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
Department of Medicine, Clinical Hospital Center Rebro, Zagreb, Croatia
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: psimic@mef.hr
1
2
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 interrelationship 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, posttransplant 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.
[Help with image viewing]
[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.
References
1. Roman ID, Fernandez-Moreno MD, Fueyo JA, et al. Cyclosporin A induced
internalization of the bile salt export pump in isolated rat hepatocyte couplets.
Toxicol Sci 2003; 71: 276-81 Ovid Full Text Bibliographic Links [Context Link]
2. Kahan BD, Flechner SM, Lorber MI, et al. Complications of cyclosporineprednisone immunosuppression in 402 renal allograft recipients exclusively
followed at a single center for from one to five years. Transplantation 1987; 43:
197-204 Buy Now Bibliographic Links [Context Link]
3. Le Thai B, Dumont M, Michael A, et al. Cholestatic effect of cyclosporine in the
rat. An inhibition of bile acid secretion. Transplantation 1988; 46: 510-2 Buy
Now Bibliographic Links [Context Link]
4. Bramow S, Ott P, Thomsen Nielsen F, et al. Cholestasis and regulation of
genes related to drug metabolism and biliary transport in the rat liver following
treatment with cyclosporine A and sirolimus (Rapamycin). Pharmacol Toxicol
2001; 89: 133-9 Ovid Full Text Bibliographic Links [Context Link]
5. Hulzebos CV, Bijleved CM, Stellaard F, et al. Cyclosporine A-induced reduction
of bile salt synthesis associated with increased plasma lipids in children after liver
transplantation. Liver Transpl 2004; 10: 872-80 Full Text Bibliographic Links
[Context Link]
6. Soresi M, Sparacino V, Pisciotta G, et al. Effects of cyclosporine A on various
indices of cholestasis in kidney transplant recipients. Minerva Urol Nefrol 1995;
47: 65-9 Bibliographic Links [Context Link]
7. Alberu J, Gatica M, Cachafeiro-Vilar M, et al. Asymptomatic gallstones and
duration of cyclosporine use in kidney transplant recipients. Rev Invest Clin
2001; 53: 396-400 Bibliographic Links [Context Link]
8. Kahan BD, Flechner SM, Lorber MI, et al. Complications of cyclosporineprednisone immunosuppression in 402 renal allograft recipients exclusively
followed at a single center for from one to five years. Transplantation 1987; 43:
197-204 Buy Now Bibliographic Links [Context Link]
9. Myara A, Cadranel JF, Dorent R, et al. Cyclosporin A-mediated cholestasis in
patients with chronic hepatitis after heart transplantation. Eur J Gastroenterol
Hepatol 1996; 8: 267-71 Buy Now Bibliographic Links [Context Link]
10. Levitsky J, Hart J, Cohen SM, et al. The effect of immunosuppressive
regimens on the recurrence of primary biliary cirrhosis after liver transplantation.
Liver Transpl 2003; 9: 733-6 Full Text Bibliographic Links [Context Link]
11. Lacerda MA, Bowers LD, Snover DC, et al. Hepatic levels of cyclosporine and
metabolites in patients after liver transplantation. Clin Transplant 1995; 9: 35-8
Bibliographic Links [Context Link]
12. Queneau PE, Bertault-Peres P, Mesdjian E, et al. Diminution of an acute
cyclosporin-induced cholestasis by tauroursodeoxy- cholate in the rat.
Transplantation 1993; 56: 530-4 Buy Now Bibliographic Links [Context Link]
13. Bahrle S, Szabo G, Stiehl A, et al. Adjuvant treatment with ursodeoxycholic
acid may reduce the incidence of acute cardiac allograft rejection. J Heart Lung
Transplant 1998; 17: 592-8 Bibliographic Links [Context Link]
14. Caroli-Bosc FX, Iliadis A, Salmon L, et al. Ursodeoxycholic acid modulates
cyclosporin A oral absorption in liver transplant recipients. Fundam Clin
Pharmacol 2000; 14: 601-9 Bibliographic Links [Context Link]
15. Gonzalez-Correa JA, De La Cruz JP, Lucena MI, et al. Effect of cyclosporin A
on platelet aggregation and thromboxane/prostacyclin balance in a model of
extrahepatic cholestasis in the rat. Thromb Res 1996; 81: 367-81 Full Text
Bibliographic Links [Context Link]
16. Bernauer W, Gratwohl A, Keller A, et al. Microvasculopathy in the ocular
fundus after bone marrow transplantation. Ann Intern Med 1991; 115: 925-30
Bibliographic Links [Context Link]
17. Yamani A, Myers-Powell BA, Whitcup SM, et al. Visual loss after renal
transplantation. Retina 2001; 21: 553-9 Ovid Full Text Bibliographic Links
[Context Link]
18. Redkar RG, Davenport M, Myers N, et al. Association of oesophageal atresia
and cholecystohepatic duct. Pediatr Surg Int 1999; 15: 21-3 Full Text
Bibliographic Links [Context Link]
19. Roche SP, Kobos R. Jaundice in adult patient. Am Fam Physician 2004; 69:
299-304 Bibliographic Links [Context Link]
Adverse drug reactions; Cholelithiasis; Ciclosporin, adverse reactions;
Immunosuppressants, therapeutic use; Thrombosis