.006Max urea (mg/dL) 41.5+ 23.1 54.6+ 22.3 40.1+ 22.8 0.008Initial creatinine (mg/dL) 1.0+ 0.5 1.0+ 0.2 1.0+ 0.6 NSMax creatinine (mg/dL) 1.1+ 0.6 1.3+ 0.7 1.1+ 0.6 NSInitial uric acid (mg/dL) 4.0+ 2.0 4.9+ 1.8 3.9+ 2.0 NSMax uric acid (mg/dL) 4.2+ 2.1 4.9+ 1.9 3.9+ 2.2 NSInitial AST (IU/L) 265.6+ 885.7 836.7+ 1630.5 203.6+ 748.8 0.004Max AST (IU/L) 1031.4+ 1816.2 2860.2+ 2494.4 832.9+ 1619.2 0.000Initial ALT (IU/L) 240.2+ 720.3 797.5+ 1489.5 179.7+ 559.1 0.005Max ALT (IU/L) 1028.7+ 1703.2 2553.4+ 2648.3 863.2+ 1491.3 0.000Initial LDH (IU/L) 563.3+ 867.8 670.3+ 509.0 554.0+ 893.1 NSMax LDH (IU/L) 1166.3+ 1815.6 2474.9+ 2783.2 1052.6+ 1676.6 0.001Initial total bilirubin (mg/dL) 1.4+ 1.5 3.6+ 3.7 1.2+ 0.9 0.004Max total bilirubin (mg/dL) 1.8+ 1.8 4.5+ 3.2 1.5+ 1.4 0.000Sodium (mEq/L) 139.0+ 3.6 136.8+ 2.9 139.2+ 3.6 0.024Potassium (mEq/L) 3.9+ 0.6 4.4+ 0.9 3.9+ 0.5 NSCalcium (mg/dL) 9.4+ 0.8 9.6+ 0.8 9.4+ 0.8 NSPhosphorus (mg/dL) 3.2+ 0.9 2.6+ 0.6 3.2+ 1.0 NSAlbumin (g/dL) 4.0+ 0.6 3.8+ 0.6 4.1+ 0.6 NSInitial platelet count (6103/mL) 217.8+ 80.7 207.9+ 73.4 218.8+ 81.7 NSMin platelet count (6103/mL) 189.1+ 80.5 122.9+ 77.5 195.8+ 78.1 0.004Initial PT (s) 17.9+ 12.0 23.7+ 16.0 17.2+ 11.4 NSMax PT (s) 24.6+ 23.9 47.9+ 42.2 22.0+ 19.7 0.002Initial INR 1.3+ 0.9 1.8+ 1.2 1.3+ 0.8 NSMax INR 1.9+ 2.0 4.6+ 4.7 1.6+ 1.2 0.002Initial APTT (s) 35.0+ 19.7 55.7+ 40.8 32.7+ 14.7 NSMax APTT (s) 43.2+ 30.8 94.0+ 58.9 37.7+ 20.0 0.001

*p value for comparisons between patients who died and those who survived.{The average level of alpha-amanitin in one member of an each family and in other remaining patients.

Note: Min, minimal; Max, maximal; NS, nonsignificant; PT, prothrombin time; INR, international normalized ratio; APTT, activated partialthromboplastin time.

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symptoms (r (correlation coefficient) ¼ 0.059, p ¼ 0.781).We found that MAP values, minimal glucose levels, sodiumlevels, and minimal platelet counts were significantly,negatively correlated with mortality. Initial and maximallevels of urea, AST, ALT, and total bilirubin and maximalvalues of LDH, PT, INR, and APTT were significantly,positively correlated with mortality. There were nosignificant correlations between the other clinical andlaboratory variables and clinical outcome (Table 4).We found that time to onset of the first rise in AST, ALT,

total bilirubin, and PT and the first appearance time ofthrombocytopenia were not significantly correlated withclinical outcome in all patient groups (Table 3).There was no significant difference in terms of time to

onset of HP between the two groups. Similarly, time toonset of HP was not significantly correlated with clinicaloutcome (r ¼ 0.081, p ¼ 0.336). Number of HP sessionsand total HP duration were significantly more in patientswho died than in patients who survived. Patients who diedwere treated with a greater number of the HP sessions.(Table 5).Forty-six patients with positive amanitin levels had HP

started within 24 h of ingestion. Forty-two of these patientssurvived. Fifty-seven patients with positive amanitin levelswere treated with HP after 24 h. Fifty-one of these patientssurvived.The most common complications of HP were as follows:

hypotension due to volume loss in 101 patients, nause in 18patients, thrombocytopenia in 18 patients, vomiting in 10patients, and fever in 8 patients. Before HP treatment, sixpatients had hypoglycemia. Eight patients developedhypoglycemia during HP treatment.Platelet counts after HP treatment were significantly

lower than that found before HP treatment (186.7+ 90.1vs. 266.8+ 93.4 (6103/mL), p ¼ 0.000; respectively).The mean of differences was calculated as 80.0 + 95.0(6103/mL).In this study, 130 patients recovered completely. The

mean duration of hospitalization of these patients recoveredcompletely was 7.6 + 4.8 days (range of 3–32 days).The 6 weeks pregnant patient developed vaginal hemor-

rhage and miscarriage. She was discharged on the 13th day.No abnormalities were detected in the 7 weeks pregnantpatient and the fetus. She was discharged on the 10th day. In

Table 3. Time to onset of the first rise in AST, ALT, total bilirubin and PT, and the first appearance time of thrombocytopenia in allpatients, patients who died, and those who survived.

VariablesAll patients(n ¼ 144)

Patients whodied (n ¼ 14)

Patients whosurvived (n ¼ 130) p* value

Correlation{

coefficient (r) p{ value

Time of the first rise in AST (h) 32.4 + 27.6 24.2 + 12.8 33.5 + 29.0 NS 70.073 NSTime of the first rise in ALT (h) 39.4 + 31.1 27.5 + 18.8 40.8 + 32.1 NS 70.120 NSTime of the first rise in total

bilirubin (h)48.8 + 26.8 33.5 + 16.3 52.6 + 27.9 NS 70.261 NS

Time of the first rise in PT (h) 38.9 + 24.3 27.5 + 18.8 40.9 + 25.0 NS 70.195 NSThe first appearance time of

thrombocytopenia (h)71.4 + 30.7 63.7 + 14.4 73.2 + 33.5 NS 70.125 NS

*p value for comparisons between patients who died and those who survived.{Correlation analysis in all patient group.

Note: NS, nonsignificant.

Table 4. Correlation analysis between the clinical and laboratoryvariables and outcome in all patients.

Variables Correlation coefficient (r) p value

Age 70.010 NSTime to onset of symptoms 0.130 NSMAP 70.297 0.000Alpha-amanitin 0.368 NSInitial glucose 0.124 NSMin glucose 70.280 0.001Initial urea 0.167 0.047Max urea 0.187 0.025Initial creatinine 70.015 NSMax creatinine 0.100 NSInitial uric acid 0.142 NSMax uric acid 0.135 NSInitial AST 0.240 0.004Max AST 0.355 0.000Initial ALT 0.234 0.005Max ALT 0.298 0.000Initial LDH 0.036 NSMax LDH 0.213 0.017Initial total bilirubin 0.447 0.000Max total bilirubin 0.460 0.000Sodium 70.201 0.022Potassium 0.170 NSCalcium 0.081 NSPhosphorus 70.245 NSAlbumin 70.127 NSInitial platelet count 70.039 NSMin platelet count 70.262 0.002Initial PT 0.162 NSMax PT 0.327 0.001Initial INR 0.173 NSMax INR 0.439 0.000Initial APTT 0.173 NSMax APTT 0.548 0.000

Note: NS, nonsignificant; MAP, mean arterial pressure; Min, minimal;Max, maximal; PT, prothrombin time; INR, international normalized ratio;APTT, activated partial thromboplastin time.

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both pregnant patients, the transaminase levels were high inthe beginning, then returned to normal values.Nineteen patients developed acute renal failure. Five of 19

patients who developed acute renal failure were oliguric.The other 14 patients with non-oliguric acute renal failurerecovered completely within 3 weeks. The five patients witholiguric acute renal failure did not have an improvement inhepatic and renal function. Therefore, the repeated doses ofHD treatment in these patients were continued. Four of 5patients with oliguric acute renal failure died on the 4th dayof hospitalization and the other patient on the 7th day.Fourteen patients developed acute hepatic failure. These

were the patients of the sub-group patients who died.Patients who survived did not develope acute hepatic failure.The 14 patients who died all developed acute hepatic failure,as defined by encephalopathy with liver function abnorm-alities. These patients died after a median interval of 4 daysfollowing hospital admission (range of 1 to 7 days). Twopatients were transferred to a transplantation center. Thesetwo patients included in the emergency list for livertransplantation died before obtaining a donor. The other12 patients were not considered for liver transplant as theydeteriorated before a donor was found.

Discussion

While it may be true that 90% of deaths due to mushroomsare from amatoxins, only a very small number of patients diefrom amatoxin-containing mushroom poisoning. Withsupportive care, the prognosis is not extremely bad. 2008Annual Report of the American Association of PoisonControl Centers has 6034 total mushroom cases with 42cyclopeptide mushrooms and 3 deaths.12 2009 AnnualReport has 5902 total mushroom exposures with 35cyclopeptide mushrooms and 1 death.13 Mortality rate hasbeen falling in 2009 compared to 2008 (2.8% vs. 7.1%,respectively). The mortality rate of 9.7% found in our studyis similar to the result obtained in 2008.It has been reported that fatal outcomes are usually

associated with advanced age. Severely intoxicated patientswere older than mildly intoxicated patients.10 In our study,age was not found as a factor associated with mortality.The most common symptoms recorded in this study were

nausea, vomiting, diarrhoea, and abdominal pain, asreported in the literature.5,6,14 These most commonsymptoms began simultaneously according to medicalhistory of patients. All of the patients stated that these most

common symptoms started almost at the same time and priorto presentation to the hospital. ‘‘Time to onset of symptoms’’in this study, this refers to the onset time of these foursymptoms. In this study, time to onset of symptoms was notassociated with poor outcome of patients. Similarly, late-onset toxicity did not appear to be associated with mortality.We found that MAP values were significantly lower in

patients who died compared to patients who survived,depending on hypovolemia and dehydration. There was asignificant negative correlation between MAP values andmortality. Also, there was a significant negative correlationbetween sodium levels and mortality. Whereas, there was asignificant positive correlation between initial and maximalurea levels and mortality. Mortality increased with falling ofsodium levels and increasing of urea levels. These patientshad severe fluid and electrolyte replacement requirement.There was no significant correlation between serum

alpha-amanitin levels and time to onset of symptoms.Similarly, there was no significant correlation betweenserum alpha-amanitin levels and outcome. How manypatients had a decrease of alpha-amanitin levels within thefirst 24 h of poisoning is unknown. A limitation of our studyis that there was only one measurement of alpha-amanitinconcentration determined.According to Ganzert et al., one of the criteria for

unfavorable outcome in patients with amatoxin poisoningwas serum creatinine level higher than 106 mmol/L.15

According to Krenova et al., increased serum creatininelevel could be a negative factor for organ recovery.16

Whereas, in our study, creatinine level did not appear toreflect a poor outcome. On the other hand, oliguria-anuriawas found as a factor associated with mortality.Serum phosphorus level has been shown to be an early

predictor of outcome in acetaminophen-induced liver fail-ure. Hyperphosphatemia after acetaminophen overdose isseen exclusively in nonsurvivors.17 In contrast, phosphoruslevel was not associated with poor outcome of patients inthis study.It has been reported that the most reliable prognostic

factor is transaminase peaks in cases of amatoxin poison-ing.10 Fantozzi et al. reported that a patient with ALT orAST level42000 IU, hepatic encephalopathy, or PT4 50 sis at serious risk for death.18 In this study, transaminases andLDH were the most useful predictors of significanthepatocellular necrosis and hepatic toxicity. We found thatAST and ALT values measured on admission to hospitaland maximal AST, ALT and LDH values measured during

Table 5. HP treatment features of all patients, patients who died, and those who survived.

Characteristics All patients (n ¼ 144) Patients who died (n ¼ 14) Patients who survived (n ¼ 130) p* value

Time to onset of HP (h) 39.5 + 26.2 46.2 + 28.0 38.7 + 26.0 NSNumber of HP sessions 1.8 + 1.0 2.3 + 1.0 1.7 + 1.0 0.013Total HP duration (h) 5.8 + 3.4 7.7 + 2.8 5.6 + 3.4 0.003

*p value for comparisons between patients who died and those who survived.Note: HP, hemoperfusion; NS, nonsignificant.

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follow-up were significantly, positively correlated withclinical outcome. Mortality increased with increasing ofAST, ALT, and LDH levels. Total bilirubin, PT, INR, andAPTT were the most helpful indicators of hepaticinsufficiency. Initial and maximal total bilirubin levels andmaximal PT, INR, and APTT values were significantly,positively correlated with clinical outcome. Increase inmortality was observed with increasing of total bilirubin,PT, INR, and APTT levels. In addition, encephalopathy andmucosal hemorrhage due to hepatic insufficiency anddecrease of coagulation factors were found as factorsassociated with mortality.Hypoglycemia has also been reported as a prognostic

factor by some authors.19,20 Hypoglycemia is the result ofseveral processes, including impaired hepatic gluconeogen-esis, increased insulin release, and tissue destruction of thepancreas.21 Hypoglycemia that occurs after 24 h may besevere.6 In our study, hypoglycemia during hospitalizationwas associated with increased likelihood of mortality.The causes of thrombocytopenia occurring after amatox-

in-containing mushroom poisoning may be clotting dis-orders (disseminated intravascular coagulopathy),5,22 bonemarrow toxicity, and HP treatment. Bone marrow toxicitywith decreased platelets has been noted in amatoxinpoisoning.6 In this study, thrombocytopenia occurringduring the hospitalization and decrease in minimal plateletcounts appear to reflect a poor outcome.The first appearance of thrombocytopenia was approxi-

mately the third day after mushroom ingestion in all patientgroups. Because patients were in hepatic failure for the thirdand fourth days, disseminated intravascular coagulopathy orHP treatment instead of bone marrow toxicity may beconsidered as a cause of thrombocytopenia.Mild transient thrombocytopenia is a major complication

of HP treatment.11,23,24 Adsorption of platelets by activatedcharcoal leads to platelet loss, with recovery of platelet countwithin 24–48 h.23,25 In this study, platelet counts after HPtreatment were significantly lower than that found before HPtreatment.There are several reports that suggest amatoxin does not

cross the placenta.26,27 A case study of 22 pregnant womenpoisoned during their pregnancy had similar outcomes to acontrol group; however, only five patients had eatenmushrooms in the first trimester.26 Both pregnant patientsidentified in our group of patients had eaten mushroomsin the first trimester. The 6 weeks pregnant patientdeveloped vaginal hemorrhage and miscarriage. Then thepatient’s clinical findings improved completely. No ab-normalities were detected in the 7 weeks pregnant patientand her fetus.In conclusion, biochemical factors such as the increase of

AST, ALT, LDH, total bilirubin, PT, INR, and APTT levelsare associated with poor outcome in the amatoxin-contain-ing mushroom poisoning. Hypoglycemia and thrombocyto-penia occurring during the hospitalization are associatedwith increased likelihood of mortality. High urea levelsand hyponatremia appear to reflect a poor outcome.

Furthermore, clinical characteristics such as low MAP,encephalopathy, mucosal hemorrhage, and oliguria-anuriaare associated with poor outcome.

Declaration of interest

The authors report no conflicts of interest. The authors aloneare responsible for the content and writing of the paper.

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