KHA-CARI Autosomal Dominant Polycystic Kidney Disease Guideline:Management of Polycystic Liver Disease

Judy Savige, MB BS, PhD, FRACP,*,† Andrew Mallett, MB BS, MMed, AFRACMA, FRACP,‡,§

David J. Tunnicliffe, MIPH,‖,¶ and Gopala K. Rangan, MB BS, PhD, FRACP**,††

GUIDELINE RECOMMENDATIONS*a. We recommend screening for polycystic liver dis-

ease in all patients diagnosed with autosomaldominant polycystic kidney disease using abdomi-nal ultrasound (1C).

b. We recommend that all female patients withautosomal dominant polycystic kidney disease andliver cysts undergo counseling regarding the risks ofpregnancy and exogenous estrogen exposure inworsening liver cyst growth (1C).

c. We recommend that females at risk of symptomsfrom hepatic cysts avoid estrogen supplements (1D).

d. We recommend that a multidisciplinary team (hep-atologist, hepatobiliary surgeon, interventional ra-diologist, and nephrologist) care for patients withsevere polycystic liver disease associated withautosomal dominant polycystic kidney disease (1D).

*Criteria used for recommendations and levels ofevidence (1,2;A-D) are described in more detail in Tables1 and 2 of Rangan G, Savige J. Introduction to the KHA-CARI Guidelines on ADPKD. Semin Nephrol.2015;35:521-3in this issue.

UNGRADED SUGGESTIONS FOR CLINICAL CARE

! In some individuals with autosomal dominantpolycystic kidney disease (ADPKD), treatment

with somatostatin analogues decreases livervolume and reduces abdominal symptoms, butfurther clinical trials are required to substantiatetheir role in clinical practice. Disadvantages ofsomatostatin analogues include the need forparenteral administration, their cost, and the riskof adverse effects.

! Rarely, liver transplantation is required in patientswith polycystic liver disease (PLD) that impairstheir quality of life.

IMPLEMENTATION AND AUDIT

Monitoring the use of estrogen therapy in women withADPKD attending renal clinics.

BACKGROUND

Many patients with ADPKD have liver cysts and mostare asymptomatic.

Mutations in two different genes account for about20% of cases with isolated liver cysts (protein kinase Csubstrate, 80K-H, PRKCSH, and SEC63, which is atranslocation protein SEC63 homologue). In general,patients with ADPKD have fewer and smaller livercysts than those with isolated PLD, and although liver

0270-9295/ - see front matter& 2015 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.semnephrol.2015.10.015

Financial support: KHA-CARI Guidelines is supported by KidneyHealth Australia, the Australian and New Zealand Society ofNephrology, Amgen Australia, and Shire Australia Pty Ltd.Guideline members were not remunerated for their work.

Conflict of interest statement: Judy Savige is a board member of theAlport foundation of Australia, a nonprofit organization; AndrewMallett received financial support from Amgen to attend ASN2013 and the 2014 Amgen symposium, and from Genzyme toattend the 2014 LSD symposium; and Gopala Rangan is amember of the advisory committee on the Safety of MedicalDevices and received financial support to attend the KDIGOControversies on Autosomal Dominant Polycystic Kidney Diseasemeeting in 2014.

*The University of Melbourne, Department of Medicine, MelbourneHealth and Northern Health, Melbourne, Australia.

†Department of Nephrology, The Royal Melbourne Hospital, Park-ville, Victoria, Australia.

‡Kidney Health Service and Conjoint Kidney Research Laboratory,Royal Brisbane and Women’s Hospital, Brisbane, Queensland,Australia.

§Centre for Kidney Disease Research, Centre for Chronic Diseaseand CKD, School of Medicine and Centre for Rare DiseasesResearch, Institute for Molecular Bioscience, The University ofQueensland, Brisbane, Queensland, Australia.

‖KHA-CARI Guidelines, Centre for Kidney Research, The Chil-dren's Hospital at Westmead, Westmead, Sydney, Australia.

¶Sydney School of Public Health, University of Sydney, Sydney,Australia.

**Department of Renal Medicine, Westmead Hospital, WesternSydney Local Health District, Sydney, Australia.

††Centre for Transplant and Renal Research, Westmead Institute forMedical Research, University of Sydney, Westmead, Sydney,Australia.

Address reprint requests to Judy Savige, MB BS, PhD, FRACP,Department of Medicine, The University of Melbourne, Parkville,VIC, Australia. E-mail: j.savige@unimelb.edu.au

618 Seminars in Nephrology, Vol 35, No 6, November 2015, pp 618–622

cysts may predominate, individuals with ADPKD alsohave renal cysts.1

Risk factors for severe cystic liver disease in ADPKDinclude increasing age, female gender, multiple preg-nancies, exogenous female hormones, increased renalcyst burden, greater renal volume,2,3 and worse renaldysfunction.1 There is no known correlation between thetype of polycystic kidney disease (PKD) gene mutationand the occurrence of liver cysts. Liver cysts emergeafter the onset of puberty and dramatically increaseduring the childbearing years. In general, liver volume ispreserved. Splenic volumes are not different with orwithout liver cysts, suggesting that portal hypertensionis rare.4 Liver function tests are normal with uncompli-cated cysts. Abnormal liver function tests (elevatedalkaline phosphatase, total bilirubin, or γ glutamyltranspeptidase),5 suggest complications.4 Ca 19-9 iselevated in PLD, but there are currently no guidelinesfor levels that predict symptomatic disease.6

Most individuals with liver cysts due to ADPKD(95%) are asymptomatic. However, some, mainly thosewith severe cystic liver disease, have abdominal painor swelling, and, less commonly, dyspepsia, earlysatiety, dyspnea, and back pain.

The severity of cystic liver disease can be assessedby magnetic resonance imaging (MRI), based on totalcyst number or total liver volume.5

Complications such as hepatic cyst infection andbleeding cause pain acutely, and are not uncommon,occurring in at least 5% of patients.7 The treatment is thesame as for infected or bleeding kidney cysts. Thus, paindue to cyst hemorrhage is treated with analgesia and rest.

Cyst infections are diagnosed on the basis of clinicalfeatures, and positive cultures and imaging (ultrasound,computed tomography [CT], or MRI). Some casereports and small series have suggested that 18-fluorodeoxyglucose-positron emission tomography(FDG-PET) combined with CT scans may help diag-nostically, but further studies are required to determinethe sensitivity and specificity of this technique, espe-cially in distinguishing hemorrhage from infection.8,9

More than half of all hepatic cyst infections are causedby Escherichia coli, and the mainstay of initial manage-ment, before the microorganism is known, is empiricaltherapy with a combination of antibiotics that includeslipophilic agents that penetrate cysts, such as quino-lones.9 However, the optimal initial antibiotic regimenrequires further study. Large infected cysts (45 cm)usually require percutaneous cyst drainage.

In general, the goal of treatment for symptomatic cystenlargement is to reduce the total liver volume.10 However,at present, no pharmacological therapies are available toreduce liver volume and the evidence for somatostatinanalogues and target of rapamycin complex 1(TORC1)inhibitors is discussed later. Tolvaptan does not reduce cystsize because liver cells do not have vasopressin receptors.

Percutaneous treatments for PLD include cyst aspi-ration and sclerotherapy, open or laparoscopic cystfenestration, transcatheter arterial embolization, andsurgical interventions including hepatic resection andliver transplantation. These are discussed further later.

Women with ADPKD and at risk from liver cystsshould avoid estrogens and hormone-replacement ther-apy. However, there is limited evidence for this recom-mendation apart from the observations in pregnancy.

Liver failure is rare but some patients developsymptoms from their massive livers. Serious livercomplications that require consideration of a livertransplant are more common in patients with ADPKDthan with PLD alone (0/19 versus 6/34; P o .0001).1

SEARCH STRATEGY

Databases Searched

Medical subject headings (MeSH) terms and textwords for ADPKD were combined with the MeSHterms and text words for PLD. This was then combinedwith further searches using the MeSH and text wordsfor diagnosis, imaging, and treatment. Animal studieswere specifically excluded. The search was carried outin Ovid MEDLINE (1946 to June 2014), Embase(1974 to May 23, 2014), PsycINFO (1806 to June2014), and the Cochrane Database of SystematicReviews and the Cochrane Registry of Clinical Trials(inception to June 2014).Date of search: June 2014.

WHAT IS THE EVIDENCE?

Supplementary evidence Tables are available online.

Diagnosis—Imaging Modality

Polycystic liver disease in ADPKD is diagnosed whenthere are 20 liver cysts. Ultrasound is used most often todetect liver cysts,11 but ultrasound, CT and MRI havenot been compared directly for their ability to detectliver cysts or to monitor changes in cyst size over time.A study of 400 patients referred to a single renal unitover 5 years (1994-1998) found 67% had liver cysts byultrasound.12 CT scans on 44 mainly symptomaticsubjects investigated for abdominal pain (n ¼ 22),disease extent (n ¼ 15), family screening (n ¼ 4), orunexplained deterioration in renal function (n ¼ 3) at asingle center found 57% had liver cysts.4 The prospec-tive multicenter Consortium for Radiologic ImagingStudies of Polycystic Kidney Disease (CRISP) studyused MRI in 400 patients aged 15 to 46 years, withpreserved estimated glomerular filtration rate, and found83% had liver cysts.13 The latter two studies indicatedthat liver cysts were more common in individuals who

KHA-CARI ADPKD management of PLD 619

were female, older (94% compared with 58% inyounger people; P o .0001), or who had more renalcysts and a larger renal volume (P ¼ .04).

A cross-sectional study from the HALT-A trial (n ¼522)14 classified PLD according to severity using livervolume on MRI corrected for height, with mild PLDdefined as less than 1,000 mL/m (n ¼ 230), moderateas 1,000 to 1,800 mL/m (n ¼ 264), and severe asgreater than 1,800 mL/m (n ¼ 28).

Pharmacological Treatments to Prevent Liver CystGrowth

A number of trials of lanreotide and octreotide haveevaluated changes in liver cyst volume.15–20 Studiesvaried in participant numbers, ranging from 14 to 54;in including single or multiple centers; and in beingplacebo-controlled in four of the five studies. Subjectswere followed up for 6 (n ¼ 1) to 12 months (n ¼ 4).In general, liver cyst size decreased by an average by3.5% to 5%, but only in some patients. The bestresponse was seen in young females, who had an 8%reduction in liver volume.20,21 However, patientstreated with the somatostatin analogues developedmore complications such as cholelithiasis than thosetreated with placebo. In addition, liver cysts redevel-oped when the somatostatin analogue was withdrawn,suggesting that treatment needed to be continued longterm.22,23 There was no additional benefit on liver sizeby adding a TORC1 inhibitor such as everolimus to thesomatostatin analogue.23

Percutaneous Procedures to Treat Polycystic LiverDisease

Invasive approaches to reducing liver cyst volumeshave been published as small series, or as reviews ofsmall series. Morbidity has varied from 0% to 9%for open and laparoscopic fenestration,24 and up to20–100% for hepatic resection without fenestration.25

Aspiration sclerotherapy has been used in patientswith a dominant cyst (45 cm) that is clearly respon-sible for symptoms. The technique involves radio-logical aspiration and administration of a sclerosingagent such as ethanol. This technique results in total orpartial regression of cysts in 41% of patients,26 butmultiple sessions are required since cysts recur.

Decortication is used where there is no response torepeated aspiration sclerotherapy. The major advantageof this technique is that multiple cysts can be treated ina single procedure, but complications occur in 23% ofpatients including bleeding, biliary leakage, ascites,and pleural effusions.10,26

Two small case studies with 30 and 21 patientsdemonstrated that arterial embolization decreased totalliver volume and intrahepatic cyst volume by 25%

and 35%, respectively,27,28 and that symptoms alsoimproved.

Surgical Management to Treat PLD

There are few reports of segmental hepatic resectionfor cysts, but this may be combined with fenestrationin the remnant segment.24

Liver transplantation has been indicated for severehepatomegaly that interferes with quality of life. The 5-year survival rate is better than for other indications fora liver transplant.24,26 This may be combined with akidney transplant.

SUMMARY OF THE EVIDENCE

Polycystic liver disease associated with ADPKD canbe detected easily with hepatic ultrasound imaging, andmost patients (95%) have mild-moderate disease withminimal clinical consequences. No pharmacologicaltherapies alter the natural history of PLD, and theavailable clinical trial data regarding somatostatinanalogues are short term and require further study.

Insufficient evidence is available to determinewhether individuals with severe symptoms benefit frominvasive interventions such as cyst aspiration, laparo-scopic decortication, or segmental liver resection. Themorbidity and mortality from these procedures may besignificant, and these interventions are not routine. Theiruse in clinical practice should involve consultation witha hepatologist and a hepatobiliary transplant surgeon.There is no evidence that these treatments alter thenatural history of PLD disease or improve the long-termoutcome. Liver transplantation is reserved for those withsignificant symptoms and impaired quality of life due toa pronounced increase in liver volume.

WHAT DO OTHER GUIDELINES SAY?

Kidney Disease Outcomes Quality Initiative: Norecommendation.UK Renal Association: No recommendation.Canadian Society of Nephrology: No recommendation.European Best Practice Guidelines: No recommen-dation.International Guidelines:

Spanish Guidelines29:

(a) Patients with moderate-to-severe polycystic liverdisease should avoid estrogens and drugs thatstimulate cyclic adenosine monophosphate accu-mulation (eg, caffeine) (level D).

(b) In patients with mild cystic liver disease, in whomhormonal-replacement therapy is planned, the

J. Savige et al.620

lowest effective dose should be used. The trans-dermal route is preferred as it may exert a differ-ent biological effect on liver cysts by avoidance ofthe first-pass effect (level D).

(c) A CT scan is recommended when a liver cystinfection is suspected. The recommended treat-ment is an antibiotic regimen with quinolones forat least 6 weeks. A third-generation cephalosporinshould be added if fever persists after 72 hours.When signs of infection persist after 3-5 days ofantibiotics, FDG-PET should be performed inorder to locate the infected cyst when CT scanor MRI is unhelpful. Percutaneous drainage maybe advisable if infection persists and the causativecyst is identified and accessible. Cyst hemorrhageshould be diagnosed with MRI and treatedwith nonopioid and opioid analgesics and rest(level D).

(d) Treatment aimed at reducing liver volume isonly indicated when the patient is highly symp-tomatic. Available options include aspirationsclerotherapy, fenestration, segmental resection,and liver transplantation. Surgery on a polycys-tic liver should only be performedby a surgeon with expertise in PLD owingto the abnormal anatomy of the liver and thehigh morbidity of these surgical procedures(level C).

SUGGESTIONS FOR FUTURE RESEARCH

! Comparison of clinical features, ultrasound, CTscan, MRI, and FDG-PET to distinguish betweencauses of acute liver pain in ADPKD (infection orbleeding).

! Determining the effect of withdrawing estrogentherapy in patients with ADPKD on liver andrenal cyst size, and estimated glomerularfiltration rate.

! Further clinical trials to substantiate the role ofsomatostatin analogues in clinical practice.

APPENDIX A. SUPPORTING INFORMATION

Supplementary data associated with this article can befound in the online version at http://dx.doi.org/10.1016/j.semnephrol.2015.10.015.

REFERENCES1. Hoevenaren IA, Wester R, Schrier RW, McFann K, Doctor RB,

JPH Drenth, et al. Polycystic liver: clinical characteristics ofpatients with isolated polycystic liver disease compared withpatients with polycystic liver and autosomal dominant poly-cystic kidney disease. Liver Int. 2008;28:264-70.

2. Bae KT, Zhu F, Chapman AB, Torres VE, Grantham JJ, Guay-Woodford LM, et al. Magnetic resonance imaging evaluation ofhepatic cysts in early autosomal-dominant polycystic kidneydisease: the Consortium for Radiologic Imaging Studies ofPolycystic Kidney Disease cohort. Clin J Am Soc Nephrol.2006;1:64-9.

3. Nicolau C, Torra R, Bianchi L, Vilana R, Gilabert R, Darnell A,et al. Abdominal sonographic study of autosomal dominantpolycystic kidney disease. J Clin Ultrasound. 2000;28:277-82.

4. Levine E, Cook LT, Grantham JJ. Liver cysts in autosomal-dominant polycystic kidney disease: clinical and computedtomographic study. AJR Am J Roentgenol. 1985;145:229-33.

5. Qian Q, Li A, King BF, Kamath PS, Lager DJ, Huston IJ, et al.Clinical profile of autosomal dominant polycystic liver disease.Hepatology. 2003;37:164-71.

6. Waanders E, Van Keimpema L, Brouwer JT, Van Oijen MG,Aerts R, Sweep FC, et al. Carbohydrate antigen 19‐9 isextremely elevated in polycystic liver disease. Liver Int.2009;29:1389-95.

7. Gall TM, Oniscu GC, Madhavan K, Parks RW, Garden OJ.Surgical management and longterm follow‐up of non‐parasitichepatic cysts. HPB (Oxford). 2009;11:235-41.

8. Jouret F, Lhommel R, Devuyst O, Annet L, Pirson Y, HassounZ, et al. Diagnosis of cyst infection in patients with autosomaldominant polycystic kidney disease: attributes and limitationsof the current modalities. Nephrol Dial Transplant. 2012;27:3746-51.

9. Sallée M, Rafat C, Zahar J-R, Paulmier B, Grünfeld J-P,Knebelmann B, et al. Cyst infections in patients with autosomaldominant polycystic kidney disease. Clin J Am Soc Nephrol.2009;4:1183-9.

10. van Keimpema L, Hockerstedt K. Treatment of polycystic liverdisease. Br J Surg. 2009;96:1379-80.

11. Gevers TJG, Drenth JPH. Diagnosis and management ofpolycystic liver disease. Nat Rev Gastroenterol Hepatol.2013;10:101-8.

12. Nicolau C, Torra R, Badenas C, Vilana R, Bianchi L, GilabertR, et al. Autosomal dominant polycystic kidney disease types1 and 2: assessment of US sensitivity for diagnosis. Radiology.1999;213:273-6.

13. Bae KT, Zhu F, Chapman AB, Torres VE, Grantham JJ, Guay-Woodford LM, et al. Consortium for Radiologic ImagingStudies of Polycystic Kidney Disease. Magnetic resonanceimaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: the Consortium for Radio-logic Imaging Studies of Polycystic Kidney Disease cohort.Clin J Am Soc Nephrol. 2006;1:64-9.

14. Hogan MC, Abebe K, Torres VE, Chapman AB, Bae KT, TaoC, et al. Liver involvement in early autosomal-dominantpolycystic kidney disease. Clin Gastroenterol Hepatol.2015;13 (155-64):e6.

15. Caroli A, Antiga L, Cafaro M, Fasolini G, Remuzzi A,Remuzzi G, et al. Reducing polycystic liver volume inADPKD: effects of somatostatin analogue octreotide. Clin JAm Soc Nephrol. 2010;5:783-9.

16. Chrispijn M, van Keimpema L, Nevens F, Vanslembrouck R,van Oijen MGH, Hoffmann AD, et al. Growth of liver volumestops after one year of lanreotide in patients with polycysticlivers. J Hepatol. 2010;52:S31.

17. Hogan MC, Masyuk TV, Page L, Holmes DR, Li X, BergstralhEJ, et al. Somatostatin analog therapy for severe polycysticliver disease: results after 2 years. Nephrol Dial Transplant.2012;27:3532-9.

KHA-CARI ADPKD management of PLD 621

18. Van Keimpema L, Nevens F, Vanslembrouck R, Van OijenMG, Hoffmann AL, Dekker HM, et al. Lanreotide reduces thevolume of polycystic liver: a randomized, double-blind,placebo-controlled trial. Hepatology. 2009;50:328A.

19. Hogan MC, Masyuk TV, Page LJ, Kubly VJ, Bergstralh EJ, LiX, et al. Randomized clinical trial of long-acting somatostatinfor autosomal dominant polycystic kidney and liver disease. JAm Soc Nephrol. 2010;21:1052-61.

20. Gevers TJ, Hol JC, Monshouwer R, Dekker HM, Wetzels JF,Drenth JP. Effect of lanreotide on polycystic liver and kidneysin autosomal dominant polycystic kidney disease: an observa-tional trial. Liver Int. 2015;35:1607-14.

21. Gevers TJG, Inthout J, Caroli A, Ruggenenti P, Hogan MC,Torres VE, et al. Young women with polycystic liver diseaserespond best to somatostatin analogues: a pooled analysis ofindividual patient data. Gastroenterology. 2013;145 (357-65):e1-e2.

22. Chrispijn M, Nevens F, Gevers TJ, Vanslembrouck R, vanOijen MG, Coudyzer W, et al. The long-term outcome ofpatients with polycystic liver disease treated with lanreotide.Aliment Pharmacol Ther. 2012;35:266-74.

23. Chrispijn M, Gevers TJG, Hol JC, Monshouwer R, DekkerHM, Drenth JPH. Everolimus does not further reduce poly-cystic liver volume when added to long acting octreotide:

results from a randomized controlled trial in polycystic liverdisease patients. J Hepatol. 2013;58:S557.

24. Russell RT, Pinson CW. Surgical management of polycysticliver disease. World J Gastroenterol. 2007;13:5052-9.

25. Arnold HL, Harrison SA. New advances in evaluation andmanagement of patients with polycystic liver disease. Am JGastroenterol. 2005;100:2569-82.

26. Drenth JP, Chrispijn M, Nagorney DM, Kamath PS, Torres VE.Medical and surgical treatment options for polycystic liverdisease. Hepatology. 2010;52:2223-30.

27. Wang MQ, Duan F, Liu FY, Wang ZJ, Song P. Treatment ofsymptomatic polycystic liver disease: transcatheter super-selective hepatic arterial embolization using a mixture ofNBCA and iodized oil. Abdom Imaging. 2013;38:465-73.

28. Takei R, Ubara Y, Hoshino J, Higa Y, Suwabe T, Sogawa Y,et al. Percutaneous transcatheter hepatic artery embolization forliver cysts in autosomal dominant polycystic kidney disease.Am J Kidney Dis. 2007;49:744-52.

29. Ars E, Bernis C, Fraga G, Martinez V, Martins J, Ortiz A, et al.Spanish Working Group on Inherited Kidney Disease. Spanishguidelines for the management of autosomal dominant poly-cystic kidney disease. Nephrol Dial Transplant. 2014;29 (Suppl4):iv95-105.

J. Savige et al.622

APPENDIX

KHA-C

ARIADPKD

managem

entof

PLD

622.e1

J.Savige

etal.

622.e2

KHA-C

ARIADPKD

managem

entof

PLD

622.e3

J.Savige

etal.

622.e4

KHA-C

ARIADPKD

managem

entof

PLD

622.e5