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Journal of Digestive Diseases 2014; 15; 105–107
doi: 10.1111/1751-2980.12112
Leading article
Tusanqi and hepatic sinusoidal obstruction syndrome Ji Yao WANG & Hong GAO Department of Gastroenterology, Zhongshan Hospital and Center of Evidence-Based Medicine, Fudan University, Shanghai, China
Hepatic sinusoidal obstruction syndrome (HSOS), characterized by hepatomegaly, ascites and hyperbilirubinemia, is caused by toxic injury to hepatic sinusoidal endothelial cells. One major etiology of HSOS in China is the intake of products containing pyrrolizidine alkaloids (PA) such as Tusanqi. The manifestations of patients with HSOS are usually nonspecific, presenting with abnormal liver function and KEY WORDS: therapy.
portal hypertension. Diagnosis of the disease depends mostly on liver histopathology when clinical and imaging data are not sufficient. A history of Tusanqi intake is mostly important for the diagnosis. Due to a lack of effective, evidence-based treatments for HSOS, avoiding the mistaken use of PA-containing products including Tusanqi is important for the prevention of HSOS.
hepatic sinusoidal obstruction syndrome, pyrrolizidine alkaloids, senecionine, seneciphyllinine,
INTRODUCTION Hepatic sinusoidal obstruction syndrome (HSOS), previously known as hepatic veno-occlusive disease, is characterized by hepatomegaly, ascites and hyperbilirubinemia induced by toxic injury to hepatic sinusoidal endothelial cells. One of the major etiologies of HSOS is the intake of pyrrolizidine alkaloids (PAs)-containing products including herbal medicine. Over 8 000 HSOS cases worldwide have been considered to be induced by the ingestion of PAs-containing products, quite a few of which have been suspected to be attributed to an exposure to Tusanqi (Gynura segetum), a traditional Chinese medicine. More than 100 Chinese patients from Zhejiang, Jiangsu, Anhui and Henan Provinces as well as Shanghai have been reported till now. The mortality rate of Correspondence to: Ji Yao WANG, Department of Gastroenterology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Email: [email protected] Conflict of interest: None. © 2013 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
HSOS caused by PAs is 6–30% due to the severity of the disease and the absence of effective therapies.1,2 WHAT IS THE RELATIONSHIP BETWEEN TUSANQI AND HSOS? There are at least 350 species including 6000 plants all over the world that contain PAs. They can cause hepatotoxicity, genotoxicity3 and pulmonary arterial hypertension4 via the ingestion of contaminated food, herbal medicines and dietary supplements. Cases of PAs poisoning were first reported in 19205 and since then, there have been outbreaks in Africa,6 Asia7 and Europe8 from time to time. In China, the first PAs-induced HSOS case was reported in 1980.9 The reported number of patients with this disease has been increasing in recent years. Tusanqi is one of the plants that have attracted attention as a medicine that causing the development of HSOS in China. According to the literature review in our study, 10 at least 116 HSOS cases in China were induced by Tusanqi. Tusanqi contains two hepatotoxic PAs (senecionine and seneciphylline) and their N-oxides as the toxins.11 We also observed that pyrrole
105
106
JY Wang and H Gao
protein adducts were found in all blood samples of the five patients who had typical clinical manifestations of HSOS and a history of Tusanqi ingestion.10 And both senecionine and seneciphylline were detected in all the three available herbal preparations ingested by the patients. The pyrrole protein adducts served as biomarkers provide direct evidence for the role of Tusanqi in patients with HSOS, confirming that Tusanqi was the cause of HSOS in these patients. DIAGNOSIS OF TUSANQI-INDUCED HSOS Clinical features in patients with Tusanqi-induced HSOS vary from asymptomatic to severe conditions. The symptoms usually appear 4–365 days after the intake of Tusanqi. The typical manifestations include abdominal distention, abdominal pain, ascites, malaise, hepatomegaly, jaundice and edema, which are non-specific and similar to the symptoms and signs in those suffering from other liver diseases such as viral hepatitis. Ultrasound, computed tomography and magnetic resonance imaging usually show hepatomegaly, splenomegaly and ascites, which give no specific information for diagnosing HSOS. Digital subtraction angiography can be used to differentiate between HSOS and Budd–Chiari syndrome. Liver biopsy can be applied to confirm the diagnosis of HSOS, the pathology of which often presents with the expansion and congestion of sinus, endothelial swelling, wall thickening and incomplete lumen occlusion of the hepatic veins. However, liver biopsy cannot be performed in patients with large amounts of ascites and/or having a poor coagulative function, which hinders its performance. A history of Tusanqi intake supplies a key clue for diagnosing HSOS. However, patients usually will not take the initiative to provide this history, and some may even mistake its use with that of Sanqi, a Chinese herb containing no PAs and is commonly used to treat traumatic injury in clinical practice. The diagnosis of HSOS induced by Tusanqi (ingested as herbal wine, powder form in a capsule and steamed herbal leaves)10,11 can be confirmed by detecting unequivocal pyrrole protein adducts in the blood samples of the patients. Here are some tips for the diagnosis of HSOS: i Patients whose chief complaints are jaundice, ascites and discomfort of the right upper abdomen should exclude from a diagnosis of Tusanqi-induced HSOS. Repeated inquiry on
Journal of Digestive Diseases 2014; 15; 105–107 whether there is a history of drug intake based on different herbal preparations in the patients is important to obtain the clues for the diagnosis of HSOS. ii Imaging study, especially digital subtraction angiography, should be performed to differentiate between HSOS and Budd–Chiari syndrome. iii Liver biopsy and hepatic venous pressure gradient measurement could further confirm the diagnosis of HSOS; however, it is not routinely practical in the clinic but is more often used in the research setting. iv The Roussel Uclaf Causality Assessment Method (RUCAM) should be used to identify the etiology of HSOS. v When a history of taking Tusanqi is provided by the patient, inquiring further about the quantity used, the duration of its use and the herbal preparation is important. Obtaining the herb itself is also necessary for detecting PAs. The serum sample of the patient could be reserved for testing pyrrole protein adducts. vi Identify the severity of disease. WHY SHOULD WE PAY ATTENTION TO TUSANQI-INDUCED HSOS? There have been no effective therapies for HSOS so far, and it is treated mainly with supportive therapies only. Diuretics, anti-coagulants and drugs that can improve microcirculation such as low molecular heparin, prostaglandin E1, salvia, dai-kenchu-to12 and glucocorticoids13,14 might be helpful for the patient’s recovery. However, there is little evidence that any form of the therapy can prevent the development of the disease and limit its severity. In light of the high mortality of severe HSOS, liver transplantation is the only way to save a patient’s life, but it is also not conclusive.15 Defibrotide, a polydisperse mixture of oligonucleotides with local antithrombotic, antiischemic and anti-inflammatory activities, appears to have a favorable profile for adverse events. It has been applied extensively despite the lack of definitive evidence for its beneficial effects.15 Unlike the other common causes of HSOS including high-dose chemotherapy before hematopoietic stem cell transplantation, Tusanqi-induced HSOS is
© 2013 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 105–107 unpredictable and cannot be prevented. As most individuals do not recognize the harmful effects of Tusanqi, prompt education on the drug to reduce the misuse of Tusanqi is a practical and important step forward and a reporting system of adverse events should be emphasized. Monitoring the quality of traditional Chinese medicine will also be helpful to protect the safety of patients. ACKNOWLEDGMENT This article is approved by Shanghai Committee of Science and Technology, China (no. 12401907400).
Tusanqi and HSOS
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REFERENCES 1 Zhu WL, Chen SH, Chen WX, Li YM. Clinical analysis of 50 cases of hepatic veno-occlusive disease. Chin J Dig 2012; 32: 620–4 (in Chinese). 2 Song Y, Fan YH. Clinical features of hepatic veno-occlusive disease induced by gynura root: analysis of 102 cases. J Clini Hepatol 2011; 27: 496–9 (in Chinese). 3 Chen T, Mei N, Fu PP. Genotoxicity of pyrrolizidine alkaloids. J Appl Toxicol 2010; 30: 183–96. 4 Stewart MJ, Steenkamp V. Pyrrolizidine poisoning: a neglected area in human toxicology. Ther Drug Monit 2001; 23: 698–708. 5 Willmot FC, Robertson GW. Senecio disease or cirrhosis of the liver due to Senecio poisoning. Lancet 1920; 2: 848–9. 6 Bane A, Seboxa T, Mesfin G et al. An outbreak of veno-occlusive liver disease in northern Ethiopia, clinical findings. Ethiop Med J 2012; 50 Suppl 2: 9–16. 7 Kakar F, Akbarian Z, Leslie T et al. An outbreak of hepatic veno-occlusive disease in Western Afghanistan associated
13
14
15
107
with exposure to wheat flour contaminated with pyrrolizidine alkaloids. J Toxicol 2010; 2010: 313280. Chauvin P, Dillon JC, Moren A. An outbreak of heliotrope food poisoning, Tadjikistan, November 1992–March 1993. Sante 1994; 4: 263–8 (in French). Hou JG. Veno-occlusive disease of the liver with report of 2 cases. Zhonghua Nei Ke Za Zhi 1980; 19: 187–91 (in Chinese). Gao H, Li N, Wang JY, Zhang SC, Lin G. Definitive diagnosis of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids. J Dig Dis 2012; 13: 33–9. Lin G, Wang JY, Li N et al. Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum. J Hepatol 2011; 54: 666–73. Narita M, Hatano E, Tamaki N et al. Dai-kenchu-to attenuates rat sinusoidal obstruction syndrome by inhibiting the accumulation of neutrophils in the liver. J Gastroenterol Hepatol 2009; 24: 1051–7. Al Beihany A, Al Omar H, Sahovic E et al. Successful treatment of hepatic veno-occlusive disease after myeloablative allogeneic hematopoietic stem cell transplantation by early administration of a short course of methylprednisolone. Bone Marrow Transplant 2008; 41: 287–91. Zhu H, Chu Y, Huo J, Chen Z, Yang L. Effect of prednisone on transforming growth factor-β1, connective tissue growth factor, nuclear factor-κBp65 and tumor necrosis factor-α expression in a murine model of hepatic sinusoidal obstruction syndrome induced by Gynura segetum. Hepatol Res 2011; 41: 795–803. Plessier A, Valla D. Budd–Chiari syndrome and sinusoidal obstruction syndrome. In: Boyer TD, Manns MP, Sanyal A, eds. Zakim and Boyer’s Hepatology, 6th edn. Philadephia, PA: Elsevier, 2011; 805–11.
© 2013 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 105–107
doi: 10.1111/1751-2980.12112
Leading article
Tusanqi and hepatic sinusoidal obstruction syndrome Ji Yao WANG & Hong GAO Department of Gastroenterology, Zhongshan Hospital and Center of Evidence-Based Medicine, Fudan University, Shanghai, China
Hepatic sinusoidal obstruction syndrome (HSOS), characterized by hepatomegaly, ascites and hyperbilirubinemia, is caused by toxic injury to hepatic sinusoidal endothelial cells. One major etiology of HSOS in China is the intake of products containing pyrrolizidine alkaloids (PA) such as Tusanqi. The manifestations of patients with HSOS are usually nonspecific, presenting with abnormal liver function and KEY WORDS: therapy.
portal hypertension. Diagnosis of the disease depends mostly on liver histopathology when clinical and imaging data are not sufficient. A history of Tusanqi intake is mostly important for the diagnosis. Due to a lack of effective, evidence-based treatments for HSOS, avoiding the mistaken use of PA-containing products including Tusanqi is important for the prevention of HSOS.
hepatic sinusoidal obstruction syndrome, pyrrolizidine alkaloids, senecionine, seneciphyllinine,
INTRODUCTION Hepatic sinusoidal obstruction syndrome (HSOS), previously known as hepatic veno-occlusive disease, is characterized by hepatomegaly, ascites and hyperbilirubinemia induced by toxic injury to hepatic sinusoidal endothelial cells. One of the major etiologies of HSOS is the intake of pyrrolizidine alkaloids (PAs)-containing products including herbal medicine. Over 8 000 HSOS cases worldwide have been considered to be induced by the ingestion of PAs-containing products, quite a few of which have been suspected to be attributed to an exposure to Tusanqi (Gynura segetum), a traditional Chinese medicine. More than 100 Chinese patients from Zhejiang, Jiangsu, Anhui and Henan Provinces as well as Shanghai have been reported till now. The mortality rate of Correspondence to: Ji Yao WANG, Department of Gastroenterology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Email: [email protected] Conflict of interest: None. © 2013 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
HSOS caused by PAs is 6–30% due to the severity of the disease and the absence of effective therapies.1,2 WHAT IS THE RELATIONSHIP BETWEEN TUSANQI AND HSOS? There are at least 350 species including 6000 plants all over the world that contain PAs. They can cause hepatotoxicity, genotoxicity3 and pulmonary arterial hypertension4 via the ingestion of contaminated food, herbal medicines and dietary supplements. Cases of PAs poisoning were first reported in 19205 and since then, there have been outbreaks in Africa,6 Asia7 and Europe8 from time to time. In China, the first PAs-induced HSOS case was reported in 1980.9 The reported number of patients with this disease has been increasing in recent years. Tusanqi is one of the plants that have attracted attention as a medicine that causing the development of HSOS in China. According to the literature review in our study, 10 at least 116 HSOS cases in China were induced by Tusanqi. Tusanqi contains two hepatotoxic PAs (senecionine and seneciphylline) and their N-oxides as the toxins.11 We also observed that pyrrole
105
106
JY Wang and H Gao
protein adducts were found in all blood samples of the five patients who had typical clinical manifestations of HSOS and a history of Tusanqi ingestion.10 And both senecionine and seneciphylline were detected in all the three available herbal preparations ingested by the patients. The pyrrole protein adducts served as biomarkers provide direct evidence for the role of Tusanqi in patients with HSOS, confirming that Tusanqi was the cause of HSOS in these patients. DIAGNOSIS OF TUSANQI-INDUCED HSOS Clinical features in patients with Tusanqi-induced HSOS vary from asymptomatic to severe conditions. The symptoms usually appear 4–365 days after the intake of Tusanqi. The typical manifestations include abdominal distention, abdominal pain, ascites, malaise, hepatomegaly, jaundice and edema, which are non-specific and similar to the symptoms and signs in those suffering from other liver diseases such as viral hepatitis. Ultrasound, computed tomography and magnetic resonance imaging usually show hepatomegaly, splenomegaly and ascites, which give no specific information for diagnosing HSOS. Digital subtraction angiography can be used to differentiate between HSOS and Budd–Chiari syndrome. Liver biopsy can be applied to confirm the diagnosis of HSOS, the pathology of which often presents with the expansion and congestion of sinus, endothelial swelling, wall thickening and incomplete lumen occlusion of the hepatic veins. However, liver biopsy cannot be performed in patients with large amounts of ascites and/or having a poor coagulative function, which hinders its performance. A history of Tusanqi intake supplies a key clue for diagnosing HSOS. However, patients usually will not take the initiative to provide this history, and some may even mistake its use with that of Sanqi, a Chinese herb containing no PAs and is commonly used to treat traumatic injury in clinical practice. The diagnosis of HSOS induced by Tusanqi (ingested as herbal wine, powder form in a capsule and steamed herbal leaves)10,11 can be confirmed by detecting unequivocal pyrrole protein adducts in the blood samples of the patients. Here are some tips for the diagnosis of HSOS: i Patients whose chief complaints are jaundice, ascites and discomfort of the right upper abdomen should exclude from a diagnosis of Tusanqi-induced HSOS. Repeated inquiry on
Journal of Digestive Diseases 2014; 15; 105–107 whether there is a history of drug intake based on different herbal preparations in the patients is important to obtain the clues for the diagnosis of HSOS. ii Imaging study, especially digital subtraction angiography, should be performed to differentiate between HSOS and Budd–Chiari syndrome. iii Liver biopsy and hepatic venous pressure gradient measurement could further confirm the diagnosis of HSOS; however, it is not routinely practical in the clinic but is more often used in the research setting. iv The Roussel Uclaf Causality Assessment Method (RUCAM) should be used to identify the etiology of HSOS. v When a history of taking Tusanqi is provided by the patient, inquiring further about the quantity used, the duration of its use and the herbal preparation is important. Obtaining the herb itself is also necessary for detecting PAs. The serum sample of the patient could be reserved for testing pyrrole protein adducts. vi Identify the severity of disease. WHY SHOULD WE PAY ATTENTION TO TUSANQI-INDUCED HSOS? There have been no effective therapies for HSOS so far, and it is treated mainly with supportive therapies only. Diuretics, anti-coagulants and drugs that can improve microcirculation such as low molecular heparin, prostaglandin E1, salvia, dai-kenchu-to12 and glucocorticoids13,14 might be helpful for the patient’s recovery. However, there is little evidence that any form of the therapy can prevent the development of the disease and limit its severity. In light of the high mortality of severe HSOS, liver transplantation is the only way to save a patient’s life, but it is also not conclusive.15 Defibrotide, a polydisperse mixture of oligonucleotides with local antithrombotic, antiischemic and anti-inflammatory activities, appears to have a favorable profile for adverse events. It has been applied extensively despite the lack of definitive evidence for its beneficial effects.15 Unlike the other common causes of HSOS including high-dose chemotherapy before hematopoietic stem cell transplantation, Tusanqi-induced HSOS is
© 2013 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 105–107 unpredictable and cannot be prevented. As most individuals do not recognize the harmful effects of Tusanqi, prompt education on the drug to reduce the misuse of Tusanqi is a practical and important step forward and a reporting system of adverse events should be emphasized. Monitoring the quality of traditional Chinese medicine will also be helpful to protect the safety of patients. ACKNOWLEDGMENT This article is approved by Shanghai Committee of Science and Technology, China (no. 12401907400).
Tusanqi and HSOS
8 9 10
11 12
REFERENCES 1 Zhu WL, Chen SH, Chen WX, Li YM. Clinical analysis of 50 cases of hepatic veno-occlusive disease. Chin J Dig 2012; 32: 620–4 (in Chinese). 2 Song Y, Fan YH. Clinical features of hepatic veno-occlusive disease induced by gynura root: analysis of 102 cases. J Clini Hepatol 2011; 27: 496–9 (in Chinese). 3 Chen T, Mei N, Fu PP. Genotoxicity of pyrrolizidine alkaloids. J Appl Toxicol 2010; 30: 183–96. 4 Stewart MJ, Steenkamp V. Pyrrolizidine poisoning: a neglected area in human toxicology. Ther Drug Monit 2001; 23: 698–708. 5 Willmot FC, Robertson GW. Senecio disease or cirrhosis of the liver due to Senecio poisoning. Lancet 1920; 2: 848–9. 6 Bane A, Seboxa T, Mesfin G et al. An outbreak of veno-occlusive liver disease in northern Ethiopia, clinical findings. Ethiop Med J 2012; 50 Suppl 2: 9–16. 7 Kakar F, Akbarian Z, Leslie T et al. An outbreak of hepatic veno-occlusive disease in Western Afghanistan associated
13
14
15
107
with exposure to wheat flour contaminated with pyrrolizidine alkaloids. J Toxicol 2010; 2010: 313280. Chauvin P, Dillon JC, Moren A. An outbreak of heliotrope food poisoning, Tadjikistan, November 1992–March 1993. Sante 1994; 4: 263–8 (in French). Hou JG. Veno-occlusive disease of the liver with report of 2 cases. Zhonghua Nei Ke Za Zhi 1980; 19: 187–91 (in Chinese). Gao H, Li N, Wang JY, Zhang SC, Lin G. Definitive diagnosis of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids. J Dig Dis 2012; 13: 33–9. Lin G, Wang JY, Li N et al. Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum. J Hepatol 2011; 54: 666–73. Narita M, Hatano E, Tamaki N et al. Dai-kenchu-to attenuates rat sinusoidal obstruction syndrome by inhibiting the accumulation of neutrophils in the liver. J Gastroenterol Hepatol 2009; 24: 1051–7. Al Beihany A, Al Omar H, Sahovic E et al. Successful treatment of hepatic veno-occlusive disease after myeloablative allogeneic hematopoietic stem cell transplantation by early administration of a short course of methylprednisolone. Bone Marrow Transplant 2008; 41: 287–91. Zhu H, Chu Y, Huo J, Chen Z, Yang L. Effect of prednisone on transforming growth factor-β1, connective tissue growth factor, nuclear factor-κBp65 and tumor necrosis factor-α expression in a murine model of hepatic sinusoidal obstruction syndrome induced by Gynura segetum. Hepatol Res 2011; 41: 795–803. Plessier A, Valla D. Budd–Chiari syndrome and sinusoidal obstruction syndrome. In: Boyer TD, Manns MP, Sanyal A, eds. Zakim and Boyer’s Hepatology, 6th edn. Philadephia, PA: Elsevier, 2011; 805–11.
© 2013 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
