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J Clin Pathol 1982;35:1086-1091
6-Thioguanine as a cause of toxic veno-occlusivedisease of the liverMB SATTI, K WEINBREN, EC GORDON-SMITH
From the Departments ofHistopathology, Surgery and Haematology, Royal Postgraduate Medical School,London W12 OHS, UK
SUMMARY Lesions of hepatic veno-occlusive disease were found in the needle biopsy specimen ofone patient suffering from chronic granulocytic leukaemia and in the liver at necropsy of a secondpatient suffering from acute myeloid leukaemia. The treatment included administration of6-thioguanine which was the only relevant compound used in the first patient and which wascombined with cytosine arabinoside in the second patient.
Occlusion of the hepatic efferent venous system is acondition which is uncommon in clinical practice'although Kelsey and Comfort described a series ofpatients in whom the lesion was found without clini-cal effects.2 The most easily recognised form ofocclusion is that involving the major hepatic veins,often in close proximity to their ostia,3 the recogni-tion of this syndrome being attributed to GeorgeBudd in 1845.4 Such major occlusions are generallydistinguishable from lesions involving smallintrahepatic veins or venous radicles which areknown to be affected in a variety of conditions.Probably the most widely distributed hepatic veno-occlusive disease (VOD) is that associated withplant toxins and such effects have been found inpatients who had ingested pyrrolizidine alkaloidsusually extracted from species belonging to Senecio,Crotalaria, Heliothropium and Cynoglossum gen-era.5 More recently, the syndrome of veno-occlusivedisease has been noted in patients not exposed tosuch plant toxins and lesions of the small hepaticveins are now known to develop after supervoltageirradiation6 and after administration of certaindrugs. These include azathioprine7 and the possibil-ity of similar changes being induced by othertherapeutic compounds has been canvassed.Urethane has been implicated8 and recently similarchanges have been reported in two patients whodied with acute myeloid leukaemia and who hadbeen treated with cytosine arabinoside and6-thioguanine.9 The authors considered that theveno-occlusive changes were associated with thecombination therapy, but were not able to identify
Accepted for publication 8 February 19821086
which of the two compounds was responsible for thelesions.The present report concerns two patients sufferingfrom leukaemia, who developed hepaticVOD whilebeing treated with 6-thioguanine and only one ofwhom had also received cytosine arabinoside.
Case reports
CASE 1A 33-year-old man was referred from Spain with adiagnosis of chronic granulocytic leukaemia. Anenlarged spleen was palpable, the WBC was raisedto 320 x 109/l, platelets to 315 x 109/l and thehaemoglobin was 15 g/dl. He had been treated fortwo weeks with busulphan 6 mg/day and allopurinol600 mg/day. He was first seen at HammersmithHospital where hepatosplenomegaly was noted aftera two-week course of busulphan. No treatment wasgiven for two weeks and the patient was then sub-jected to leukopheresis and the cells were cryo-preserved. At this time he was given 50 mg busulphanand this was followed a week later by 100 mg busul-phan. Over the next four months, he received inter-mittent courses of 6-thioguanine at 80 or 40 mg/dayat the end of which time the total dosage of6-thioguanine was 7*64 g. Splenectomy was thencarried out and a wedge biopsy specimen was takenof the liver including what the surgeon described asa "mottled white patch." He developed a severeintraperitoneal haemorrhage two days later forwhich he had a second laparotomy and melaena forwhich he was treated with cimetidine. He made agood recovery and appeared quite well six monthsafter his first attendance at the hospital.
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6-Thioguanine as a cause of toxic veno-occlusive disease of the liver
CASE 2A 33-year-old woman was referred from Hollandwith a diagnosis of acute myeloid leukaemia. Shehad been treated (1976) four years previously forHodgkin's disease (stage IIa mixed cellularity) byirradiation to neck, axilla, mediastinum and lumbarregions using Telecobalt x-ray in 30 fractions withnormal mantel field shielding. For six months afterthis treatment, vinblastine had been administeredand the result was reported as complete remission.
In March 1980, acute myeloid leukaemia wasdiagnosed and three cycles of combination therapyadministered. This included 6-thioguanine (5.04 g),cytosine arabinoside (4.2 g) and daunorubicin(0.54 g) with partial remission. Thereafter a form ofmaintenance therapy was given in Holland, thedetails of which are not available. In August 1980,the patient was prepared for bone-marrow trans-plant with 6-thioguanine (1.76 g), cytosinearabinoside (1.76 g), daunorubicin (0.252 g) and800 rads total body irradiation, the transplant beingperformed on 13 August.
Diarrhoea developed two days later, pyrexia after
six days and jaundice and distention 10 days posttransplant. Although a graft versus host reaction wasentertained clinically a skin rash was neverobserved.The patient died on the 16th post graft day with
oedema, ascites and renal failure. At limited nec-ropsy ascitic fluid (2200 ml) was found and a liverweighing 2300 g, showing the mottled appearanceassociated with venous occlusion. No thrombosiswas found in major hepatic veins or ostia.
LIVER LESIONSCase 1Sinusoids in several parts of the section surroundinghepatic venous radicles of the resected wedge ofliver tissue were crowded with erythrocytes, theintervening hepatic plates being compressed andrich in lipofuscin pigment (Fig. 1). Much hepatocytehyperplasia was noted in remaining parenchyma,particularly in periportal regions of the liver inwhich vascular relations appeared to be retained(Fig. 1). Some of the hepatic venous radicles showedintimal hyperplasia which in parts included excessive
B.s
Fig. 1 Case 1-liver biopsyspecimen. Accumulation oferythrocytes in sinusoids anda perisinusoidal spaces with
1 compression ofinterveninghepatocyte plates. Hepatocytehyperplasia in uncongestedregions. Partly occluded hepatic
* 4gffi * X ' venous radicles. Haematoxylin andi ^^2=*'ZJeosinxl50
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Satti, Weinbren, Gordon-Smith
4.
Fig. 2 Same section as shown in Fig. 1. Partial occlusionofthick-walled hepatic vein with surrounding collagen andfibroblasts. Haematoxylin and eosin x400.
A
Fig. 3 Same section as shown in Fig. 2 after decolourisingand reticulin silver impregnation. Gordon and Sweet x400
Fig. 4 Liver from case 2, showing much irregular congestion with intervening hepatocyte hyperplasia. All hepatic veinsare macroscopically patent as is the IVC.
collagen (Figs. 2 and 3). Foci of extramedullaryhaemopoiesis were present.
Case 2Macroscopically foci of congestion involving irregu-lar regions throughout the liver were separated bypale hyperplastic regions in which large lobules
could be identified. Large hepatic veins, hepatic veinostia and inferior vena cava did not contain thrombi(Fig. 4). There was evidence of much erythrocyteaccumulation in sinusoids with destruction ofhepatocyte plates and sinusoidal distention (Fig. 5).The sublobular hepatic veins and hepatic venousradicles showed marked intimal fibrosis and
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6-Thioguanine as a cause of toxic veno-occlusive disease of the liver
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Fig. 5 Accumulation oferythrocytes in sinusoids withdestruction ofhepatocyte plates. Haematoxylin and eosinxlSO
oedema with striking reduction of lumina (Fig. 6and 7). In some parts of the venous wall erythro-cytes had accumulated. The features representedVOD.
Discussion
So far as the first patient is concerned, theintrasinusoidal crowding of erythrocytes togetherwith venous radicular changes indicate VOD. Amajor ostial occlusion seems unlikely because of thescattering and separation of the lesions with inter-vening normal parenchyma. Of the possible causesfor these changes, it is certain that no iffadiation wasadministered and the patient had never, so far as hewas aware, taken pyrrolizidine alkaloids or otherunusual form of plant extract. Of the compounds hereceived, busulphan was given on only three occa-sions and the last dose was administered fourmonths before the biopsy section was taken. In anycase busulphan is reported as inducing cholestaticjaundice only.'° Allopurinol sometimes associatedwith a mild hepatitis and granulomas"' 12 but not
VOD was given for a short period, four monthsbefore the biopsy was taken. The main therapy was6-thioguanine. The second patient showed clear evi-dence of VOD lesions in the veins and was alsotreated with 6-thioguanine. Cytosine arabinosideand other chemotherapeutic agents had beenadministered about the time of her transplant andthese cannot be excluded as contributory factors.The whole body irradiation is unlikely to haveplayed any part as the level of hepatic irradiationusually reported with VOD changes is generallyabout 3000 rads.14 Although our first patientappears to be the first who has developed thesechanges after receiving 6-thioguanine withoutcytosine arabinoside, several patients havedeveloped signs of hepatotoxicity with veno-occlusive changes while being treated with6-thioguanine and cytosine arabinoside as occurredin our second patient. Thus the patient of Jacobset al'3 could well have suffered veno-occlusive dis-ease as a result of 6-thioguanine although thetherapy included whole body irradiation as well ascytosine arabinoside. The dosage of irradiation(1000 rads) is lower than that usually associatedwith irradiation veno-occlusive hepatic changes'4and the lesion is likely to be a result of drug toxicity.The two patients of Griner et a19 also clearly showedsigns of VOD and the main chemotherapy included6-thioguanine and cytosine arabinoside althoughone had some exposure to cyclophosphamide. Themorphological changes were similar in the liver sec-tions taken at necropsy from the above mentionedthree patients. The letter of Penta's and his colleaguesincludes reports on liver biopsy sections of fivepatients who had sinusoidal congestion "withoutchanges in caliber of the central veins." The authorsdo not stipulate the therapy particular patientsreceived but it appears from their Table that somemay have had 6-thioguanine, either alone or com-bined with other therapy. VOD has been describedalso in patients'6 ' showing the lesions of graft ver-sus host disease after bone marrow transplantation.All the patients with this lesion had been treatedwith radiotherapy and chemotherapy. Both patientsdescribed by Sloane and his colleagues'6 had beengiven a variety of chemical compounds including6-thioguanine and of the three patients who had notreceived radiotherapy in the series by Berk et all7two had been given 6-thioguanine together withother compounds and one was reported as receivingonly cyclophosphamide. This compound had notbeen given to one of the patients reported here.Although our first patient has not been investigatedby anatomical dissection of the veins, the microscop-ical findings are sufficient to make a clear diagnosisof VOD. In our second patient, the ostia were clear.
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Fig. 6 Conspicuous oedematousand fibrous occlusion ofsublobular vein with intramuralerythrocytes. Haematoxylin andeosin X400
Fig. 7 Reticulin silverimpregnation ofsame lesion asshown in Fig. 6. Gordon and Sweetx400
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6-Thioguanine as a cause of toxic veno-occlusive disease of the liver
The diagnosis in our first patient is probably the firstbiopsy report of VOD associated only with6-thioguanine toxicity and the survival of the patientafter the biopsy has permitted a follow-up of thepatient's course. It seems that the lesion is not pro-gressive provided the therapy is discontinued. Thequestion of the fatal outcome in our second patientmay be related possibly to an increased concentra-tion of 6-thioguanine in the liver which could resultfrom simultaneous absorption of cytosinearabinoside, a phenomenon known in animalexperimental work.'8 In respect of the dosage used,it is interesting that our first patient survived with adose of 7-64 g of 6-thioguanine without cytosinearabinoside and three others, all adults, in which wehave been able to calculate dosage (two of Grineret al and our second patient) had lower doses of6-thioguanine (7.0, 6*9, and 6-8 g).
Thanks are due to Dr D Catovsky for permission toinclude the report of case 1, Mr W Hinkes forphotography, Professor DJ Evans for advice withcase 2.
References
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(Baltimore) 1959;38:369-402.4Budd G. On disease of the liver London: Churchill, 1845:147.Lyford CL, Vergara GG, Moeller DD. Hepatic veno-occlusive
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6 Reed GB, Cox AJ. The human liver after radiation injury. Am JPathol 1966;48:597-61 1.
Marubbio AT, Danielson B. Hepatic veno-occlusive disease in arenal transplant patient receiving azathioprine. Gastroenterol-ogy 1975;69:739-43.
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9Griner PF, Elbadawi A, Packman CH: Veno-occlusive disease ofthe liver after chemotherapy of acute leukaemia. Ann InternMed 1976;85:578-82.
0 Underwood JCE, Shahani RT, Blackburn EK. Jaundice aftertreatment of leukaemia with Busulphan. Br Med J 1971;556.
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12Espiritu CR, Alalu J, Glueckauf LG, Lubin J. Allopurinol-induced granulomatous hepatitis. Am J Dig Dis1976;21:804-6.
3 Jacobs P, Miller JL, Uys CJ, Dietrich BE. Fatal veno-occlusivedisease of the liver after chemotherapy, whole body irradiationand bone marrow transplantation for refractory acuteleukaemia. S Afr Med J 1979;55:5-10.
4 Lewin K, Millis RR. Human radiation hepatitis. Arch Pathol1973;96:21-6.
5 Penta JS, Von Hoff DD, Muggia FM. Hepatotoxicity of combi-nation chemotherapy for acute myelocytic leukaemia. AnnIntern Med 1977;87:247.
16 Sloane JP, Farthing MJG, Powles RL. Histopathological changesin the liver after allogeneic bone marrow transplantation. JClin Pathol 1980;33:344.
"Berk PD, Popper H, Krueger GRF, Decter J, Herzig G, GrawRG: Veno-occlusive disease of the liver after allogeneic bonemarrow transplantation possible association with graft versushost disease. Ann Intern Med 1979;90: 158-4.
Pittillo RF, Woolley C. Disposition of arabinosylcytosine(NSC-63878) and 6-thioguanine (NSC-572) in solid L1210leukaemia tumour-bearing mice. Cancer Chemother Rep1973;57:275.
Requests for reprints to: Professor K Weinbren, RoyalPostgraduate Medical School, Du Cane Road, LondonW12 OHS, England.
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