+Model
ARTICLE IN PRESS
CLINRE-640; No. of Pages 3
Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx.e1—xxx.e3
Available online at
ScienceDirect www.sciencedirect.com
LETTER TO THE EDITOR
Severe cholestasis and hepatic dysfunction in a case of fatal paraquat poisoning Pesticides account for a significant proportion of suicidal deaths in developing nations, where agriculture is still the primary occupation. Paraquat, a widely employed herbicide is associated with significant mortality. Poisoning with paraquat affects mucosa, lungs, kidneys and liver. Though severe damage to any of these organs is possible, death is usually a result of lung injury and the resultant fibrosis. Although abnormal liver functions are seen in majority of the patients, liver failure is distinctly uncommon. Here we report the case of a 30-year-old female who developed severe cholestasis (to an extent, not documented in literature before), yet no signs of hepatic failure. We recently encountered a 30-year-old female who had ingested 20—30 mL of 24% paraquat dichloride (‘Gramoxone’) with a suicidal intent. She developed vomiting, which improved transiently and recurred subsequently on the third day of illness. The patient was admitted for persistent vomiting, severe odynophagia and oral ulcerations. After four days of illness, she was referred to our facility for reduced urine output and progressive breathlessness. At presentation, the respiratory rate was 36/minute, and saturation in room air was 90%. She had resting tachycardia of 122 beats/minute and a blood pressure of 120/90 mmHg. There was icterus and auscultation of the chest revealed inspiratory crackles bilaterally. Rest of the examination was unremarkable. Investigations showed deranged renal and liver functions since day 1 of ingestion. Complete blood count revealed thrombocytopenia (100 × 109 /L). Serum creatinine was 6.7 mg/dL and increased further to reach a trough of 7.34 mg/dL. Urine examination was unremarkable. Her urine output normalized with conservative management and two sessions of hemodialysis. Subsequently over the next ten days creatinine decreased to 2.3 mg/dL. The conjugated hyperbilirubinemia, however progressively worsened over the next few days, reaching a peak of 54 mg/dL (Fig. 1). Alkaline phosphatase rose to a maximum of 16 times the upper limit of normal; while aspartate and alanine aminotransferase rose to 5 and 10 times respectively (200 and of 356 U/L). Despite the tremendous increase in serum
bilirubin, there were no symptoms or signs of overt/minimal hepatic encephalopathy. Prothrombin time was prolonged by 2 seconds when the bilirubin was at its peak and there was no evidence of shrunken liver or dilated biliary tree on ultrasonography. Her breathlessness continued to worsen, despite treatment with pulse dose of methylprednisolone (15 mg/kg per day for three days) and intravenous cyclophosphamide 10 mg/kg per day for two days (from day four to day 6 of illness). On the eighth day of illness, she was endotracheally intubated and mechanically ventilated for worsening respiratory failure. Chest radiograph and high resolution computed tomography of the chest revealed bilateral lower lobe consolidation. Cultures of tracheal aspirate, blood and urine were sterile. She improved with best supportive care and was extubated after five days of intubation. A week later she was reintubated as respiratory failure recurred. The course was further complicated by hospital acquired pneumonia due to Acinetobacter baumanni, which was treated with imipenem-cilastatin. However, sepsis worsened and she succumbed to her illness 18 days after paraquat consumption. Post-mortem liver biopsy showed maintained lobular architecture of the liver (Fig. 2A). A single portal triad was identified which did not show any inflammation or bile ductular proliferation. There was canalicular cholestasis however no significant lobular inflammation or hepatocyte loss was appreciated (Fig. 2B).
60 54 50 42.6
40.5 36.3
40 30
26.21
20 10
D4
D6
18
D15
D16
7
6.3 3.3 2
0
16
2.5 D9 Bilirubin(mg/dL)
4 D11
D12
ALP(number of mes ULN)
Figure 1 Trend of bilirubin and alkaline phosphatase in the index patient.
http://dx.doi.org/10.1016/j.clinre.2014.07.013 2210-7401/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Muthu V, et al. Severe cholestasis and hepatic dysfunction in a case of fatal paraquat poisoning. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.07.013
+Model CLINRE-640; No. of Pages 3
ARTICLE IN PRESS
xxx.e2
Letter to the editor
Figure 2 Photomicrographs from liver showing. A. Maintained lobular architecture. B. Hepatic parenchyma with canalicular cholestasis. No significant hepatocyte loss or lobular inflammation is seen.
Liver is a common target for injury by drugs and poisons for two reasons: • all ingested substances reach the systemic circulation via the portal circulation and liver, • liver plays an important role in metabolism and excretion of xenobiotics. Paraquat is a widely used pesticide, particularly in developing nations. Paraquat toxicity is dose dependent; affecting liver and kidney, apart from the well-known lung toxicity [1]. When exposure to paraquat occurs through inhaled or percutaneous route the toxicity is less severe, as compared to the severe and fatal toxicity seen with oral ingestion. Since paraquat is corrosive, significant mucosal injury occurs (as in the index patient) and emetics are better avoided. Several case series have shown a case fatality rate of 50% or even more with paraquat poisoning and lung injury is the major cause of death [1,2]. Immunosuppression with glucocorticoids and cyclophosphamide to prevent paraquat-induced lung fibrosis has been found to be effective in reducing mortality [2—4]. Other factors predicting poor outcome in paraquat poisoning are: advanced age, presence of acidosis, leukocytosis, and organ failure (liver and renal) [1,5]. The mechanism behind various organ failures remains unclear; oxidative damage and free radical mediated injury are the primary mechanisms proposed [6]. Post-mortem studies of patients with paraquat toxicity and experimental studies on animals have provided some insight into the pathogenic mechanism behind this fatal herbicide poisoning. Intrahepatic cholestasis to the extent seen in the index patient has not been observed with paraquat toxicity previously. Severe hepatic dysfunction has been associated with severe renal and lung injury. Despite hepatic dysfunction, these patients do not develop hepatic complications and death is usually a result of lung injury rather than the hepatic/renal injury (as observed in the index case) [7]. In the largest series of paraquat induced toxic hepatitis, the maximum level of bilirubin noted by Yang et al. was 16.3 mg/dL (against 54 mg/dL in the index patient). Moreover, 67 of their 87 patients had potential risk factors for underlying liver injury (hepatitis B carrier in 10, alcohol consumption in 57 patients) [7]. The index patient however had
no episodes of jaundice in the past, no alcohol or other substance/drug abuse and markers of viral hepatitis (A, B, C and E) were negative. Sepsis as a cause of worsening hepatic dysfunction seems unlikely as the maximum rise in bilirubin was observed well before the onset of sepsis and began declining when sepsis was at its acme. Therefore, the most likely explanation here seems to be toxic hepatitis related to paraquat. The pathogenesis of liver injury with paraquat is not clear. The available evidence indicates that during the initial phase of toxicity, hepatocellular damage occurs and after few days of initial insult, bile duct injury sets in [8]. The early recovery of hepatocellular damage might explain the absence of liver failure in paraquat poisoning as opposed to other hepatotoxins. Severe jaundice on the other hand could be attributed to the late recovery of bile duct injury, which leads to prolonged cholestasis [9]. An experimental study on rat liver showed that biliary cells underwent degeneration and necrosis within few hours of direct instillation of paraquat. Recovery however occurred after three weeks and was marked by periductal fibrosis surrounding the regenerating bile duct epithelium [10]. Liver dysfunction in our patient was possibly a result of this persisting biliary damage as evidenced by the presence of intracanalicular and intrahepatic cholestasis with dilated sinusoids in biopsy. The absence of clinical liver failure is explained by the presence of intact hepatic parenchymal cells in the biopsy.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Consent: informed consent has been obtained for postmortem liver biopsy and publication. Funding: No financial disclosures.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.clinre.2014.07.013.
Please cite this article in press as: Muthu V, et al. Severe cholestasis and hepatic dysfunction in a case of fatal paraquat poisoning. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.07.013
+Model CLINRE-640; No. of Pages 3
ARTICLE IN PRESS
Letter to the editor
References [1] Lee EY, Hwang KY, Yang JO, Hong SY. Predictors of survival after acute paraquat poisoning. Toxic Ind Health 2002;18(4):201—6. [2] Agarwal R, Srinivas R, Aggarwal AN, Gupta D. Experience with paraquat poisoning in a respiratory intensive care unit in North India. Singapore Med J 2006;47(12):1033—7. [3] Li LR, Sydenham E, Chaudhary B, You C. Glucocorticoid with cyclophosphamide for paraquat-induced lung fibrosis. Cochrane Database Syst Rev 2014;8 [CD008084]. [4] Agarwal R, Srinivas R, Aggarwal AN, Gupta D. Immunosuppressive therapy in lung injury due to paraquat poisoning: a meta-analysis. Singapore Med J 2007;48(11):1000—5. [5] Hong SY, Yang DH, Hwang KY. Associations between laboratory parameters and outcome of paraquat poisoning. Toxicol Lett 2000;118(1—2):53—9. [6] Togashi H, Shinzawa H, Wakabayashi H, Nakamura T, Yong H, Yamada N, et al. Superoxide is involved in the pathogenesis of paraquat-induced injury in cultured rat liver slices. Hepatology 1991;14(4 Pt 1):707—14. [7] Yang CJ, Lin JL, Lin-Tan DT, Weng CH, Hsu CW, Lee SY, et al. Spectrum of toxic hepatitis following intentional paraquat ingestion: analysis of 187 cases. Liver Int 2012;32(9):1400—6. [8] Matsumoto T, Matsumori H, Kuwabara N, Fukuda Y, Ariwa R. A histopathological study of the liver in paraquat poisoning — an analysis of fourteen autopsy cases with emphasis on bile duct injury. Acta Pathol Jpn 1980;(6):859—70.
xxx.e3 [9] Vadnay I. Hepatic alterations in experimental paraquat intoxication. Exp Toxicol Pathol 1993;45(5—6):355—64. [10] Matsumoto T, Matsumori H, Hosokawa Y, Abe H, Uekusa T, Kuwabara N, et al. A light and electron microscopic study of the regenerative epithelium in the intrahepatic bile duct. Experimental study of local direct instillation of paraquat into the intrahepatic bile ducts of rats. Acta Pathol Jpn 1986;36(8): 1163—80.
Valliappan Muthu a,∗ Ashim Das b Amanjit Bal b Ritesh Agarwal a a Department of Pulmonary medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India b Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India ∗
Corresponding author at: Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India-160012; Tel.: +91 985 598 9599; fax: +91 172 274 8215. E-mail address: [email protected] (V. Muthu)
Please cite this article in press as: Muthu V, et al. Severe cholestasis and hepatic dysfunction in a case of fatal paraquat poisoning. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.07.013
ARTICLE IN PRESS
CLINRE-640; No. of Pages 3
Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx.e1—xxx.e3
Available online at
ScienceDirect www.sciencedirect.com
LETTER TO THE EDITOR
Severe cholestasis and hepatic dysfunction in a case of fatal paraquat poisoning Pesticides account for a significant proportion of suicidal deaths in developing nations, where agriculture is still the primary occupation. Paraquat, a widely employed herbicide is associated with significant mortality. Poisoning with paraquat affects mucosa, lungs, kidneys and liver. Though severe damage to any of these organs is possible, death is usually a result of lung injury and the resultant fibrosis. Although abnormal liver functions are seen in majority of the patients, liver failure is distinctly uncommon. Here we report the case of a 30-year-old female who developed severe cholestasis (to an extent, not documented in literature before), yet no signs of hepatic failure. We recently encountered a 30-year-old female who had ingested 20—30 mL of 24% paraquat dichloride (‘Gramoxone’) with a suicidal intent. She developed vomiting, which improved transiently and recurred subsequently on the third day of illness. The patient was admitted for persistent vomiting, severe odynophagia and oral ulcerations. After four days of illness, she was referred to our facility for reduced urine output and progressive breathlessness. At presentation, the respiratory rate was 36/minute, and saturation in room air was 90%. She had resting tachycardia of 122 beats/minute and a blood pressure of 120/90 mmHg. There was icterus and auscultation of the chest revealed inspiratory crackles bilaterally. Rest of the examination was unremarkable. Investigations showed deranged renal and liver functions since day 1 of ingestion. Complete blood count revealed thrombocytopenia (100 × 109 /L). Serum creatinine was 6.7 mg/dL and increased further to reach a trough of 7.34 mg/dL. Urine examination was unremarkable. Her urine output normalized with conservative management and two sessions of hemodialysis. Subsequently over the next ten days creatinine decreased to 2.3 mg/dL. The conjugated hyperbilirubinemia, however progressively worsened over the next few days, reaching a peak of 54 mg/dL (Fig. 1). Alkaline phosphatase rose to a maximum of 16 times the upper limit of normal; while aspartate and alanine aminotransferase rose to 5 and 10 times respectively (200 and of 356 U/L). Despite the tremendous increase in serum
bilirubin, there were no symptoms or signs of overt/minimal hepatic encephalopathy. Prothrombin time was prolonged by 2 seconds when the bilirubin was at its peak and there was no evidence of shrunken liver or dilated biliary tree on ultrasonography. Her breathlessness continued to worsen, despite treatment with pulse dose of methylprednisolone (15 mg/kg per day for three days) and intravenous cyclophosphamide 10 mg/kg per day for two days (from day four to day 6 of illness). On the eighth day of illness, she was endotracheally intubated and mechanically ventilated for worsening respiratory failure. Chest radiograph and high resolution computed tomography of the chest revealed bilateral lower lobe consolidation. Cultures of tracheal aspirate, blood and urine were sterile. She improved with best supportive care and was extubated after five days of intubation. A week later she was reintubated as respiratory failure recurred. The course was further complicated by hospital acquired pneumonia due to Acinetobacter baumanni, which was treated with imipenem-cilastatin. However, sepsis worsened and she succumbed to her illness 18 days after paraquat consumption. Post-mortem liver biopsy showed maintained lobular architecture of the liver (Fig. 2A). A single portal triad was identified which did not show any inflammation or bile ductular proliferation. There was canalicular cholestasis however no significant lobular inflammation or hepatocyte loss was appreciated (Fig. 2B).
60 54 50 42.6
40.5 36.3
40 30
26.21
20 10
D4
D6
18
D15
D16
7
6.3 3.3 2
0
16
2.5 D9 Bilirubin(mg/dL)
4 D11
D12
ALP(number of mes ULN)
Figure 1 Trend of bilirubin and alkaline phosphatase in the index patient.
http://dx.doi.org/10.1016/j.clinre.2014.07.013 2210-7401/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Muthu V, et al. Severe cholestasis and hepatic dysfunction in a case of fatal paraquat poisoning. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.07.013
+Model CLINRE-640; No. of Pages 3
ARTICLE IN PRESS
xxx.e2
Letter to the editor
Figure 2 Photomicrographs from liver showing. A. Maintained lobular architecture. B. Hepatic parenchyma with canalicular cholestasis. No significant hepatocyte loss or lobular inflammation is seen.
Liver is a common target for injury by drugs and poisons for two reasons: • all ingested substances reach the systemic circulation via the portal circulation and liver, • liver plays an important role in metabolism and excretion of xenobiotics. Paraquat is a widely used pesticide, particularly in developing nations. Paraquat toxicity is dose dependent; affecting liver and kidney, apart from the well-known lung toxicity [1]. When exposure to paraquat occurs through inhaled or percutaneous route the toxicity is less severe, as compared to the severe and fatal toxicity seen with oral ingestion. Since paraquat is corrosive, significant mucosal injury occurs (as in the index patient) and emetics are better avoided. Several case series have shown a case fatality rate of 50% or even more with paraquat poisoning and lung injury is the major cause of death [1,2]. Immunosuppression with glucocorticoids and cyclophosphamide to prevent paraquat-induced lung fibrosis has been found to be effective in reducing mortality [2—4]. Other factors predicting poor outcome in paraquat poisoning are: advanced age, presence of acidosis, leukocytosis, and organ failure (liver and renal) [1,5]. The mechanism behind various organ failures remains unclear; oxidative damage and free radical mediated injury are the primary mechanisms proposed [6]. Post-mortem studies of patients with paraquat toxicity and experimental studies on animals have provided some insight into the pathogenic mechanism behind this fatal herbicide poisoning. Intrahepatic cholestasis to the extent seen in the index patient has not been observed with paraquat toxicity previously. Severe hepatic dysfunction has been associated with severe renal and lung injury. Despite hepatic dysfunction, these patients do not develop hepatic complications and death is usually a result of lung injury rather than the hepatic/renal injury (as observed in the index case) [7]. In the largest series of paraquat induced toxic hepatitis, the maximum level of bilirubin noted by Yang et al. was 16.3 mg/dL (against 54 mg/dL in the index patient). Moreover, 67 of their 87 patients had potential risk factors for underlying liver injury (hepatitis B carrier in 10, alcohol consumption in 57 patients) [7]. The index patient however had
no episodes of jaundice in the past, no alcohol or other substance/drug abuse and markers of viral hepatitis (A, B, C and E) were negative. Sepsis as a cause of worsening hepatic dysfunction seems unlikely as the maximum rise in bilirubin was observed well before the onset of sepsis and began declining when sepsis was at its acme. Therefore, the most likely explanation here seems to be toxic hepatitis related to paraquat. The pathogenesis of liver injury with paraquat is not clear. The available evidence indicates that during the initial phase of toxicity, hepatocellular damage occurs and after few days of initial insult, bile duct injury sets in [8]. The early recovery of hepatocellular damage might explain the absence of liver failure in paraquat poisoning as opposed to other hepatotoxins. Severe jaundice on the other hand could be attributed to the late recovery of bile duct injury, which leads to prolonged cholestasis [9]. An experimental study on rat liver showed that biliary cells underwent degeneration and necrosis within few hours of direct instillation of paraquat. Recovery however occurred after three weeks and was marked by periductal fibrosis surrounding the regenerating bile duct epithelium [10]. Liver dysfunction in our patient was possibly a result of this persisting biliary damage as evidenced by the presence of intracanalicular and intrahepatic cholestasis with dilated sinusoids in biopsy. The absence of clinical liver failure is explained by the presence of intact hepatic parenchymal cells in the biopsy.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Consent: informed consent has been obtained for postmortem liver biopsy and publication. Funding: No financial disclosures.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.clinre.2014.07.013.
Please cite this article in press as: Muthu V, et al. Severe cholestasis and hepatic dysfunction in a case of fatal paraquat poisoning. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.07.013
+Model CLINRE-640; No. of Pages 3
ARTICLE IN PRESS
Letter to the editor
References [1] Lee EY, Hwang KY, Yang JO, Hong SY. Predictors of survival after acute paraquat poisoning. Toxic Ind Health 2002;18(4):201—6. [2] Agarwal R, Srinivas R, Aggarwal AN, Gupta D. Experience with paraquat poisoning in a respiratory intensive care unit in North India. Singapore Med J 2006;47(12):1033—7. [3] Li LR, Sydenham E, Chaudhary B, You C. Glucocorticoid with cyclophosphamide for paraquat-induced lung fibrosis. Cochrane Database Syst Rev 2014;8 [CD008084]. [4] Agarwal R, Srinivas R, Aggarwal AN, Gupta D. Immunosuppressive therapy in lung injury due to paraquat poisoning: a meta-analysis. Singapore Med J 2007;48(11):1000—5. [5] Hong SY, Yang DH, Hwang KY. Associations between laboratory parameters and outcome of paraquat poisoning. Toxicol Lett 2000;118(1—2):53—9. [6] Togashi H, Shinzawa H, Wakabayashi H, Nakamura T, Yong H, Yamada N, et al. Superoxide is involved in the pathogenesis of paraquat-induced injury in cultured rat liver slices. Hepatology 1991;14(4 Pt 1):707—14. [7] Yang CJ, Lin JL, Lin-Tan DT, Weng CH, Hsu CW, Lee SY, et al. Spectrum of toxic hepatitis following intentional paraquat ingestion: analysis of 187 cases. Liver Int 2012;32(9):1400—6. [8] Matsumoto T, Matsumori H, Kuwabara N, Fukuda Y, Ariwa R. A histopathological study of the liver in paraquat poisoning — an analysis of fourteen autopsy cases with emphasis on bile duct injury. Acta Pathol Jpn 1980;(6):859—70.
xxx.e3 [9] Vadnay I. Hepatic alterations in experimental paraquat intoxication. Exp Toxicol Pathol 1993;45(5—6):355—64. [10] Matsumoto T, Matsumori H, Hosokawa Y, Abe H, Uekusa T, Kuwabara N, et al. A light and electron microscopic study of the regenerative epithelium in the intrahepatic bile duct. Experimental study of local direct instillation of paraquat into the intrahepatic bile ducts of rats. Acta Pathol Jpn 1986;36(8): 1163—80.
Valliappan Muthu a,∗ Ashim Das b Amanjit Bal b Ritesh Agarwal a a Department of Pulmonary medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India b Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India ∗
Corresponding author at: Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India-160012; Tel.: +91 985 598 9599; fax: +91 172 274 8215. E-mail address: [email protected] (V. Muthu)
Please cite this article in press as: Muthu V, et al. Severe cholestasis and hepatic dysfunction in a case of fatal paraquat poisoning. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.07.013
