Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 561–563
doi: 10.1111/jcpt.12173
Case Report
Astragalus membranaceus as a cause of increased CA19-9 and liver and kidney cysts: a case report X. Tong* PhD, D. Xiao† MS, F. Yao‡ BM and T. Huang* PhD *Department of Oncology, Jiading Hospital of Traditional Chinese Medicine, Shanghai, , †Department of Gastroenterology, Jiading Hospital of Traditional Chinese Medicine, Shanghai, and ‡Medical Services Department, Jiading Hospital of Traditional Chinese Medicine, Shanghai, China
Received 9 April 2014, Accepted 15 April 2014
Keywords: adverse effect, Astragalus membranaceus, carbohydrate antigen 19-9
a partially purified extract of A. membranaceus, has been reported to significantly improve cancer-related fatigue.4 Rare adverse effects of Astragalus have been reported in the literature. Most of them are case reports and mainly related to Astragalus injection which appear adverse effects including fever, allergic shock,5 discomfort of the gastrointestinal tract, dizziness and facial flushing, etc.6 Carbohydrate antigen 19-9 (CA19-9), a tumour maker also called sialyl Lewis-a, tested with a single monoclonal antibody 1116-NS-19-9, is secreted by the gastric, intestinal and pancreatic epithelium.7 CA19-9 is increased in a variety of cancers, including pancreatic ductal adenocarcinoma and colorectal carcinoma,8–10 and in benign diseases, including cholangitis, pancreatitis and hepatitis.7,11,12 Liver and kidney cysts can be both congenital and acquired. Liver cysts are related to the development of an abnormal bile duct, whereas kidney cysts originate from diverticulae of the distal convoluted tubules or collecting ducts.13,14 The shell of a cyst is composed of dense connective tissue and internally covered by epithelial cells. Herein, we report a case of extremely high level of serum CA199 and the formation of liver and kidney cysts, following oral ingestion of A. membranaceus.
SUMMARY What is known and objective: Astragalus membranaceus, one of the most common Chinese herbs, is widely used to prevent and treat a variety of diseases. Very few adverse reactions, caused by A. membranaceus, have been reported in the literature. The purpose of this article was to report a case of marked increase in carbohydrate antigen 19-9 (CA19-9) and the formation of liver and kidney cysts following oral administration of A. membranaceus. Case summary: A 38-year-old woman was found to have a high serum CA19-9 level (156 U/mL) at her routine annual examination. On follow-up, several small cysts were found in her left kidney and liver by CT scan. Her medical history showed that she had taken Astragalus tea every day for 1 month. One month after she stopped taking it, the CA19-9 level decreased to 4019 U/mL. Ten months later, PET-CT showed that there were no liver and kidney cysts. However, she took Astragalus powder again in the second year and 1 month later her CA19-9 level increased again to more than 1000 U/mL. Several small cysts were again seen in her left kidney and liver by enhanced CT. Her CA19-9 level gradually became normal after she stopped taking the Astragalus powder. What is new and conclusion: This case strongly suggests that oral administration of A. membranaceus may lead to increase in CA19-9 and the formation of liver and kidney cysts.
Details of the Case A 38-year-old woman was found to have a high serum carbohydrate antigen 19-9 (CA 19-9) level of 156 U/mL (normal range, 0– 37 U/mL) at an annual routine medical check-up in December 2008. She reported no systemic symptoms. Both magnetic resonance cholangiopancreatography (MRCP) and colonoscopy identified nothing abnormal. The results of biochemical testing for liver function, renal function, fasting blood glucose, triglycerides, total cholesterol, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA-125) showed nothing remarkable. Several small cysts were found in her left kidney and liver by CT scan of the upper abdomen. Chronic erosive antral gastritis was observed by gastroscopy. Medical history showed that she drank Astragalus tea every day the previous month. After consulting a doctor, she stopped taking it. One month later, her CA19-9 level decreased to 4019 U/mL. During the next 8 months, her CA19-9 level remained in a range of 40–52 U/mL. Ten months later, PET-CT showed small nodules in her right side of the thyroid and slightly higher endometrial metabolism, but no remarkable liver or kidney cysts.
WHAT IS KNOWN AND OBJECTIVE Astragalus membranaceus, one of the most commonly used Chinese herbs, contains substances such as polysaccharides, triterpenoid saponins and flavonoids. It has been used as an adjunctive therapy for kidney diseases, chronic heart failure and some cancers. Recent clinical trials report that Astragalus injection has renal protective effects in diabetic nephropathy patients;1 Astragalus granule has also been reported to improve heart contraction and quality of life (QOL) of patients with chronic heart failure.2 Astragalus polysaccharide has been reported to significantly improve the QOL of patients with advanced non-small-cell lung cancer undergoing treatment with vinorelbine and cisplatin;3 PG2, Correspondence: D. Xiao, Department of Gastroenterology, Jiading Hospital of Traditional Chinese Medicine, 222, Bole Road, Jiading District, Shanghai 201800, China. Tel.: +862139921270; fax: +862139929731; e-mail: [email protected]
© 2014 John Wiley & Sons Ltd
561
CA199 concentrations (U/mL)
Astragalus cause increased CA19-9 and cysts
X. Tong et al.
1200
Table 1. Naranjo’s adverse drug reaction probability scale in the case
1000 800 600 400
1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after the suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reaction reappear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could have, on their own, caused the reaction? 6. Did the reaction appear when a placebo was given? 7. Was the drug detected in the blood (or other fluids) in concentration known to be toxic? 8. Was the reaction more severe when the dose was increased or less severe when dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence? Total score
200 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17
Time
Fig. 1. Changes in carbohydrate antigen 19-9 (CA19-9) concentration over time. Time 1, and period 6–7 – patient was taking Astragalus membranaceus. For the other times, the herb was withdrawn.
In the second year, she again took Astragalus powder daily. One month later, her CA19-9 level rose to more than 1000 U/mL. and liver and left kidney cysts were found. A small amount of pelvic fluid was found in an abdominal and pelvic enhanced CT. Ultrasonography showed nodules on both sides of her thyroid. However, her thyroid function, as indicated in tests for thyroidstimulating hormone, total triiodothyronine, free triiodothyronine, total thyroxine and free thyroxine, was normal. When she stopped taking Astragalus powder, her CA19-9 level gradually decreased and became normal 10 months later (Fig. 1). Further examination, including gastrointestinal endoscopy, MRCP, CT, PET-CT and ultrasonography, ruled out the common causes of increased CA19-9. Because of the temporal relationship between Astragalus and the changes in CA19-9 and the appearance of liver and kidney cysts, particularly on re-challenge, the herb is suspected to be the cause of both events. The Naranjo adverse drug reaction probability scale was used to assess the relationship between Astragalus and the increased CA199, and liver and kidney cysts. The Naranjo probability scale includes 10 questions and is widely used to assess adverse drug reaction. The conclusion is definite if higher than 9; probably when the score ranges between 5 and 8; possible when the score ranges between 1 and 4; doubtfully when the score is 0 or less.15 This case scored 9 on the scale (Table 1). Animal experiments show that the maximum dosage of A. membranaceus is 399 g/kg for rats and 1995 g/kg for beagle dogs, which is 70 and 35 times that for humans, respectively.16 The main side effects of Huangqi injection, an extract of A. membranaceus, are reported to be discomfort of the gastrointestinal tract, dizziness and facial flushing.6 To our knowledge, our case is the first report of A. membranaceus inducing a high CA19-9 level and the formation of liver and kidney cysts. The CA19-9 of cyst fluid is significantly increased in both polycystic liver disease and simple hepatic cyst, whereas serum CA19-9 is significantly increased only in polycystic liver disease.17 Increased serum CA19-9 caused by renal cysts has also been reported.18–20 But there has not been any report of simultaneous appearance of about both renal and liver cysts. Other cysts, including huge splenic cysts, oesophageal cysts and bronchogenic cysts, have also been reported.21–26 The mechanism is not clear, but probably related to the cyst fluid leaking out into the circulation.17 In the reported cases, immunohistochemical staining showed positive expression of CA19-9 in the cyst epithelia.17,21
Do not know
Yes
No
Score
+1
0
0
0
+2
1
0
+2
+1
0
0
+1
+2
1
0
+2
1
+2
0
+2
1
+1
0
0
+1
0
0
0
+1
0
0
+1
+1
0
0
0
+1
0
0
+1 9
Definite: Score ≥ 9; Probable: 5–8; Possible: 1–4; Doubtful: ≤0.
In autosomal dominant polycystic kidney disease, when the VEGF/VEGFR-2/Raf-1/MAPK/ERK signalling pathway is inhibited, apoptosis of cyst-lining epithelial cells increases.27 In some diseases, the growth of the cyst is related to vascular endothelial growth factor (VEGF) and vascular permeability factor. Extracts of A. membranaceus can promote the expression of VEGF.27–30 Therefore, in this case, we suppose that A. membranaceus promotes the expression of VEGF, thereby stimulating the growth of liver and kidney cysts. Moreover, the cysts’ epithelium secretes CA19-9, which then leaks out into the blood. Another interesting finding in this study is the relationship between the product presentation and its effect on the CA19-9 level. When the patient drank Astragalus tea, the serum CA19-9 level rose to about four times the upper limit of the reference range (URL). However, while she took Astragalus powder, the serum CA19-9 level was about 27 times of URL. When Astragalus is taken as a tea, its concentration is lower than in Astragalus powder. So we suspect that the differences observed were dose-related. WHAT IS NEW AND CONCLUSION This is the first report of a case of marked increase in CA19-9 and the formation of liver and kidney cysts, following oral administration of A. membranaceus. Although we cannot definitely conclude from this single case that A. membranaceus induces high CA19-9 level, and new liver and kidney cysts, the marked temporal relationships show that herb is most likely the cause.
© 2014 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 561–563 562
Astragalus cause increased CA19-9 and cysts
X. Tong et al.
ACKNOWLEDGEMENTS
CONFLICT OF INTEREST
We are thankful to Jing Zhang, the English teacher of Shanghai University for language support.
The authors declare no conflict of interest.
REFERENCES 1. Li M, Wang W, Xue J et al. Meta-analysis of the clinical value of Astragalus membranaceus in diabetic nephropathy. J Ethnopharmacol, 2011;133:412–419. 2. Yang QY, Lu S, Sun HR. Clinical effect of Astragalus granule of different dosages on quality of life in patients with chronic heart failure. Chin J Integr Med, 2011;17:146–149. 3. Guo L, Bai SP, Zhao L et al. Astragalus polysaccharide injection integrated with vinorelbine and cisplatin for patients with advanced non-small cell lung cancer: effects on quality of life and survival. Med Oncol, 2012;29:1656–1662. 4. Chen HW, Lin IH, Chen YJ et al. A novel infusible botanically-derived drug, PG2, for cancer-related fatigue: a phase II doubleblind, randomized placebo-controlled study. Clin Invest Med, 2012;35:E1–E11. 5. Lu S, Chen K, Yang Q et al. Progress in the research of Radix Astragali in treating chronic heart failure: effective ingredients, doseeffect relationship and adverse reaction. Chin J Integr Med, 2011;17:473–477. 6. Fu S, Zhang J, Menniti-Ippolito F et al. Huangqi injection (a traditional Chinese patent medicine) for chronic heart failure: a systematic review. PLoS ONE, 2011;6:e19604. 7. Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal. J Gastrointest Oncol, 2012;3:105–119. 8. Charbel H, Al-Kawas FH. Cholangiocarcinoma: epidemiology, risk factors, pathogenesis, and diagnosis. Curr Gastroenterol Rep, 2011;13:182–187. 9. Bhat K, Wang F, Ma Q et al. Advances in biomarker research for pancreatic cancer. Curr Pharm Des, 2012;18:2439–2451. 10. Bolocan A, Ion D, Ciocan DN et al. Prognostic and predictive factors in colorectal cancer. Chirurgia (Bucur), 2012;107:555–563. 11. Charatcharoenwitthaya P, Enders FB, Halling KC et al. Utility of serum tumor
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology, 2008;48:1106–1117. Ong SL, Sachdeva A, Garcea G et al. Elevation of carbohydrate antigen 19.9 in benign hepatobiliary conditions and its correlation with serum bilirubin concentration. Dig Dis Sci, 2008;53:3213–3217. Eknoyan G. A clinical view of simple and complex renal cysts. J Am Soc Nephrol, 2009;20:1874–1876. Gall TM, Oniscu GC, Madhavan K et al. Surgical management and longterm followup of non-parasitic hepatic cysts. HPB (Oxford), 2009;11:235–241. Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther, 1981;30:239–245. Yu SY, Ouyang HT, Yang JY et al. Subchronic toxicity studies of Radix Astragali extract in rats and dogs. J Ethnopharmacol, 2007;110:352–355. Waanders E, van Keimpema L, Brouwer JT et al. Carbohydrate antigen 19-9 is extremely elevated in polycystic liver disease. Liver Int, 2009;29:1389–1395. Okuda Y, Fujisawa M, Fujioka H et al. A giant renal cyst in a young man with increased carbohydrate antigen 19-9 in serum and cystic fluid. J Urol, 2001;165:509– 510. Ulla Rocha JL, Alvarez Sanchez MV, Paz Esquete J et al. Evaluation of the biliopancreatic region using endoscopic ultrasonography in patients referred with and without abdominal pain and CA 19-9 serum level elevation. JOP, 2007;8:191–197. Kisoka PMG, Warzee P, Hoebeke Y. A giant abdominal cyst with raised levels of carbohydrate antigen 19-9. Acta Gastroenterol Belg, 2013;76:439–440. Goto T, Maeshima A, Oyamada Y et al. Esophageal cyst producing CA19-9 and
© 2014 John Wiley & Sons Ltd
22.
23.
24.
25.
26.
27.
28.
29.
30.
CA125. Interact Cardiovasc Thorac Surg, 2010;10:448–450. Brauner E, Person B, Ben-Ishay O et al. Huge splenic cyst with high level of CA 199: the rule or the exception? Isr Med Assoc J, 2012;14:710–711. Hoshino ANY, Suzuki H, Mizutani S et al. Giant epidermoid cyst of the spleen with elevated CA 19-9 production managed laparoscopically: report of a case. J Nippon Med Sch, 2013;80:470–474. Vo QD, Monnard E, Hoogewoud HM. Epidermoid cyst of the spleen. BMJ Case Rep, 2013; doi: 10.1136/bcr-2013-009707. Yoh TWS, Kobayashi A, Nakamura Y, Kato T, Nakayama H, Okamura R. Laparoscopic splenectomy for a large multilocular splenic cyst with elevated CA19-9: report of a case. Int J Surg Case Rep, 2013;4:319–321. Brauner E, Person B, Ben-Ishay O, Kluger Y. Huge splenic cyst with high level of CA 19-9 the rule or the exception? Isr Med Assoc J, 2013;14:710–711. Xu T, Wang NS, Fu LL et al. Celecoxib inhibits growth of human autosomal dominant polycystic kidney cyst-lining epithelial cells through the VEGF/Raf/MAPK/ERK signaling pathway. Mol Biol Rep, 2012;39:7743–7753. Strugar JG, Criscuolo GR, Rothbart D et al. Vascular endothelial growth/permeability factor expression in human glioma specimens: correlation with vasogenic brain edema and tumor-associated cysts. J Neurosurg, 1995;83:682–689. Sato K, Miyakawa M, Onoda N et al. Increased concentration of vascular endothelial growth factor/vascular permeability factor in cyst fluid of enlarging and recurrent thyroid nodules. J Clin Endocrinol Metab, 1997;82:1968–1973. Zhang L, Yang Y, Wang Y et al. Astragalus membranaceus extract promotes neovascularisation by VEGF pathway in rat model of ischemic injury. Pharmazie, 2011;66:144–150.
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 561–563 563
doi: 10.1111/jcpt.12173
Case Report
Astragalus membranaceus as a cause of increased CA19-9 and liver and kidney cysts: a case report X. Tong* PhD, D. Xiao† MS, F. Yao‡ BM and T. Huang* PhD *Department of Oncology, Jiading Hospital of Traditional Chinese Medicine, Shanghai, , †Department of Gastroenterology, Jiading Hospital of Traditional Chinese Medicine, Shanghai, and ‡Medical Services Department, Jiading Hospital of Traditional Chinese Medicine, Shanghai, China
Received 9 April 2014, Accepted 15 April 2014
Keywords: adverse effect, Astragalus membranaceus, carbohydrate antigen 19-9
a partially purified extract of A. membranaceus, has been reported to significantly improve cancer-related fatigue.4 Rare adverse effects of Astragalus have been reported in the literature. Most of them are case reports and mainly related to Astragalus injection which appear adverse effects including fever, allergic shock,5 discomfort of the gastrointestinal tract, dizziness and facial flushing, etc.6 Carbohydrate antigen 19-9 (CA19-9), a tumour maker also called sialyl Lewis-a, tested with a single monoclonal antibody 1116-NS-19-9, is secreted by the gastric, intestinal and pancreatic epithelium.7 CA19-9 is increased in a variety of cancers, including pancreatic ductal adenocarcinoma and colorectal carcinoma,8–10 and in benign diseases, including cholangitis, pancreatitis and hepatitis.7,11,12 Liver and kidney cysts can be both congenital and acquired. Liver cysts are related to the development of an abnormal bile duct, whereas kidney cysts originate from diverticulae of the distal convoluted tubules or collecting ducts.13,14 The shell of a cyst is composed of dense connective tissue and internally covered by epithelial cells. Herein, we report a case of extremely high level of serum CA199 and the formation of liver and kidney cysts, following oral ingestion of A. membranaceus.
SUMMARY What is known and objective: Astragalus membranaceus, one of the most common Chinese herbs, is widely used to prevent and treat a variety of diseases. Very few adverse reactions, caused by A. membranaceus, have been reported in the literature. The purpose of this article was to report a case of marked increase in carbohydrate antigen 19-9 (CA19-9) and the formation of liver and kidney cysts following oral administration of A. membranaceus. Case summary: A 38-year-old woman was found to have a high serum CA19-9 level (156 U/mL) at her routine annual examination. On follow-up, several small cysts were found in her left kidney and liver by CT scan. Her medical history showed that she had taken Astragalus tea every day for 1 month. One month after she stopped taking it, the CA19-9 level decreased to 4019 U/mL. Ten months later, PET-CT showed that there were no liver and kidney cysts. However, she took Astragalus powder again in the second year and 1 month later her CA19-9 level increased again to more than 1000 U/mL. Several small cysts were again seen in her left kidney and liver by enhanced CT. Her CA19-9 level gradually became normal after she stopped taking the Astragalus powder. What is new and conclusion: This case strongly suggests that oral administration of A. membranaceus may lead to increase in CA19-9 and the formation of liver and kidney cysts.
Details of the Case A 38-year-old woman was found to have a high serum carbohydrate antigen 19-9 (CA 19-9) level of 156 U/mL (normal range, 0– 37 U/mL) at an annual routine medical check-up in December 2008. She reported no systemic symptoms. Both magnetic resonance cholangiopancreatography (MRCP) and colonoscopy identified nothing abnormal. The results of biochemical testing for liver function, renal function, fasting blood glucose, triglycerides, total cholesterol, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA-125) showed nothing remarkable. Several small cysts were found in her left kidney and liver by CT scan of the upper abdomen. Chronic erosive antral gastritis was observed by gastroscopy. Medical history showed that she drank Astragalus tea every day the previous month. After consulting a doctor, she stopped taking it. One month later, her CA19-9 level decreased to 4019 U/mL. During the next 8 months, her CA19-9 level remained in a range of 40–52 U/mL. Ten months later, PET-CT showed small nodules in her right side of the thyroid and slightly higher endometrial metabolism, but no remarkable liver or kidney cysts.
WHAT IS KNOWN AND OBJECTIVE Astragalus membranaceus, one of the most commonly used Chinese herbs, contains substances such as polysaccharides, triterpenoid saponins and flavonoids. It has been used as an adjunctive therapy for kidney diseases, chronic heart failure and some cancers. Recent clinical trials report that Astragalus injection has renal protective effects in diabetic nephropathy patients;1 Astragalus granule has also been reported to improve heart contraction and quality of life (QOL) of patients with chronic heart failure.2 Astragalus polysaccharide has been reported to significantly improve the QOL of patients with advanced non-small-cell lung cancer undergoing treatment with vinorelbine and cisplatin;3 PG2, Correspondence: D. Xiao, Department of Gastroenterology, Jiading Hospital of Traditional Chinese Medicine, 222, Bole Road, Jiading District, Shanghai 201800, China. Tel.: +862139921270; fax: +862139929731; e-mail: [email protected]
© 2014 John Wiley & Sons Ltd
561
CA199 concentrations (U/mL)
Astragalus cause increased CA19-9 and cysts
X. Tong et al.
1200
Table 1. Naranjo’s adverse drug reaction probability scale in the case
1000 800 600 400
1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after the suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reaction reappear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could have, on their own, caused the reaction? 6. Did the reaction appear when a placebo was given? 7. Was the drug detected in the blood (or other fluids) in concentration known to be toxic? 8. Was the reaction more severe when the dose was increased or less severe when dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence? Total score
200 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17
Time
Fig. 1. Changes in carbohydrate antigen 19-9 (CA19-9) concentration over time. Time 1, and period 6–7 – patient was taking Astragalus membranaceus. For the other times, the herb was withdrawn.
In the second year, she again took Astragalus powder daily. One month later, her CA19-9 level rose to more than 1000 U/mL. and liver and left kidney cysts were found. A small amount of pelvic fluid was found in an abdominal and pelvic enhanced CT. Ultrasonography showed nodules on both sides of her thyroid. However, her thyroid function, as indicated in tests for thyroidstimulating hormone, total triiodothyronine, free triiodothyronine, total thyroxine and free thyroxine, was normal. When she stopped taking Astragalus powder, her CA19-9 level gradually decreased and became normal 10 months later (Fig. 1). Further examination, including gastrointestinal endoscopy, MRCP, CT, PET-CT and ultrasonography, ruled out the common causes of increased CA19-9. Because of the temporal relationship between Astragalus and the changes in CA19-9 and the appearance of liver and kidney cysts, particularly on re-challenge, the herb is suspected to be the cause of both events. The Naranjo adverse drug reaction probability scale was used to assess the relationship between Astragalus and the increased CA199, and liver and kidney cysts. The Naranjo probability scale includes 10 questions and is widely used to assess adverse drug reaction. The conclusion is definite if higher than 9; probably when the score ranges between 5 and 8; possible when the score ranges between 1 and 4; doubtfully when the score is 0 or less.15 This case scored 9 on the scale (Table 1). Animal experiments show that the maximum dosage of A. membranaceus is 399 g/kg for rats and 1995 g/kg for beagle dogs, which is 70 and 35 times that for humans, respectively.16 The main side effects of Huangqi injection, an extract of A. membranaceus, are reported to be discomfort of the gastrointestinal tract, dizziness and facial flushing.6 To our knowledge, our case is the first report of A. membranaceus inducing a high CA19-9 level and the formation of liver and kidney cysts. The CA19-9 of cyst fluid is significantly increased in both polycystic liver disease and simple hepatic cyst, whereas serum CA19-9 is significantly increased only in polycystic liver disease.17 Increased serum CA19-9 caused by renal cysts has also been reported.18–20 But there has not been any report of simultaneous appearance of about both renal and liver cysts. Other cysts, including huge splenic cysts, oesophageal cysts and bronchogenic cysts, have also been reported.21–26 The mechanism is not clear, but probably related to the cyst fluid leaking out into the circulation.17 In the reported cases, immunohistochemical staining showed positive expression of CA19-9 in the cyst epithelia.17,21
Do not know
Yes
No
Score
+1
0
0
0
+2
1
0
+2
+1
0
0
+1
+2
1
0
+2
1
+2
0
+2
1
+1
0
0
+1
0
0
0
+1
0
0
+1
+1
0
0
0
+1
0
0
+1 9
Definite: Score ≥ 9; Probable: 5–8; Possible: 1–4; Doubtful: ≤0.
In autosomal dominant polycystic kidney disease, when the VEGF/VEGFR-2/Raf-1/MAPK/ERK signalling pathway is inhibited, apoptosis of cyst-lining epithelial cells increases.27 In some diseases, the growth of the cyst is related to vascular endothelial growth factor (VEGF) and vascular permeability factor. Extracts of A. membranaceus can promote the expression of VEGF.27–30 Therefore, in this case, we suppose that A. membranaceus promotes the expression of VEGF, thereby stimulating the growth of liver and kidney cysts. Moreover, the cysts’ epithelium secretes CA19-9, which then leaks out into the blood. Another interesting finding in this study is the relationship between the product presentation and its effect on the CA19-9 level. When the patient drank Astragalus tea, the serum CA19-9 level rose to about four times the upper limit of the reference range (URL). However, while she took Astragalus powder, the serum CA19-9 level was about 27 times of URL. When Astragalus is taken as a tea, its concentration is lower than in Astragalus powder. So we suspect that the differences observed were dose-related. WHAT IS NEW AND CONCLUSION This is the first report of a case of marked increase in CA19-9 and the formation of liver and kidney cysts, following oral administration of A. membranaceus. Although we cannot definitely conclude from this single case that A. membranaceus induces high CA19-9 level, and new liver and kidney cysts, the marked temporal relationships show that herb is most likely the cause.
© 2014 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 561–563 562
Astragalus cause increased CA19-9 and cysts
X. Tong et al.
ACKNOWLEDGEMENTS
CONFLICT OF INTEREST
We are thankful to Jing Zhang, the English teacher of Shanghai University for language support.
The authors declare no conflict of interest.
REFERENCES 1. Li M, Wang W, Xue J et al. Meta-analysis of the clinical value of Astragalus membranaceus in diabetic nephropathy. J Ethnopharmacol, 2011;133:412–419. 2. Yang QY, Lu S, Sun HR. Clinical effect of Astragalus granule of different dosages on quality of life in patients with chronic heart failure. Chin J Integr Med, 2011;17:146–149. 3. Guo L, Bai SP, Zhao L et al. Astragalus polysaccharide injection integrated with vinorelbine and cisplatin for patients with advanced non-small cell lung cancer: effects on quality of life and survival. Med Oncol, 2012;29:1656–1662. 4. Chen HW, Lin IH, Chen YJ et al. A novel infusible botanically-derived drug, PG2, for cancer-related fatigue: a phase II doubleblind, randomized placebo-controlled study. Clin Invest Med, 2012;35:E1–E11. 5. Lu S, Chen K, Yang Q et al. Progress in the research of Radix Astragali in treating chronic heart failure: effective ingredients, doseeffect relationship and adverse reaction. Chin J Integr Med, 2011;17:473–477. 6. Fu S, Zhang J, Menniti-Ippolito F et al. Huangqi injection (a traditional Chinese patent medicine) for chronic heart failure: a systematic review. PLoS ONE, 2011;6:e19604. 7. Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal. J Gastrointest Oncol, 2012;3:105–119. 8. Charbel H, Al-Kawas FH. Cholangiocarcinoma: epidemiology, risk factors, pathogenesis, and diagnosis. Curr Gastroenterol Rep, 2011;13:182–187. 9. Bhat K, Wang F, Ma Q et al. Advances in biomarker research for pancreatic cancer. Curr Pharm Des, 2012;18:2439–2451. 10. Bolocan A, Ion D, Ciocan DN et al. Prognostic and predictive factors in colorectal cancer. Chirurgia (Bucur), 2012;107:555–563. 11. Charatcharoenwitthaya P, Enders FB, Halling KC et al. Utility of serum tumor
12.
13.
14.
15.
16.
17.
18.
19.
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21.
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