- Email: [email protected]
Liver Failure in Transplanted Liver Due to Amanita Falloides
Liver Failure in Transplanted Liver Due to Amanita Falloides H.F. Kucuk, Z. Karasu, M. Kılıc, and D. Nart ABSTRACT Two patients underwent liver transplantation due to Amanita falloides poisoning. In one of them the clinical symptoms, signs, and laboratory findings related to liver failure were similar to the findings before the transplantation. The patient died and the pathological examination of the liver was similar to the patient’s earlier explanted liver.
W
ILD MUSHROOM POISONING with Amanita falloides occurs sporadically but is highly mortal. Even with aggressive medical therapy, hepatic and multiorgan failure occur. Orthotropic liver transplantation (OLT) is indicated in mushroom poisoning when medical therapy fails. Forty-one patients with mushroom ingestion were admitted to our hospital in 2002. Supportive treatment was sufficient in 30 whereas 11 patients needed intensive care. Five of 11 patients died; four recovered with medical therapy, and two patients underwent orthotopic liver transplantation. In this paper, we report two cases of mushroom poisoning who underwent OLT.
histopathological appearance of the grafted liver to be similar to the patient’s earlier explanted liver (Fig 3). Case 2
A 20-year-old female was admitted with nausea, vomiting, and diarrhea 2 days after ingestion of wild mushroom. She had confusion, lethargy, and agitation that supported the diagnosis of grade 2 hepatic encephalopathy. There was
CASE REPORTS Case 1
A 44-year-old man, previously in good health, was admitted with sudden onset of nausea, severe abdominal pain, and diarrhea. He declared that he had consumed wild mushrooms 8 hours before the symptoms. Despite medical treatment his liver function tests worsened. Grade 3 encephalopathy developed on the day 4. He underwent OLT with the diagnosis of fulminant hepatitis. A cadaveric graft was transplanted with an 11-hour cold ischemia period. The cut surface of the explanted liver was hemorrhagic and had a nutmeg appearance. Massive hemorrhagic necrosis was observed on microscopic examination (Fig 1). Cyclosporine and prednisolone were used for immunosuppressive treatment. After transplantation the liver function tests decreased gradually to nadir values 1 week after OLT. Then they again started to increase suddenly and the clinical situation of the patient worsened. Table 1 shows the laboratory values. There was no vascular abnormality on the Doppler ultrasound examination. Trucut liver biopsy showed massive hemorrhagic necrosis, the same as that in the explanted liver (Fig 2). The patient died 10 days after transplantation. An autopsy showed the gross anatomic and
Fig 1. Centrolobular hemorrhagic necrosis and fatty degeneration were seen. (HE⫻100.)
also a laboratory finding of fulminant hepatitis (Table 2). Cadaveric OLT was performed with after a 10-hour cold From the Ege University Medical Faculty, General Surgery, Izmir, Turkey. Address reprint requests to Dr Hasan Fehmi Kucuk, Ege University Medical Faculty, General Surgery, petrol-is mh. Sh. Dursun Bakan Sk., Hilal sit. A blok D:21 Kartal, Instanbul 81410, Turkey. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.03.107
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2224
Transplantation Proceedings, 37, 2224 –2226 (2005)
LIVER FAILURE DUE TO AMANITA FALLOIDES
2225
Table 1. Laboratory Values of Case 1 SGOT (U/L)
Preoperatively Postoperative day 1 5 9 10
SGPT (U/L)
Biluribin (mg/dL)
Glucose (mg/dL)
2220
1420
3.3
171
1.7
8.2
1495 92 3276 10,270
1821 437 2507 5670
3.2 3.73 11.29 23.75
146 181 90 78
1.6 1.5 2.95 4.26
7.7 10.8 9.84 8.0
ischemia period. Centrilobular massive hemorrhagic necrosis and fatty degeneration areas were observed on pathological examination of the explanted liver (Fig 4). After postoperative day 2 the patients showed signs of neurological recovery. Her transplanted liver functioned well and the liver function tests decreased to normal levels by day 20 posttransplantation (Table 2). DISCUSSION
It has been reported that one mushroom is sufficient to kill the average adult.1 Phalloidin and amanitins are toxins that can be isolated from the mushroom Amanita phalloides. Phalloidin is a cyclic heptapeptide with a molecular weight of 900 daltons. It interrupts the actin polymerizationdepolymerization cycle, thus impairing cell membrane function. This toxin is responsible for the initial gastrointestinal symptoms of poisoning.2,3 Amanitins are the other group of amanita toxins. ␣-Amanitin is thermostable toxin with molecular weight 900 daltons. After ingestion, it is rapidly absorbed through intestines, binding weakly to serum proteins.4 It rapidly penetrates cell membranes inhibiting RNA polymerase-II in the cytosol, leading to interference with messenger RNA synthesis. Ultimately the failure of production of structural proteins results in cell necrosis.5 Centrilobular necrosis with hemorrhage and fatty degeneration are seen on pathological examination of the liver.2
Fig 2. In trucut bropsy; massive hemorrhagic necrosis was observed. (HE⫻100.)
INR
Hgb (g/dL)
WBC
PLT
6400
66,000
6700 14,300 11,200 7900
68,000 8370 6000 7000
In the clinical presentation, there is initial latent period of 6 to 48 hours. Then severe gastrointestinal symptoms such as vomiting, diarrhea, and abdominal pain start and continue for 12 to 24 hours. A hepatic phase occurs 48 to 96 hours after ingestion with elevations of serum aminotransferases, coagulopathy, and jaundice. Fulminant hepatic failure develops rapidly within 6 to 16 days after ingestions.6 – 8 Early, aggressive medical management with fluid therapy and treatment of coagulation disorders with fresh-frozen plasma is essential.2 Early gastrointestinal lavage and use of charcoal, intravenous penicillin, and silibin administration are also needed.1,9,10 Once, hepatic coma develops in a patient with mushroom poisoning, the prognosis is poor.5 In the case of encephalopathy, OLT is indicated. Klein et al suggested that prolongation of prothrombin time more than twice normal despite replacement with fresh-frozen plasma, hypoglycemia requiring glucose support, and serum bilirubin levels greater than 25 mg/dL are other indications for transplantation.11 OLT was performed herein for the diagnosis of fulminant hepatic failure and encephalopathy. There was no postoperative problem in case 2; she was discharged with clinical improvement. Although the clinical situation seemed to be good— encephalopathy and hepatic failure improved in early postoprerative period in case 1— he died at 9 days with similar clinical findings as to be pretransplant liver failure. We could not perform toxicolog-
Fig 3. Centrolobulor hemorrhage, necrosis, and fatty degeneration. (HE ⫻200.)
2226
KUCUK, KARASU, KILIC ET AL Table 2. Laboratory Values of Case 2
Preoperatively Postoperative day 1 5 10 20
SGOT (U/L)
SGPT (U/L)
Biluribin (mg/dL)
Glucose (mg/dL)
3220
4280
3.44
284
6.2
9.9
9100
6000
1140 149 73 20
2440 1157 512 51
2.41 0.95 1.42 0.57
112 199 105 82
1.6 1.24 1.16 1.12
8.6 9.7 10.4 10.3
6400 12,600 10,800 10,300
7000 65,700 304,000 357,000
ical examination of the explanted liver. However, both explants of case 1 (naive liver and transplanted liver in autopsy) showed similar macroscopic and microscopic findings that were in accordance with classical findings in mushroom poisoning. Considering the data that the halflife of mushroom toxins is 2 to 3 days, it is difficult to explain reintoxication of the transplanted liver. It could be speculated that poisons of amanita phalloides were deposites in tissues other than liver causing recurrence of mushroom poisoning after OLT with evidence of clinical symptoms and pathological signs. Another speculation is that some other toxic molecules (nonphalloidin and nonamanitins), which are not yet, described may have caused a fatal outcome.
Fig 4. Centrolobular hemorrhage, necrosis, and fatty degeneration. (HE ⫻200.)
INR
Hgb (g/dL)
WBC
PLT
In conclusion, OLT may be a lifesaving option for fulminant hepatic failure secondary to mushroom poisoning. But more descriptive studies are needed to identify toxic molecules, as well as pharmacokinetic and pharmacodynamic effects of these toxic molecules. REFERENCES 1. Serne EH, Toorians AW, Gietma JA, et al: Amanita phalloides, a potentially lethal mushroom: its clinical presentation and therapeutic options. Neth J Med 49:19, 1996 2. Bartolini ST, Omer F, Giannini A: Amanita poisoning: a clinical-histopathological study of 64 cases of intoxication. Hepatogastroenterol 32:229, 1985 3. Chang IM, Yon HS, Kim YX, et al: Aucibin: potential antidote for alpha-amanitin poisoning. J Toxicol Clin Toxicol 22:77, 1984 4. Kroncke KD, Fricker G, Meier PJ, A Alpha-amanitin uptake into hepatocytes. J Biol Chem 261:12562, 1986 5. Passo B, Harrison DC: A new look at and old problem: mushroom poisoninig. Am J Med 58:505, 1975 6. Alves A, Ferreira MG, Paulo J, et al: Mushroom poisoning with amanita phalloides—a case report of four cases. Eur J Int Med 12:64, 2001 7. Litowitz TL, Clark IR, Soloway RA: 1993 annual report of the American association of poison control center toxic exposures surveillance system. Am J Emerg Med 12:546, 1994 8. Floersheim GL: Treatment of human amatoxin mushroom poisoning: myths and advances in therapy. Med Toxicol Adverse Drug Exp 2:1, 1987 9. Fantozzi R, Ledda F, Caramelli L, et al: Clinical findings and follow-up evaluation of an out break of mushroom poisoningsurvey of Amanita Phalloides poisoning. Klin Wochenschr 64:38, 1986 10. Faulstich H, Zilker TR: Amatoxins. In Spoerke DG, Rumack BH (eds.): Handbook of Mushroom Poisoning, Diagnosis and Treatment. Boca Raton, FL: CRC Press: 1994, pp. 233 11. Klein AS, Hart J, Brems JJ, et al: Amanita poisoning: treatment and role of liver transplantation. Am J Med 86:187, 1989
W
ILD MUSHROOM POISONING with Amanita falloides occurs sporadically but is highly mortal. Even with aggressive medical therapy, hepatic and multiorgan failure occur. Orthotropic liver transplantation (OLT) is indicated in mushroom poisoning when medical therapy fails. Forty-one patients with mushroom ingestion were admitted to our hospital in 2002. Supportive treatment was sufficient in 30 whereas 11 patients needed intensive care. Five of 11 patients died; four recovered with medical therapy, and two patients underwent orthotopic liver transplantation. In this paper, we report two cases of mushroom poisoning who underwent OLT.
histopathological appearance of the grafted liver to be similar to the patient’s earlier explanted liver (Fig 3). Case 2
A 20-year-old female was admitted with nausea, vomiting, and diarrhea 2 days after ingestion of wild mushroom. She had confusion, lethargy, and agitation that supported the diagnosis of grade 2 hepatic encephalopathy. There was
CASE REPORTS Case 1
A 44-year-old man, previously in good health, was admitted with sudden onset of nausea, severe abdominal pain, and diarrhea. He declared that he had consumed wild mushrooms 8 hours before the symptoms. Despite medical treatment his liver function tests worsened. Grade 3 encephalopathy developed on the day 4. He underwent OLT with the diagnosis of fulminant hepatitis. A cadaveric graft was transplanted with an 11-hour cold ischemia period. The cut surface of the explanted liver was hemorrhagic and had a nutmeg appearance. Massive hemorrhagic necrosis was observed on microscopic examination (Fig 1). Cyclosporine and prednisolone were used for immunosuppressive treatment. After transplantation the liver function tests decreased gradually to nadir values 1 week after OLT. Then they again started to increase suddenly and the clinical situation of the patient worsened. Table 1 shows the laboratory values. There was no vascular abnormality on the Doppler ultrasound examination. Trucut liver biopsy showed massive hemorrhagic necrosis, the same as that in the explanted liver (Fig 2). The patient died 10 days after transplantation. An autopsy showed the gross anatomic and
Fig 1. Centrolobular hemorrhagic necrosis and fatty degeneration were seen. (HE⫻100.)
also a laboratory finding of fulminant hepatitis (Table 2). Cadaveric OLT was performed with after a 10-hour cold From the Ege University Medical Faculty, General Surgery, Izmir, Turkey. Address reprint requests to Dr Hasan Fehmi Kucuk, Ege University Medical Faculty, General Surgery, petrol-is mh. Sh. Dursun Bakan Sk., Hilal sit. A blok D:21 Kartal, Instanbul 81410, Turkey. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.03.107
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2224
Transplantation Proceedings, 37, 2224 –2226 (2005)
LIVER FAILURE DUE TO AMANITA FALLOIDES
2225
Table 1. Laboratory Values of Case 1 SGOT (U/L)
Preoperatively Postoperative day 1 5 9 10
SGPT (U/L)
Biluribin (mg/dL)
Glucose (mg/dL)
2220
1420
3.3
171
1.7
8.2
1495 92 3276 10,270
1821 437 2507 5670
3.2 3.73 11.29 23.75
146 181 90 78
1.6 1.5 2.95 4.26
7.7 10.8 9.84 8.0
ischemia period. Centrilobular massive hemorrhagic necrosis and fatty degeneration areas were observed on pathological examination of the explanted liver (Fig 4). After postoperative day 2 the patients showed signs of neurological recovery. Her transplanted liver functioned well and the liver function tests decreased to normal levels by day 20 posttransplantation (Table 2). DISCUSSION
It has been reported that one mushroom is sufficient to kill the average adult.1 Phalloidin and amanitins are toxins that can be isolated from the mushroom Amanita phalloides. Phalloidin is a cyclic heptapeptide with a molecular weight of 900 daltons. It interrupts the actin polymerizationdepolymerization cycle, thus impairing cell membrane function. This toxin is responsible for the initial gastrointestinal symptoms of poisoning.2,3 Amanitins are the other group of amanita toxins. ␣-Amanitin is thermostable toxin with molecular weight 900 daltons. After ingestion, it is rapidly absorbed through intestines, binding weakly to serum proteins.4 It rapidly penetrates cell membranes inhibiting RNA polymerase-II in the cytosol, leading to interference with messenger RNA synthesis. Ultimately the failure of production of structural proteins results in cell necrosis.5 Centrilobular necrosis with hemorrhage and fatty degeneration are seen on pathological examination of the liver.2
Fig 2. In trucut bropsy; massive hemorrhagic necrosis was observed. (HE⫻100.)
INR
Hgb (g/dL)
WBC
PLT
6400
66,000
6700 14,300 11,200 7900
68,000 8370 6000 7000
In the clinical presentation, there is initial latent period of 6 to 48 hours. Then severe gastrointestinal symptoms such as vomiting, diarrhea, and abdominal pain start and continue for 12 to 24 hours. A hepatic phase occurs 48 to 96 hours after ingestion with elevations of serum aminotransferases, coagulopathy, and jaundice. Fulminant hepatic failure develops rapidly within 6 to 16 days after ingestions.6 – 8 Early, aggressive medical management with fluid therapy and treatment of coagulation disorders with fresh-frozen plasma is essential.2 Early gastrointestinal lavage and use of charcoal, intravenous penicillin, and silibin administration are also needed.1,9,10 Once, hepatic coma develops in a patient with mushroom poisoning, the prognosis is poor.5 In the case of encephalopathy, OLT is indicated. Klein et al suggested that prolongation of prothrombin time more than twice normal despite replacement with fresh-frozen plasma, hypoglycemia requiring glucose support, and serum bilirubin levels greater than 25 mg/dL are other indications for transplantation.11 OLT was performed herein for the diagnosis of fulminant hepatic failure and encephalopathy. There was no postoperative problem in case 2; she was discharged with clinical improvement. Although the clinical situation seemed to be good— encephalopathy and hepatic failure improved in early postoprerative period in case 1— he died at 9 days with similar clinical findings as to be pretransplant liver failure. We could not perform toxicolog-
Fig 3. Centrolobulor hemorrhage, necrosis, and fatty degeneration. (HE ⫻200.)
2226
KUCUK, KARASU, KILIC ET AL Table 2. Laboratory Values of Case 2
Preoperatively Postoperative day 1 5 10 20
SGOT (U/L)
SGPT (U/L)
Biluribin (mg/dL)
Glucose (mg/dL)
3220
4280
3.44
284
6.2
9.9
9100
6000
1140 149 73 20
2440 1157 512 51
2.41 0.95 1.42 0.57
112 199 105 82
1.6 1.24 1.16 1.12
8.6 9.7 10.4 10.3
6400 12,600 10,800 10,300
7000 65,700 304,000 357,000
ical examination of the explanted liver. However, both explants of case 1 (naive liver and transplanted liver in autopsy) showed similar macroscopic and microscopic findings that were in accordance with classical findings in mushroom poisoning. Considering the data that the halflife of mushroom toxins is 2 to 3 days, it is difficult to explain reintoxication of the transplanted liver. It could be speculated that poisons of amanita phalloides were deposites in tissues other than liver causing recurrence of mushroom poisoning after OLT with evidence of clinical symptoms and pathological signs. Another speculation is that some other toxic molecules (nonphalloidin and nonamanitins), which are not yet, described may have caused a fatal outcome.
Fig 4. Centrolobular hemorrhage, necrosis, and fatty degeneration. (HE ⫻200.)
INR
Hgb (g/dL)
WBC
PLT
In conclusion, OLT may be a lifesaving option for fulminant hepatic failure secondary to mushroom poisoning. But more descriptive studies are needed to identify toxic molecules, as well as pharmacokinetic and pharmacodynamic effects of these toxic molecules. REFERENCES 1. Serne EH, Toorians AW, Gietma JA, et al: Amanita phalloides, a potentially lethal mushroom: its clinical presentation and therapeutic options. Neth J Med 49:19, 1996 2. Bartolini ST, Omer F, Giannini A: Amanita poisoning: a clinical-histopathological study of 64 cases of intoxication. Hepatogastroenterol 32:229, 1985 3. Chang IM, Yon HS, Kim YX, et al: Aucibin: potential antidote for alpha-amanitin poisoning. J Toxicol Clin Toxicol 22:77, 1984 4. Kroncke KD, Fricker G, Meier PJ, A Alpha-amanitin uptake into hepatocytes. J Biol Chem 261:12562, 1986 5. Passo B, Harrison DC: A new look at and old problem: mushroom poisoninig. Am J Med 58:505, 1975 6. Alves A, Ferreira MG, Paulo J, et al: Mushroom poisoning with amanita phalloides—a case report of four cases. Eur J Int Med 12:64, 2001 7. Litowitz TL, Clark IR, Soloway RA: 1993 annual report of the American association of poison control center toxic exposures surveillance system. Am J Emerg Med 12:546, 1994 8. Floersheim GL: Treatment of human amatoxin mushroom poisoning: myths and advances in therapy. Med Toxicol Adverse Drug Exp 2:1, 1987 9. Fantozzi R, Ledda F, Caramelli L, et al: Clinical findings and follow-up evaluation of an out break of mushroom poisoningsurvey of Amanita Phalloides poisoning. Klin Wochenschr 64:38, 1986 10. Faulstich H, Zilker TR: Amatoxins. In Spoerke DG, Rumack BH (eds.): Handbook of Mushroom Poisoning, Diagnosis and Treatment. Boca Raton, FL: CRC Press: 1994, pp. 233 11. Klein AS, Hart J, Brems JJ, et al: Amanita poisoning: treatment and role of liver transplantation. Am J Med 86:187, 1989