- Email: [email protected]
Intravascular embolization therapy in a patient with an enlarged polycystic liver
Intravascular Embolization Therapy in a Patient With an Enlarged Polycystic Liver Yoshifumi Ubara, MD, Ryouji Takei, MD, Jyunichi Hoshino, MD, Tetsuo Tagami, Naoki Sawa, MD, Masafumi Yokota, MD, Hideyuki Katori, MD, Fumi Takemoto, MD, Shigeko Hara, MD, and Kenmei Takaichi, MD ● Because the kidneys in patients with autosomal dominant polycystic kidney disease (ADPKD) are usually supplied by well-developed arteries, the authors attempted renal contraction therapy in such patients with renal transcatheter arterial embolization (TAE) using intravascular coils. In most patients with marked nephromegaly, renal TAE was effective. However, in patients with marked hepatomegaly without significant nephromegaly, renal TAE was not effective, and hepatic treatment was always required. In June 2001, the authors obtained approval for a new treatment,“TAE for enlarged polycystic liver,” from an ethics committee discussing new treatment at their hospital. A 56-year-old man undergoing hemodialysis for 2 months was referred to the authors’ institute with the complaint of severe abdominal distension and loss of appetite in March 2001. Most of the liver (about 90%) had been replaced by multiple cysts, and near-intact hepatic parenchyma was quite scarce. The kidneys were quite small compared with the liver. Angiography results showed that almost all hepatic arterial branches were well developed, although most of the portal vein was obstructed, and only the left medial portal vein was spared; the former corresponded to the hepatic region replaced by multiple cysts and the latter to the preserved intact hepatic parenchyma. The target of TAE was the hepatic arterial branches of the former. Microcoils were used as embolization material. Two years after TAE, abdominal distension has markedly decreased because of decrease in liver size (to 54% of the previous value), and muscle and fat volume in the thoracic region have increased owing to improvement of appetite. Ascites became obscure. Nutrition and activities of daily living have improved. Hepatic TAE may be an option for treatment of patients in poor condition with symptomatic polycystic liver. Am J Kidney Dis 43:733-738. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Autosomal dominant polycystic kidney disease (ADPKD); angiogenesis; vascular endothelial growth factor (VEGF); transcatheter arterial embolization (TAE); polycystic liver; intravascular embolization therapy; angio-arteriogenesis.
I
N PATIENTS WITH autosomal dominant polycystic kidney disease (ADPKD), the kidneys usually are supplied by well-developed arteries. We developed renal cyst contraction therapy using renal transcatheter arterial embolization (TAE) for enlarged kidneys.1,2 From 1996 to 2003, renal TAE was performed in about 180 patients on dialysis. This therapy was effective in most of these patients; however, it was not effective in patients with marked hepatomegaly without significant nephromegaly, in whom hepatic treatment was always required. When polycystic liver becomes symptomatic because of severe hepatomegaly, there are several options for conventional treatment, eg, percutaneous cyst aspiration and sclerosis, laparoscopic fenestration, open surgical cyst fenestration and partial hepatectomy,3,4 or hepatic transplantation.5-7 The first 3 methods usually are not used for patients with poor nutritional status, massive ascites, and renal failure. Hepatic transplantation is a good treatment. Combined liver-kidney transplantation has also been indicated as a therapeutic approach for ADPKD patients on dialysis.
However, in Japan, where cadaveric donors are very small in number, hepatic transplantation is performed less frequently. Because TAE was successful in treating enlarged kidneys, we hope that hepatic TAE may become a new treatment option for patients with very poor general condition who are unable to undergo hepatic transplantation. APPROVAL OF AN ETHICS COMMITTEE DISCUSSING NEW TREATMENT
Many symptomatic patients with severe polycystic liver visited our institute desiring any
From the Nephrology Center and the Department of Radiology, Toranomon Hospital, Tokyo, Japan. Received August 28, 2003; accepted in revised form December 4, 2003. Address reprint requests to Yoshifumi Ubara, MD, Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Takatsu-ku, Kawasaki-shi, Kanagawa-ken 213-0015, Japan. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4304-0017$30.00/0 doi:10.1053/j.ajkd.2003.12.035
American Journal of Kidney Diseases, Vol 43, No 4 (April), 2004: pp 733-738
733
734
UBARA ET AL
effective treatment. Therefore, in June 2001, we obtained approval for a new treatment, “TAE for enlarged polycystic liver,”from an ethics committee discussing new treatment at our hospital. Then, after patients had given consent on being fully informed about the new procedure, we decided to try, for the first time in the world, treatment using TAE in patients who had no other practical and effective treatment. We present 1 representative case with a 2-year follow-up. CASE REPORT A 56-year-old man was referred to our institute with complaint of severe abdominal distension and loss of appetite on March 5, 2001. ADPKD had been diagnosed by ultrasonography during a health check-up in 1991. His father and elder sister had the same disease. His abdomen subsequently became progressively distended as a result of hepatic enlargement and ascites. In December 2000, surgery for umbilical hernia was performed. Even after hemodialysis was started for chronic renal failure in January 2001, massive ascites persisted without change. Ascitic fluid had been removed at a rate of 1,000 to 2,000 mL by needle aspiration every 2 weeks. On admission, he was 162 cm in height. He was totally anuric, and his dry weight was 67.4 kg. Blood pressure was 110/76 mm Hg. The abdomen was markedly distended, and his maximum abdominal circumference was 115 cm. Heart sounds were normal, but inspirations and expirations were short, and the lung-liver border was elevated. Emaciation was prominent in the thoracic region and upper extremities. Laboratory findings were as follows: on complete blood count, erythrocytes were 2.28 ⫻ 106/L, hemoglobin was 7.7 g/dL (77 g/L), hematocrit was 22.4%, leukocytes were 4,600/L, and thrombocytes were 12.3 ⫻ 104/L. On blood chemistry, total protein was 7.5 g/dL (75 g/L), albumin was 1.8 g/dL (18 g/L), urea nitogen was 109 mg/dL (38.9 mmol/L), creatinine was 10.2 mg/dL (902 mol/L), and total cholesterol was 114 mg/dL (2.95 mmol/L). Total bilirubin was 0.9 mg/dL (15 mol/L), aspartate aminotransferase (AST) was 14 IU/L, alanine aminotransferase (ALT) was 11 IU/L, lactate dehydrogenase (LDH) was 219 IU/L, alkaline phosphatase (ALP) was 497 IU/L, gamma-glutamyl transpeptidase (␥-GTP) was 149 IU/L, leucine aminopeptidase (LAP) was 61 IU/L, and indocyanine green test (ICG) (15) was 31%. On viral examination, serum was negative for hepatitis C virus antibody (enzyme immunoassay [EIA]) and hepatitis B surface antigen (EIA). C reactive protein (CRP) was 1.0 mg/dL, and the erythrocyte sedimentation rate was 36 mm/h. Somatomedin-C was 182 ng/mL, and erythropoietin level was 28.8 mU/mL. Chest radiography showed elevation of the diaphragm and decreased lung size. Liver size was calculated to be 12,354 cm3 (based on integration of each volume of hepatic parenchyma taken at intervals of 1 cm by computed tomography (CT) using NIH image analysis), with marked hepatomegaly (Fig 1). Most of the liver (about 90%) had been replaced by multiple cysts, and near-intact hepatic parenchyma existed only in the medial segment and was quite scarce. Kidney size was calculated to be 1,612 cm3
on the right and 2,033 cm3 on the left by CT and was very small compared with liver size. We first performed renal TAE on April 11, 2001. An angiographic procedure was performed according to a previous method.2 Because it was not effective, we performed TAE for the hepatic artery on June 25, 2001. Angiography of the hepatic artery was performed with a 4-F Cobra catheter (Terumo, Shibuya, Tokyo). A 2.6-F microcatheter (Excelsior; Boston Scientific, Boston, MA) was inserted into the smaller peripheral branches of the hepatic artery through an intra-Cobra catheter led by the guidewire (Transend EX; Boston Scientific). The guidewire catheter was removed, and the platinum microcoil (Tornado R, Cook Group Co, Bloomington, IN) was introduced by the pusher (Trupush R; Johnson & Johnson Company, NJ). Normal liver generally exhibits hepatic arterial branches and portal venous branches running parallel in the same segment anatomically. In the current case, however, angiography results showed that almost all hepatic arterial branches were well developed (Fig 2A) but that most of the portal venous branches were obstructed, with sparing of only a left medial portal vein (Fig 2B). This medial segment corresponded to the region with preserved intact hepatic parenchyma. The other hepatic segments had been replaced by multiple cysts and had only extremely small regions of intact hepatic parenchyma. Except for the middle hepatic artery, every hepatic arterial branch, including the right (anterior and posterior) and left (ventrolateral and dorsolateral) branches, were selected as a site for embolization. The first target of TAE was the right hepatic artery (anterior and posterior branches). Twenty-eight pieces of platinum microcoil, 4 to 10 cm in length (Tornado R, Cook Group Co, Bloomington, IN), were used as embolization material. Spiking fever up to 38.2°C and mild right flank pain appeared immediately after the procedure. Fever and pain subsided after 2 days. ALP rose to a maximum value of 767 IU/L after 1 month. AST, ALT, and LDH rose to 94 IU/L, 34 IU/L, and 350 IU/L, respectively, after 1 day. ␥-GTP rose to 447 IU/L after 3 days, LAP to 65 IU/L after 8 days, and CRP to 14.2 mg/dL after 3 days. On September 7, 2001, a second hepatic TAE was performed. The target of TAE was mainly the left hepatic artery (ventrolateral and dorsolateral branches; Fig 2C). Ten pieces of microcoil were used. Furthermore, TAE was added to recanalized right hepatic arteries using 4 pieces of microcoil. Spiking fever up to 37.8°C and mild left flank pain appeared immediately after the procedure. Fever and pain subsided after 1 day. ALP rose from 557 IU/L to a maximum value of 986 IU/L after 22 days. AST, ALT, and LDH rose from 21 IU/L, 12 IU/L, and 172 IU/L to 63 IU/L, 22 IU/L, and 366 IU/L, respectively, after 1 day. ␥-GTP rose from 179 IU/L to 188 IU/L after 3 days, LAP from 58 IU/L to 65 IU/L after 8 days, and CRP from 3.6 to 14.2 mg/dL after 3 days. The times required for AST, ALT, and ALP to return to their minimum values of 10 IU/L, 6 IU/L, and 333 IU/L were, respectively, 2, 2, and 3 months after the second hepatic TAE. After TAE, abdominal distension was markedly improved owing to a decrease in liver size. Ascites became obscure. Since the second hepatic TAE, needle aspiration of ascites has not been performed. The patient was able to leave the hospital and return to work.
EMBOLIZATION TO POLYCYSTIC LIVER
Fig 1. Left, CT scans of the patient before hepatic TAE (Pre TAE). Liver size was calculated to be 12,354 cm3, with marked hepatomegaly. Most of the liver (about 90%) had been replaced by multiple cysts, and near-intact hepatic parenchyma existed only in the medial segment, and was quite scarce. Right, CT scans of the patient 2 years after hepatic TAE (Post TAE). Liver size was decreased to 54% of the previous value.
735
736
UBARA ET AL
Two years after TAE, liver size has decreased to 54.0% of the previous value (Fig 1; Table 1), and muscle and fat volume in the thoracic region and upper and lower extremities have increased because of improvement of appetite. The abdominal circumference of 115 cm decreased to 95 cm. Data before TAE and 2 years after TAE were as follows: serum albumin, 1.8 g/dL (18 g/L) to 2.8 g/dL (28 g/L); total cholesterol, 114 mg/dL (1.95 mmol/L) to 171 mg/dL (4.42 mmol/L); somatomedin-C, 182 ng/mL to 285 ng/mL; hematocrit, 22.4% to 36.5% (erythropoietin derivatives were discontinued). However, ICG was unchanged at 32%. Dry weight continued to decrease to 58.5 kg until 5 months after the second hepatic TAE and then increased to 64.0 kg as the patient’s appetite improved. Increase in fat and muscle volume because of improvement of appetite probably compensated for the decrease in liver size and ascites. Nutrition and activities of daily living improved. On chest radiography, however, height in the diaphragm improved only 1 cm after TAE despite marked decrease in liver size.
DISCUSSION
Patients with ADPKD have an important feature, that is, increase in renal size is inversely proportional to deterioration of renal function, which other renal disorders lack. When patients with ADPKD became symptomatic because of enlarged kidneys, 5 conventional methods have been reported to reduce renal enlargement: (1) needle aspiration of cysts followed by injection of sclerosing agents,8-10 (2) surgical fenestration,11,12 (3) laparoscopic fenestration,12 (4) laparoscopic nephrectomy,13,14 and (5) surgical nephrectomy.15,16 These may be called external treatments, because they are performed via a transabdominal approach. We have developed a safer and more effective method of treatment using the technique of intravascular radiology, which we call internal treatment, because the renal arteries feeding the cysts are its target.1,2 4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™ Fig 2. (A) Angiography of hepatic arteries of the patient before hepatic TAE. Almost all hepatic arterial branches were well developed. (a) The right hepatic artery (anterior and posterior branches), (b) the left medial hepatic artery, and (c) the left hepatic artery (ventrolateral and dorsolateral branches). (B) Angiography of portal vein of the patient before hepatic TAE. Most of the portal vein branches were obstructed with sparing of only a left medial portal vein (arrow). This medial segment corresponded to the region with the preserved intact hepatic parenchyma. (C) Angiography of hepatic arteries of the patient immediately after the second hepatic TAE. The right hepatic artery (anterior and posterior branches) (a) and the left hepatic artery (ventrolateral and dorsolateral branches) (c) were embolized by microcois. Arrows show microcoils.
EMBOLIZATION TO POLYCYSTIC LIVER Table 1.
Liver size (cm3) Kidney size (cm3) (right) Kidney size (cm3) (left) Abdominal circumference (cm) Dry weight (kg) Ascites (needle aspiration) Occupation
737 Clinical Findings in Pre-TAE and Post-TAE Pre-TAE
Post-TAE (2 y after TAE)
12,354 1612 2033 115 67.4 Every 2 wk Absence from work
6,671 483 610 95 64.0 None Return to work
Because this intravascular embolization therapy was effective in decreasing the size of enlarged cysts, a close relationship between nephromegaly secondary to cyst growth and angiogenesis of renal arteries appears to exist. This mechanism was also supported by results of the histomorphometric analysis by Bello-Reuss et al.17 They concluded that angiogenesis in ADPKD may be necessary for cyst cell growth and increase in vascular permeability facilitating fluid secretion into the cysts via vascular endothelial growth factor.18-21 In general, angiogenesis by vascular endothelial growth factor secretion is induced via hypoxia. This phenomenon has been shown in ischemic coronary artery, cancer, and diabetic proliferative retinopathy.22,23 The angiogenesis observed in these disorders was limited to capillaries and very small arteries. However, renal arteries of patients with ADPKD reach the length of long arteries of about 10 to 20 cm. This vascular abnormality might better be called angioarteriogenesis than angiogenesis. Next, when polycystic liver becomes symptomatic because of severe hepatomegaly, there are several options for conventional treatment, as for enlarged kidneys, eg, percutaneous cyst aspiration and sclerosis, laparoscopic fenestration, open surgical cyst fenestration, and partial hepatectomy3,4 or hepatic transplantation.5-7 Percutaneous cyst aspiration with sclerosis and laparoscopic fenestration was selected only for patients who had one or a few extremely large cysts easily accessible to percutaneous intervention but was not considered indicated for patients with multiple diffuse liver cysts. Open surgical cyst fenestration and partial hepatectomy has been reported to be effective for patients with symptomatic polycystic liver.3,4 This method, however, has been limited to patients younger than 60 years of age with normal or mildly decreased renal function. He-
patic transplantation for symptomatic polycystic liver has been reported to yield excellent results.5-7 Combined liver-kidney transplantation also has been indicated as a therapeutic approach for ADPKD patients on dialysis. However, this treatment has been challenging for patients with malnutrition because of massive ascites and intractible cyst infection. Particularly in Japan, where cadaveric donors are very small in number, hepatic transplantation is less frequently performed. Because TAE was successful in treating enlarged kidneys, we hope that hepatic TAE will become a new treatment option for patients with symptomatic polycystic liver. Normal liver generally exhibits hepatic artery branches and portal vein branches running in parallel in the same segment anatomically. In the current case, however, we found hepatic arteries and portal vein running in a different fashion; almost all hepatic arterial branches were well developed, although the portal venous branches included in hepatic segments replaced by multiple cysts were obstructed. We attempted to perform TAE to hepatic arterial branches belonging to hepatic regions with neither an intact portal vein nor intact hepatic parenchyma. The mechanism of growth of hepatic cysts remains unknown. However, because most patients with enlarged polycystic liver are women and have had multiple pregnancies, estrogen has been suspected to contribute to cyst growth in the liver. No more information on cyst growth exists. We add the following speculation concerning the mechanism of growth of hepatic cysts, based on the analysis of this case. Hepatic segments occupied by cysts are rigid. Perhaps such cystic segments compress the portal vein of neighboring intact hepatic segments. Because the hepatic parenchyma is mainly fed by the portal vein,
738
UBARA ET AL
after the softened portal vein is compressed by rigid cystic hepatic segments, the hepatic parenchyma will disappear as a result of portal venous ischemia. Robust hepatic arteries may grow into the collapsed hepatic parenchyma. In addition, since, as a result, hepatic arteries continue to boost cyst growth, these hepatic segments will become replaced by rigid cysts. Repetition of this process establishes polycystic liver with severe hepatomegaly. In addition to this case, we have performed TAE therapy for more than 10 patients with symptomatic polycystic liver and have not yet experienced serious complications with this method. However, a longer observation period will be needed to judge whether our treatment is effective in most patients. We are preparing a report on the advantages and disadvantages of this treatment. Hepatic TAE may be a new option for treatment of patients in poor condition with symptomatic polycystic liver. REFERENCES 1. Ubara Y, Katori H, Tagami T, et al: Transcatheter renal arterial enbolization therapy on a patient with polycystic kidney disease on hemodialysis. Am J Kidney Dis 34:926931, 1999 2. Ubara Y, Tagami T, Sawa N, et al: Renal contraction therapy for enlarged polycystic kidneys by transcatheter arterial embolization in hemodialysis patients. Am J Kidney Dis 39: 571-579, 2002 3. Que F, Nagorney DM, Gross JB Jr, Torres VE: Liver resection and cyst fenestration in the treatment of severe polycystic liver disease. Gastroentelogy 108:487-494, 1995 4. Soravia C, Mentha G, Giostra E, Morel P, Rohner A: Surgery for adult polycystic liver disease. Surgery 117:272275, 1995 5. Lang H, Woellwarth JV, Oldhafer KJ, et al: Liver transplantation in patients with polycystic liver disease. Transplant Proc 29:2832-2833, 1997 6. Swenson K, Seu P, Kinkhabwala M, et al: Liver transplantation for adult polycystic liver disease. Hepatology 28:412-415, 1998 7. Jeyarajan DR, Gonwa TA, Testa G, et al: Liver and kidney transplantation for polycystic disease. Transplant 66:529-532, 1998 8. Segura TW, King BF, Towsey SG, Martin P, Zincke H: Chronic pain and its medical and surgical management in renal cystic diseases, in Watson ML, Torres VE (eds):
Polycystic Kidney Disease. Oxford, Oxford University Press, 1996, pp 462-480 9. Bennett WM, Elzinga L, Golper TA, Barry JM: Reduction of cyst volume for symptomatic management of autosomal dominant polycystic kidney disease. J Urol 137:620622, 1987 10. Uemasu J, Fujiwara M, Munemura C, Tokumoto A, Kawasaki H: Effects of topical instillation of monocycline hydrochloride on cyst size and renal function in polycystic kidney disease. Clin Nephrol 39:140-144, 1993 11. Elzinga LW, Barry JM, Bennett WM: Surgery in the management of autosomal dominant polycystic kidney disease. Am J Kidney Dis 19:89-92, 1992 12. Elzinga LW, Barry JM, Torres VE, et al: Cyst decompression surgery for autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2:219-226, 1992 13. Elashry OM, Nakada SY, Wolf JS, McDougall EM, Clayman RV: Laparoscopy for adult polycystic kidney disease: A promising alternative. Am J Kidney Dis 27:224-233, 1996 14. Dunn MD, Portis AJ, Elbahnsy AM, et al: Laparoscopic nephrectomy in patients with end-stage renal disease and autosomal dominant polycystic kidney disease. Am J Kidney Dis 35:720-725, 2000 15. Mandelsson DC, Harding ME, Cardella CJ, Cook GT, Uldall PR: Management of end-stage autosomal dominant polycystic kidney disease with hemodialysis and transplantation. Clin Nephrol 30:315-319, 1988 16. Cassuto-Viguier E, Quintens H, Cbevallier D, et al: Transplantation and nephrectomy in autosomal dominant polycystic disease. Clin Nephrol 36:105-106, 1991 17. Bello-Reuss E, Holubec K, Rajaraman S: Angiogenesis in autosomal-dominant polycystic kidney disease. Kidney Int 60:37-45, 2001 18. Simon M, Grone HJ, Johren J, et al: Expression of vascular endothelial growth factor and it receptors in human renal ontogenesis and in adult kidney. Am J Physiol 268: F240-F250, 1995 19. Brooks PC, Silletti S, Von Schalcha TL, Cheresh DA: Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase-2 fragment with integrin binding activity. Cell 92:391-400, 1998 20. Ferrara N: Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int 56:794-814, 1999 21. Senger SR, Galli SJ, Dvorak AM, et al: Tumor cells secrete a vascular permiability factor that promotes accumulation of ascitis fluid. Science 219:983-985, 1983 22. Hashimoto E, Ogita T, Nakaoka T, Matsuoka R, Takao A, Kita Y: Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart. Am J Physiol 267:H1948-H 1954, 1994 23. Carmeliet P, Jain RK: Angiogenesis in cancer and other diseases. Nature 407:249-257, 2000
I
N PATIENTS WITH autosomal dominant polycystic kidney disease (ADPKD), the kidneys usually are supplied by well-developed arteries. We developed renal cyst contraction therapy using renal transcatheter arterial embolization (TAE) for enlarged kidneys.1,2 From 1996 to 2003, renal TAE was performed in about 180 patients on dialysis. This therapy was effective in most of these patients; however, it was not effective in patients with marked hepatomegaly without significant nephromegaly, in whom hepatic treatment was always required. When polycystic liver becomes symptomatic because of severe hepatomegaly, there are several options for conventional treatment, eg, percutaneous cyst aspiration and sclerosis, laparoscopic fenestration, open surgical cyst fenestration and partial hepatectomy,3,4 or hepatic transplantation.5-7 The first 3 methods usually are not used for patients with poor nutritional status, massive ascites, and renal failure. Hepatic transplantation is a good treatment. Combined liver-kidney transplantation has also been indicated as a therapeutic approach for ADPKD patients on dialysis.
However, in Japan, where cadaveric donors are very small in number, hepatic transplantation is performed less frequently. Because TAE was successful in treating enlarged kidneys, we hope that hepatic TAE may become a new treatment option for patients with very poor general condition who are unable to undergo hepatic transplantation. APPROVAL OF AN ETHICS COMMITTEE DISCUSSING NEW TREATMENT
Many symptomatic patients with severe polycystic liver visited our institute desiring any
From the Nephrology Center and the Department of Radiology, Toranomon Hospital, Tokyo, Japan. Received August 28, 2003; accepted in revised form December 4, 2003. Address reprint requests to Yoshifumi Ubara, MD, Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Takatsu-ku, Kawasaki-shi, Kanagawa-ken 213-0015, Japan. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4304-0017$30.00/0 doi:10.1053/j.ajkd.2003.12.035
American Journal of Kidney Diseases, Vol 43, No 4 (April), 2004: pp 733-738
733
734
UBARA ET AL
effective treatment. Therefore, in June 2001, we obtained approval for a new treatment, “TAE for enlarged polycystic liver,”from an ethics committee discussing new treatment at our hospital. Then, after patients had given consent on being fully informed about the new procedure, we decided to try, for the first time in the world, treatment using TAE in patients who had no other practical and effective treatment. We present 1 representative case with a 2-year follow-up. CASE REPORT A 56-year-old man was referred to our institute with complaint of severe abdominal distension and loss of appetite on March 5, 2001. ADPKD had been diagnosed by ultrasonography during a health check-up in 1991. His father and elder sister had the same disease. His abdomen subsequently became progressively distended as a result of hepatic enlargement and ascites. In December 2000, surgery for umbilical hernia was performed. Even after hemodialysis was started for chronic renal failure in January 2001, massive ascites persisted without change. Ascitic fluid had been removed at a rate of 1,000 to 2,000 mL by needle aspiration every 2 weeks. On admission, he was 162 cm in height. He was totally anuric, and his dry weight was 67.4 kg. Blood pressure was 110/76 mm Hg. The abdomen was markedly distended, and his maximum abdominal circumference was 115 cm. Heart sounds were normal, but inspirations and expirations were short, and the lung-liver border was elevated. Emaciation was prominent in the thoracic region and upper extremities. Laboratory findings were as follows: on complete blood count, erythrocytes were 2.28 ⫻ 106/L, hemoglobin was 7.7 g/dL (77 g/L), hematocrit was 22.4%, leukocytes were 4,600/L, and thrombocytes were 12.3 ⫻ 104/L. On blood chemistry, total protein was 7.5 g/dL (75 g/L), albumin was 1.8 g/dL (18 g/L), urea nitogen was 109 mg/dL (38.9 mmol/L), creatinine was 10.2 mg/dL (902 mol/L), and total cholesterol was 114 mg/dL (2.95 mmol/L). Total bilirubin was 0.9 mg/dL (15 mol/L), aspartate aminotransferase (AST) was 14 IU/L, alanine aminotransferase (ALT) was 11 IU/L, lactate dehydrogenase (LDH) was 219 IU/L, alkaline phosphatase (ALP) was 497 IU/L, gamma-glutamyl transpeptidase (␥-GTP) was 149 IU/L, leucine aminopeptidase (LAP) was 61 IU/L, and indocyanine green test (ICG) (15) was 31%. On viral examination, serum was negative for hepatitis C virus antibody (enzyme immunoassay [EIA]) and hepatitis B surface antigen (EIA). C reactive protein (CRP) was 1.0 mg/dL, and the erythrocyte sedimentation rate was 36 mm/h. Somatomedin-C was 182 ng/mL, and erythropoietin level was 28.8 mU/mL. Chest radiography showed elevation of the diaphragm and decreased lung size. Liver size was calculated to be 12,354 cm3 (based on integration of each volume of hepatic parenchyma taken at intervals of 1 cm by computed tomography (CT) using NIH image analysis), with marked hepatomegaly (Fig 1). Most of the liver (about 90%) had been replaced by multiple cysts, and near-intact hepatic parenchyma existed only in the medial segment and was quite scarce. Kidney size was calculated to be 1,612 cm3
on the right and 2,033 cm3 on the left by CT and was very small compared with liver size. We first performed renal TAE on April 11, 2001. An angiographic procedure was performed according to a previous method.2 Because it was not effective, we performed TAE for the hepatic artery on June 25, 2001. Angiography of the hepatic artery was performed with a 4-F Cobra catheter (Terumo, Shibuya, Tokyo). A 2.6-F microcatheter (Excelsior; Boston Scientific, Boston, MA) was inserted into the smaller peripheral branches of the hepatic artery through an intra-Cobra catheter led by the guidewire (Transend EX; Boston Scientific). The guidewire catheter was removed, and the platinum microcoil (Tornado R, Cook Group Co, Bloomington, IN) was introduced by the pusher (Trupush R; Johnson & Johnson Company, NJ). Normal liver generally exhibits hepatic arterial branches and portal venous branches running parallel in the same segment anatomically. In the current case, however, angiography results showed that almost all hepatic arterial branches were well developed (Fig 2A) but that most of the portal venous branches were obstructed, with sparing of only a left medial portal vein (Fig 2B). This medial segment corresponded to the region with preserved intact hepatic parenchyma. The other hepatic segments had been replaced by multiple cysts and had only extremely small regions of intact hepatic parenchyma. Except for the middle hepatic artery, every hepatic arterial branch, including the right (anterior and posterior) and left (ventrolateral and dorsolateral) branches, were selected as a site for embolization. The first target of TAE was the right hepatic artery (anterior and posterior branches). Twenty-eight pieces of platinum microcoil, 4 to 10 cm in length (Tornado R, Cook Group Co, Bloomington, IN), were used as embolization material. Spiking fever up to 38.2°C and mild right flank pain appeared immediately after the procedure. Fever and pain subsided after 2 days. ALP rose to a maximum value of 767 IU/L after 1 month. AST, ALT, and LDH rose to 94 IU/L, 34 IU/L, and 350 IU/L, respectively, after 1 day. ␥-GTP rose to 447 IU/L after 3 days, LAP to 65 IU/L after 8 days, and CRP to 14.2 mg/dL after 3 days. On September 7, 2001, a second hepatic TAE was performed. The target of TAE was mainly the left hepatic artery (ventrolateral and dorsolateral branches; Fig 2C). Ten pieces of microcoil were used. Furthermore, TAE was added to recanalized right hepatic arteries using 4 pieces of microcoil. Spiking fever up to 37.8°C and mild left flank pain appeared immediately after the procedure. Fever and pain subsided after 1 day. ALP rose from 557 IU/L to a maximum value of 986 IU/L after 22 days. AST, ALT, and LDH rose from 21 IU/L, 12 IU/L, and 172 IU/L to 63 IU/L, 22 IU/L, and 366 IU/L, respectively, after 1 day. ␥-GTP rose from 179 IU/L to 188 IU/L after 3 days, LAP from 58 IU/L to 65 IU/L after 8 days, and CRP from 3.6 to 14.2 mg/dL after 3 days. The times required for AST, ALT, and ALP to return to their minimum values of 10 IU/L, 6 IU/L, and 333 IU/L were, respectively, 2, 2, and 3 months after the second hepatic TAE. After TAE, abdominal distension was markedly improved owing to a decrease in liver size. Ascites became obscure. Since the second hepatic TAE, needle aspiration of ascites has not been performed. The patient was able to leave the hospital and return to work.
EMBOLIZATION TO POLYCYSTIC LIVER
Fig 1. Left, CT scans of the patient before hepatic TAE (Pre TAE). Liver size was calculated to be 12,354 cm3, with marked hepatomegaly. Most of the liver (about 90%) had been replaced by multiple cysts, and near-intact hepatic parenchyma existed only in the medial segment, and was quite scarce. Right, CT scans of the patient 2 years after hepatic TAE (Post TAE). Liver size was decreased to 54% of the previous value.
735
736
UBARA ET AL
Two years after TAE, liver size has decreased to 54.0% of the previous value (Fig 1; Table 1), and muscle and fat volume in the thoracic region and upper and lower extremities have increased because of improvement of appetite. The abdominal circumference of 115 cm decreased to 95 cm. Data before TAE and 2 years after TAE were as follows: serum albumin, 1.8 g/dL (18 g/L) to 2.8 g/dL (28 g/L); total cholesterol, 114 mg/dL (1.95 mmol/L) to 171 mg/dL (4.42 mmol/L); somatomedin-C, 182 ng/mL to 285 ng/mL; hematocrit, 22.4% to 36.5% (erythropoietin derivatives were discontinued). However, ICG was unchanged at 32%. Dry weight continued to decrease to 58.5 kg until 5 months after the second hepatic TAE and then increased to 64.0 kg as the patient’s appetite improved. Increase in fat and muscle volume because of improvement of appetite probably compensated for the decrease in liver size and ascites. Nutrition and activities of daily living improved. On chest radiography, however, height in the diaphragm improved only 1 cm after TAE despite marked decrease in liver size.
DISCUSSION
Patients with ADPKD have an important feature, that is, increase in renal size is inversely proportional to deterioration of renal function, which other renal disorders lack. When patients with ADPKD became symptomatic because of enlarged kidneys, 5 conventional methods have been reported to reduce renal enlargement: (1) needle aspiration of cysts followed by injection of sclerosing agents,8-10 (2) surgical fenestration,11,12 (3) laparoscopic fenestration,12 (4) laparoscopic nephrectomy,13,14 and (5) surgical nephrectomy.15,16 These may be called external treatments, because they are performed via a transabdominal approach. We have developed a safer and more effective method of treatment using the technique of intravascular radiology, which we call internal treatment, because the renal arteries feeding the cysts are its target.1,2 4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™ Fig 2. (A) Angiography of hepatic arteries of the patient before hepatic TAE. Almost all hepatic arterial branches were well developed. (a) The right hepatic artery (anterior and posterior branches), (b) the left medial hepatic artery, and (c) the left hepatic artery (ventrolateral and dorsolateral branches). (B) Angiography of portal vein of the patient before hepatic TAE. Most of the portal vein branches were obstructed with sparing of only a left medial portal vein (arrow). This medial segment corresponded to the region with the preserved intact hepatic parenchyma. (C) Angiography of hepatic arteries of the patient immediately after the second hepatic TAE. The right hepatic artery (anterior and posterior branches) (a) and the left hepatic artery (ventrolateral and dorsolateral branches) (c) were embolized by microcois. Arrows show microcoils.
EMBOLIZATION TO POLYCYSTIC LIVER Table 1.
Liver size (cm3) Kidney size (cm3) (right) Kidney size (cm3) (left) Abdominal circumference (cm) Dry weight (kg) Ascites (needle aspiration) Occupation
737 Clinical Findings in Pre-TAE and Post-TAE Pre-TAE
Post-TAE (2 y after TAE)
12,354 1612 2033 115 67.4 Every 2 wk Absence from work
6,671 483 610 95 64.0 None Return to work
Because this intravascular embolization therapy was effective in decreasing the size of enlarged cysts, a close relationship between nephromegaly secondary to cyst growth and angiogenesis of renal arteries appears to exist. This mechanism was also supported by results of the histomorphometric analysis by Bello-Reuss et al.17 They concluded that angiogenesis in ADPKD may be necessary for cyst cell growth and increase in vascular permeability facilitating fluid secretion into the cysts via vascular endothelial growth factor.18-21 In general, angiogenesis by vascular endothelial growth factor secretion is induced via hypoxia. This phenomenon has been shown in ischemic coronary artery, cancer, and diabetic proliferative retinopathy.22,23 The angiogenesis observed in these disorders was limited to capillaries and very small arteries. However, renal arteries of patients with ADPKD reach the length of long arteries of about 10 to 20 cm. This vascular abnormality might better be called angioarteriogenesis than angiogenesis. Next, when polycystic liver becomes symptomatic because of severe hepatomegaly, there are several options for conventional treatment, as for enlarged kidneys, eg, percutaneous cyst aspiration and sclerosis, laparoscopic fenestration, open surgical cyst fenestration, and partial hepatectomy3,4 or hepatic transplantation.5-7 Percutaneous cyst aspiration with sclerosis and laparoscopic fenestration was selected only for patients who had one or a few extremely large cysts easily accessible to percutaneous intervention but was not considered indicated for patients with multiple diffuse liver cysts. Open surgical cyst fenestration and partial hepatectomy has been reported to be effective for patients with symptomatic polycystic liver.3,4 This method, however, has been limited to patients younger than 60 years of age with normal or mildly decreased renal function. He-
patic transplantation for symptomatic polycystic liver has been reported to yield excellent results.5-7 Combined liver-kidney transplantation also has been indicated as a therapeutic approach for ADPKD patients on dialysis. However, this treatment has been challenging for patients with malnutrition because of massive ascites and intractible cyst infection. Particularly in Japan, where cadaveric donors are very small in number, hepatic transplantation is less frequently performed. Because TAE was successful in treating enlarged kidneys, we hope that hepatic TAE will become a new treatment option for patients with symptomatic polycystic liver. Normal liver generally exhibits hepatic artery branches and portal vein branches running in parallel in the same segment anatomically. In the current case, however, we found hepatic arteries and portal vein running in a different fashion; almost all hepatic arterial branches were well developed, although the portal venous branches included in hepatic segments replaced by multiple cysts were obstructed. We attempted to perform TAE to hepatic arterial branches belonging to hepatic regions with neither an intact portal vein nor intact hepatic parenchyma. The mechanism of growth of hepatic cysts remains unknown. However, because most patients with enlarged polycystic liver are women and have had multiple pregnancies, estrogen has been suspected to contribute to cyst growth in the liver. No more information on cyst growth exists. We add the following speculation concerning the mechanism of growth of hepatic cysts, based on the analysis of this case. Hepatic segments occupied by cysts are rigid. Perhaps such cystic segments compress the portal vein of neighboring intact hepatic segments. Because the hepatic parenchyma is mainly fed by the portal vein,
738
UBARA ET AL
after the softened portal vein is compressed by rigid cystic hepatic segments, the hepatic parenchyma will disappear as a result of portal venous ischemia. Robust hepatic arteries may grow into the collapsed hepatic parenchyma. In addition, since, as a result, hepatic arteries continue to boost cyst growth, these hepatic segments will become replaced by rigid cysts. Repetition of this process establishes polycystic liver with severe hepatomegaly. In addition to this case, we have performed TAE therapy for more than 10 patients with symptomatic polycystic liver and have not yet experienced serious complications with this method. However, a longer observation period will be needed to judge whether our treatment is effective in most patients. We are preparing a report on the advantages and disadvantages of this treatment. Hepatic TAE may be a new option for treatment of patients in poor condition with symptomatic polycystic liver. REFERENCES 1. Ubara Y, Katori H, Tagami T, et al: Transcatheter renal arterial enbolization therapy on a patient with polycystic kidney disease on hemodialysis. Am J Kidney Dis 34:926931, 1999 2. Ubara Y, Tagami T, Sawa N, et al: Renal contraction therapy for enlarged polycystic kidneys by transcatheter arterial embolization in hemodialysis patients. Am J Kidney Dis 39: 571-579, 2002 3. Que F, Nagorney DM, Gross JB Jr, Torres VE: Liver resection and cyst fenestration in the treatment of severe polycystic liver disease. Gastroentelogy 108:487-494, 1995 4. Soravia C, Mentha G, Giostra E, Morel P, Rohner A: Surgery for adult polycystic liver disease. Surgery 117:272275, 1995 5. Lang H, Woellwarth JV, Oldhafer KJ, et al: Liver transplantation in patients with polycystic liver disease. Transplant Proc 29:2832-2833, 1997 6. Swenson K, Seu P, Kinkhabwala M, et al: Liver transplantation for adult polycystic liver disease. Hepatology 28:412-415, 1998 7. Jeyarajan DR, Gonwa TA, Testa G, et al: Liver and kidney transplantation for polycystic disease. Transplant 66:529-532, 1998 8. Segura TW, King BF, Towsey SG, Martin P, Zincke H: Chronic pain and its medical and surgical management in renal cystic diseases, in Watson ML, Torres VE (eds):
Polycystic Kidney Disease. Oxford, Oxford University Press, 1996, pp 462-480 9. Bennett WM, Elzinga L, Golper TA, Barry JM: Reduction of cyst volume for symptomatic management of autosomal dominant polycystic kidney disease. J Urol 137:620622, 1987 10. Uemasu J, Fujiwara M, Munemura C, Tokumoto A, Kawasaki H: Effects of topical instillation of monocycline hydrochloride on cyst size and renal function in polycystic kidney disease. Clin Nephrol 39:140-144, 1993 11. Elzinga LW, Barry JM, Bennett WM: Surgery in the management of autosomal dominant polycystic kidney disease. Am J Kidney Dis 19:89-92, 1992 12. Elzinga LW, Barry JM, Torres VE, et al: Cyst decompression surgery for autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2:219-226, 1992 13. Elashry OM, Nakada SY, Wolf JS, McDougall EM, Clayman RV: Laparoscopy for adult polycystic kidney disease: A promising alternative. Am J Kidney Dis 27:224-233, 1996 14. Dunn MD, Portis AJ, Elbahnsy AM, et al: Laparoscopic nephrectomy in patients with end-stage renal disease and autosomal dominant polycystic kidney disease. Am J Kidney Dis 35:720-725, 2000 15. Mandelsson DC, Harding ME, Cardella CJ, Cook GT, Uldall PR: Management of end-stage autosomal dominant polycystic kidney disease with hemodialysis and transplantation. Clin Nephrol 30:315-319, 1988 16. Cassuto-Viguier E, Quintens H, Cbevallier D, et al: Transplantation and nephrectomy in autosomal dominant polycystic disease. Clin Nephrol 36:105-106, 1991 17. Bello-Reuss E, Holubec K, Rajaraman S: Angiogenesis in autosomal-dominant polycystic kidney disease. Kidney Int 60:37-45, 2001 18. Simon M, Grone HJ, Johren J, et al: Expression of vascular endothelial growth factor and it receptors in human renal ontogenesis and in adult kidney. Am J Physiol 268: F240-F250, 1995 19. Brooks PC, Silletti S, Von Schalcha TL, Cheresh DA: Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase-2 fragment with integrin binding activity. Cell 92:391-400, 1998 20. Ferrara N: Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int 56:794-814, 1999 21. Senger SR, Galli SJ, Dvorak AM, et al: Tumor cells secrete a vascular permiability factor that promotes accumulation of ascitis fluid. Science 219:983-985, 1983 22. Hashimoto E, Ogita T, Nakaoka T, Matsuoka R, Takao A, Kita Y: Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart. Am J Physiol 267:H1948-H 1954, 1994 23. Carmeliet P, Jain RK: Angiogenesis in cancer and other diseases. Nature 407:249-257, 2000