Cholelithiasis and Thrombosis of the Central Retinal Vein in a Renal Transplant Recipient Treated with Cyclosporin
[Case Report]
Simic, Petra1; Gasparovic, Vladimir1; Skegro, Mate2; Stern-Padovan, Ranka3
1 Department of Medicine, Clinical Hospital Center Rebro, Zagreb, Croatia
2 Department of Surgery, Clinical Hospital Center Rebro, Zagreb, Croatia
3 Department of Radiology, Clinical Hospital Center Rebro, Zagreb, Croatia
Correspondence and offprints: Dr Petra Simic, Salata 11, 1000, Zagreb, Croatia. E-mail:
Abstract
The use of cyclosporin has been associated with the development of cholelithiasis in transplant recipients. Cholelithiasis in turn enhances the effects of cyclosporin on increased platelet aggregation.
In this report, a patient who had undergone a renal transplantation as a result of malignant hypertension, and who was on immunosuppressive therapy consisting of cyclosporin, prednisone and azathioprine, developed thrombosis of the central retinal vein 5 years following the transplantation. Seven years after the transplantation, cholelithiasis, cholecystitis, cholangitis and subsequently secondary chronic biliary sclerosis were detected. Latero-lateral anastomosis between the common bile duct and duodenum was performed during explorative laparotomy and ursodeoxycholic acid treatment was introduced. The possible inter-relationship of the cholestatis, central retinal vein thrombosis and immunosuppression are discussed.
Introduction
Cyclosporin is a powerful immunosuppressant drug widely used in transplantation procedures and in the treatment of several autoimmune diseases. However, treatment with cyclosporin is associated with numerous adverse effects, especially dose- and time-related nephrotoxicity and hepatotoxicity.[1]Hepatotoxicity usually consists of cholestasis with hyperbilirubinaemia, increased transaminases and serum bile salt levels in humans, especially in transplant recipients,[2]and with decreased bile flow in animals.[3]Proposed mechanisms of action are inhibition of the uptake, synthesis and/or ATP-dependent canalicular transport of bile salts in the liver,[4,5]but the mechanisms underlying these effects remain largely unknown. In this report, we describe a case of cyclosporin-induced cholelithiasis and thrombosis of the central retinal vein in a patient following renal transplantation.
Case Report
A 30-year-old woman was admitted to our hospital in December 2004 with fever, chills and persistent right-upper quadrant pain that had started 3 days earlier. Her medical history showed congenital oesophageal stenosis, chronic kidney failure with malignant hypertension at the age of 21 years, and allogeneic kidney transplant in November 1997, after 2 years of chronic haemodialysis. Since the transplant she had been receiving immunosuppressive therapy consisting of cyclosporin 100mg twice daily, prednisone 10mg daily and azathioprine 25mg daily. Serum cyclosporin concentrations were 197.4 ± 87.5 ng/mL. She was taking no other medications and had no other diseases. Blood pressure was normal: 130/70mm Hg on average. Five years after the kidney transplant, she had thrombosis of the left central retinal vein. Diagnosis was made on the basis of a fundoscopic finding of retinal vein dilation in association with retinal haemorrhages and cotton-wool spots. Despite treatment with prednisone 80mg in the acute phase, the disease resulted in complete blindness in the left eye. The patient did not have diabetes, hypertension, hyperhomocysteinaemia, antiphospholipid antibodies or other factors that have been linked with central retinal vein thrombosis.
Two years later and 7 years following the kidney transplant, physical examination on admission revealed blindness in the left eye, post-transplant abdominal surgical wound and pain in the right epigastrium. Laboratory tests showed decreased red blood cells to 2670/mm3 (normal range 3900–5200/mm3), with 18% reticulocytes (normal range 0.5–2%), haemoglobin 85 g/L (normal range 120–160 g/L) and haematocrit 26% (normal range 36–46%), while white blood cells were increased to 12 300/mm3 (normal range 4500–11 000/mm3). The erythrocyte sedimentation rate was 130 mm/h (normal <=30 mm/h), and C-reactive protein level was 130 mg/L (normal <=5 mg/L). Her complete blood chemistry was mainly normal but the alkaline phosphatase level was 238 U/L (normal range 30–100 U/L), total cholesterol was 246 mg/dL (normal <=190 mg/dL), triglyceride was 3.2 mmol/L (normal range 0.45–1.69 mmol/L), creatinine was 134 µmol/L (normal range 50–-110 µmol/L) and uric acid was 569 µmol/L (normal range 140–420 µmol/L). Abdominal ultrasonographic examination was performed and showed a normal-sized liver but with hyperechogenic dilated bile ducts (figure 1 a). The gallbladder was normal in size and contained few visible gallstones. The common bile duct was dilated and had the appearance of a tortoise shell, possibly full of concrements. The transplanted kidney had a normal parenchyma.
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[Email Jumpstart To Image] / Fig. 1. (a) Ultrasonographic imaging of the liver. Arrows indicate hyperechogenic dilated bile ducts; (b) multislice CT scan showing the dilated common bile duct (CD), gallbladder (GB) and intrahepatic biliary ducts (BD) filled with thick bile; (c) endoscopic retrograde cholangiopancreatography showing the dilated common bile duct full of polygonal and oval filling defects; (d) pathophysiology showing proliferation of fibrous tissue (F) and disappearance of bile ducts in some of the portal spaces (white arrow), and the damaged bile duct (black arrow) [Mallory staining, magnification 12.5×]. Higher magnification (e) shows infiltration of connective tissue with neutrophils and Kupffer cells (hemalaun-eosin staining, magnification 50×).
To further evaluate the status of the biliary system, we performed multislice computerised tomo- graphy (msCT) of the upper abdomen, which revealed dilatation of the intrahepatic bile ducts, with the main bile ducts dilated to 1cm, the common bile duct 1.5–2cm in width (figure 1 b), and the gallbladder 12 × 3cm in size. Suspecting cholangitis resulting from gallstones, ceftriaxone 2 g/day intravenously was started empirically and the patient was referred to our endoscopic unit for endoscopic retrograde cholangiopancreatography (ERCP). ERCP showed a dilated common bile duct full of polygonal and oval filling defects that resembled a mass of concrements (figure 1 c). Intrahepatic bile ducts were also dilated and full of filling defects. A provisional diagnosis of cholelithiasis and cholangitis was made and explorative laparotomy was performed. The surgeon found the common bile duct to be 2cm wide and full of gallstones. Gallbladder and intrahepatic bile ducts were also full of organic gallstones. The gallbladder and common bile duct were resected and the gallstones were removed, but it was impossible to remove all the gallstones from the intrahepatic bile ducts. Therefore, latero-lateral anastomosis between the common bile duct and duodenum was performed. During the surgical procedure a liver sample was taken for pathophysiological analysis.
The patient recovered fully after surgery. Pathohistological analysis of the liver sample showed oedematous portal spaces with proliferation of fibrous tissue (figure 1 d). Bile ducts and surrounding connective tissue, with islands of focal necrosis, were infiltrated with neutrophils and Kupffer cells (figure 1 e). Some of the portal spaces showed disappearance of bile ducts (figure 1 d). These analyses suggest that the patient had chronic cholecystitis and cholangitis, and subsequently secondary biliary sclerosis. Infrared spectroscopy of gallstones showed that they contained cholesterol.
The patient was discharged from the hospital with the recommendation to take ursodeoxycholic acid 10 mg/kg/day in order to reduce intrahepatic lithiasis. A week later the patient was readmitted to the hospital with similar symptoms to the first admission. msCT showed dilatation of the left hepatic duct and its branches, an obstructed connection between the left and right hepatic ducts, and gas in the right hepatic duct. The patient was treated with cefepime 2 g/day intravenously. Three days after this hospitalisation the status of the biliary system was re-evaluated by magnetic resonance cholangio- pancreatography (MRCP). MRCP showed propulsion of gas in the left hepatic duct, suggesting the elimination of its obstruction. Hepatic ducts and the common bile duct were dilated and were shown to still contain a few concrements. After cessation of symptoms the patient was discharged from the hospital.
Discussion
The case presented here is a further example of the occurrence of cholelithiasis in a transplant patient treated with cyclosporin.[6]It has been reported that 22% of kidney transplant recipients develop gallstones if treated with cyclosporin for >24 months and 16% if treated for <24 months.[7]Although abnormalities in hepatic biochemical para- meters are common among cyclosporin-treated patients, other studies suggest that clinically overt cholelithiasis is relatively rare.[6,8]Cholestasis has also been detected in patients receiving cyclosporin following both heart and liver transplantation.[9,10]Nevertheless, no correlation was found between cyclosporin serum concentrations and serum bilirubin levels or the degree of cholestasis in liver biopsy specimens.[11]In addition, there was no difference in risk for cholelithiasis between those patients administered cyclosporin or those administered tacrolimus for immunosuppression, with tacrolimus having a more pronounced nephrotoxic effect.[10]
We have described here a patient with cholelithiasis detected 7 years following kidney transplantation. There was no previous medical record of liver examination, although pathohistological examination showed chronic cholangitis and secondary biliary sclerosis suggesting a chronic course of the disease. It has been shown that ursodeoxycholic acid reduces cholestasis induced by cyclosporin by preventing cyclosporin-induced hepatocyte membrane damage and by easing biliary excretion of cyclosporin.[12]Furthermore, adjuvant treatment with ursodeoxycholic acid, because of its immuno- modulatory capacity, may reduce the incidence of acute cardiac allograft rejection.[13]Ursodeoxy- cholic acid modifies oral absorption of cyclosporin in liver transplant recipients and thus could have an impact on graft outcomes.[14]It is possible that if the ursodeoxycholic acid had been given to the patient earlier, acute cholangitis might have been avoided.
Published studies have also shown that cholestasis enhances the effects of cyclosporin on platelet aggregation and the thromboxane/prostacyclin balance.[15]This might have been the cause of central retinal vein thrombosis in our patient. Therefore, it is of great importance to reduce cholestasis in cyclosporin-treated patients. This patient had no other risk factors for central retinal vein occlusion such as hypertension, diabetes, hyperhomocysteinaemia or antiphospholipid antibodies. Cyclo- sporin has been linked with retinal microvasculopathy in patients receiving the drug along with conditioning regimens for bone marrow transplantation;[16]however, bone marrow transplantation influences platelet aggregation per se. There is a case report of a cyclosporin-treated kidney transplant recipient who developed retinal vasculopathy and vision loss.[17]
The connection between cholestasis and oesophageal atresia has been shown in a few cases, but in association with cholecystohepatic duct.[18]Our patient had congenital oesophageal stenosis, but surgical examination of the biliary system revealed no anomalies. Haemolysis also induces formation of gallstones, but these are usually black pigment gallstones.[19]Furthermore, haemolytic anaemia was excluded in our patient since the number of reticulocytes was normal.
Our case report aims to draw attention to the view that cholestasis should be taken into account in transplant recipients treated with cyclosporin. The role of ursodeoxycholic acid in preventing hepatic complications of cyclosporin deserves further research.
Acknowledgements
No funding was used to assist in the preparation of this report, and the authors have no potential conflicts of interest that are directly relevant to the contents of this report.
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Adverse drug reactions; Cholelithiasis; Ciclosporin, adverse reactions; Immunosuppressants, therapeutic use; Thrombosis