Clin J Gastroenterol (2015) 8:97–102 DOI 10.1007/s12328-015-0553-3
CASE REPORT
Successful living donor liver transplantation for acute liver failure after acetylsalicylic acid overdose Tomoki Shirota • Toshihiko Ikegami • Satoshi Sugiyama • Kouji Kubota Akira Shimizu • Yasunari Ohno • Atsuyoshi Mita • Koichi Urata • Yuichi Nakazawa • Akira Kobayashi • Mai Iwaya • Shinichi Miyagawa
•
Received: 30 June 2014 / Accepted: 27 December 2014 / Published online: 25 February 2015 Ó Springer Japan 2015
Abstract A 20-year-old woman was admitted to an emergency hospital after ingesting 66 g of acetylsalicylic acid in a suicide attempt. Although she was treated with gastric lavage, oral activated charcoal, and intravenous hydration with sodium bicarbonate, her hepatic and renal function gradually deteriorated and serum amylase levels increased. Steroid pulse therapy, plasma exchange, and continuous hemodiafiltration did not yield any improvement in her hepatic or renal function, and she was transferred to our hospital for living donor liver transplantation. Nine days after drug ingestion, she developed hepatic encephalopathy: thus, we diagnosed the patient with acute liver failure with hepatic coma accompanied by acute pancreatitis due to the overdose of acetylsalicylic acid. Living donor liver transplantation was immediately performed using a left lobe graft from the patient’s mother. Following transplantation, the patient’s renal and hepatic function and consciousness improved, and she was discharged. In this report, we describe a rare case of acetylsalicylic acid-induced acute liver failure with acute hepatic coma and concomitant acute pancreatitis and acute renal failure, which were treated successfully with emergency living donor liver transplantation.
T. Shirota (&) T. Ikegami S. Sugiyama K. Kubota A. Shimizu Y. Ohno A. Mita K. Urata Y. Nakazawa A. Kobayashi S. Miyagawa First Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan e-mail: [email protected] T. Ikegami e-mail: [email protected] M. Iwaya Department of Pathology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
Keywords Acetylsalicylic acid Acute liver failure Acute renal failure Acute pancreatitis Abbreviations ALF Acute liver failure LDLT Living donor liver transplantation ASA Acetylsalicylic acid PT-INR Prothrombin time-international normalized ratio MELD Model for end-stage liver disease PE Plasma exchange CHDF Continuous hemodiafiltration WBC White blood cell count HB Hepatitis B T-bil Total bilirubin Cr Creatinine CT Computed tomography SLV Standard liver volume NSAID Nonsteroidal anti-inflammatory drug
Introduction Acetylsalicylic acid (ASA), or aspirin, is often used as an analgesic, anti-inflammatory, antipyretic, anticoagulant, and/or anti-rheumatic agent. ASA-induced hepatic injury is a well-known adverse effect of this drug; however, acute liver failure (ALF) and renal failure associated with ASA overdose are very rare. In this case report, we describe the clinical course of a 20-year-old woman diagnosed with ALF and hepatic coma concomitant with acute renal failure and acute pancreatitis following an overdose of ASA. She was treated successfully with emergency living donor liver transplantation (LDLT) using a left liver graft from her mother.
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Case report A 20-year-old woman (height, 162.0 cm; weight, 52.0 kg) was admitted to an emergency hospital after swallowing 200 tablets of ASA (equivalent to 66 g of ASA) in an attempted suicide. On admission her vital signs were stable and she was alert; laboratory examinations on admission demonstrated almost normal hepatic and renal function, with a slightly elevated white blood cell count, and a blood salicylate concentration of 1,180 lg/mL. Tests for markers of acute infection [including hepatitis B (HB) surface antigen, anti-HBc immunoglobulin (Ig) M, anti-hepatitis C virus, anti-hepatitis A virus, anti-hepatitis E virus, Epstein– Barr virus IgG, and anti-cytomegalovirus IgM], and antinuclear and anti-mitochondrial autoantibodies yielded negative results, except for the anti-HBs antibody test, which showed positive results due to previous vaccination (Table 1). The patient received gastric lavage, oral activated charcoal, and intravenous hydration with sodium bicarbonate for decontamination. However, her hepatic and renal function deteriorated on day 3 (Fig. 1). On day 5, the patient was alert and conscious, but developed a fever (body temperature, 39.4 °C) and jaundice; moreover, her hepatic and renal function worsened further. In addition, the serum amylase level and prothrombin time-
international normalized ratio (PT-INR) were both elevated, and her model for end-stage liver disease (MELD) score was 28. Computed tomography (CT) on day 6 demonstrated hepatic atrophy and diffuse low-density areas in the hepatic parenchyma, along with peripancreatic edema, indicating the possibility of pancreatitis. The patient was diagnosed with acute liver failure induced by ASA overdose, and steroid pulse therapy, plasma exchange (PE), and continuous hemodiafiltration (CHDF) were initiated on day 6. Ulinastatin was also administered for acute pancreatitis. Despite these intensive treatments, her PTINR did not improve, and she developed oliguria along with increased serum total bilirubin (T-bil) levels. She was subsequently referred to Shinshu University Hospital for LDLT on day 7 and admitted on day 8. On admission to our hospital, she weighed 63.8 kg, with apparent jaundice and general edema with persistent oliguria; however, she remained alert and conscious, with a MELD score of 42. CT was performed on day 9 and revealed hepatic atrophy with moderate ascites, bilateral pleural effusion, peripancreatic edema, and fluid collection indicating pancreatitis (Fig. 2a, b). Abdominal magnetic resonance imaging demonstrated diffuse atrophy and steatosis of the liver. CHDF was continued, and fresh frozen plasma was administered to correct the deranged clotting. According to the scoring system for predicting the outcome of patients
Table 1 Laboratory data on first admission to hospital Biochemistry
Hematology
Infectious marker
TP
5.3 g/dL
WBC
15.0 9 103/lL
HBs Ag
Negative
Alb
3.2 g/dL
RBC
4.08 9 106/lL
HBs Ab
Positive
BUN
5 mg/dL
Hb
11.9 g/dL
HBe Ag
Negative
Cr
2.98 mg/dL
Hct
36.3 %
HBe Ab
Negative
T-bil
8.36 mg/dL
PLT
7.7 9 104/lL
HBc Ab-IgM
Negative
D-bil
4.47 mg/dL
HBV-DNA
Negative
AST
559 IU/L
HCV Ab
Negative
ALT
1102 IU/L
PT
45.4 s
HAV Ab
Negative
LDH
1440 IU/L
PT %
12.7 %
HEV Ab
Negative
ALP
283 IU/L
PT-INR
3.65
EBV-IgG
Negative
c-GTP AMY
23 IU/L 712 IU/L
APTT
43.1 s
CMV-IgM
Negative
P-AMY
656 IU/L
Na
135 mEq/dL
K
4.1 mEq/dL
Cl
96 mEq/dL
CRP
0.33 mg/dL
NH3
41 lg/dL
Coagulation
TP total protein, Alb albumin, BUN blood urea nitrogen, Cre creatinine, T-bil total bilirubin, D-bil direct bilirubin, AST asparate aminotransferase, ALT alanine aminotransferase, ALP alkaline phosphatase, c-GTP gamma-glutamyl transpeptidase, AMY amylase, P-AMY pancreasamylase, Na sodium, K potassium, Cl chloraide, CRP C-reactive protein, WBC white blood cells, RBC red blood cells, Hb Hemoglobin, Hct hematocrit, Plt platelets, PT prothrombin time, PT-INR prothrombin time-international, APTT activated partial thromboplastin time, Ag antigen, Ab antibody, HBs hepatitis B surface, HBe hepatitis B envelope, HBc hepatitis B core, IgM immunoglobulin M, HBV hepatitis B virus, HCV hepatitis C virus, HAV hepatitis A virus, HEV hepatitis E virus, EBV Epstein–Barr virus, IgG immunoglobulin G, CMV cytomegalovirus
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Fig. 1 Clinical course of the present case. Despite plasma exchange (PE) and continuous hemodiafiltration (CHDF), the patient’s hepatic and renal function deteriorated. However, after living donor liver transplantation (LDLT) was performed, the patient’s laboratory examination results gradually improved and CHDF was discontinued on day 22. Closed circles: aspartate aminotransferase (AST); open circles: total bilirubin (T-bil); closed triangle: prothrombin timeinternational normalized ratio (PT-INR); and closed square: creatinine (Cr). The horizontal axis indicates the hospital day (the date of admission to the 1st hospital is Day 1), and the vertical axis shows the AST, T-bil, PT-INR, and Cr levels
with acute liver failure and late onset hepatic failure established by the Intractable Hepato-Biliary Diseases Study Group [1], her score on day 10 was 4. However, the patient developed disorientation with flapping tremors, and triphasic waves were noted on electroencephalography. She was diagnosed with ALF and acute hepatic coma. Therefore, we judged that LDLT was necessary. On day 11, the patient underwent LDLT with her blood type-compatible mother acting as the donor. She received PE and CHDF during the operation. At laparotomy, the patient’s liver was atrophic, and 2,100 mL of ascites was aspirated. The pancreas was found to be edematous, and the saponification reaction was observed on the peritoneum of the pancreas. Prior to the removal of the recipient’s liver, a temporary shunt was created between the right portal vein and the inferior vena cava to avoid portal venous congestion, according to a previously described technique [2]. Thereafter, a left hepatic lobe graft from her mother was
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Fig. 2 Plain abdominal computed tomography (CT) demonstrated a hepatic atrophy with moderate ascites, and b the presence of peripancreatic edema (arrow)
transplanted without any complications. The graft weight was 406 g, which was equivalent to 37.3 % of the patient’s calculated standard liver volume (SLV) [3]. The resected liver weighed 660 g (60.6 % of patient’s SLV) and had a smooth hepatic surface (Fig. 3a). Cholestasis was observed on the resected hepatic surface (Fig. 3b). Histopathological findings included the loss of hepatocytes, cholestasis, and neutrophil infiltration around the periportal region. The remaining hepatocytes were edematous and contained small vascular structures, indicating microvesicular steatosis. All these findings indicated the presence of drug-induced hepatic injury (Fig. 4a, b). Following LDLT, the patient was placed on ventilation support and CHDF. Induction immunosuppression consisted of methylprednisolone and FK506, which was replaced with ciclosporin as convulsions developed on day 12. Nafamostat mesilate (20 mg/day) was used to treat acute pancreatitis. Low-molecular-weight heparin was used for CHDF and post-transplantation anticoagulation therapy, with a dose targeted at maintaining the activation clotting time levels between 140 and 150 s [4]. Carperitide 2,000 lg/day was administered to improve renal blood flow in order to enhance recovery from acute renal failure.
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Fig. 3 Macroscopic findings are shown. a The surface of the liver is smooth, with no cirrhosis. b Cholestasis is observed on the resected surface of the liver
On day 14, the patient’s encephalopathy symptoms improved, and she was subsequently extubated. Gradually, renal function recovered, and the urine volume increased to a sufficient extent such that CHDF was stopped on day 22. Laboratory values, including those of hepatic as well as renal function tests and amylase levels, also improved after LDLT (Fig. 1). The patient recovered fully and was discharged on day 53. Two years after the surgery, she remains healthy, continues to receive psychiatric treatment, and has not attempted suicide again. The mother was discharged from the hospital 12 days after operation without any obvious complications, and has remained healthy.
Discussion ALF is a relatively uncommon syndrome in Japan and is defined as an acute liver disease associated with prothrombin time values of B40 % of the standardized values, or international normalized ratios (INRs) of C1.5 within 8 weeks of the onset of disease symptoms. ALF is classified
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Fig. 4 Histopathological findings from the resected hepatic tissue are shown. a The structure of the hepatic lobule is unclear and cholestasis is observed. b Loss of hepatocytes and neutrophil infiltration around the periportal region are seen. Hematoxylin and eosin stain, 9400
as ‘‘ALF without hepatic coma’’ when no or grade I hepatic encephalopathy is present and as ‘‘ALF with hepatic coma’’ when grade II or higher hepatic encephalopathy is present. ALF with hepatic coma is further subdivided into 2 groups (acute or subacute hepatic encephalopathy) according to the clinical course. Acute hepatic encephalopathy develops within 10 days of ALF onset, and the subacute type develops 11 or more days after ALF onset [5]. The present case was classified as ALF with acute hepatic coma, as grade II hepatic encephalopathy developed 9 days after ALF onset. ALF with hepatic coma remains a devastating disease. It is accepted worldwide that liver transplantation is the most effective treatment for patients with ALF. According to the scoring system for predicting the outcomes of patients with acute liver failure and late onset hepatic failure established by the Intractable Hepato-Biliary Diseases Study Group in 2011, the predicted mortality is 84.1 % in patients with a total score of C5, and less than 30.3 % in those with a total score of B4. Therefore the prognosis for patients with a
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total score of C5 by this scoring system is death [1]. This patient’s score at transplantation was 4; however, the mortality rate for patients with an ALF score of 4 who received conventional medical care was reported to be 50–60 % [1], and furthermore the Japanese Society for the Study of Liver Transplantation showed that the 1-year survival rate after LDLT was 75 % in patients with acute liver failure [6]. Because the patient showed deterioration of hepatic encephalopathy and no evidence of renal function improvement under intensive medical care, we chose to perform emergency LDLT. ASA-induced hepatic injury is a well-known dose-related phenomenon related to the intrinsic hepatotoxicity of salicylate [7]; however, ASA-induced ALF is a rare entity. A plasma salicylate concentration of 350–700 lg/mL is considered to be toxic, and a concentration of C700 lg/mL causes severe poisoning [8]. In the present case, ALF was induced by an overdose of ASA in a suicide attempt, and the resulting salicylate concentration of 1,180 lg/mL was consistent with the premortem serum salicylate concentrations of 0.34–1.93 mg/mL described in a group of patients who died from ASA poisoning in Ontario [9]. Reye’s syndrome is an infrequently diagnosed condition that primarily affects children. The etiology, epidemiology, and natural history of Reye’s syndrome remain largely unknown. The use of ASA, diclofenac sodium, amiodarone, and certain other drugs are known to cause Reye’s syndrome [10], which has been classically associated with acute viral infections in children [11]. To our knowledge, only Cag et al. have described a clinical case of fulminant hepatitis with Reye’s syndrome, which occurred in a 6-month-old infant [12]. That case, in which the infant received an adapted dose of aspirin 12 h prior to the onset of the symptoms, was successfully treated with auxiliary partial orthotopic liver transplantation. Pathologically, a liver with Reye’s syndrome is characterized by microvesicular steatosis, glycogen depletion, and nuclear changes indicating regenerative activity, with a lack of significant necrosis, inflammation, cholestasis, or biliary proliferation [13–15]. In the present case, the patient was an adult who overdosed on ASA without an antecedent viral infection. The histopathological examination of her resected liver specimen showed swelling and microvesicular steatosis consistent with Reye’s syndrome; however, the presence of cholestasis and neutrophil infiltration around the periportal region in the current case contraindicated a diagnosis of Reye’s syndrome. Fontana et al. [16] reported the histological features of 4 patients with ALF due to the administration of therapeutic doses of bromfenac, a nonsteroidal anti-inflammatory drug (NSAID). On histopathological examination, all the livers showed extensive confluent parenchymal necrosis that possibly started in the central zone, which was suggestive
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of a toxic cause. In addition, severe lobular and periportal hepatitis with the presence of primarily lymphocytes was noted. A similar wide range of histological findings in patients presenting with ALF due to drugs and other causes has been noted [17]. Depla et al. and Fraser et al. [18, 19] have reported that ALF cases induced by NSAIDs show marked microvesicular steatosis on pathological examination. In the present case, loss of hepatocytes, cholestasis, neutrophil infiltration around the periportal region, and microvesicular steatosis were observed. On pathological examination, we considered that neutrophil infiltration around the periportal region and microvesicular steatosis in the liver were important findings. Moreover, in the present case, the serum amylase levels increased, and peripancreatic edema was detected on abdominal CT; however, no clinical symptoms of pancreatitis were apparent. Serum amylase levels can increase in acute renal failure, and peripancreatic edema can develop in addition to the general edema caused by ALF. However, a positive saponification reaction was observed on the surface of the pancreas at laparotomy, which suggested the presence of acute pancreatitis. Although a few reports have described cases of salicylic acid-induced pancreatitis [20– 23], no causal relationship between salicylic acid and acute pancreatitis has been elucidated. Following LDLT in this patient, the amylase levels in both the serum and ascites samples improved immediately, indicating that the pancreatitis was not severe. In the present case, renal dysfunction developed gradually during the perioperative period, along with a decrease in urine volume that subsequently led to acute renal failure. The acute renal failure could have been a complication of ALF or a side effect of ASA, which is believed to contribute to renal dysfunction due to the reduction in prostaglandin synthesis [24, 25]. Liver transplantation is an important therapeutic option for patients with ALF; however, the optimal timing of the transplantation is difficult to determine since ALF can occasionally resolve completely without transplantation. Therefore, the advantages of an early transplantation must be considered against the disadvantages of an unnecessary transplantation with all its consequences. In this case, LDLT was chosen since the patient’s condition had worsened despite conservative therapy. Although deceased donor liver transplantation is ideal in this situation, this procedure is not frequently performed in Japan, and LDLT is considered a viable alternative [26]. When the patient was admitted to our hospital, we immediately evaluated her mother as a donor candidate, and hence we were prepared for LDLT if it was needed. Fortunately, the mother had no contraindications as an LDLT donor, and the procedure was successfully performed 3 days after the patient’s admission to our hospital.
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In conclusion, in this report we describe a case of ASAinduced ALF with concomitant acute pancreatitis and acute renal failure that was successfully treated by emergency LDLT. All the symptoms related to the ASA overdose in the present case were completely resolved following LDLT. Disclosures Conflict of Interest: conflict of interest
Tomoki Shirota and co-authors have no
Human/Animal Rights: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008(5). Informed Consent: Informed consent was obtained from all patients for being included in the study.
References 1. Naiki T, Nakayama N, Mochida S, et al. Novel scoring system as a useful model to predict the outcome of patients with acute liver failure: application to indication criteria for liver transplantation. Hepatol Res. 2012;42:68–75. 2. Kawasaki S, Hashikura Y, Matsunami H, et al. Temporary shunt between right portal vein and vena cava in living related liver transplantation. J Am Coll Surg. 1996;183:74–6. 3. Urata K, Kawasaki S, Matsunami H, et al. Calculation of child and adult standard liver volume for liver transplantation. Hepatology. 1995;21:1317–21. 4. Uchikawa Y, Ikegami T, Masuda Y, et al. Administration of dalteparin based on the activated clotting time for prophylaxis of hepatic vessel thrombosis in living donor liver transplantation. Transplant Proc. 2009;41:3784–90. 5. Mochida S, Tkikawa Y, Nakayama N, et al. Diagnostic criteria of acute liver failure: a report by the intractable Hepato-Biliary Diseases Study Group of Japan. Hepatol Res. 2011;41:805–12. 6. Japanese Society for the study of Liver Transplantation. Reports on the registered cases for liver transplantation in Japan. Ishoku (Transplant). 2014;49:261–74 (in Japanese). 7. Zimmerman HJ. Effects of aspirin and acetaminophen on the liver. Arch Intern Med. 1981;141:333–42. 8. Chan TY. The risk of severe salicylate poisoning following the ingestion of topical medicaments or aspirin. Postgrad Med J. 1996;72:109–12.
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9. McGuigan MA. A two-year review of salicylate deaths in Ontario. Arch Intern Med. 1987;147:510–2. 10. Trost LC, Lemasters JJ. Role of mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye’s syndrome. Toxicol Appl Pharmacol. 1997;147:431–41. 11. Corey L, Rubin RJ, Hattwick MA, et al. A nationwide outbreak of Reye’s syndrome. Its epidemiologic relation of influenza B. Am J Med. 1976;61:615–25. 12. Cag M, Saouli AC, Audet M, et al. Reye syndrome and liver transplantation. Turk J Pediatr. 2010;52:662–4. 13. Brown RE, Johnson FB, Mullick FG. Hepatic lipid in Reye’s syndrome: histochemical and ultrastructural characteristics. Pa Med. 1974;77:39–41. 14. Bove KE, McAdams AJ, Partin JC, et al. The hepatic lesion in Reye’s syndrome. Gastroenterology. 1975;69:685–97. 15. Starko KM, Mullick FG. Hepatic and cerebral pathology findings in children with fatal salicylate intoxication: further evidence for a causal relation between salicylate and Reye’s syndrome. Lancet. 1983;1:326–9. 16. Fontana RJ, McCashland TM, Benner KG, et al. Acute liver failure associated with prolonged use of bromfenac leading to liver transplantation. Liver Transpl Surg. 1999;5:480–4. 17. Hanau C, Munoz SJ, Rubin R. Histopathological heterogeneity in fulminant hepatic failure. Hepatology. 1995;21:345–51. 18. Depla AC, Vermeersch PH, Van Gorp LH, et al. Fatal acute liver failure associated with piprofen. Report of a case and review of the literature. Neth J Med. 1990;37:32–6. 19. Fraser JL, Antonioli DA, Chopra S, et al. Prevalence and nonspecificity of microvesicular fatty change in the liver. Mod Pathol. 1995;8:65–70. 20. Mallory A, Kern F Jr. Drug-induced pancreatitis: a critical review. Gastroenterology. 1980;78:813–20. 21. Cabooter M, Elewaut A, Barbier F. Salicylate-induced pancreatitis. Gastroenterology. 1981;80:214. 22. Miltiadous G, Anthopoulou A, Elisaf M. Acute pancreatitis possibly associated with combined salicylate and atorvastatin therapy. JOP. 2003;4:20–1. 23. Wedgwood KR, Adler G, Kern H, et al. Effects of oral agents on pancreatic duct permeability. A model of acute alcoholic pancreatitis. Dig Dis Sci. 1986;10:1081–8. 24. Huerta C, Castellsague J, Varas-Lorenzo C, et al. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. Am J Kidney Dis. 2005;45:531–9. 25. Murray MD, Brater DC. Renal toxicity of the nonsteroidal antiinflammatory drugs. Annu Rev Pharmacol Toxicol. 1993;33:435–65. 26. Matsunami H, Makuuchi M, Kawasaki S, et al. Living-related liver transplantation in fulminant hepatic failure. Lancet. 1992;340:1411–2.
CASE REPORT
Successful living donor liver transplantation for acute liver failure after acetylsalicylic acid overdose Tomoki Shirota • Toshihiko Ikegami • Satoshi Sugiyama • Kouji Kubota Akira Shimizu • Yasunari Ohno • Atsuyoshi Mita • Koichi Urata • Yuichi Nakazawa • Akira Kobayashi • Mai Iwaya • Shinichi Miyagawa
•
Received: 30 June 2014 / Accepted: 27 December 2014 / Published online: 25 February 2015 Ó Springer Japan 2015
Abstract A 20-year-old woman was admitted to an emergency hospital after ingesting 66 g of acetylsalicylic acid in a suicide attempt. Although she was treated with gastric lavage, oral activated charcoal, and intravenous hydration with sodium bicarbonate, her hepatic and renal function gradually deteriorated and serum amylase levels increased. Steroid pulse therapy, plasma exchange, and continuous hemodiafiltration did not yield any improvement in her hepatic or renal function, and she was transferred to our hospital for living donor liver transplantation. Nine days after drug ingestion, she developed hepatic encephalopathy: thus, we diagnosed the patient with acute liver failure with hepatic coma accompanied by acute pancreatitis due to the overdose of acetylsalicylic acid. Living donor liver transplantation was immediately performed using a left lobe graft from the patient’s mother. Following transplantation, the patient’s renal and hepatic function and consciousness improved, and she was discharged. In this report, we describe a rare case of acetylsalicylic acid-induced acute liver failure with acute hepatic coma and concomitant acute pancreatitis and acute renal failure, which were treated successfully with emergency living donor liver transplantation.
T. Shirota (&) T. Ikegami S. Sugiyama K. Kubota A. Shimizu Y. Ohno A. Mita K. Urata Y. Nakazawa A. Kobayashi S. Miyagawa First Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan e-mail: [email protected] T. Ikegami e-mail: [email protected] M. Iwaya Department of Pathology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
Keywords Acetylsalicylic acid Acute liver failure Acute renal failure Acute pancreatitis Abbreviations ALF Acute liver failure LDLT Living donor liver transplantation ASA Acetylsalicylic acid PT-INR Prothrombin time-international normalized ratio MELD Model for end-stage liver disease PE Plasma exchange CHDF Continuous hemodiafiltration WBC White blood cell count HB Hepatitis B T-bil Total bilirubin Cr Creatinine CT Computed tomography SLV Standard liver volume NSAID Nonsteroidal anti-inflammatory drug
Introduction Acetylsalicylic acid (ASA), or aspirin, is often used as an analgesic, anti-inflammatory, antipyretic, anticoagulant, and/or anti-rheumatic agent. ASA-induced hepatic injury is a well-known adverse effect of this drug; however, acute liver failure (ALF) and renal failure associated with ASA overdose are very rare. In this case report, we describe the clinical course of a 20-year-old woman diagnosed with ALF and hepatic coma concomitant with acute renal failure and acute pancreatitis following an overdose of ASA. She was treated successfully with emergency living donor liver transplantation (LDLT) using a left liver graft from her mother.
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Case report A 20-year-old woman (height, 162.0 cm; weight, 52.0 kg) was admitted to an emergency hospital after swallowing 200 tablets of ASA (equivalent to 66 g of ASA) in an attempted suicide. On admission her vital signs were stable and she was alert; laboratory examinations on admission demonstrated almost normal hepatic and renal function, with a slightly elevated white blood cell count, and a blood salicylate concentration of 1,180 lg/mL. Tests for markers of acute infection [including hepatitis B (HB) surface antigen, anti-HBc immunoglobulin (Ig) M, anti-hepatitis C virus, anti-hepatitis A virus, anti-hepatitis E virus, Epstein– Barr virus IgG, and anti-cytomegalovirus IgM], and antinuclear and anti-mitochondrial autoantibodies yielded negative results, except for the anti-HBs antibody test, which showed positive results due to previous vaccination (Table 1). The patient received gastric lavage, oral activated charcoal, and intravenous hydration with sodium bicarbonate for decontamination. However, her hepatic and renal function deteriorated on day 3 (Fig. 1). On day 5, the patient was alert and conscious, but developed a fever (body temperature, 39.4 °C) and jaundice; moreover, her hepatic and renal function worsened further. In addition, the serum amylase level and prothrombin time-
international normalized ratio (PT-INR) were both elevated, and her model for end-stage liver disease (MELD) score was 28. Computed tomography (CT) on day 6 demonstrated hepatic atrophy and diffuse low-density areas in the hepatic parenchyma, along with peripancreatic edema, indicating the possibility of pancreatitis. The patient was diagnosed with acute liver failure induced by ASA overdose, and steroid pulse therapy, plasma exchange (PE), and continuous hemodiafiltration (CHDF) were initiated on day 6. Ulinastatin was also administered for acute pancreatitis. Despite these intensive treatments, her PTINR did not improve, and she developed oliguria along with increased serum total bilirubin (T-bil) levels. She was subsequently referred to Shinshu University Hospital for LDLT on day 7 and admitted on day 8. On admission to our hospital, she weighed 63.8 kg, with apparent jaundice and general edema with persistent oliguria; however, she remained alert and conscious, with a MELD score of 42. CT was performed on day 9 and revealed hepatic atrophy with moderate ascites, bilateral pleural effusion, peripancreatic edema, and fluid collection indicating pancreatitis (Fig. 2a, b). Abdominal magnetic resonance imaging demonstrated diffuse atrophy and steatosis of the liver. CHDF was continued, and fresh frozen plasma was administered to correct the deranged clotting. According to the scoring system for predicting the outcome of patients
Table 1 Laboratory data on first admission to hospital Biochemistry
Hematology
Infectious marker
TP
5.3 g/dL
WBC
15.0 9 103/lL
HBs Ag
Negative
Alb
3.2 g/dL
RBC
4.08 9 106/lL
HBs Ab
Positive
BUN
5 mg/dL
Hb
11.9 g/dL
HBe Ag
Negative
Cr
2.98 mg/dL
Hct
36.3 %
HBe Ab
Negative
T-bil
8.36 mg/dL
PLT
7.7 9 104/lL
HBc Ab-IgM
Negative
D-bil
4.47 mg/dL
HBV-DNA
Negative
AST
559 IU/L
HCV Ab
Negative
ALT
1102 IU/L
PT
45.4 s
HAV Ab
Negative
LDH
1440 IU/L
PT %
12.7 %
HEV Ab
Negative
ALP
283 IU/L
PT-INR
3.65
EBV-IgG
Negative
c-GTP AMY
23 IU/L 712 IU/L
APTT
43.1 s
CMV-IgM
Negative
P-AMY
656 IU/L
Na
135 mEq/dL
K
4.1 mEq/dL
Cl
96 mEq/dL
CRP
0.33 mg/dL
NH3
41 lg/dL
Coagulation
TP total protein, Alb albumin, BUN blood urea nitrogen, Cre creatinine, T-bil total bilirubin, D-bil direct bilirubin, AST asparate aminotransferase, ALT alanine aminotransferase, ALP alkaline phosphatase, c-GTP gamma-glutamyl transpeptidase, AMY amylase, P-AMY pancreasamylase, Na sodium, K potassium, Cl chloraide, CRP C-reactive protein, WBC white blood cells, RBC red blood cells, Hb Hemoglobin, Hct hematocrit, Plt platelets, PT prothrombin time, PT-INR prothrombin time-international, APTT activated partial thromboplastin time, Ag antigen, Ab antibody, HBs hepatitis B surface, HBe hepatitis B envelope, HBc hepatitis B core, IgM immunoglobulin M, HBV hepatitis B virus, HCV hepatitis C virus, HAV hepatitis A virus, HEV hepatitis E virus, EBV Epstein–Barr virus, IgG immunoglobulin G, CMV cytomegalovirus
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Fig. 1 Clinical course of the present case. Despite plasma exchange (PE) and continuous hemodiafiltration (CHDF), the patient’s hepatic and renal function deteriorated. However, after living donor liver transplantation (LDLT) was performed, the patient’s laboratory examination results gradually improved and CHDF was discontinued on day 22. Closed circles: aspartate aminotransferase (AST); open circles: total bilirubin (T-bil); closed triangle: prothrombin timeinternational normalized ratio (PT-INR); and closed square: creatinine (Cr). The horizontal axis indicates the hospital day (the date of admission to the 1st hospital is Day 1), and the vertical axis shows the AST, T-bil, PT-INR, and Cr levels
with acute liver failure and late onset hepatic failure established by the Intractable Hepato-Biliary Diseases Study Group [1], her score on day 10 was 4. However, the patient developed disorientation with flapping tremors, and triphasic waves were noted on electroencephalography. She was diagnosed with ALF and acute hepatic coma. Therefore, we judged that LDLT was necessary. On day 11, the patient underwent LDLT with her blood type-compatible mother acting as the donor. She received PE and CHDF during the operation. At laparotomy, the patient’s liver was atrophic, and 2,100 mL of ascites was aspirated. The pancreas was found to be edematous, and the saponification reaction was observed on the peritoneum of the pancreas. Prior to the removal of the recipient’s liver, a temporary shunt was created between the right portal vein and the inferior vena cava to avoid portal venous congestion, according to a previously described technique [2]. Thereafter, a left hepatic lobe graft from her mother was
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Fig. 2 Plain abdominal computed tomography (CT) demonstrated a hepatic atrophy with moderate ascites, and b the presence of peripancreatic edema (arrow)
transplanted without any complications. The graft weight was 406 g, which was equivalent to 37.3 % of the patient’s calculated standard liver volume (SLV) [3]. The resected liver weighed 660 g (60.6 % of patient’s SLV) and had a smooth hepatic surface (Fig. 3a). Cholestasis was observed on the resected hepatic surface (Fig. 3b). Histopathological findings included the loss of hepatocytes, cholestasis, and neutrophil infiltration around the periportal region. The remaining hepatocytes were edematous and contained small vascular structures, indicating microvesicular steatosis. All these findings indicated the presence of drug-induced hepatic injury (Fig. 4a, b). Following LDLT, the patient was placed on ventilation support and CHDF. Induction immunosuppression consisted of methylprednisolone and FK506, which was replaced with ciclosporin as convulsions developed on day 12. Nafamostat mesilate (20 mg/day) was used to treat acute pancreatitis. Low-molecular-weight heparin was used for CHDF and post-transplantation anticoagulation therapy, with a dose targeted at maintaining the activation clotting time levels between 140 and 150 s [4]. Carperitide 2,000 lg/day was administered to improve renal blood flow in order to enhance recovery from acute renal failure.
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Fig. 3 Macroscopic findings are shown. a The surface of the liver is smooth, with no cirrhosis. b Cholestasis is observed on the resected surface of the liver
On day 14, the patient’s encephalopathy symptoms improved, and she was subsequently extubated. Gradually, renal function recovered, and the urine volume increased to a sufficient extent such that CHDF was stopped on day 22. Laboratory values, including those of hepatic as well as renal function tests and amylase levels, also improved after LDLT (Fig. 1). The patient recovered fully and was discharged on day 53. Two years after the surgery, she remains healthy, continues to receive psychiatric treatment, and has not attempted suicide again. The mother was discharged from the hospital 12 days after operation without any obvious complications, and has remained healthy.
Discussion ALF is a relatively uncommon syndrome in Japan and is defined as an acute liver disease associated with prothrombin time values of B40 % of the standardized values, or international normalized ratios (INRs) of C1.5 within 8 weeks of the onset of disease symptoms. ALF is classified
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Fig. 4 Histopathological findings from the resected hepatic tissue are shown. a The structure of the hepatic lobule is unclear and cholestasis is observed. b Loss of hepatocytes and neutrophil infiltration around the periportal region are seen. Hematoxylin and eosin stain, 9400
as ‘‘ALF without hepatic coma’’ when no or grade I hepatic encephalopathy is present and as ‘‘ALF with hepatic coma’’ when grade II or higher hepatic encephalopathy is present. ALF with hepatic coma is further subdivided into 2 groups (acute or subacute hepatic encephalopathy) according to the clinical course. Acute hepatic encephalopathy develops within 10 days of ALF onset, and the subacute type develops 11 or more days after ALF onset [5]. The present case was classified as ALF with acute hepatic coma, as grade II hepatic encephalopathy developed 9 days after ALF onset. ALF with hepatic coma remains a devastating disease. It is accepted worldwide that liver transplantation is the most effective treatment for patients with ALF. According to the scoring system for predicting the outcomes of patients with acute liver failure and late onset hepatic failure established by the Intractable Hepato-Biliary Diseases Study Group in 2011, the predicted mortality is 84.1 % in patients with a total score of C5, and less than 30.3 % in those with a total score of B4. Therefore the prognosis for patients with a
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total score of C5 by this scoring system is death [1]. This patient’s score at transplantation was 4; however, the mortality rate for patients with an ALF score of 4 who received conventional medical care was reported to be 50–60 % [1], and furthermore the Japanese Society for the Study of Liver Transplantation showed that the 1-year survival rate after LDLT was 75 % in patients with acute liver failure [6]. Because the patient showed deterioration of hepatic encephalopathy and no evidence of renal function improvement under intensive medical care, we chose to perform emergency LDLT. ASA-induced hepatic injury is a well-known dose-related phenomenon related to the intrinsic hepatotoxicity of salicylate [7]; however, ASA-induced ALF is a rare entity. A plasma salicylate concentration of 350–700 lg/mL is considered to be toxic, and a concentration of C700 lg/mL causes severe poisoning [8]. In the present case, ALF was induced by an overdose of ASA in a suicide attempt, and the resulting salicylate concentration of 1,180 lg/mL was consistent with the premortem serum salicylate concentrations of 0.34–1.93 mg/mL described in a group of patients who died from ASA poisoning in Ontario [9]. Reye’s syndrome is an infrequently diagnosed condition that primarily affects children. The etiology, epidemiology, and natural history of Reye’s syndrome remain largely unknown. The use of ASA, diclofenac sodium, amiodarone, and certain other drugs are known to cause Reye’s syndrome [10], which has been classically associated with acute viral infections in children [11]. To our knowledge, only Cag et al. have described a clinical case of fulminant hepatitis with Reye’s syndrome, which occurred in a 6-month-old infant [12]. That case, in which the infant received an adapted dose of aspirin 12 h prior to the onset of the symptoms, was successfully treated with auxiliary partial orthotopic liver transplantation. Pathologically, a liver with Reye’s syndrome is characterized by microvesicular steatosis, glycogen depletion, and nuclear changes indicating regenerative activity, with a lack of significant necrosis, inflammation, cholestasis, or biliary proliferation [13–15]. In the present case, the patient was an adult who overdosed on ASA without an antecedent viral infection. The histopathological examination of her resected liver specimen showed swelling and microvesicular steatosis consistent with Reye’s syndrome; however, the presence of cholestasis and neutrophil infiltration around the periportal region in the current case contraindicated a diagnosis of Reye’s syndrome. Fontana et al. [16] reported the histological features of 4 patients with ALF due to the administration of therapeutic doses of bromfenac, a nonsteroidal anti-inflammatory drug (NSAID). On histopathological examination, all the livers showed extensive confluent parenchymal necrosis that possibly started in the central zone, which was suggestive
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of a toxic cause. In addition, severe lobular and periportal hepatitis with the presence of primarily lymphocytes was noted. A similar wide range of histological findings in patients presenting with ALF due to drugs and other causes has been noted [17]. Depla et al. and Fraser et al. [18, 19] have reported that ALF cases induced by NSAIDs show marked microvesicular steatosis on pathological examination. In the present case, loss of hepatocytes, cholestasis, neutrophil infiltration around the periportal region, and microvesicular steatosis were observed. On pathological examination, we considered that neutrophil infiltration around the periportal region and microvesicular steatosis in the liver were important findings. Moreover, in the present case, the serum amylase levels increased, and peripancreatic edema was detected on abdominal CT; however, no clinical symptoms of pancreatitis were apparent. Serum amylase levels can increase in acute renal failure, and peripancreatic edema can develop in addition to the general edema caused by ALF. However, a positive saponification reaction was observed on the surface of the pancreas at laparotomy, which suggested the presence of acute pancreatitis. Although a few reports have described cases of salicylic acid-induced pancreatitis [20– 23], no causal relationship between salicylic acid and acute pancreatitis has been elucidated. Following LDLT in this patient, the amylase levels in both the serum and ascites samples improved immediately, indicating that the pancreatitis was not severe. In the present case, renal dysfunction developed gradually during the perioperative period, along with a decrease in urine volume that subsequently led to acute renal failure. The acute renal failure could have been a complication of ALF or a side effect of ASA, which is believed to contribute to renal dysfunction due to the reduction in prostaglandin synthesis [24, 25]. Liver transplantation is an important therapeutic option for patients with ALF; however, the optimal timing of the transplantation is difficult to determine since ALF can occasionally resolve completely without transplantation. Therefore, the advantages of an early transplantation must be considered against the disadvantages of an unnecessary transplantation with all its consequences. In this case, LDLT was chosen since the patient’s condition had worsened despite conservative therapy. Although deceased donor liver transplantation is ideal in this situation, this procedure is not frequently performed in Japan, and LDLT is considered a viable alternative [26]. When the patient was admitted to our hospital, we immediately evaluated her mother as a donor candidate, and hence we were prepared for LDLT if it was needed. Fortunately, the mother had no contraindications as an LDLT donor, and the procedure was successfully performed 3 days after the patient’s admission to our hospital.
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In conclusion, in this report we describe a case of ASAinduced ALF with concomitant acute pancreatitis and acute renal failure that was successfully treated by emergency LDLT. All the symptoms related to the ASA overdose in the present case were completely resolved following LDLT. Disclosures Conflict of Interest: conflict of interest
Tomoki Shirota and co-authors have no
Human/Animal Rights: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008(5). Informed Consent: Informed consent was obtained from all patients for being included in the study.
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