Postgraduate Medical Journal (1988) 64, 950-952
Clinical Reports
Portal hypertension secondary to azathioprine inmyasthenia gravis
V. Fonseca & C.W.H. Havard
Royal Free Hospital, Pond Street, London NW3 2QG, UK.
Summary: A 52 year old man with myasthenia gravis and normal liver function was treated withneostigmine, prednisolone and azathioprine. Three years after starting azathioprine he developedclinical evidence of portal hypertension. A liver biopsy showed nodular regenerative hyperplasia(NRH).The development of NRH following azathioprine treatment in a patient with myasthenia gravis
strengthens the case for a causal role of azathioprine in producing in producing NRH and portalhypertension.
Introduction
Portal hypertension association with nodular re-generative hyperplasia of the liver (NRH) secondaryto immunosuppressive therapy has been previouslydescribed, usually after renal transplantation. 1,2A patient with myasthenia gravis who recentlydeveloped NRH following treatment with azathio-prine has recently been reported.3 We report afurther case in a patient with myasthenia graviswho was treated with azathioprine.
Case report
A 52 year old man presented with diplopia, ptosisand dysphonia. A diagnosis of myasthenia graviswas made on the basis of a positive edrophoniumtest. Acetylcholine receptor antibodies were present.There was no past history of jaundice and he didnot abuse alcohol. There were no signs of liverdisease and the liver and spleen were impalpable.He was treated with neostigmine. He underwentthymectomy and 3 months later was started onprednisolone, which was tapered to a maintenancedose of 20mg on alternate days. Due to continuingweakness he was started on azathioprine 150 mgdaily, 6 months later. At the time of initiation ofazathioprine the following investigations werecarried out: haemoglobin 15.6 g/dl, MCV 94 fl,
white cell count 9.9 x 109/1, urea 5.5 mmol/l (normalrange 3.0-6.5), total protein 66 g/l (60-80), albumin44 g/l (30-50), bilirubin 15 jmol/l (5-17), aspartatetransaminase (AST) 14 U/I (5-40), alkaline phos-phatase (ALP) 75 U/l (35-130).Over the next 2 years his myasthenia improved
and he remained in good general health. His MCVrose to 115 fl and platelet count fell to 110 x 109/1.These changes were considered to be the result ofazathioprine therapy.
Three years after starting azathioprine the spleenwas found to be enlarged 4cm in the mid clavicularline below the costal margin, on routine physicalexamination. He had no other symptoms or signssuggestive of liver disease. Investigations: haemo-globin 12.1 g/dl, white cell count 3.4 x 109/l, MCV113 fl, platelets 103 x 109/1; urea 4.3 mmol/l, bili-rubin 70,mol/l; AST 40 U/1; ALP 107 U/1; gammaglutamyl transferase (GGT) 125 U/I (10-48); amy-lase 85 U/I (0-220). Ultrasound: small liver, portalvein and splenic vein enlarged. Spleen grosslyenlarged with several prominent vessels around thehilum. Liver biopsy (3 cylinders each 1 cm) showednodular regenerative hyperplasia, characterized bysmall hyperplastic nodules with intervening atrophybut no substantial degree of fibrosis (see Figure 1).
Azathioprine was stopped and cyclophosphamidecommenced but he developed haemorrhagic cystitisand cyclophosphamide had to be discontinued. Sixmonths after discontinuation of azathioprinesplenomegaly persists but his MCV has fallen to
© The Fellowship of Postgraduate Medicine, 1988
Correspondence: V. Fonseca M.D., M.R.C.P.Accepted: 7 June 1988
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CLINICAL REPORTS 951
Figure 1 Liver biopsy: (a) nodules not surrounded by fibrous tissue. Reticulin fibres are compressed. Gordonand Sweets' reticulin method x 80. (b) Same field as in (a), haematoxylin and eosin stain x 80.
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952 CLINICAL REPORTS
94 fl and bilirubin to 21 pmol/I although GGTremains elevated at 127 IU/1.
Discussion
The development of portal hypertension in thispatient appears to be related to treatment withazathioprine. Biopsy confirmed that the increasedportal venous pressure was associated with nodularregenerative hyperplasia.
Hepatic dysfunction is not uncommon in patientstreated with azathioprine. This usually manifests asa reversible acute cholestatic hepatitis4 or occasion-ally as acute focal hepatocellular necrosis5 or veno-occlusive disease.6 Nodular regenerative hyperplasialeading to portal hypertension has previously beendescribed in patients taking azathioprinel' 2 butmost of the patients described were on anotherimmunosuppressive therapy as well. The largest
proportion of patients with this complication havehad renal transplantation.' As renal disease andtransplantation is associated with an increased inci-dence of vascular events, azathioprine, while sus-pected of being the cause of liver changes, couldnot be conclusively incriminated. Myasthenia gravisis not associated with recorded increased risk ofocclusive vascular disease, nor are treatment withsteroids and neostigmine. Azathioprine therefore islikely to be the sole agent responsible for thedevelopment of portal hypertension in this patientand strengthens the case for a causal role ofazathioprine in producing these effects.
Acknowledgement
We wish to thank Professor P.J. Scheuer for his valuablehelp and guidance.
References
1. Nataf, C., Feldmann, G., Lebrec, D. et al. Idiopathicportal hypertension (perisinusoidal fibrosis) after renaltransplantation. Gut 1979, 20: 531-537.
2. Stromeyer, F.W. & Ishak, K.G. Nodular trans-formation (nodular regenerative hyperplasia) of theliver. Hum Pathol 1981, 12: 60-71.
3. Eliakum, R., Ligurnsky, M., Jurim, 0. & Shouval, D.Nodular regenerative hyperplasia with portal hyper-tension in a patient with myasthenia gravis. Am JGastroenterol 1987, 82: 674-676.
4. Simon, N. & Del Greco, F. Intrahepatic cholestasis dueto azathioprine. Gastroenterology 1969, 57: 439-441.
5. Cooper, C., Cotton, D.W.K., Minihane, N. & Cawley,M.I.D. Azathioprine hypersensitivity manifesting asacute focal hepatocellular necrosis. J R Soc Med 1986,79: 171-173.
6. Marubbio, A.T. & Danielson, B. Hepatic veno-occlusive disease in a renal transplant patient receivingazathioprine. Gastroenterology 1975, 69: 739-743.
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