Gut 1995; 36: 142-145

CASE REPORTS

Hepatic venous outflow obstruction in patientswith polycystic liver disease: pathogenesis andtreatment

W Uddin, J K Ramage, B Portmann, P Wilson, I Benjamin, K-C Tan, Roger Williams

AbstractPolycystic liver disease is commonlyasymptomatic but may present withhepatomegaly, abdominal distension, anddull abdominal pain. Transudative ascitesis a rare manifestation in these patients butmay occur when portal hypertension ispresent resulting from associated hepaticfibrosis or after deroofing procedure ofa cyst. Exudative ascites might suggesthepatic venous outflow obstruction. Fourcases are described where hepatic venousoutflow obstruction occurred in patientswith polycystic liver disease. Threepatients had orthotopic liver transplanta-tion and one had a mesocaval shunt. Ofthetwo patients that survived orthotopic livertransplantation both have shown consider-able improvement in their symptoms.None of the patients had any confirmedprocoagulant disorder. The mechanism ofhepatic venous outflow obstruction in thesepatients seems to be mechanical compres-sion of hepatic veins by the cysts andassociated formation of thrombi in smallhepatic vein tributaries. Patients withsevere polycystic kidney/liver disease are atrisk of hepatic venous outflow obstructionand the onset of this complication isheralded by tender hepatomegaly andpresence ofexudative ascites.(Gut 1995; 36: 142-145)

Keywords: polycystic liver disease, hepatic venousoutflow.

Autosomal dominant polycystic kidney/liverdisease is the second most common inheritedmonogenic disease after familial hyper-cholesterolaemia. 1 It has a prevalence that

Liverfunction tests and original ascitic protein and cell content

Serum Ascites

Bilirubin TP Albumin AST ALP Protein Cells(molIA) (g/l) (g/l) (IU/l) (IU/l) (gil) (/mm')

Case 1 8 67 35 16 131 36 75Case 2 11 68 44 19 123 58 36Case 3 12 69 39 14 64 42 89Case 4 10 65 35 12 113 40 105

TP=total protein; AST=aspartate aminotransferase; ALP=alkaline phosphatase.

ranges from 1 in 200 to 1 in 1000 in differentpopulations. Liver cysts represent the mostfrequent extra renal manifestation of auto-somal dominant polycystic kidney disease. Theincidence of liver polycystosis in these patientsranges from 1 5-40%.2 This incidenceincreases with age, reaching a frequency of65% in patients above 60 years of age.34Symptoms caused by the polycystic liverbecome manifest in only 10-15% of patients,but the percentage is rising with the prolongedsurvival of patients receiving renal replacementtreatment.Most patients with liver polycystic disease

present with a dull aching abdominal pain,but jaundice (which may be caused by anassociated cholangiocarcinoma) and severeabdominal pain are also important presentingsymptoms.5 Ascites is uncommon and isusually seen late in the disease.6 When present,it is usually transudative and is caused byportal hypertension related to associatedhepatic fibrosis. Occasionally a ruptured cystmay also present as ascites, which again hascharacteristics of a transudate.

Finding exudative ascites in patients withpolycystic liver/kidney disease has to dateimplied a second disorder. We describefour cases of autosomal dominant polycystickidney/liver disease who presented withexudative ascites, in whom the mechanismwas shown to be hepatic venous outflowobstruction caused by compression of thehepatic veins leading to thrombotic occlusionof small hepatic vein branches.

Case histories

CASE 1A 51 year old woman, was referred withmassive ascites and gross pedal oedema. Shehad been diagnosed as having polycystickidney/liver disease 25 years ago and neededP blockers for control of hypertension. Fouryears previously she had developed ascites,which had become progressively worse. Forthe past six months she had been greatlyincapacitated by massive ascites and oedema ofthe feet. She was confined to a wheel chair, wasbreathless on minimum exertion, could not lieflat in bed, and could only manage a few steps

Institute of LiverStudiesW UddinJ K RamageB PortmannRoger Williams

Department ofDiagnostic RadiologyP Wilson

Department ofSurgeryI BenjaminK-C Tan

King's CollegeHospital, London

Correspondence to:Dr Roger Williams CBE,King's College Hospital,Denmark Hill, LondonSE5 9RS.Accepted for publication12 April 1994

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Hepatic venous outflow obstruction in patients with polycystic liver disease: pathogenesis and treatment

A

Figure 1: (A) Case 3, hepatic venography. Digitalsubtraction image with catheter in the right hepatic veinshowing distortion of the right main hepatic vein andcollateralisation of more peripheral branches; (B) computedtomography showing paucity of liver cysts (case 4) andenormous caudate hyperplasia.

on her own. Investigations showed: haemo-globin 9.9 g/dl, white cell count 9.1x109/l,platelets 31OX109/l. The Table shows theresults of the liver function tests. Serumelectrolytes were normal but creatininewas raised to 199 pumolI1. Twenty fourhour urinary protein was normal. The asciticprotein content was 36 g/l; cytology andmicrobiological investigations were negative.Ultrasound and computed tomography ofthe abdomen showed a very large liver withmultiple cysts varying in size from a fewmillimetres to 6 cm. Aortoportography showeda normal portal vein. Hepatic venographyshowed that the hepatic veins were grosslydistorted with multiple collaterals, changesconsistent with hepatic venous outflowobstruction.

She had an orthotopic liver transplantationin January 1993 and at operation 17 litresof ascitic fluid was drained and the liverweighed 8.9 kg. The patient has done wellafter her transplant. She is ambulatorywith considerable improvement in herquality of life. Although there has been some

reaccumulation of transudative ascites(protein 21 g/l), this is easily controlled withdiuretics.

CASE 2

A 47 year old woman with a seven year historyof asymptomatic polycystic disease of the liverand kidney was referred to the gynaecologydepartment because of ascites and a uterinemass. Investigations showed haemoglobin10.1 g/dl, white cell count 56 X 109/1, platelets289 X 109/1. The urea, liver functions tests, andelectrolytes were normal and plasma albuminwas 44 g/l. Ascitic protein content was 58 g/land microbiological and cytology investiga-

tions were negative. Ultrasound and computedtomography confirmed a uterine masswith inconclusive fibroid like features. Afterhysterectomy she was well for one monthbefore ascites recurred.On examination a cystic liver was easily

palpable below the umbilicus. Ascitic proteincontent was again high at 56 g/l. Ultrasoundand Doppler studies showed a patent portalvein but the left hepatic vein was occluded.Hepatic venography confirmed occlusion ofthe left hepatic vein. Evaluation for a hyper-coagulable state showed that the antithrombinIII, cardiolipin antibody, protein C and S,Ham's test, and clot lysis test were all normal.Marrow aspirate was normal and cultureshowed no excess of megakaryocyte colonies.Reaccumulation of ascites required repeatedparacenteses and she therefore had anorthotopic liver transplantation. During thereperfusion phase of the operation shedeveloped severe hypotension from which shecould not be resuscitated. The removedpolycystic liver weighed 5.9 kg.

CASE 3A 42 year old woman diagnosed as havingpolycystic kidney/liver disease 12 yearspreviously was referred for transplantassessment because of resistant ascites. Shehad been well except for occasional mildpain in the right upper quadrant untilSeptember 1992, when she rapidly developedascites and gross pedal oedema, whichwas resistant to high dose diuretics.On physical examination the liver was

enlarged to 10 cm below the costal margin, butthe kidneys were not palpable because ofvery tense ascites. Ultrasound confirmed thefindings of an enlarged liver with multiple cystsvarying in size from a few millimetres to 5 cm.The kidneys were also enlarged with multiplecysts. Investigations showed haemoglobin 11.5g/dl, white cell count 6*7X 109/1, platelets185X 109/1. Creatinine was 168 RumolI, but24 hour urinary protein excretion wasnormal. Ascitic fluid protein content was42 g/l with a negative microbiology andcytology examination.A hepatic venogram showed grossly

distorted hepatic veins with multiple collateralsconsistent with hepatic venous outflowobstruction (Figure 1A). The patient had anorthotopic liver transplantation. The removedliver weighed 7.7 kg and macroscopicexamination showed multiple cysts varyingfrom a few millimetres to 8 cm in size.The patient had an uneventful post

transplant course and although she continuesto have some ascites it requires only lowdose diuretic treatment for control. Theascites is now transudative with proteincontent of 16 g/l.

CASE 4A 52 year old woman was referred to the localhospital by her general practitioner in April1991 when she suddenly developed severe pain

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Uddin, Ramage, Portmann, Wilson, Benjamin, Tan, Williams

Figure 2: Posterior view of the polycystic liver in patient 1 Figure 3: Liver histological examination. There is extensiveshowing the caudate lobe (CL) and the major hepatic vein congestion andparenchymal loss nearby a cyst (Cy). Notebranches whose lumens (arrowed) are patent, though a hepatic vein branch (HV) whose lumen is narrowed byconsiderably distorted, seemingly squeezed between cysts. an organised thrombus. Haematoxylin and eosin, original

magnification X60.

in her right abdomen. Ultrasound showedmultiple cysts in the liver and a few cysts inboth kidneys. Between April 1991 and July1992 she required three liver cyst aspirations,necessitated by pain. In July 1992 one of thelarge hepatic cysts was deroofed. Within twoweeks of surgery she was admitted again withacute onset of abdominal distension andtransient confusion. On examination she wasfound to have ascites for the first time.Investigations showed haemoglobin 12 g/dl,white cell count 9-2X 109/1, platelets213 X 109/l. The urea, electrolytes, and liverfunction tests were normal with a plasmaalbumin of 40 g/l. Ascitic fluid protein contentwas 40 g/l, with negative microbiology andcytology. The patient improved during herhospital stay and remained well untilDecember 1992 when the ascites reappeared.Her diuretic dose was increased resulting insome improvement. She was admitted again inFebruary 1993 with painful and tenderhepatomegaly. Ultrasound and computedtomography showed an enlarged left lobe and aconsiderably enlarged caudate, the right lobeshowing a few small cysts (Fig 1B). Dopplerultrasound showed that the portal vein waspatent with normal flow. The right andmiddle hepatic veins were occluded and lefthepatic vein, although distorted, was patent onhepatic venography. All haematological andbiochemical investigations were normal.Investigations for procoagulant states showed anormal antithrombin III, and protein C and S.Plasminogen values were also normal.Autologous erythroid cultures in erythro-poietin poor media were negative. The patientsuccessfully had a mesocaval shunt, withlowering of portal venous pressure and relief ofsymptoms of the grossly enlarged caudate lobe,and is at present asymptomatic while receivinga small dose of diuretics.

Pathological examinationThe livers removed at transplantation in cases1 to 3 weighed respectively 8-9 kg, 5 9 kg, and7.7 kg and were similar on gross examination.Their surface was considerably distorted bynumerous protruding cysts, which on thecut section were diffusely distributed andextensively replaced the liver parenchyma.

Their sizes ranged from a few millimetres to8 cm in maximum diameter. They variablycontained serous fluid, yellow or lightly bilestained jelly like material, or altered blood. Theamount of intervening parenchyma rangedfrom inconspicuous to sleeves of tissues up to5 cm in thickness. There were broad areasshowing red haemorrhagic mottling, some aslarge as a liver segment, though a precisedistribution could not be identified because ofthe complete obliteration of the liver anatomyby the cysts. Appearances were those oflocalised Budd-Chiari. The less affectedparenchyma exhibited a slight nodularitysuggesting regenerative hyperplasia. The mainbranches of the hepatic veins were free fromthrombosis, though they were considerablydistorted, seemingly compressed in betweenor stretched at the periphery of major cysts(Fig 2).

Histologically, most of the cysts werelined by flattened biliary epithelium. Scatteredbiliary hamartomas (von Meyenburgcomplexes) were present in the interveningparenchyma, their lumens being filled withinspissated bile. There were extensive areas ofsinusoidal dilatation and congestion associatedwith hepatocyte loss affecting the whole ofacinar zones 2 and 3, and to a lesser extent andfocally zone 1. Appearances were typical ofvenous outflow block (Fig 3). In these areas,small supralobular branches of the hepatic veinhad their lumens narrowed or occluded byloose fibrous tissue containing entrapped redcells and neolumens in keeping with organisedthrombi.

DiscussionPolycystic liver disease is thought to be causedby a failure of excess intralobular bile ducts toinvolute during embryonic development.7-8The disease is genetically determined with anautosomal dominant mode of inheritance.Associated polycystic kidney disease is oftenpresent. Most patients with liver polycysticdisease remain asymptomatic. Abdominalpain and distension are common presentingcomplaints in symptomatic patients and arecaused by the enlarging liver. Ascites is themost common clinical manifestation of hepaticvenous outflow block, being present in

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90-96%9 of patients. Abdominal pain andtender hepatomegaly are also common. Asciticfluid has a high protein content, which mostprobably results from the high permeabilityto proteins of the sinusoidal walls. Increasedsinusoidal pressure enhances the filtrationof interstitial fluid and when drainage capacityof hepatic lymphatics is exceeded, filtration offluid through the liver capsules occurs.Most patients with polycystic liver disease

do not require any treatment. Active treatmentshould be considered only when patientsbecome symptomatic or develop complicationssecondary to cysts. Uncomplicated butsymptomatic polycystic liver disease requirestreatment that varies from simple aspiration ofthe cyst to deroofing of the cyst, partial hepaticresection or orthotopic liver transplantation.The choice of procedure depends on thenumber and size of the cysts, severity ofsymptoms, degree of portal hypertension, andunderlying hepatic function. 10 Patients whodevelop complications secondary to cystsmore commonly require active treatment.Hepatic venous outflow obstruction secondaryto liver polycystosis can be treated initiallywith diuretics and oral anticoagulants.Anticoagulation should be used very cautiouslybecause of the association of this conditionwith intracranial berry aneurysms. Porto-systemic shunting remains a good optionassuming that hepatic venous outflow obstruc-tion is not long standing, and that patientshave reasonable synthetic liver function.When patients have severe symptoms fromhuge liver cysts and resistant ascites, or havelongstanding venous outflow block with poorliver function, orthotopic liver transplantationis the only logical choice.

It is unlikely that all patients with multiplelarge liver cysts need longterm anticoagulationtreatment to prevent the uncommon complica-tion of hepatic venous outflow obstruction,especially as there is an association of intra-cranial berry aneurysms with polycystic disease.

Orthotopic liver transplantation seems to be asuccessful treatment option in patients withpolycystic liver disease and hepatic venous out-flow obstruction and the role of the mesocavalshunt remains unproved. We describe here fourcases of hepatic venous outflow obstruction inpolycystic liver disease (one of which, case 2,has been reported before' 1). Three of the caseshad an orthotopic liver transplant and in thesecases the hepatic veins were clearly distorted bythe large cysts. In case 4 the cysts were smallerand mainly confined to the right lobe. As theliver has not been removed, it cannot be provedthat the cysts caused hepatic vein compressionin this case. No procoagulant state was identi-fied, however, and the vein occlusion was of theright vein (in the area where cysts were present)and it is probable that the cystic disease andvenous occlusion were related. These casesshow the different ways in which the conditioncan present and give a clearer picture of thepathogenesis and treatment of this unusualsyndrome.

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4 Levine E, Cook LT, Grantham JJ. Liver cysts in autosomaldominant polycystic kidney disease. Clinical and comput-erised tomographic study. Am _7 Roentgenol 1985; 145:229-33.

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