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EASL Clinical Practice Guidelines on the management of cystic liver diseases

      Summary

      The advent of enhanced radiological imaging techniques has facilitated the diagnosis of cystic liver lesions. Concomitantly, the evidence base supporting the management of these diseases has matured over the last decades. As a result, comprehensive clinical guidance on the subject matter is warranted. These Clinical Practice Guidelines cover the diagnosis and management of hepatic cysts, mucinous cystic neoplasms of the liver, biliary hamartomas, polycystic liver disease, Caroli disease, Caroli syndrome, biliary hamartomas and peribiliary cysts. On the basis of in-depth review of the relevant literature we provide recommendations to navigate clinical dilemmas followed by supporting text. The recommendations are graded according to the Oxford Centre for Evidence-Based Medicine system and categorised as ‘weak’ or ‘strong’. We aim to provide the best available evidence to aid the clinical decision-making process in the management of patients with cystic liver disease.

      Introduction

      The advent of enhanced radiological imaging techniques has facilitated the mapping of cystic liver lesions. Following the discovery of these lesions, it is now pertinent to provide guidance on the diagnosis and management of these lesions. These Clinical Practice Guidelines (CPGs) by the European Association for the Study of the Liver (EASL) were commissioned to provide guidance on the clinical management of non-infectious cystic liver diseases. These lesions encompass simple hepatic cysts, mucinous cystic neoplasms (MCNs) of the liver, polycystic liver disease (PLD), Caroli disease, Caroli syndrome, biliary hamartomas and peribiliary cysts. The disorders described in these CPGs are broadly termed fibrocystic diseases. Fibrocystic liver disease encompasses a group of congenital and rare diseases that result from perturbed development of the embryonic ductal plate. Fibrocystic liver diseases are also part of a much wider group of developmental diseases termed “ciliopathies” because they share cilia dysfunction in their pathogenesis.
      • Lasagni A.
      • Cadamuro M.
      • Morana G.
      • Fabris L.
      • Strazzabosco M.
      Fibrocystic liver disease: novel concepts and translational perspectives.
      The prevalence of cystic liver lesions varies by disease; simple hepatic cysts are quite common (prevalence rate of 2.5–18.0%),
      • Mortelé K.J.
      • Ros P.R.
      Cystic focal liver lesions in the adult: differential CT and MR imaging features.
      ,
      • Carrim Z.I.
      • Murchison J.T.
      The prevalence of simple renal and hepatic cysts detected by spiral computed tomography.
      while PLD (prevalence rate of 1/10,000–1/158,000) and MCNs (estimated prevalence <5% compared to simple hepatic cysts) are rare.
      • Soares K.C.
      • Arnaoutakis D.J.
      • Kamel I.
      • Anders R.
      • Adams R.B.
      • Bauer T.W.
      • et al.
      Cystic neoplasms of the liver: biliary cystadenoma and cystadenocarcinoma.
      • Suwabe T.
      • Chamberlain A.M.
      • Killian J.M.
      • King B.F.
      • Gregory A.V.
      • Madsen C.D.
      • et al.
      Epidemiology of autosomal-dominant polycystic liver disease in Olmsted county.
      • Van Keimpema L.
      • De Koning D.B.
      • Van Hoek B.
      • Van Den Berg A.P.
      • Van Oijen M.G.
      • De Man R.A.
      • et al.
      Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases.
      • Willey C.J.
      • Blais J.D.
      • Hall A.K.
      • Krasa H.B.
      • Makin A.J.
      • Czerwiec F.S.
      Prevalence of autosomal dominant polycystic kidney disease in the European Union.
      Hepatic cysts are defined as fluid-filled lesions lined by a single cell layer. The pathogenesis of cysts involves abnormal foetal ductal plate maturation. The ductal plate is a double cylinder of hepatoblasts encircling portal vein branches that provides the scaffold for bile duct development. Cysts arise as a result of ductal plate malformation when the ductal plate disconnects from the biliary tree and progresses into cystic structures. Epithelial cells in the cyst retain a secretory function and fluid production generates a positive luminal pressure that contributes to the cyst’s architecture. Cyst fluid consists of water and electrolytes and its composition mirrors that of bile but is devoid of bile acids or bilirubin.
      • Patterson M.
      • Gonzalez-Vitale J.C.
      • Fagan C.J.
      Polycystic liver disease: a study of cyst fluid constituents.
      MCNs are extremely rare and they may also be referred to as ‘biliary cystadenoma’ or ‘biliary cystadenocarcinoma’ in the literature. These lesions present as an important clinical challenge since malignant transformation rates of up to 30% have been described.
      • Devaney K.
      • Goodman Z.D.
      • Ishak K.G.
      Hepatobiliary cystadenoma and cystadenocarcinoma: a light microscopic and immunohistochemical study of 70 patients.
      PLD is defined by the presence of >10 hepatic parenchymal cysts that are unconnected to the bile duct system. It may be inherited in an autosomal dominant fashion and, depending on the most prominent phenotype, 2 different entities have been categorised: autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD).
      • Cnossen W.R.
      • Drenth J.P.
      Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.
      Patients with ADPKD are diagnosed using previously established criteria based on the presence of kidney cysts; affected patients may develop hepatic cysts.
      • Pei Y.
      • Obaji J.
      • Dupuis A.
      • Paterson A.D.
      • Magistroni R.
      • Dicks E.
      • et al.
      Unified criteria for ultrasonographic diagnosis of ADPKD.
      Patients with ADPLD do not meet the ADPKD criteria and cysts are typically restricted to the liver.
      Caroli disease (or type V lesions based on the Todani classification) is characterised by dilatation of intrahepatic bile ducts.
      • Todani T.
      • Watanabe Y.
      • Narusue M.
      • Tabuchi K.
      • Okajima K.
      Congenital bile duct cysts: classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst.
      While Caroli disease is limited to the dilatation of larger intrahepatic bile ducts, Caroli syndrome combines small bile duct dilatation and congenital hepatic fibrosis.
      • Caroli J.
      • Soupault R.
      • Kossakowski J.
      • Plocker L.
      • Paradowska
      Congenital polycystic dilation of the intrahepatic bile ducts; attempt at classification.
      Biliary hamartomas, also called Von Meyenburg complexes, are considered to be part of the spectrum of ductal plate malformations.
      • Cnossen W.R.
      • Drenth J.P.
      Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.
      Multiple bile duct hamartomas are typically recognised as tiny (<1 cm) hypodense lesions scattered throughout the liver with normal extra- and intrahepatic bile ducts. Recognition of this entity is crucial because they may mimic liver metastases at first sight.
      Currently, comprehensive clinical guidance on cystic liver diseases is lacking, even though there is one guideline that includes PLD.
      • Savige J.
      • Mallett A.
      • Tunnicliffe D.J.
      • Rangan G.K.
      KHA-CARI autosomal dominant polycystic kidney disease guideline: management of polycystic liver disease.
      The evidence base supporting clinical management of cystic diseases of the liver has matured over the last decades to the point that these EASL CPGs are warranted.
      These EASL CPGs cover the diagnosis and management of non-infectious cystic liver diseases. A discussion on choledochal cysts falls outside the remit of these CPGs. We aim to provide practitioners with the best available evidence to support the clinical decision-making process when faced with patients with cystic liver diseases.

      Methods

      The EASL Governing Board initiated these CPGs in August 2020 by selecting a panel of experts and describing the remit of the assignment. The development of these CPGs followed a standard operating procedure set out by EASL and meets the international standards for CPGs set out by the Guidelines International Network. The process involves identification of a number of key questions pertinent to the subject matter. The CPG panel drafted questions according to the PICO format. P – patient, problem or population, I – intervention, C – comparison, control or comparator, O – outcome. PICO questions were vetted through a simplified Delphi process in the broader community including 41 physicians, scientists, patients and other stakeholders competent in the field of cystic liver diseases beyond the CPG panel and the EASL Governing Board. This was followed by a systematic literature review process, a literature search was performed using PubMed, and expanding to Embase, Google Scholar and Scopus when needed. Additional articles were obtained through citation snowballing to locate primary sources. Search terms and results can be found in the supplementary information. Each expert took responsibility, made proposals for statements for a specific section of the guideline and shared tables of evidence and text with the full panel. The panel met virtually on 10 occasions, and all recommendations were discussed and approved by all participants. The level of evidence was graded according to the Oxford Centre for Evidence-Based Medicine (OCEBM) system (Table 1) and the strength of the recommendations was categorised as either ‘weak’ or ‘strong’ (Table 2).

      OCEBM Levels of Evidence Working Group∗. "The Oxford 2011 Levels of Evidence".

      The higher the quality of the evidence, the more likely a strong recommendation was made. If no clear evidence was available, recommendations were based on the expert opinion of the panel members. All recommendations were subsequently approved through a second Delphi round and were ultimately brought to the attention of the EASL Governing Board for final approval.
      Table 1Level of evidence based on the Oxford Centre for Evidence-based Medicine.
      LevelCriteriaSimple model for high, intermediate and low evidence
      1Systematic Reviews (SR) (with homogeneity) of Randomised controlled trials (RCT)Further research is unlikely to change our confidence in the estimate of benefit and risk
      2Randomised controlled trials (RCT) or observational studies with dramatic effects;

      Systematic Reviews (SR) of lower quality studies (i.e. non-randomised, retrospective)
      3Systematic Reviews (SR) of lower quality studies (i.e. non-randomised, retrospective)Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate
      4Case-series, case-control, or historically controlled studies (systematic review is generally better than an individual study)
      5Expert opinion (Mechanism-based Reasoning)Any estimate of effect is uncertain
      Table 2Grades of recommendation.
      GradeWordingCriteria
      StrongMust, shall, should, is recommended

      Shall not, should not, is not recommended
      Evidence, consistency of studies, risk-benefit ratio, patient preferences, ethical obligations, feasibility
      Weak or openCan, may, is suggested

      May not, is not suggested

      Questions and recommendations

      Which imaging technique is recommended to diagnose cystic liver lesions?

      Recommendations
      • Ultrasound should be the first imaging modality used to diagnose simple hepatic cysts and PLD (LoE 3, strong recommendation, 100% consensus).
      • Hepatic cysts demonstrating complex features (e.g. atypical cyst wall or content), either solitary or in the context of PLD, require further evaluation using additional imaging (LoE 3, strong recommendation, 100% consensus).
      • MRI or CT can be used in PLD to evaluate the distribution of cysts within the liver parenchyma and the relation to hepatic vasculature (LoE 2, weak recommendation, 100% consensus).
      • Biliary hamartomas should be diagnosed by MRI with heavily T2-weighted sequences and MR cholangiography sequences (LoE 4, strong recommendation, 100% consensus).
      Statement
      • The number of lesions (solitary vs. multiple) and architecture (simple vs. complex cyst) are key elements in the description of hepatic cyst(s) (LoE 3, strong recommendation, 100% consensus).
      Hepatic cysts are most often discovered incidentally on imaging and accurate diagnosis is needed to differentiate between benign and malignant causes. On ultrasound, hepatic cysts are recognised by their anechoic content with posterior enhancement. A CT image identifies cysts as homogeneous and hypoattenuating lesions on non-enhanced scans, without enhancement of their content after administration of contrast material. MRI helps to identify a strong signal on T2-weighted sequences, similar to other fluids (cerebrospinal fluid) and a low T1-weighted signal. Two features are key to characterise cysts: number of lesions (solitary vs. multiple) and architecture (simple vs. complicated vs. complex cyst). Complicated and complex cysts are defined by the presence of complex features within a lesion, including calcifications, septations, mural thickening or nodularity, debris-containing fluid, haemorrhagic or proteinaceous contents, fluid levels, wall enhancement, and associated bile duct dilatation.
      • Mavilia M.G.
      • Pakala T.
      • Molina M.
      • Wu G.Y.
      Differentiating cystic liver lesions: a review of imaging modalities, diagnosis and management.
      Complications of hepatic cysts are referred to as complicated cysts throughout the manuscript; complex cysts are defined as cysts with atypical and complex features.
      Ultrasound and MRI are the best imaging modalities to characterise cystic liver lesions. Ultrasound explores content and wall thickness while MRI is able to identify haemorrhagic or proteinaceous contents and wall enhancement. The sensitivity and specificity of ultrasound for the diagnosis of cystic liver lesions is about 90%.
      • Lantinga M.A.
      • Gevers T.J.
      • Drenth J.P.
      Evaluation of hepatic cystic lesions.
      Ultrasound has many strengths: it is widely available, inexpensive and lacks radiation exposure.
      • Mavilia M.G.
      • Pakala T.
      • Molina M.
      • Wu G.Y.
      Differentiating cystic liver lesions: a review of imaging modalities, diagnosis and management.
      Contrast-enhanced ultrasound is indicated for complex cysts and helps to identify malignant cystic lesions by demonstrating vascularised septation or wall enhancement, features that are absent in benign lesions.
      • Corvino A.
      • Sandomenico F.
      • Setola S.V.
      • Corvino F.
      • Tafuri D.
      • Catalano O.
      Morphological and dynamic evaluation of complex cystic focal liver lesions by contrast-enhanced ultrasound: current state of the art.
      CT may detect gas or calcification but is less accurate for assessing cyst contents. In patients with impaired renal function, administration of contrast-agents may play a role in selecting the appropriate imaging modality.
      Among the different MRI sequences, half-Fourier single-shot turbo spin echo sequences are most useful as they allow for differentiation between solid tumours, haemangiomas, and cystic lesions.
      • Yu J.S.
      • Kim K.W.
      • Kim Y.H.
      • Jeong E.K.
      • Chien D.
      Comparison of multishot turbo spin echo and HASTE sequences for T2-weighted MRI of liver lesions.
      Conversely, the role of diffusion-weighted MRI in diagnosing cystic liver lesions is more controversial.
      • Mavilia M.G.
      • Pakala T.
      • Molina M.
      • Wu G.Y.
      Differentiating cystic liver lesions: a review of imaging modalities, diagnosis and management.
      Indeed, a complete MRI protocol should be performed including contrast-enhanced sequences.

      Simple hepatic cyst

      Ultrasound is the modality of choice to diagnose a simple hepatic cyst. Simple cysts are round or oval-shaped, anechoic with sharp and smooth borders with thin walls, and strong acoustic posterior enhancement.
      • Spiegel R.M.
      • King D.L.
      • Green W.M.
      Ultrasonography of primary cysts of the liver.
      Once diagnosed on ultrasound, CT and MRI are not indicated to further characterise simple hepatic cysts.
      Simple hepatic cysts may induce compression of bile ducts, but this is infrequent. At imaging, the peripheral bile duct dilatation inducing cyst is usually centrally (liver segment 4) located. These patients may present with rising alkaline phosphatase and even jaundice.
      • Cappell M.S.
      Obstructive jaundice from benign, nonparasitic hepatic cysts: identification of risk factors and percutaneous aspiration for diagnosis and treatment.

      Complicated hepatic cyst

      The most common complications of hepatic cysts are haemorrhage (see question 9) and infection (see question 5). In both, diagnosis requires imaging beyond ultrasound. Cyst haemorrhage is regularly observed in clinical practice but incidence rates remain unknown. The diagnostic criteria for cyst haemorrhage are detailed in question 9. Infected hepatic cysts that result from secondary bacterial infection of simple hepatic cysts are generally assumed to be rare.
      • Yoshida H.
      • Onda M.
      • Tajiri T.
      • Mamada Y.
      • Taniai N.
      • Mineta S.
      • et al.
      Infected hepatic cyst.
      Current diagnostic criteria rely on clinical, biochemical, microbial and radiological parameters as discussed in question 5.
      • Ihara K.
      • Naito S.
      • Yamaguchi W.
      • Mori Y.
      • Toda T.
      • Rai T.
      • et al.
      Hepatic cyst infection in an autosomal dominant polycystic kidney disease patient diagnosed by right pleural effusion.
      ,
      • Lantinga M.A.
      • Drenth J.P.
      • Gevers T.J.
      Diagnostic criteria in renal and hepatic cyst infection.

      Polycystic liver disease

      Current diagnosis of PLD is made in the presence of >10 hepatic cysts. On ultrasound, CT and MRI, PLD will appear as multiple hepatic cysts with the same features as simple solitary cysts. In the absence of symptoms or complications, no other imaging examination is required. CT or MRI is instrumental to evaluate the distribution of cysts in the liver, the presence of hepatic or portal vein compression and the volume of non-affected liver. Clinically apparent portal hypertension resulting from hepatic venous outflow obstruction is extremely rare. Currently, several systems can be used to classify PLD. These classifications such as Gigot’s, Kim’s and Schnelldorfer’s rely on number, size and distribution of hepatic cysts.
      • Gigot J.F.
      • Jadoul P.
      • Que F.
      • Van Beers B.E.
      • Etienne J.
      • Horsmans Y.
      • et al.
      Adult polycystic liver disease: is fenestration the most adequate operation for long-term management?.
      • Schnelldorfer T.
      • Torres V.E.
      • Zakaria S.
      • Rosen C.B.
      • Nagorney D.M.
      Polycystic liver disease: a critical appraisal of hepatic resection, cyst fenestration, and liver transplantation.
      • Kim H.
      • Park H.C.
      • Ryu H.
      • Kim K.
      • Kim H.S.
      • Oh K.H.
      • et al.
      Clinical correlates of mass effect in autosomal dominant polycystic kidney disease.
      In this regard, MRI should be preferred over CT, particularly in patients with renal insufficiency. Overall, MRI is superior to ultrasound and CT, and allows for better detection of small cysts in young individuals.
      • Bae K.T.
      • Zhu F.
      • Chapman A.B.
      • Torres V.E.
      • Grantham J.J.
      • Guay-Woodford L.M.
      • et al.
      Magnetic resonance imaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort.
      Complications of hepatic cysts in patients with PLD are similar to those seen in patients with simple hepatic cysts.

      Caroli disease

      Caroli disease (or type V lesions based on the Todani classification) is characterised by dilatation of intrahepatic bile ducts.
      • Todani T.
      • Watanabe Y.
      • Narusue M.
      • Tabuchi K.
      • Okajima K.
      Congenital bile duct cysts: classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst.
      Caroli disease needs to be distinguished from Caroli syndrome.
      • Caroli J.
      • Soupault R.
      • Kossakowski J.
      • Plocker L.
      • Paradowska
      Congenital polycystic dilation of the intrahepatic bile ducts; attempt at classification.
      Caroli syndrome features congenital liver fibrosis and kidney cysts in addition to type V biliary dilatations. CT and MRI typically demonstrate segmental intrahepatic saccular or fusiform cystic areas. The central dot sign that represents fibrovascular bundles within the dilated cystic intrahepatic ducts is typical of Caroli disease. Contrast-enhanced imaging reveals the continuity between cystic lesions and draining bile ducts.
      • Zangger P.
      • Grossholz M.
      • Mentha G.
      • Lemoine R.
      • Graf J.D.
      • Terrier F.
      MRI findings in Caroli's disease and intrahepatic pigmented calculi.
      Diagnostic accuracy is highest with magnetic resonance cholangiopancreaticography, as this allows for the optimal visualisation of the biliary tree. The diagnosis may best be confirmed in expert disease centres.

      Biliary hamartomas

      Biliary hamartomas may be hypoechoic, hyperechoic or mixed heterogenic echoic structures on ultrasound. The echogenicity is dependent on the presence of dilated bile ducts and fibrocollagenous stroma with biliary hamartomas. The size of hamartomas is typically between 2 to 10 mm.
      • Lev-Toaff A.S.
      • Bach A.M.
      • Wechsler R.J.
      • Hilpert P.L.
      • Gatalica Z.
      • Rubin R.
      The radiologic and pathologic spectrum of biliary hamartomas.
      ,
      • Saló J.
      • Bru C.
      • Vilella A.
      • Ginès P.
      • Gilabert R.
      • Castells A.
      • et al.
      Bile-duct hamartomas presenting as multiple focal lesions on hepatic ultrasonography.
      In addition, multiple “comet-tail” artifacts (a dense tapering trail of echoes just distal to a strongly reflecting structure) may be present in biliary hamartomas.
      • Luo T.Y.
      • Itai Y.
      • Eguchi N.
      • Kurosaki Y.
      • Onaya H.
      • Ahmadi Y.
      • et al.
      Von Meyenburg complexes of the liver: imaging findings.
      • Watanabe M.
      • Shiozawa K.
      • Ikehara T.
      • Sato A.
      • Matsui D.
      • Ogino Y.
      • et al.
      A case of solitary bile duct hamartoma with advanced gastric carcinoma: findings in contrast-enhanced ultrasonography.
      • Lung P.F.
      • Jaffer O.S.
      • Akbar N.
      • Sidhu P.S.
      • Ryan S.M.
      Appearances of von meyenburg complex on cross sectional imaging.
      • Hohmann J.
      • Loddenkemper C.
      • Albrecht T.
      Assessment of a biliary hamartoma with contrast-enhanced sonography using two different contrast agents.
      • Berry J.D.
      • Boxer M.E.
      • Rashid H.I.
      • Sidhu P.S.
      Case report: microbubble contrast-enhanced ultrasound characteristics of multiple biliary hamartomas (von Meyenberg Complexes).
      • Shi Q.S.
      • Xing L.X.
      • Jin L.F.
      • Wang H.
      • Lv X.H.
      • Du L.F.
      Imaging findings of bile duct hamartomas: a case report and literature review.
      On CT, biliary hamartomas appear as multiple hypoattenuating lesions, predominantly in the subcapsular and periportal areas, that are round or irregular in shape. No enhancement is observed, but they are more clearly visible after intravenous administration of iodinated contrast material.
      • Pech L.
      • Favelier S.
      • Falcoz M.T.
      • Loffroy R.
      • Krause D.
      • Cercueil J.P.
      Imaging of Von Meyenburg complexes.
      With MRI, biliary hamartomas are hypointense on T1-weighted sequences, and show markedly high intensity on T2-weighted sequences. They often possess an irregular shape with well-defined margins – features which have led to the term “starry sky” appearance. MR cholangiography has a high diagnostic sensitivity and may be used to confirm the absence of communication with the biliary tree.
      • Pech L.
      • Favelier S.
      • Falcoz M.T.
      • Loffroy R.
      • Krause D.
      • Cercueil J.P.
      Imaging of Von Meyenburg complexes.
      ,
      • Boraschi P.
      • Scalise P.
      • Tarantini G.
      • Colombatto P.
      • Donati F.
      MR imaging features of multiple biliary hamartomas (Von Meyenburg Complex): a pictorial review and differential diagnosis.
      On contrast-enhanced MR sequences, biliary hamartomas may display different patterns: no enhancement, or thin and regular rim of enhancement, or small enhancing mural nodule.
      • Tohmé-Noun C.
      • Cazals D.
      • Noun R.
      • Menassa L.
      • Valla D.
      • Vilgrain V.
      Multiple biliary hamartomas: magnetic resonance features with histopathologic correlation.

      Peribiliary cysts

      Peribiliary cysts are characterised by their peculiar distribution (predominantly perihilar and on both sides of the bile ducts) and small size (<1 cm). They are often observed in patients with portal hypertension and cirrhosis and may appear as discrete cysts, tubular structures paralleling the portal structures, or a string of cysts that simulate abnormal bile ducts.
      • Baron R.L.
      • Campbell W.L.
      • Dodd 3rd, G.D.
      Peribiliary cysts associated with severe liver disease: imaging-pathologic correlation.
      Ultrasound, CT or MRI may be used as diagnostic modalities (Fig. 1).
      • Itai Y.
      • Ebihara R.
      • Tohno E.
      • Tsunoda H.S.
      • Kurosaki Y.
      • Saida Y.
      • et al.
      Hepatic peribiliary cysts: multiple tiny cysts within the larger portal tract, hepatic hilum, or both.
      ,
      • Terayama N.
      • Matsui O.
      • Hoshiba K.
      • Kadoya M.
      • Yoshikawa J.
      • Gabata T.
      • et al.
      Peribiliary cysts in liver cirrhosis: US, CT, and MR findings.
      Figure thumbnail gr1
      Fig. 1Imaging characteristics of Caroli disease, biliary hamartomas and peribiliary cyts.
      (A,B) Caroli disease, contrast-enhanced T1-weighted MRI and MRI cholangiography showing intrahepatic bile duct dilatation with both saccular and fusiform features; (C) biliary hamartomas, MRI cholangiography showing small innumerable T2 hyperintense cystic lesions scattered throughout the hepatic parenchyma without any communication with bile ducts, which resembles a “starry sky”; (D) peribiliary cysts, coronal T2-weighted MRI showing well-demarcated hyperintense cysts in a hilar distribution.

      Which imaging technique is recommended for follow-up of cystic liver lesions?

      Recommendations
      • It is not recommended to follow asymptomatic patients because of simple hepatic cysts, biliary hamartomas or peribiliary cysts (LoE 3, strong recommendation, 96% consensus).
      • Ultrasound should be the first diagnostic modality used if symptoms occur in patients with simple hepatic cysts (LoE 3, strong recommendation, 96% consensus).
      • Routine follow-up with imaging after aspiration sclerotherapy or surgical procedures for hepatic cysts is not recommended (LoE 3, strong recommendation, 92% consensus).
      Follow-up of cystic liver lesions varies depending on the pathologic entity.

      Simple hepatic cysts

      Simple hepatic cysts are benign lesions that typically follow an indolent course without significant changes in size over time. Incidentally, cysts may grow and it is unclear why some simple cysts grow and others remain stable. There is no indication for follow-up of simple hepatic cysts whatever the size. If patients become symptomatic, imaging (ultrasound first) will assess the size and look for complications and compression. Symptomatic hepatic cysts can be treated surgically or with percutaneous aspiration sclerotherapy (see question 4). Post treatment imaging is not indicated, as treatment success is defined by symptom relief and not by volume reduction of hepatic cysts.
      • Neijenhuis M.K.
      • Wijnands T.F.M.
      • Kievit W.
      • Ronot M.
      • Gevers T.J.G.
      • Drenth J.P.H.
      Symptom relief and not cyst reduction determines treatment success in aspiration sclerotherapy of hepatic cysts.
      If imaging is performed post-treatment, CT or MRI allow for a good estimation of the volume of remnant cyst.

      Complicated hepatic cyst

      While intracystic haemorrhage within a hepatic cyst resolves spontaneously and does not require any treatment, an infected hepatic cyst necessitates active management. Treatment options for hepatic cyst infection are discussed in questions 6 to 8. Here, the need for imaging is dictated by the presence of symptoms or ongoing acute phase response. These patients may benefit from a contrast-enhanced CT, MRI or, if necessary, 18-fluorodeoxyglucose positron emission tomography-CT (18FDG PET-CT) and/or cyst aspiration. The diagnostic criteria for cyst haemorrhage and infection are discussed in questions 9 and 5.

      Polycystic liver disease

      Most patients with PLD are, and will remain, asymptomatic; hence imaging follow-up is not indicated. In others, the increasing volume of cysts may result in massive enlargement of the liver with abdominal pain, back pain, early satiety, dyspnoea, malnutrition and a significant impairment in quality of life.
      • Gabow P.A.
      • Johnson A.M.
      • Kaehny W.D.
      • Manco-Johnson M.L.
      • Duley I.T.
      • Everson G.T.
      Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease.
      Treatment may be considered when quality of life is altered, or in case of local complications as further discussed in question 18.
      • Boillot O.
      • Cayot B.
      • Guillaud O.
      • Crozet-Chaussin J.
      • Hervieu V.
      • Valette P.J.
      • et al.
      Partial major hepatectomy with cyst fenestration for polycystic liver disease: indications, short and long-term outcomes.
      Routine post treatment imaging is not indicated.
      • Neijenhuis M.K.
      • Wijnands T.F.M.
      • Kievit W.
      • Ronot M.
      • Gevers T.J.G.
      • Drenth J.P.H.
      Symptom relief and not cyst reduction determines treatment success in aspiration sclerotherapy of hepatic cysts.

      Caroli disease and Caroli syndrome

      Surveillance in Caroli disease and syndrome is mainly focused on the detection of cholangiocarcinoma. This is further discussed in question 22.

      Biliary hamartomas and peribiliary cysts

      To date, only a few case studies have reported a possible association between biliary hamartomas and hepatic malignancies, the majority of which were intrahepatic cholangiocarcinoma.
      • Orii T.
      • Ohkohchi N.
      • Sasaki K.
      • Satomi S.
      • Watanabe M.
      • Moriya T.
      Cholangiocarcinoma arising from preexisting biliary hamartoma of liver--report of a case.
      • Heinke T.
      • Pellacani L.B.
      • Costa Hde O.
      • Fuziy R.A.
      • Franco M.
      Hepatocellular carcinoma in association with bile duct hamartomas: report on 2 cases and review of the literature.
      • Xu A.M.
      • Xian Z.H.
      • Zhang S.H.
      • Chen X.F.
      Intrahepatic cholangiocarcinoma arising in multiple bile duct hamartomas: report of two cases and review of the literature.
      It is suggested that the presence of persistent chronic inflammation in some of the reported patients might explain the malignant transformation. We do not recommended imaging to follow patients with biliary hamartomas not associated with congenital hepatic fibrosis or Caroli disease. It is not recommended to follow patients because of peribiliary cysts.

      When should blood and cyst fluid measures of CEA, CA19-9 and TAG-72 be used for diagnosis in cystic liver diseases?

      Recommendations
      • The tumour markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in blood or cyst fluid cannot be used to discriminate between hepatic cysts (solitary or in PLD) and MCNs of the liver (LoE 2, strong recommendation, 100% consensus).
      • Tumour-associated glycoprotein 72 (TAG-72) in cyst fluid may help to distinguish between simple hepatic cysts and MCNs of the liver (LoE 3, weak recommendation, 95% consensus).
      Serum CA19-9 levels are elevated in up to 50% of patients with simple hepatic cysts or PLD, in 6-100% of patients with biliary cystadenomas and in 28-73% of biliary cystadenocarcinomas. No significant differences in serum CA19-9 levels were consistently observed between simple cysts and MCNs.
      • Arnaoutakis D.J.
      • Kim Y.
      • Pulitano C.
      • Zaydfudim V.
      • Squires M.H.
      • Kooby D.
      • et al.
      Management of biliary cystic tumors: a multi-institutional analysis of a rare liver tumor.
      • Choi H.K.
      • Lee J.K.
      • Lee K.H.
      • Lee K.T.
      • Rhee J.C.
      • Kim K.H.
      • et al.
      Differential diagnosis for intrahepatic biliary cystadenoma and hepatic simple cyst: significance of cystic fluid analysis and radiologic findings.
      • Fliszkiewicz M.
      • Niemczyk M.
      • Kulesza A.
      • Pączek L.
      Carbohydrate antigen 19-9 level in patients with autosomal dominant polycystic kidney disease.
      • Fukasawa H.
      • Kaneko M.
      • Niwa H.
      • Yasuda H.
      • Kumagai H.
      • Furuya R.
      Carbohydrate antigen 19-9 is significantly elevated in autosomal dominant polycystic kidney disease.
      • Kanaan N.
      • Goffin E.
      • Pirson Y.
      • Devuyst O.
      • Hassoun Z.
      Carbohydrate antigen 19-9 as a diagnostic marker for hepatic cyst infection in autosomal dominant polycystic kidney disease.
      • Lee C.W.
      • Tsai H.I.
      • Lin Y.S.
      • Wu T.H.
      • Yu M.C.
      • Chen M.F.
      Intrahepatic biliary mucinous cystic neoplasms: clinicoradiological characteristics and surgical results.
      • Sang X.
      • Sun Y.
      • Mao Y.
      • Yang Z.
      • Lu X.
      • Yang H.
      • et al.
      Hepatobiliary cystadenomas and cystadenocarcinomas: a report of 33 cases.
      • Waanders E.
      • van Keimpema L.
      • Brouwer J.T.
      • van Oijen M.G.
      • Aerts R.
      • Sweep F.C.
      • et al.
      Carbohydrate antigen 19-9 is extremely elevated in polycystic liver disease.
      • Zhang F.B.
      • Zhang A.M.
      • Zhang Z.B.
      • Huang X.
      • Wang X.T.
      • Dong J.H.
      Preoperative differential diagnosis between intrahepatic biliary cystadenoma and cystadenocarcinoma: a single-center experience.
      CA19-9 is expressed by the epithelial cells of (even benign) hepatic cysts and is released into serum and cyst fluid. The epithelial expression translates into higher concentrations of CA19-9 in cyst fluid compared to serum. The serum CA19-9 levels correlate with total hepatic cyst volume. However, CA19-9 levels in cyst fluid hardly discriminate between simple and malignant cysts (AUC 0.71, accuracy 19%) or between cystadenomas and cystadenocarcinomas.
      • Choi H.K.
      • Lee J.K.
      • Lee K.H.
      • Lee K.T.
      • Rhee J.C.
      • Kim K.H.
      • et al.
      Differential diagnosis for intrahepatic biliary cystadenoma and hepatic simple cyst: significance of cystic fluid analysis and radiologic findings.
      ,
      • Lee C.W.
      • Tsai H.I.
      • Lin Y.S.
      • Wu T.H.
      • Yu M.C.
      • Chen M.F.
      Intrahepatic biliary mucinous cystic neoplasms: clinicoradiological characteristics and surgical results.
      ,
      • Waanders E.
      • van Keimpema L.
      • Brouwer J.T.
      • van Oijen M.G.
      • Aerts R.
      • Sweep F.C.
      • et al.
      Carbohydrate antigen 19-9 is extremely elevated in polycystic liver disease.
      ,
      • Fuks D.
      • Voitot H.
      • Paradis V.
      • Belghiti J.
      • Vilgrain V.
      • Farges O.
      Intracystic concentrations of tumour markers for the diagnosis of cystic liver lesions.
      • Koffron A.
      • Rao S.
      • Ferrario M.
      • Abecassis M.
      Intrahepatic biliary cystadenoma: role of cyst fluid analysis and surgical management in the laparoscopic era.
      • Labib P.L.
      • Aroori S.
      • Bowles M.
      • Stell D.
      • Briggs C.
      Differentiating simple hepatic cysts from mucinous cystic neoplasms: radiological features, cyst fluid tumour marker analysis and multidisciplinary team outcomes.
      Serum CEA is normal in patients with simple hepatic cysts and elevated in up to 49% of patients with cystadenoma and in up to 75% with cystadenocarcinoma. However, serum CEA levels do not differ between patients with simple cysts and those with a cystadenoma and they had a low diagnostic accuracy for the distinction between cystadenomas and cystadenocarcinomas (AUC 0.69).
      • Arnaoutakis D.J.
      • Kim Y.
      • Pulitano C.
      • Zaydfudim V.
      • Squires M.H.
      • Kooby D.
      • et al.
      Management of biliary cystic tumors: a multi-institutional analysis of a rare liver tumor.
      ,
      • Choi H.K.
      • Lee J.K.
      • Lee K.H.
      • Lee K.T.
      • Rhee J.C.
      • Kim K.H.
      • et al.
      Differential diagnosis for intrahepatic biliary cystadenoma and hepatic simple cyst: significance of cystic fluid analysis and radiologic findings.
      ,
      • Lee C.W.
      • Tsai H.I.
      • Lin Y.S.
      • Wu T.H.
      • Yu M.C.
      • Chen M.F.
      Intrahepatic biliary mucinous cystic neoplasms: clinicoradiological characteristics and surgical results.
      ,
      • Zhang F.B.
      • Zhang A.M.
      • Zhang Z.B.
      • Huang X.
      • Wang X.T.
      • Dong J.H.
      Preoperative differential diagnosis between intrahepatic biliary cystadenoma and cystadenocarcinoma: a single-center experience.
      ,
      • Yu Q.
      • Chen T.
      • Wan Y.L.
      • Min J.
      • Cheng Y.
      • Guo H.
      Intrahepatic biliary cystadenocarcinoma: clinical analysis of 4 cases.
      Similar to CA19-9, CEA levels are elevated in hepatic cyst fluid compared to serum, but intracystic concentrations can hardly differentiate between different cyst entities, e.g., with an AUC of 0.71 and an accuracy of 22% for the distinction between benign and malignant cysts.
      • Choi H.K.
      • Lee J.K.
      • Lee K.H.
      • Lee K.T.
      • Rhee J.C.
      • Kim K.H.
      • et al.
      Differential diagnosis for intrahepatic biliary cystadenoma and hepatic simple cyst: significance of cystic fluid analysis and radiologic findings.
      ,
      • Lee C.W.
      • Tsai H.I.
      • Lin Y.S.
      • Wu T.H.
      • Yu M.C.
      • Chen M.F.
      Intrahepatic biliary mucinous cystic neoplasms: clinicoradiological characteristics and surgical results.
      ,
      • Fuks D.
      • Voitot H.
      • Paradis V.
      • Belghiti J.
      • Vilgrain V.
      • Farges O.
      Intracystic concentrations of tumour markers for the diagnosis of cystic liver lesions.
      • Koffron A.
      • Rao S.
      • Ferrario M.
      • Abecassis M.
      Intrahepatic biliary cystadenoma: role of cyst fluid analysis and surgical management in the laparoscopic era.
      • Labib P.L.
      • Aroori S.
      • Bowles M.
      • Stell D.
      • Briggs C.
      Differentiating simple hepatic cysts from mucinous cystic neoplasms: radiological features, cyst fluid tumour marker analysis and multidisciplinary team outcomes.
      TAG-72 (also referred to as carbohydrate antigen 72-4 [CA72-4]) in cyst fluid has shown the best diagnostic capabilities for discriminating between malignant cysts (>25 U/ml) and simple hepatic cysts (sensitivity 79%; Specificity 97%, AUC 0.98). However, the number of observations is low and the results are biased because the sample consists of only surgically acquired (symptomatic) cysts.
      • Fuks D.
      • Voitot H.
      • Paradis V.
      • Belghiti J.
      • Vilgrain V.
      • Farges O.
      Intracystic concentrations of tumour markers for the diagnosis of cystic liver lesions.
      ,
      • Zurli L.
      • Dembinski J.
      • Robert B.
      • Regimbeau J.M.
      Atypic large hepatic cyst with persistent elevated CA19.9 serum value: utility of intracystic CA72.4 dosage for a mini-invasive management.

      Which simple hepatic cysts should be treated with volume-reducing therapy?

      Recommendation
      • Symptomatic simple hepatic cysts without biliary communication should be treated with the best locally available volume-reducing therapy (LoE 2, strong recommendation, 100% consensus).
      Symptomatic simple hepatic cysts are usually treated by either percutaneous aspiration sclerotherapy, or cyst fenestration as volume-reducing therapy. With aspiration sclerotherapy, the cyst is first drained and temporarily exposed to a sclerosing agent. Cyst fenestration procedures entail a laparoscopy, followed by drainage and resection of the extrahepatic cyst wall. High quality randomised-controlled trials that directly compare these volume-reducing therapies have not yet been published. The available studies have a retrospective single centre design.
      • Antonacci N.
      • Ricci C.
      • Taffurelli G.
      • Casadei R.
      • Minni F.
      Systematic review of laparoscopic versus open surgery in the treatment of non-parasitic liver cysts.
      • Furumaya A.
      • van Rosmalen B.V.
      • de Graeff J.J.
      • Haring M.P.D.
      • de Meijer V.E.
      • van Gulik T.M.
      • et al.
      Systematic review on percutaneous aspiration and sclerotherapy versus surgery in symptomatic simple hepatic cysts.
      • Moorthy K.
      • Mihssin N.
      • Houghton P.W.
      The management of simple hepatic cysts: sclerotherapy or laparoscopic fenestration.
      • Qiu J.G.
      • Wu H.
      • Jiang H.
      • Huang J.W.
      • Pankaj P.
      • Xu Y.L.
      • et al.
      Laparoscopic fenestration vs open fenestration in patients with congenital hepatic cysts: a meta-analysis.
      • Wijnands T.F.
      • Görtjes A.P.
      • Gevers T.J.
      • Jenniskens S.F.
      • Kool L.J.
      • Potthoff A.
      • et al.
      Efficacy and safety of aspiration sclerotherapy of simple hepatic cysts: a systematic review.
      • Zhang J.Y.
      • Liu Y.
      • Liu H.Y.
      • Chen L.
      • Su D.W.
      • Wang Y.B.
      Comparison of the recurrence rates of nonparasitic hepatic cysts treated with laparoscopy or with open fenestration: a meta-analysis.
      Mere aspiration of cyst fluids invariably results in refilling of the cyst cavity with fluid.
      • Saini S.
      • Mueller P.R.
      • Ferrucci Jr., J.T.
      • Simeone J.F.
      • Wittenberg J.
      • Butch R.J.
      Percutaneous aspiration of hepatic cysts does not provide definitive therapy.
      Therefore, aspiration of cyst fluid without subsequent sclerotherapy should not be considered as definitive volume-reducing therapy. Sclerotherapy is possible with multiple substances such as 100% ethanol, 20% saline, tetracycline or polidocanol without clear evidence for superiority of any of the agents.
      • Wijnands T.F.
      • Görtjes A.P.
      • Gevers T.J.
      • Jenniskens S.F.
      • Kool L.J.
      • Potthoff A.
      • et al.
      Efficacy and safety of aspiration sclerotherapy of simple hepatic cysts: a systematic review.
      It is important to highlight that the volume reduction after aspiration sclerotherapy is slow in onset and may take at least 6 months. We advise against reintervention in the first 6 months after aspiration sclerotherapy. Reported volume reductions after aspiration sclerotherapy range between 76-100%, while symptom relief is obtained in 72-100% of cases and symptom disappearance occurs in 56-100%. The most frequent peri-interventional complications, e.g., ethanol intoxication and local pain, are seen after long duration (>1 hour) sclerotherapy with high-volume ethanol. The combination with the somatostatin analogue pasireotide does not improve the volume-reducing effect or patient-reported outcomes of aspiration sclerotherapy with ethanol.
      • Wijnands T.F.M.
      • Gevers T.J.G.
      • Lantinga M.A.
      • Te Morsche R.H.
      • Schultze Kool L.J.
      • Drenth J.P.H.
      Pasireotide does not improve efficacy of aspiration sclerotherapy in patients with large hepatic cysts, a randomized controlled trial.
      Laparoscopic and open cyst deroofing/fenestration are associated with a low (<8%) recurrence rate.
      • Furumaya A.
      • van Rosmalen B.V.
      • de Graeff J.J.
      • Haring M.P.D.
      • de Meijer V.E.
      • van Gulik T.M.
      • et al.
      Systematic review on percutaneous aspiration and sclerotherapy versus surgery in symptomatic simple hepatic cysts.
      Laparoscopy is preferred over laparotomy in view of the shorter procedural time, reduced postoperative hospital stays and less postoperative pain, while recurrence rates and symptom relief are comparable to the open approach.
      • Antonacci N.
      • Ricci C.
      • Taffurelli G.
      • Casadei R.
      • Minni F.
      Systematic review of laparoscopic versus open surgery in the treatment of non-parasitic liver cysts.
      ,
      • Qiu J.G.
      • Wu H.
      • Jiang H.
      • Huang J.W.
      • Pankaj P.
      • Xu Y.L.
      • et al.
      Laparoscopic fenestration vs open fenestration in patients with congenital hepatic cysts: a meta-analysis.
      ,
      • Zhang J.Y.
      • Liu Y.
      • Liu H.Y.
      • Chen L.
      • Su D.W.
      • Wang Y.B.
      Comparison of the recurrence rates of nonparasitic hepatic cysts treated with laparoscopy or with open fenestration: a meta-analysis.
      More extensive surgical procedures such as partial hepatectomy combined with cyst fenestration in PLD have been associated with a perioperative mortality rate of up to 14% and postoperative liver failure (mean follow-up time up of 6 and 8 years) with the need for liver transplantation in 2-3% of patients.
      • Boillot O.
      • Cayot B.
      • Guillaud O.
      • Crozet-Chaussin J.
      • Hervieu V.
      • Valette P.J.
      • et al.
      Partial major hepatectomy with cyst fenestration for polycystic liver disease: indications, short and long-term outcomes.
      ,
      • Chebib F.T.
      • Harmon A.
      • Irazabal Mira M.V.
      • Jung Y.S.
      • Edwards M.E.
      • Hogan M.C.
      • et al.
      Outcomes and durability of hepatic reduction after combined partial hepatectomy and cyst fenestration for massive polycystic liver disease.
      Different volume-reducing therapies have not been directly compared in the literature and as a consequence robust evidence on the superiority of any of available volume-reducing therapies is absent. As success of volume-reducing therapies is defined by symptom relief and not volume reduction, volume-reducing therapies should only be performed in symptomatic patients.
      Spontaneous rupture is rare, occurs in large hepatic cysts and may result from (minor) trauma. The rupture causes emptying of cyst contents into the peritoneal cavity or more rarely into the pleural cavity or duodenum.
      • Maki T.
      • Omi M.
      • Kaneko H.
      • Misu K.
      • Inomata H.
      • Nihei K.
      Spontaneous rupture of non-parasitic or non-neoplastic multiple and giant liver cysts: report of a case.
      Imaging shows cystic liver lesions are often irregular and associated with extrahepatic fluid effusion. The evidence base on the rupture of hepatic cysts comes from a few case reports.
      • Fong Z.V.
      • Wolf A.M.
      • Doria C.
      • Berger A.C.
      • Rosato E.L.
      • Palazzo F.
      Hemorrhagic hepatic cyst: report of a case and review of the literature with emphasis on clinical approach and management.
      • Imaoka Y.
      • Ohira M.
      • Kobayashi T.
      • Shimizu S.
      • Tahara H.
      • Kuroda S.
      • et al.
      Elective laparoscopic deroofing to treat the spontaneous rupture of a large simple liver cyst: a case report.
      • Inoue K.
      • Iguchi T.
      • Ito S.
      • Ohga T.
      • Nozoe T.
      • Shirabe K.
      • et al.
      Rerupture of nonparasitic liver cyst treated with cyst fenestration: a case report.
      • Marion Y.
      • Brevartt C.
      • Plard L.
      • Chiche L.
      Hemorrhagic liver cyst rupture: an unusual life-threatening complication of hepatic cyst and literature review.
      • Park J.
      Traumatic rupture of a non-parasitic simple hepatic cyst presenting as an acute surgical abdomen: case report.
      These studies reported a median cyst size (prior to rupture) of >10 cm (range 2-35 cm). Risk factors for cyst rupture include cyst haemorrhage, cyst infection, trauma and intervention. Imaging demonstrates new onset ascites and signs of ruptured hepatic cyst wall, accompanied by cyst haemorrhage in about half of cases. It is unclear whether cyst haemorrhage (with increased intracystic pressure) is a cause or consequence of cyst rupture. Given the low number of observations and the relatively high prevalence of simple hepatic cysts in the population (up to 18%), symptomatic cyst rupture must be a rare event. Although most case reports documented a full recovery of patients after cyst rupture, a few fatal outcomes have been reported. These outcomes do not justify a recommendation on pre-emptive volume-reducing therapy.

      What are the diagnostic criteria for hepatic cyst infection?

      Recommendations
      • Hepatic cyst infection should be considered as definite in the presence of neutrophil debris and/or microorganisms in cyst aspirate showing evidence of infection (LoE 4, strong recommendation, 100% consensus).
      • Hepatic cyst infection should be considered as likely in the presence of the features listed in Table 3 (LoE 4, strong recommendation, 100% consensus).
      • Radiological findings listed in Table 3 may suggest hepatic cyst infections and may be used during the diagnostic work-up (LoE 3, weak recommendation, 100% consensus).
      Hepatic cyst infection may be a complication of simple hepatic cysts as well as PLD. While the diagnosis may seem elementary, hepatic cyst infections often present a diagnostic conundrum. A cyst aspirate showing evidence of infection (neutrophil debris and/or microorganism) is the golden standard to establish a cyst infection.
      • Lantinga M.A.
      • Drenth J.P.
      • Gevers T.J.
      Diagnostic criteria in renal and hepatic cyst infection.
      ,
      • Sallée M.
      • Rafat C.
      • Zahar J.R.
      • Paulmier B.
      • Grünfeld J.P.
      • Knebelmann B.
      • et al.
      Cyst infections in patients with autosomal dominant polycystic kidney disease.
      • Jouret F.
      • Lhommel R.
      • Beguin C.
      • Devuyst O.
      • Pirson Y.
      • Hassoun Z.
      • et al.
      Positron-emission computed tomography in cyst infection diagnosis in patients with autosomal dominant polycystic kidney disease.
      • Piccoli G.B.
      • Arena V.
      • Consiglio V.
      • Deagostini M.C.
      • Pelosi E.
      • Douroukas A.
      • et al.
      Positron emission tomography in the diagnostic pathway for intracystic infection in adpkd and "cystic" kidneys. a case series.
      • Suwabe T.
      • Ubara Y.
      • Sumida K.
      • Hayami N.
      • Hiramatsu R.
      • Yamanouchi M.
      • et al.
      Clinical features of cyst infection and hemorrhage in ADPKD: new diagnostic criteria.
      However, this finding is relatively rare and does not contribute to the diagnosis in the majority of cases. Cyst infections are more frequently diagnosed using other clinical, laboratory and imaging findings: fever (temperature >38.5° C for >3 days) without other sources of fever detectable, CT or MRI detecting gas in a cyst, 18FDG PET-CT showing increased FDG avidity of the cyst lining relative to normal parenchyma, tenderness in the liver area, increased C-reactive protein, increased leukocyte count (>11,000/L) or positive blood culture.
      • Lantinga M.A.
      • Drenth J.P.
      • Gevers T.J.
      Diagnostic criteria in renal and hepatic cyst infection.
      ,
      • Sallée M.
      • Rafat C.
      • Zahar J.R.
      • Paulmier B.
      • Grünfeld J.P.
      • Knebelmann B.
      • et al.
      Cyst infections in patients with autosomal dominant polycystic kidney disease.
      • Jouret F.
      • Lhommel R.
      • Beguin C.
      • Devuyst O.
      • Pirson Y.
      • Hassoun Z.
      • et al.
      Positron-emission computed tomography in cyst infection diagnosis in patients with autosomal dominant polycystic kidney disease.
      • Piccoli G.B.
      • Arena V.
      • Consiglio V.
      • Deagostini M.C.
      • Pelosi E.
      • Douroukas A.
      • et al.
      Positron emission tomography in the diagnostic pathway for intracystic infection in adpkd and "cystic" kidneys. a case series.
      • Suwabe T.
      • Ubara Y.
      • Sumida K.
      • Hayami N.
      • Hiramatsu R.
      • Yamanouchi M.
      • et al.
      Clinical features of cyst infection and hemorrhage in ADPKD: new diagnostic criteria.
      • Suwabe T.
      • Ubara Y.
      • Higa Y.
      • Nakanishi S.
      • Sogawa Y.
      • Nomura K.
      • et al.
      Infected hepatic and renal cysts: differential impact on outcome in autosomal dominant polycystic kidney disease.
      Other infectious causes, e.g. urinary tract infections or pneumonia, should be excluded using urine culture tests and chest x-rays .
      Table 3Criteria for hepatic cyst infection and radiological findings suggestive of hepatic cyst infection.
      Criteria definite hepatic cyst infectionCriteria likely hepatic cyst infection (after exclusion of other sources)
      • Cyst aspiration showing evidence of infection (neutrophil debris and/or microorganism)
      • Fever (temperature >38.5°C for >3 days) with no other source of fever detectable
      • CT or MRI detecting gas in a cyst
      • 18FDG PET-CT showing increased FDG activity lining a cyst compared to normal parenchyma
      • Tenderness in the liver area
      • Increased C-reactive protein
      • Increased leukocyte count (>11,000/L)
      • Positive blood culture
      Radiological findings suggestive of hepatic cyst infection
      • Liver ultrasound: debris with a thick wall and/or a distal acoustic enhancement in at least one cyst
      • Liver CT/MRI: enhanced wall thickening and/or perilesional inflammation in at least one cyst
      • MRI: high signal intensity on diffusion-weighted images, fluid-fluid level, wall thickening, or gas in at least one cyst
      • Positron emission tomography scan (18FDG PET-CT): increased FDG activity lining a cyst compared to normal parenchyma
      18FDG PET-CT, 18fluorodeoxyglucose positron emission tomography-CT.
      Serum liver tests play no role in the diagnosis of hepatic cyst infections.
      • Jouret F.
      • Hogan M.C.
      • Chebib F.T.
      A practical guide for the management of acute abdominal pain with fever in patients with autosomal dominant polycystic kidney disease.
      In case reports, elevated serum CA19-9 levels compared to baseline measurements may be observed.
      • Kanaan N.
      • Goffin E.
      • Pirson Y.
      • Devuyst O.
      • Hassoun Z.
      Carbohydrate antigen 19-9 as a diagnostic marker for hepatic cyst infection in autosomal dominant polycystic kidney disease.
      However, we do not recommend routine determination of CA19-9 due to the low level of this evidence and the unspecific nature of this disease marker as discussed in question 3.
      Standard radiological imaging is of little help in establishing hepatic cyst infection due to the absence of reliable features that differentiate infected and non-infected hepatic cysts.
      • Oh J.
      • Shin C.I.
      • Kim S.Y.
      Infected cyst in patients with autosomal dominant polycystic kidney disease: analysis of computed tomographic and ultrasonographic imaging features.
      ,
      • Suwabe T.
      • Ubara Y.
      • Ueno T.
      • Hayami N.
      • Hoshino J.
      • Imafuku A.
      • et al.
      Intracystic magnetic resonance imaging in patients with autosomal dominant polycystic kidney disease: features of severe cyst infection in a case-control study.
      Inflammation parameters, e.g. enhanced wall thickening, high signal intensity on diffusion-weighted images, fluid-fluid level, or intracystic gas bubbles observed on CT or MRI may substantiate the diagnosis of hepatic cyst infection. Other non-specific features observed in infected hepatic cysts include heterogenous cyst content and steep increase in the cystic diameter compared to previous evaluations. 18FDG PET-CT is superior to other imaging modalities and can be used to support the diagnosis of infected cysts in doubtful cases.
      • Jouret F.
      • Lhommel R.
      • Beguin C.
      • Devuyst O.
      • Pirson Y.
      • Hassoun Z.
      • et al.
      Positron-emission computed tomography in cyst infection diagnosis in patients with autosomal dominant polycystic kidney disease.
      ,
      • Piccoli G.B.
      • Arena V.
      • Consiglio V.
      • Deagostini M.C.
      • Pelosi E.
      • Douroukas A.
      • et al.
      Positron emission tomography in the diagnostic pathway for intracystic infection in adpkd and "cystic" kidneys. a case series.
      ,
      • Pijl J.P.
      • Glaudemans A.
      • Slart R.
      • Kwee T.C.
      (18)F-FDG PET/CT in autosomal dominant polycystic kidney disease patients with suspected cyst infection.
      • Neuville M.F.
      • Lovinfosse P.
      • Jadoul A.
      • Thys M.
      • Seidel L.
      • Hustinx R.
      • et al.
      The use of a visual 4-point scoring scale improves the yield of (18)F-FDG PET-CT imaging in the diagnosis of renal and hepatic cyst infection in patients with autosomal dominant polycystic kidney disease.
      • Ronsin C.
      • Bailly C.
      • Le Turnier P.
      • Ville S.
      Value of FDG-PET/CT in monitoring cyst infections in patients with autosomal dominant polycystic renal disease.
      • Morii K.
      • Yamamoto T.
      • Nakamura S.
      • Okushin H.
      Infectious hepatic cyst: an underestimated complication.
      • Bleeker-Rovers C.P.
      • de Sévaux R.G.
      • van Hamersvelt H.W.
      • Corstens F.H.
      • Oyen W.J.
      Diagnosis of renal and hepatic cyst infections by 18-F-fluorodeoxyglucose positron emission tomography in autosomal dominant polycystic kidney disease.
      If the diagnosis of infection is equivocal, fluid aspiration can be performed to confirm the diagnosis.

      Which antibiotic therapy is recommended in cyst infection?

      Recommendations
      • Fluoroquinolones and third-generation cephalosporins are recommended as empirical first-line antibiotics for hepatic cyst infection (LoE 2, strong recommendation, 90% consensus).
      • The recommended duration of antibiotic therapy is 4-6 weeks (LoE 4, strong recommendation, 100% consensus).
      Antibiotic therapy of hepatic cyst infections is of utmost importance and should be administered as soon as possible according to local practice formularies. Without adequate treatment, hepatic cyst infections can lead to sepsis and ultimately death. Most hepatic cyst infections are caused by gut bacteria. Escherichia coli is the most frequent isolate, fuelling the concept that bacterial translocation from the gut is pivotal.
      • Lantinga M.A.
      • de Sévaux R.G.L.
      • Gevers T.J.G.
      • Oyen W.J.G.
      • de Fijter J.W.
      • Soonawala D.
      • et al.
      Clinical predictors of escalating care in hepatic and renal cyst infection in autosomal dominant polycystic kidney and liver disease.
      ,
      • Suwabe T.
      • Araoka H.
      • Ubara Y.
      • Kikuchi K.
      • Hazue R.
      • Mise K.
      • et al.
      Cyst infection in autosomal dominant polycystic kidney disease: causative microorganisms and susceptibility to lipid-soluble antibiotics.
      Antibiotics, in particular monotherapy, are not universally successful and a meta-analysis documented treatment failure in up to 70%.
      • Jouret F.
      • Hogan M.C.
      • Chebib F.T.
      A practical guide for the management of acute abdominal pain with fever in patients with autosomal dominant polycystic kidney disease.
      ,
      • Lantinga M.A.
      • Geudens A.
      • Gevers T.J.
      • Drenth J.P.
      Systematic review: the management of hepatic cyst infection.
      Antibiotic penetrance is a key success factor. Carbapenems and cefazolin poorly penetrate into the cyst fluid.
      • Hamanoue S.
      • Suwabe T.
      • Ubara Y.
      • Kikuchi K.
      • Hazue R.
      • Mise K.
      • et al.
      Cyst infection in autosomal dominant polycystic kidney disease: penetration of meropenem into infected cysts.
      ,
      • Lantinga M.A.
      • Wijnands T.F.
      • Te Morsche R.H.
      • de Sévaux R.G.
      • Kuipers S.
      • Allegaert K.
      • et al.
      Hepatic cyst penetration of cefazolin in patients receiving aspiration sclerotherapy.
      In renal cysts, trimethoprim-sulfamethoxazole performs better but data in hepatic cysts are lacking.
      • Elzinga L.W.
      • Golper T.A.
      • Rashad A.L.
      • Carr M.E.
      • Bennett W.M.
      Trimethoprim-sulfamethoxazole in cyst fluid from autosomal dominant polycystic kidneys.
      Antibiotic diffusion into infected cysts may be further affected by inflammation-induced hyperpermeability of blood vessels.
      • Elzinga L.W.
      • Golper T.A.
      • Rashad A.L.
      • Carr M.E.
      • Bennett W.M.
      Trimethoprim-sulfamethoxazole in cyst fluid from autosomal dominant polycystic kidneys.
      ,
      • Bennett W.M.
      • Elzinga L.
      • Pulliam J.P.
      • Rashad A.L.
      • Barry J.M.
      Cyst fluid antibiotic concentrations in autosomal-dominant polycystic kidney disease.
      Repeated antibiotic courses, drainage and surgical procedures may contribute to the emergence of resistant bacterial strains.
      • Suwabe T.
      • Araoka H.
      • Ubara Y.
      • Kikuchi K.
      • Hazue R.
      • Mise K.
      • et al.
      Cyst infection in autosomal dominant polycystic kidney disease: causative microorganisms and susceptibility to lipid-soluble antibiotics.
      ,
      • Wijnands T.F.
      • Lantinga M.A.
      • Drenth J.P.
      Hepatic cyst infection following aspiration sclerotherapy: a case series.
      Fluoroquinolones (ciprofloxacin) and third-generation cephalosporins remain the standard of care treatment for hepatic cyst infections.
      • Jouret F.
      • Hogan M.C.
      • Chebib F.T.
      A practical guide for the management of acute abdominal pain with fever in patients with autosomal dominant polycystic kidney disease.
      Although there is no evidence for combination of ciprofloxacin with a cephalosporin, it may be reasonable in severe cases.
      • Sallée M.
      • Rafat C.
      • Zahar J.R.
      • Paulmier B.
      • Grünfeld J.P.
      • Knebelmann B.
      • et al.
      Cyst infections in patients with autosomal dominant polycystic kidney disease.
      There is no data on the efficacy of alternative delivery strategies of antibiotics such as flushing cysts with antibiotics or instillation of antibiotics into cysts.
      When faced with hepatic cyst infection, patients and clinicians should adhere to clinical reasoning comparable to other systemic infections: i) use quick sequential organ failure assessment in the clinical algorithm, ii) tailor antibiotic therapy to blood cultures (though these are often negative in hepatic cyst infections), iii) adjust antibiotic therapy to the local resistance profile, iv) adapt drug dosage to renal function and v) suspect fungal infection if antibiotics do not lead to clinical improvement. Efficacy of antibiotic treatment and infection eradication are defined by the disappearance of symptoms such as fever, normalisation of C-reactive protein levels, and at least 2 negative blood cultures. While formal evidence for duration of antibiotic therapy is lacking, a regimen of parenteral treatment followed by a prolonged course of oral antibiotics (4-6 weeks total antibiotic treatment) seems reasonable.
      Most cyst infections will be singular events, but some patients, especially those with a compromised immune system, e.g. after renal transplantation in ADPKD, are at risk of recurrence. In patients with recurrent cyst infections that severely compromise quality of life, liver transplantation may be considered.
      • Kirchner G.I.
      • Rifai K.
      • Cantz T.
      • Nashan B.
      • Terkamp C.
      • Becker T.
      • et al.
      Outcome and quality of life in patients with polycystic liver disease after liver or combined liver-kidney transplantation.
      ,
      • Issa Z.
      • Ciccarelli O.
      • Devresse A.
      • Kanaan N.
      • Larranaga Lapique E.
      • De Greef J.
      • et al.
      Sequential liver-kidney transplantation for recurrent liver cysts infection in a patient with autosomal dominant polycystic kidney disease: a case report.

      Should antibiotics/probiotics be used in hepatic cyst infection to prevent recurrence?

      Recommendation
      • Secondary prophylaxis for hepatic cyst infection is not recommended. (LoE 5, strong recommendation, 92% consensus).
      Statement
      • Robust evidence to recommend selective decontamination of the digestive tract to prevent hepatic cyst infection is lacking (LoE 4, 100% consensus).
      Different approaches to secondary prophylaxis for hepatic cyst infection can be proposed: i) Continuous use of antibiotics, and ii) selective decontamination of the digestive tract. Currently, no evidence for systematic secondary prophylaxis using antibiotics or probiotics is available. Selective decontamination of the digestive tract controls overgrowth of potential pathogens in the gut and intends to prevent opportunistic infections. It may reduce the incidence of recurrent hepatic cyst infection. Polymyxin with neomycin may be a good option for selective decontamination of the digestive tract,
      • Bernts L.H.P.
      • Dekker S.E.I.
      • Soonawala D.
      • Brüggemann R.J.M.
      • Wertheim H.F.L.
      • de Fijter J.W.
      • et al.
      Efficacy and safety of selective decontamination of the digestive tract (SDD) to prevent recurrent hepatic cyst infections in polycystic liver disease: a retrospective case series.
      but there is currently insufficient evidence available to fully recommend its application to prevent hepatic cyst infection.

      In which patients is drainage indicated for cyst infection?

      Recommendation
      • Drainage of infected hepatic cysts may be pursued in the presence of any (combination) of the factors listed in Box 1 (LoE 3, weak recommendation, 90% consensus).
      Drainage of infected hepatic cysts may be considered in some cases. The main goals for drainage reported are: i) non-response to antibiotic treatment and ii) recurrence of cyst infections after initial antibiotic therapy. In several studies, drainage and antibiotics prove more effective than antibiotics alone.
      • Sallée M.
      • Rafat C.
      • Zahar J.R.
      • Paulmier B.
      • Grünfeld J.P.
      • Knebelmann B.
      • et al.
      Cyst infections in patients with autosomal dominant polycystic kidney disease.
      ,
      • Jouret F.
      • Lhommel R.
      • Beguin C.
      • Devuyst O.
      • Pirson Y.
      • Hassoun Z.
      • et al.
      Positron-emission computed tomography in cyst infection diagnosis in patients with autosomal dominant polycystic kidney disease.
      ,
      • Telenti A.
      • Torres V.E.
      • Gross Jr., J.B.
      • Van Scoy R.E.
      • Brown M.L.
      • Hattery R.R.
      Hepatic cyst infection in autosomal dominant polycystic kidney disease.
      A meta-analysis found that 64% of infected cysts required drainage.
      • Lantinga M.A.
      • Geudens A.
      • Gevers T.J.
      • Drenth J.P.
      Systematic review: the management of hepatic cyst infection.
      This may be a consequence of the severity of the infection, the inability of antibiotics to adequately penetrate the cyst, or patient-specific factors. Patients with larger cysts, defined as a diameter >5 cm are more likely to require drainage.
      • Sallée M.
      • Rafat C.
      • Zahar J.R.
      • Paulmier B.
      • Grünfeld J.P.
      • Knebelmann B.
      • et al.
      Cyst infections in patients with autosomal dominant polycystic kidney disease.
      Drainage may also be pursued in patients who do not respond to empirical antibiotic therapy, after isolation of pathogens from a cyst aspirate, in patients with a severely compromised immune system and when intracystic gas is detected on imaging. 18FDG PET-CT may aid in the identification of the localisation of infected cysts (see question 5) .
      We advise caution in pursuing drainage of infected hepatic cysts in patients with PLD. It is difficult to identify the incriminated cyst in PLD and the infection may spread to adjacent cysts if drainage is performed. Percutaneous or laparoscopic drainage should be performed in a similar fashion as for pyogenic liver abscesses.

      Which imaging technique is recommended to diagnose cystic haemorrhage?

      Recommendations
      • Imaging to detect intracystic haemorrhage may be performed in patients with sudden and severe abdominal pain (LoE 4, weak recommendation, 96% consensus).
      • Ultrasound (showing sediment or mobile septations) and/or MRI (heterogeneous and intense signal on both T1- and T2-weighted sequences) may be used to diagnose cyst haemorrhage (LoE 3, weak recommendation, 96% consensus).
      • CT is not recommended to diagnose cyst haemorrhage (LoE 4, strong recommendation, 91% consensus).
      Intracystic haemorrhage results from injury to fragile blood vessels of the cyst wall lining and is by far the most frequent complication of hepatic cysts. Cyst haemorrhage is mostly seen in patients with larger (arbitrarily defined as >8 cm) cysts
      • Shehi E.
      • Fortuzi K.
      • Ghazanfar H.
      • Mehershahi S.
      • Balar B.
      Apixaban causing hepatic cystic bleeding: a rare but a life-threatening complication.
      and may occur spontaneously, as a complication of percutaneous aspiration sclerotherapy, or as a consequence of a cyst rupture.
      Clinical manifestations consist of sudden, severe pain (observed in 80% of patients) without haemodynamic instability and the risk increases with the size of the cyst.
      • Fong Z.V.
      • Wolf A.M.
      • Doria C.
      • Berger A.C.
      • Rosato E.L.
      • Palazzo F.
      Hemorrhagic hepatic cyst: report of a case and review of the literature with emphasis on clinical approach and management.
      Local abdominal pain will resolve in few days to weeks. A drop in haemoglobin levels is exceptional, but may occur.
      • Hanazaki K.
      • Wakabayashi M.
      • Mori H.
      • Sodeyama H.
      • Yoshizawa K.
      • Yokoyama S.
      • et al.
      Hemorrhage into a simple liver cyst: diagnostic implications of a recent case.
      Serum concentrations of CA19-9 may increase and have been reported to decrease after the acute episode.
      • Yoshida H.
      • Onda M.
      • Tajiri T.
      • Mamada Y.
      • Taniai N.
      • Uchida E.
      • et al.
      Intracystic hemorrhage of a simple hepatic cyst.
      Conservative management is preferred and interventions such as aspiration (with or without sclerotherapy) of cyst content, or laparoscopic deroofing of the cyst dome should be avoided in active haemorrhage.
      • Fong Z.V.
      • Wolf A.M.
      • Doria C.
      • Berger A.C.
      • Rosato E.L.
      • Palazzo F.
      Hemorrhagic hepatic cyst: report of a case and review of the literature with emphasis on clinical approach and management.
      At ultrasonography, heterogenous hyperechoic and mobile material, corresponding to clots, and thin mobile septations may be observed in haemorrhagic cysts (Fig. 2). On contrast-enhanced ultrasound, the lack of enhancement of the intracystic structures is highly suggestive of clotting.
      • Akiyama T.
      • Inamori M.
      • Saito S.
      • Takahashi H.
      • Yoneda M.
      • Fujita K.
      • et al.
      Levovist ultrasonography imaging in intracystic hemorrhage of simple liver cyst.
      CT is usually unable to detect intracystic haemorrhage but can be used to detect extravasation of cyst contents in the abdominal cavity in rare cases of cyst wall rupture.
      • Mavilia M.G.
      • Pakala T.
      • Molina M.
      • Wu G.Y.
      Differentiating cystic liver lesions: a review of imaging modalities, diagnosis and management.
      ,
      • Fong Z.V.
      • Wolf A.M.
      • Doria C.
      • Berger A.C.
      • Rosato E.L.
      • Palazzo F.
      Hemorrhagic hepatic cyst: report of a case and review of the literature with emphasis on clinical approach and management.
      ,
      • Wilcox D.M.
      • Weinreb J.C.
      • Lesh P.
      MR imaging of a hemorrhagic hepatic cyst in a patient with polycystic liver disease.
      MRI is very specific as haemorrhagic cysts are hyperintense on both T1- and T2-weighted sequences
      • Vilgrain V.
      • Silbermann O.
      • Benhamou J.P.
      • Nahum H.
      MR imaging in intracystic hemorrhage of simple hepatic cysts.
      (Fig. 2). The heterogeneous hyperintensity on T1- and T2-weighted sequences may persist for several months.
      • Kawano Y.
      • Yoshida H.
      • Mamada Y.
      • Taniai N.
      • Mineta S.
      • Yoshioka M.
      • et al.
      Intracystic hemorrhage required no treatment from one of multiple hepatic cysts.
      In most cases, the signal is heterogeneous on T1-weighted sequences and thickened wall and fluid-fluid level (represented by blood-filled lakes between septa) may be seen. Very rarely, round mural nodules (some of them enhancing) are seen in haemorrhagic cysts, mimicking MCNs of the liver.
      • Kitajima Y.
      • Okayama Y.
      • Hirai M.
      • Hayashi K.
      • Imai H.
      • Okamoto T.
      • et al.
      Intracystic hemorrhage of a simple liver cyst mimicking a biliary cystadenocarcinoma.
      Interestingly in a series of 14 patients with haemorrhagic hepatic cysts, all cases showed wall calcifications.
      • Kohno S.
      • Arizono S.
      • Isoda H.
      • Yoshizawa A.
      • Togashi K.
      Imaging findings of hemorrhagic hepatic cysts with enhancing mural nodules.
      In patients with multiple cysts, MRI may show varying intensities in the cyst contents, which is related to different degrees and durations since haemorrhage.
      • Davis P.L.
      • Kanal E.
      • Farnum G.N.
      • Van Thiel D.H.
      • Iwatsuki S.M.
      MR imaging of multiple hepatic cysts in a patient with polycystic liver disease.
      Calcification of the cyst lining may ensue after cyst haemorrhage and is visible by high attenuation values on CT scan.
      Figure thumbnail gr2
      Fig. 2Haemorrhagic hepatic cyst and post-haemorrhage calcification.
      (A-C) haemorrhagic hepatic cyst. Ultrasound (panel A) shows a cystic lesion surrounded by a thin wall. Presence of multiple septations that do not enhance on contrast-enhanced ultrasound (not shown). On MRI (T1- and T2-weighted MRI) the lesion is strongly hyperintense on T2 and has intermediate signal on T1. Internal septations are strongly hyperintense on T1 and correspond to haemorrhagic septations. (D) Calcification after cyst haemorrhage.

      Should anticoagulants and antiplatelet therapy be stopped in patients with cyst haemorrhage?

      Recommendations
      • Temporary interruption of anticoagulants in hepatic cyst haemorrahge is recommended (LoE 5, strong recommendation, 96% consensus).
      • Anticoagulants may be resumed between 7–15 days after the onset of hepatic cyst haemorrhage (LoE 5, weak recommendation, 100% consensus).
      Use of anticoagulation, especially in the setting of supratherapeutic international normalised ratio is an important risk factor for cyst haemorrhage. There are no randomised data that can guide how to handle anticoagulants during cyst haemorrhage, but it is reasonable to extrapolate data from gastrointestinal haemorrhage management. To aid conservative management and to stop ongoing haemorrhage, immediate interruption of all anticoagulants is prudent. There is no role for the administration of vitamin K, intravenous prothrombin complex concentrate or fresh frozen plasma in hepatic cyst haemorrhage, unless in unusual cases of haemodynamic instability.
      • Gralnek I.M.
      • Stanley A.J.
      • Morris A.J.
      • Camus M.
      • Lau J.
      • Lanas A.
      • et al.
      Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2021.
      Anticoagulant therapy can be reinitiated in most patients after haemostasis is achieved but is subject to a number of considerations. Available evidence from non-cystic haemorrhage literature indicates that restarting anticoagulants between 7–15 days after the onset of haemorrhage may best balance the risk of recurrent haemorrhage, and thromboembolism.
      • Witt D.M.
      What to do after the bleed: resuming anticoagulation after major bleeding.
      ,
      • Milling T.J.
      • Refaai M.A.
      • Sengupta N.
      Anticoagulant reversal in gastrointestinal bleeding: review of treatment guidelines.
      Given the non-life threatening nature of cyst bleeding, anticoagulants may be restarted earlier in cases with high risks for thromboembolisms. It seems reasonable to assume that the risks and benefits of resuming newer direct oral anticoagulants are largely similar to those of vitamin K antagonists in view of similar efficacy and safety in clinical trials. Antiplatelet agents include low-dose aspirin and thienopyridines (such as clopidogrel, prasugrel, ticlopidine) that irreversibly inhibit platelet aggregation, ticagrelor a reversible P2Y12 receptor antagonist, and vorapaxar, a protease-activated receptor antagonist that inhibits thrombin. We advise interrupting aspirin for 3 days following the onset of cyst haemorrhage and, in patients receiving double antiplatelet therapy, continuing the P2Y12 inhibitor and interrupting aspirin for 3 days.
      • Halvorsen S.
      • Storey R.F.
      • Rocca B.
      • Sibbing D.
      • Ten Berg J.
      • Grove E.L.
      • et al.
      Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis.

      Which worrisome features distinguish hepatic cysts from MCNs of the liver and warrant the need for surgical intervention?

      Recommendations
      • A combination of ≥1 major and ≥1 minor feature listed in Table 4 may be considered as worrisome features for MCNs of the liver (LoE 3, weak recommendation, 95% consensus).
      • MRI should be used to characterise hepatic cysts with worrisome features (LoE 3, strong recommendation, 100% consensus).
      MCNs of the bile ducts are rare cystic lesions of the liver, formerly referred to as “biliary cystadenoma,” “biliary cystadenocarcinoma”. They are defined as a cystic epithelial neoplasm lined by cuboidal, columnar, or flattened mucin-producing epithelium overlying ovarian-like hypercellular stroma.
      • Nakanuma Y.K.D.
      • Zen Y.
      • Komuta M.
      Mucinous cystic neoplasm of the liver and biliary system.
      Presence of ovarian-like hypercellular stroma and absence of bile duct communication are the 2 hallmarks that differentiate MCNs from intraductal papillary neoplasms of the bile duct. Caution is warranted when interpreting the literature published prior to the distinction of these 2 entities .
      Table 4Worrisome features in mucinous cystic neoplasms of the liver.
      Major worrisome featuresMinor worrisome features
      Thick septationUpstream biliary dilatation
      NodularityThin septations
      Internal haemorrhage
      Perfusional change
      <3 coexistent hepatic cysts
      MCNs mostly occur in middle-aged women.
      • Arnaoutakis D.J.
      • Kim Y.
      • Pulitano C.
      • Zaydfudim V.
      • Squires M.H.
      • Kooby D.
      • et al.
      Management of biliary cystic tumors: a multi-institutional analysis of a rare liver tumor.
      ,
      • Zen Y.
      • Jang K.T.
      • Ahn S.
      • Kim D.H.
      • Choi D.W.
      • Choi S.H.
      • et al.
      Intraductal papillary neoplasms and mucinous cystic neoplasms of the hepatobiliary system: demographic differences between Asian and Western populations, and comparison with pancreatic counterparts.
      MCNs are commonly symptomatic (86%), with various clinical manifestations: abdominal pain, fullness, or early satiety due to large size and mass effect.
      • Arnaoutakis D.J.
      • Kim Y.
      • Pulitano C.
      • Zaydfudim V.
      • Squires M.H.
      • Kooby D.
      • et al.
      Management of biliary cystic tumors: a multi-institutional analysis of a rare liver tumor.
      MCNs may present with low-grade dysplasia, high-grade dysplasia, or invasive carcinoma. The vast majority of MCNs are benign, 3-6% are invasive carcinoma, usually observed in older patients.
      • Lee M.H.
      • Katabathina V.S.
      • Lubner M.G.
      • Shah H.U.
      • Prasad S.R.
      • Matkowskyj K.A.
      • et al.
      Mucin-producing cystic hepatobiliary neoplasms: updated nomenclature and clinical, pathologic, and imaging features.
      Serum tumour markers such as CEA and CA 19-9 may be elevated, particularly in patients with invasive carcinoma, without good diagnostic accuracy (see question 3).
      • Klompenhouwer A.J.
      • Ten Cate D.W.G.
      • Willemssen F.
      • Bramer W.M.
      • Doukas M.
      • de Man R.A.
      • et al.
      The impact of imaging on the surgical management of biliary cystadenomas and cystadenocarcinomas; a systematic review.
      On imaging, MCNs are typically solitary, large, well-circumscribed cystic lesions, either multiloculated (90%) or unilocular, that predominantly form in the left liver lobe. MCNs commonly do not communicate with the biliary tree and upstream ductal dilatation, if present, is attributed to the mass effect. MCNs often contain enhancing septa, mural calcifications, and mural nodules, the latter being associated with malignancy if larger than 1 cm.
      • Choi B.I.
      • Lim J.H.
      • Han M.C.
      • Lee D.H.
      • Kim S.H.
      • Kim Y.I.
      • et al.
      Biliary cystadenoma and cystadenocarcinoma: CT and sonographic findings.
      • Korobkin M.
      • Stephens D.H.
      • Lee J.K.
      • Stanley R.J.
      • Fishman E.K.
      • Francis I.R.
      • et al.
      Biliary cystadenoma and cystadenocarcinoma: CT and sonographic findings.
      • Pojchamarnwiputh S.
      • Na Chiangmai W.
      • Chotirosniramit A.
      • Lertprasertsuke N.
      Computed tomography of biliary cystadenoma and biliary cystadenocarcinoma.
      • Xu H.X.
      • Lu M.D.
      • Liu L.N.
      • Zhang Y.F.
      • Guo L.H.
      • Liu C.
      • et al.
      Imaging features of intrahepatic biliary cystadenoma and cystadenocarcinoma on B-mode and contrast-enhanced ultrasound.
      Typically, the septa arise from the cyst wall without associated wall indentation.
      • Kovacs M.D.
      • Sheafor D.H.
      • Burchett P.F.
      • Picard M.M.
      • Hardie A.D.
      Differentiating biliary cystadenomas from benign hepatic cysts: preliminary analysis of new predictive imaging features.
      Multiloculated MCNs may have different imaging patterns, and T1 signal intensity on MRI may be variable, reflecting differences in protein-rich or haemorrhagic cyst content. Differentiation between benign MCNs and MCNs with invasive carcinoma is difficult, a meta-analysis found that mural nodules, wall enhancement, and calcifications are significantly associated with malignancy.
      • Klompenhouwer A.J.
      • Ten Cate D.W.G.
      • Willemssen F.
      • Bramer W.M.
      • Doukas M.
      • de Man R.A.
      • et al.
      The impact of imaging on the surgical management of biliary cystadenomas and cystadenocarcinomas; a systematic review.
      Complicated hepatic cysts (cyst infection or haemorrhage) may present with imaging findings that mimic MCNs, leading to inaccurate attribution.
      • Doussot A.
      • Gluskin J.
      • Groot-Koerkamp B.
      • Allen P.J.
      • De Matteo R.P.
      • Shia J.
      • et al.
      The accuracy of pre-operative imaging in the management of hepatic cysts.
      Distinguishing hepatic cysts from MCNs is still challenging and requires expertise of a multidisciplinary team involving hepatogastroenterologists, abdominal radiologists, abdominal surgeons, and expert pathologists.
      There are a number of CT and MRI features that may help to differentiate MCNs from simple hepatic cysts. A number of studies reported that septations/thick septations, mural nodules, and biliary dilatation are associated with MCNs
      • Choi H.K.
      • Lee J.K.
      • Lee K.H.
      • Lee K.T.
      • Rhee J.C.
      • Kim K.H.
      • et al.
      Differential diagnosis for intrahepatic biliary cystadenoma and hepatic simple cyst: significance of cystic fluid analysis and radiologic findings.
      ,
      • Doussot A.
      • Gluskin J.
      • Groot-Koerkamp B.
      • Allen P.J.
      • De Matteo R.P.
      • Shia J.
      • et al.
      The accuracy of pre-operative imaging in the management of hepatic cysts.
      ,
      • Kim H.J.
      • Yu E.S.
      • Byun J.H.
      • Hong S.M.
      • Kim K.W.
      • Lee J.S.
      • et al.
      CT differentiation of mucin-producing cystic neoplasms of the liver from solitary bile duct cysts.
      (Fig. 3). A recent study (13 MCNs and 71 simple cysts) saw that thick septations/nodularity, upstream biliary dilatation, thin septations, internal haemorrhage, perfusional change, and fewer than 3 coexistent hepatic cysts were more frequent in MCNs than in simple cysts. The combination of thick septations/nodularity and at least 1 additional associated feature carried high specificity for MCNs (94-98%),
      • Anderson M.A.
      • Dhami R.S.
      • Fadzen C.M.
      • Molina G.
      • Taylor M.S.
      • Deshpande V.
      • et al.
      CT and MRI features differentiating mucinous cystic neoplasms of the liver from pathologically simple cysts.
      and here MRI was more accurate than CT. The morphology of septations may be helpful as septations arising from a cyst wall without external indentation have a very high association with MCNs.
      • Kovacs M.D.
      • Sheafor D.H.
      • Burchett P.F.
      • Picard M.M.
      • Hardie A.D.
      Differentiating biliary cystadenomas from benign hepatic cysts: preliminary analysis of new predictive imaging features.
      ,
      • Boyum J.H.
      • Sheedy S.P.
      • Graham R.P.
      • Olson J.T.
      • Babcock A.T.
      • Bolan C.W.
      • et al.
      Hepatic mucinous cystic neoplasm versus simple biliary cyst: assessment of distinguishing imaging features using CT and MRI.
      Internal haemorrhage may be seen in MCNs but is much more frequent in simple hepatic cysts and does not represent a worrisome finding.
      Figure thumbnail gr3
      Fig. 3Worrisome features in mucinous cystic neoplasms of the liver.
      (A) Malignant mucinous cystic tumour. Contrast-enhanced CT during the portal venous phase showing multiseptated cystic lesion of the right liver with multiple nodularity. (B,D) malignant mucinous cystic tumour. T2-weighted MRI sequence showing cystic lesion of the left liver with thick septations. Pathologic examination shows thick septations and internal nodularity. (C) Low-grade mucinous cystic tumour. Coronal T2-weighted MR sequence showing cystic lesion of the right liver with a thin septation at the lower part of the lesion.

      In which situation should surgery be applied for suspected MCNs of the liver?

      Recommendation
      • Surgical resection is the gold standard for suspected MCNs of the liver, and complete resection should be aimed for (LoE 3, strong recommendation, 100% consensus).
      The MCN recurrence rates after incomplete resection in the literature are high, but data may be overestimated due to discovery and reporting bias. Similarly, malignant transformation of MCNs is reported frequently, but data may be susceptible to a similar bias.
      • Devaney K.
      • Goodman Z.D.
      • Ishak K.G.
      Hepatobiliary cystadenoma and cystadenocarcinoma: a light microscopic and immunohistochemical study of 70 patients.
      Complete surgical removal of these lesions in reported case series yield good long-term outcomes with a very low recurrence rate. The presence of malignancy is a significant factor associated with poorer outcome. While recurrences do occur in 0 to 26% of reported cases, recurrences with malignant MCNs in patients who initially had non-malignant MCNs are rare.
      • Lee C.W.
      • Tsai H.I.
      • Lin Y.S.
      • Wu T.H.
      • Yu M.C.
      • Chen M.F.
      Intrahepatic biliary mucinous cystic neoplasms: clinicoradiological characteristics and surgical results.
      ,
      • Läuffer J.M.
      • Baer H.U.
      • Maurer C.A.
      • Stoupis C.
      • Zimmerman A.
      • Büchler M.W.
      Biliary cystadenocarcinoma of the liver: the need for complete resection.
      • Teoh A.Y.
      • Ng S.S.
      • Lee K.F.
      • Lai P.B.
      Biliary cystadenoma and other complicated cystic lesions of the liver: diagnostic and therapeutic challenges.
      • Pitchaimuthu M.
      • Aidoo-Micah G.
      • Coldham C.
      • Sutcliffe R.
      • Roberts J.K.
      • Muiesan P.
      • et al.
      Outcome following resection of biliary cystadenoma: a single centre experience and literature review.
      • Lewis W.D.
      • Jenkins R.L.
      • Rossi R.L.
      • Munson L.
      • ReMine S.G.
      • Cady B.
      • et al.
      Surgical treatment of biliary cystadenoma. A report of 15 cases.
      • Ratti F.
      • Ferla F.
      • Paganelli M.
      • Cipriani F.
      • Aldrighetti L.
      • Ferla G.
      Biliary cystadenoma: short- and long-term outcome after radical hepatic resection.
      • Wang K.
      • Kong F.
      • Dong M.
      • Zhou J.
      • Li Y.
      Diagnosis and treatment of intrahepatic biliary cystadenoma: experience with 14 cases in a single center.
      • Lee J.H.
      • Lee K.G.
      • Park H.K.
      • Lee K.S.
      Biliary cystadenoma and cystadenocarcinoma of the liver: 10 cases of a single center experience.
      • Song Y.
      • Kang M.J.
      • Jang J.Y.
      • Lee K.U.
      • Suh K.S.
      • Kim S.W.
      Clinical outcome and long term results after surgical treatment of biliary cystadenoma and cystadenocarcinoma.
      Fenestration is associated with higher rates of tumour recurrence.
      • Lee C.W.
      • Tsai H.I.
      • Lin Y.S.
      • Wu T.H.
      • Yu M.C.
      • Chen M.F.
      Intrahepatic biliary mucinous cystic neoplasms: clinicoradiological characteristics and surgical results.
      It may be difficult to distinguish simple cysts from cystadenoma even with extensive pre-operative work-up. Indeed, a number of studies found that 20-50% of MCNs had not been properly identified before surgery.
      • Teoh A.Y.
      • Ng S.S.
      • Lee K.F.
      • Lai P.B.
      Biliary cystadenoma and other complicated cystic lesions of the liver: diagnostic and therapeutic challenges.
      ,
      • Ratti F.
      • Ferla F.
      • Paganelli M.
      • Cipriani F.
      • Aldrighetti L.
      • Ferla G.
      Biliary cystadenoma: short- and long-term outcome after radical hepatic resection.
      ,
      • Song Y.
      • Kang M.J.
      • Jang J.Y.
      • Lee K.U.
      • Suh K.S.
      • Kim S.W.
      Clinical outcome and long term results after surgical treatment of biliary cystadenoma and cystadenocarcinoma.
      Case reports of recurrence after fenestration provide additional circumstantial evidence to support complete resection.
      Major liver resections, including extended hemihepatectomy, have been performed in some cases to allow for complete removal of the cyst. Enucleation with free margins is also considered an option, e.g., for centrally located tumours. More extensive/complex procedures, including total vascular exclusion
      • Facy O.
      • Rode A.
      • Mabrut J.Y.
      Segment I intrahepatic biliary cystadenocarcinoma impinging on the hepatic vein.
      and liver transplantation
      • Romagnoli R.
      • Patrono D.
      • Paraluppi G.
      • David E.
      • Tandoi F.
      • Strignano P.
      • et al.
      Liver transplantation for symptomatic centrohepatic biliary cystadenoma.
      after unsuccessful attempts at resection resulting in an intrahepatic biliary injury, have been described in case reports.
      As a consequence of the low prevalence of MCNs and the difficulty in establishing a reliable diagnosis on imaging, data is mostly obtained from retrospective studies including only surgically treated patients with pathologic confirmation of the surgical specimen. While head-to-head comparison of outcomes of different treatment options, including surveillance, are absent, the current literature provides compelling evidence to recommend complete surgical resection of MCNs.

      Who should be screened for PLD and how?

      Recommendations
      • Abdominal ultrasound to screen for PLD should be offered to all patients diagnosed with ADPKD (LoE 2, strong recommendation, 100% consensus).
      • Genetic testing should not be used to screen for PLD (LoE 3, strong recommendation, 100% consensus).
      Screening for PLD can be initiated from different perspectives. Many patients with ADPKD are referred because of a family history of the disease. Indeed, the Kidney Disease Improving Global Outcomes guidelines recommend abdominal ultrasound for all patients diagnosed with ADPKD to screen for PLD.
      • Hogan M.C.
      • Abebe K.
      • Torres V.E.
      • Chapman A.B.
      • Bae K.T.
      • Tao C.
      • et al.
      Liver involvement in early autosomal-dominant polycystic kidney disease.
      Many others, especially patients with ADPLD, are seen because of the incidental finding of PLD on abdominal imaging or symptoms. Two sources of information are relevant to counsel patients: i) the anatomy of the liver on imaging and ii) presence of symptoms that can be attributed to PLD.
      There is no need to screen for PLD unless symptoms and signs develop that require a change of management. In those cases, volumetry data aids clinical decision-making. A pooled analysis showed that liver volume in PLD increases by 1.8% (or by 4.8% in females aged <48 years) within 6–12 months.
      • Gevers T.J.
      • Inthout J.
      • Caroli A.
      • Ruggenenti P.
      • Hogan M.C.
      • Torres V.E.
      • et al.
      Young women with polycystic liver disease respond best to somatostatin analogues: a pooled analysis of individual patient data.
      Patients with a growth pattern that deviates from the average growth pattern in PLD should be counselled regarding whether a change of management is warranted. There is no need to screen family members of patients with PLD for the presence of hepatic cysts unless symptoms are present.
      Genetic testing plays an insignificant role in screening of patients with PLD. While almost all cases of ADPKD can be mapped to PKD1, PKD2, and GANAB, the Kidney Disease Improving Global Outcomes guideline suggests that genetic testing is not required for the diagnosis of ADPKD with the exception of equivocal or atypical renal imaging findings (early and severe PKD, markedly asymmetric PKD, renal failure without significant kidney enlargement, marked discordant disease within family) and sporadic PKD without family history.
      • Hogan M.C.
      • Abebe K.
      • Torres V.E.
      • Chapman A.B.
      • Bae K.T.
      • Tao C.
      • et al.
      Liver involvement in early autosomal-dominant polycystic kidney disease.
      In ADPLD, at least 6 genes (PRKCSH, SEC63, ALG8, SEC61B, GANAB, LRP5) account for 30-45% of ADPLD cases; the other 55-70% remain genetically resolved.
      • Lee-Law P.Y.
      • van de Laarschot L.F.M.
      • Banales J.M.
      • Drenth J.P.H.
      Genetics of polycystic liver diseases.
      The phenotype of patients with ADPLD does not vary with the gene involved or type of mutation. As a result, there is little room for genetic testing of these variants for clinical purposes as results are not likely to inform clinical decision-making unless there are questions about the differential diagnosis between ADPKD or ADPLD.
      A number of tools help to triage patients with PLD and to design individualised management plans. Liver volume is a prognostic marker and the main endpoint for trials that explore novel therapeutic strategies, as it impacts both symptom burden and quality of life.
      • D'Agnolo H.M.
      • Kievit W.
      • van Munster K.N.
      • van der Laan J.J.
      • Nevens F.
      • Drenth J.P.
      Center is an important indicator for choice of invasive therapy in polycystic liver disease.
      CT or MRI is necessary to measure volume and assess the extent of PLD. It also allows for measurement of (height-adjusted) liver volume, which is currently used as an endpoint in clinical trials.

      Which patients with PLD require follow-up?

      Recommendation
      • Referral to centres of expertise and counselling of patients with symptomatic PLD is recommended (LoE 3, strong recommendation, 100% consensus).
      In PLD, are usually referred to hepatologists for 3 reasons: i) to counsel patients with the incidental finding of PLD, ii) to develop a management plan for patients with symptomatic PLD, and iii) to manage hepatic complications of PLD.
      There are 2 populations with PLD, those with ADPKD and ADPLD. Most patients with ADPKD receive regular clinical follow-up given their renal disease, while patients with ADPLD receive clinical attention specifically because of their PLD. While at least 80% of individuals with ADPKD aged >30 years will have hepatic cysts, most will be asymptomatic at the time of screening and these patients will benefit from counselling. Counselling patients with PLD requires an informed clinician who is acquainted with the presentation, natural history, prognosis, and management options. It is relevant to recognise the compressive symptoms that patients may have and to acknowledge the disease burden.
      There is an age-dependent increase in hepatic cyst burden, and in particular females may develop progressive disease. It is estimated that some 20% of patients with ADPKD will eventually develop symptomatic PLD.
      • Abu-Wasel B.
      • Walsh C.
      • Keough V.
      • Molinari M.
      Pathophysiology, epidemiology, classification and treatment options for polycystic liver diseases.
      Symptoms in severe PLD are associated with massive abdominal distension as a result of hepatomegaly, leading to a feeling of fullness, abdominal pain and discomfort, abdominal wall hernias, back pain, and dyspnoea in the supine position. Patients reduce their meal size because of early satiety and malnutrition eventually leads to muscle mass loss and sarcopenia.
      • Qian Q.
      • Li A.
      • King B.F.
      • Kamath P.S.
      • Lager D.J.
      • Huston 3rd, J.
      • et al.
      Clinical profile of autosomal dominant polycystic liver disease.
      A number of tools help to triage patients with PLD and to develop individualised management plans. CT or MRI is necessary as a tool to obtain an impression of the extent of PLD. It also allows for measurement of (height-adjusted) liver volume which is currently used as an endpoint in clinical trials.
      • D'Agnolo H.M.A.
      • Casteleijn N.F.
      • Gevers T.J.G.
      • de Fijter H.
      • van Gastel M.D.A.
      • Messchendorp A.L.
      • et al.
      The association of combined total kidney and liver volume with pain and gastrointestinal symptoms in patients with later stage autosomal dominant polycystic kidney disease.
      While volume measurement accurately quantifies PLD, it does not address symptom burden. The last metric is patient-reported outcome measures and 2 validated scales: the polycystic liver disease questionnaire (PLD-Q) and polycystic liver disease complaint-specific assessment (POLCA) have been developed for PLD. PLD-Q and POLCA are further discussed in question 16.
      A number of liver-related complications of PLD require attention from the hepatologist: cyst rupture, haemorrhage and infection (see question 4 and 5) and compression of the portal circulation or hepatic veins due to strategically located hepatic cysts.
      • Bernts L.H.P.
      • Drenth J.P.H.
      • Tjwa E.
      Management of portal hypertension and ascites in polycystic liver disease.
      The latter results in hepatic venous outflow obstruction, which is characterised by reduction of the outflow of venous blood from the liver into the vena cava. These patients develop portal hypertension and ascites and/or hepatic hydrothorax. Of patients with PLD scheduled for a liver resection, 78% (35/45) had moderate stenosis of hepatic veins and 22% (10/45) had severe venous stenosis.
      • Barbier L.
      • Ronot M.
      • Aussilhou B.
      • Cauchy F.
      • Francoz C.
      • Vilgrain V.
      • et al.
      Polycystic liver disease: hepatic venous outflow obstruction lesions of the noncystic parenchyma have major consequences.
      Primary hepatic vein stenting has become the intervention of choice for hepatic venous outflow obstruction with patency rates >80%.
      Mitral valve malformations have been reported as possible extrahepatic manifestations of PLD but bear low clinical significance and patients should only be assessed once cardiovascular signs or symptoms arise. Some patients with ADPKD report a history of cerebral aneurysm in their families. According to the Kidney Disease Improving Global Outcomes guideline those patients may be screened for the presence of asymptomatic intracerebral aneurysms while those without a family history should be counselled about the risks of intracerebral aneurysms that are associated with ADPKD.
      • Hogan M.C.
      • Abebe K.
      • Torres V.E.
      • Chapman A.B.
      • Bae K.T.
      • Tao C.
      • et al.
      Liver involvement in early autosomal-dominant polycystic kidney disease.

      What diet or lifestyle adjustments are recommended for patients with PLD?

      Recommendations
      • CT is suggested to assess sarcopenia in patients with PLD and massive hepatomegaly that displaces adjacent organs (e.g. stomach and bowels), as these patients are at risk of malnutrition (LoE 3, weak recommendation, 87% consensus).
      • Patients with PLD and sarcopenia should receive intensive nutrition and exercise rehabilitation under the supervision of dieticians and physical therapists (LoE 5, strong recommendation, 100% consensus).
      Malnutrition is the most threatening complication of PLD and is an indication for liver transplantation referral.
      • Ryu H.
      • Kim H.
      • Park H.C.
      • Kim H.
      • Cho E.J.
      • Lee K.B.
      • et al.
      Total kidney and liver volume is a major risk factor for malnutrition in ambulatory patients with autosomal dominant polycystic kidney disease.
      It is seen in the most severe PLD cases, especially in combination with renal impairment that requires dialysis. In these patients, compression of the liver on the stomach leads to early satiety, nausea and vomiting and precludes consumption of large food portions. Consequently, patients in this situation need to optimise their food intake by eating small portions of food several times a day and are advised to do physical exercise multiple times a week in order to optimise their muscular mass.
      • Lai J.C.
      • Tandon P.
      • Bernal W.
      • Tapper E.B.
      • Ekong U.
      • Dasarathy S.
      • et al.
      Malnutrition, frailty, and sarcopenia in patients with cirrhosis: 2021 practice guidance by the American Association for the Study of Liver Diseases.
      There are no data from patients with PLD that indicate whether a specific dietary intervention prevents this evolution.
      • Maditz K.H.
      • Benedito V.A.
      • Oldaker C.
      • Nanda N.
      • Lateef S.S.
      • Livengood R.
      • et al.
      Feeding soy protein isolate and n-3 PUFA affects polycystic liver disease progression in a PCK rat model of autosomal polycystic kidney disease.
      Weight loss due to malnutrition in patients with PLD is underestimated due to the extra weight of the enlarged liver. The presence of malnutrition can be assessed by measuring the mid-arm circumference in the non-dominant arm (<23.8 cm for men and <23.1 cm for women).
      • Arrazola L.
      • Moonka D.
      • Gish R.G.
      • Everson G.T.
      Model for end-stage liver disease (MELD) exception for polycystic liver disease.
      Though easy to perform, there are several pitfalls with this measurement. Indeed, this marker has never been validated for patients with PLD, there is a high inter-observer variability and it does not take into consideration the physique of the individual.
      Measurement of sarcopenia by CT scan provides an objective measurement of the malnourished status of the patient with PLD. Height-corrected skeletal muscle mass (cm2) and subcutaneous adipose tissue (cm2) can be calculated by using a single-slice quantitative image at the lumbar 3 level with 5-mm-thick axial images. This represents the skeletal muscle index (cm2/m2). The inter-observer variability and agreement are excellent. Severe skeletal muscle depletion or sarcopenia is defined by a skeletal muscle index <38.5 cm2/h2 in females and <52.4 cm2/h2 in males, as previously defined in a cancer population.
      • Tandon P.
      • Ney M.
      • Irwin I.
      • Ma M.M.
      • Gramlich L.
      • Bain V.G.
      • et al.
      Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value.
      Muscle wasting, malnutrition and functional decline can be assessed with the frailty index (based on grip strength, chair stands and balance). This index is a well validated prognostic test for patients with end-stage liver disease and its utility in PLD should be explored.
      • Lai J.C.
      • Covinsky K.E.
      • Dodge J.L.
      • Boscardin W.J.
      • Segev D.L.
      • Roberts J.P.
      • et al.
      Development of a novel frailty index to predict mortality in patients with end-stage liver disease.
      Standard medical treatment for patients with severe symptomatic disease consists of somatostatin analogues. Although they reduce liver volume and can improve food intake, it is unclear whether somatostatin analogues prevent muscle wasting and sarcopenia.
      • Temmerman F.
      • Ho T.A.
      • Vanslembrouck R.
      • Coudyzer W.
      • Billen J.
      • Dobbels F.
      • et al.
      Lanreotide reduces liver volume, but might not improve muscle wasting or weight loss, in patients with symptomatic polycystic liver disease.

      When should symptom severity and quality-of-life questionnaires be used in patients with PLD?

      Recommendations
      • Disease-specific symptom severity questionnaires may be used upon the emergence of symptoms to assess disease severity in patients with PLD (LoE 3, weak recommendation, 95% consensus).
      • Disease-specific symptom severity questionnaires should be applied in patients with PLD to assess treatment efficacy (LoE 1, strong recommendation, 96% consensus).
      Most patients with PLD remain asymptomatic, but 2–5% of them will develop symptomatic hepatomegaly as a result of the continuous increase in volume and number of hepatic cysts. The most frequently reported symptoms include abdominal distension, early satiety and abdominal pain. Hepatomegaly-induced complaints represent the single most prominent indication for medical or surgical treatment. Complaints expressed by patients with PLD and their interpretation by clinicians in terms of severity and impact on health-related quality of life are subjective, yet highly relevant, as they count heavily towards decisions on medical treatment and even the indication for liver transplantation.
      Generic questionnaires lack sensitivity to capture PLD-related symptoms, which may explain why some trials failed to identify significant effects on quality-of-life measures.
      • van Keimpema L.
      • Nevens F.
      • Vanslembrouck R.
      • van Oijen M.G.
      • Hoffmann A.L.
      • Dekker H.M.
      • et al.
      Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.
      For that reason, disease-specific symptom severity questionnaires were recently developed: the PLD-Q and POLCA. These questionnaires capture disease-specific symptoms in PLD, regardless of treatment side effects, comorbidity or mental problems. The PLD-Q is a valid, reproducible, and sensitive disease-specific questionnaire that has been validated both in a European and American cohort.
      • Neijenhuis M.K.
      • Gevers T.J.
      • Hogan M.C.
      • Kamath P.S.
      • Wijnands T.F.
      • van den Ouweland R.C.
      • et al.
      Development and validation of a disease-specific questionnaire to assess patient-reported symptoms in polycystic liver disease.
      It is currently used in clinical practice, randomised clinical trials and observational cohorts to evaluate the effect of treatment in patients with PLD.
      • Neijenhuis M.K.
      • Wijnands T.F.M.
      • Kievit W.
      • Ronot M.
      • Gevers T.J.G.
      • Drenth J.P.H.
      Symptom relief and not cyst reduction determines treatment success in aspiration sclerotherapy of hepatic cysts.
      ,
      • Bernts L.H.P.
      • Neijenhuis M.K.
      • Edwards M.E.
      • Sloan J.A.
      • Fischer J.
      • Smoot R.L.
      • et al.
      Symptom relief and quality of life after combined partial hepatectomy and cyst fenestration in highly symptomatic polycystic liver disease.
      ,
      • Neijenhuis M.K.
      • Kievit W.
      • Verheesen S.M.
      • D'Agnolo H.M.
      • Gevers T.J.
      • Drenth J.P.
      Impact of liver volume on polycystic liver disease-related symptoms and quality of life.
      The POLCA score (https://www.uzleuven.be/polca) has been developed to guide decision-making with respect to liver transplantation, and it has been validated in a prospective trial.
      • Billiet A.
      • Temmerman F.
      • Coudyzer W.
      • Van Den Ende N.
      • Colle I.
      • Francque S.
      • et al.
      Prospective validation of the polycystic liver disease complaint-specific assessment (POLCA) score: influence of menopause and somatostatin-analogues.
      A POLCA score ≥16.5 predicts the need for liver transplantation, with a sensitivity of 81.3% and a specificity of 88.9%.
      • Temmerman F.
      • Dobbels F.
      • Ho T.A.
      • Pirson Y.
      • Vanslembrouck R.
      • Coudyzer W.
      • et al.
      Development and validation of a polycystic liver disease complaint-specific assessment (POLCA).
      Both PLD-Q and POLCA distinguish patients on the basis of symptoms and serve as useful outcome measures for clinical trials but they do not define symptom thresholds that could guide decision-making in the management of patients with PLD.

      What is the recommendation for use of exogenous female sex hormones in patients with PLD?

      Recommendation
      • Stopping exogenous oestrogen administration is recommended in female patients with PLD (LoE 3, strong recommendation, 100% consensus).
      There is a major sex imbalance in PLD, with women overrepresented (>80%) in large cohorts. This effect is independent of the genetic cause of the disease and is seen both in patients with ADPKD and ADPLD. PLD follows a more aggressive disease course, with earlier onset and faster progression, in females. As a consequence, females account for over >80% of liver transplants for PLD.
      • Aapkes S.E.
      • Bernts L.H.P.
      • Barten T.R.M.
      • van den Berg M.
      • Gansevoort R.T.
      • Drenth J.P.H.
      Estrogens in polycystic liver disease: a target for future therapies?.
      These observations indicate that oestrogen exposure is an important risk factor for PLD.
      Liver volume in PLD increases during the reproductive years, and volume stabilises postmenopausally, coinciding with the decrease of endogenous oestrogen production.
      • Chebib F.T.
      • Jung Y.
      • Heyer C.M.
      • Irazabal M.V.
      • Hogan M.C.
      • Harris P.C.
      • et al.
      Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease.
      This finding was corroborated by a controlled trial which demonstrated that 1-year oestrogen treatment in 19 anovulatory postmenopausal patients with ADPKD selectively increased hepatic cyst volume (oestrogen +7%, control −2%) without an impact on renal cystic disease.
      • Sherstha R.
      • McKinley C.
      • Russ P.
      • Scherzinger A.
      • Bronner T.
      • Showalter R.
      • et al.
      Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease.
      Another observational study demonstrated that every year of exposure to low-dose oestrogen-containing oral contraceptives led to a 1.45% larger liver volume in premenopausal patients with PLD, equivalent to a 15.5% higher liver volume for every 10 years of use.
      • van Aerts R.M.M.
      • Bernts L.H.P.
      • Gevers T.J.G.
      • Kievit W.
      • Koopmans L.
      • Nieboer T.E.
      • et al.
      Estrogen-containing oral contraceptives are associated with polycystic liver disease severity in premenopausal patients.
      There is controversy regarding the effects of pregnancy on PLD severity. Some studies suggest an increase in liver volume after pregnancy
      • Gabow P.A.
      • Johnson A.M.
      • Kaehny W.D.
      • Manco-Johnson M.L.
      • Duley I.T.
      • Everson G.T.
      Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease.
      while this association is absent in other observational cohorts.
      • Hogan M.C.
      • Abebe K.
      • Torres V.E.
      • Chapman A.B.
      • Bae K.T.
      • Tao C.
      • et al.
      Liver involvement in early autosomal-dominant polycystic kidney disease.
      ,
      • Chebib F.T.
      • Jung Y.
      • Heyer C.M.
      • Irazabal M.V.
      • Hogan M.C.
      • Harris P.C.
      • et al.
      Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease.
      ,
      • van Aerts R.M.M.
      • Bernts L.H.P.
      • Gevers T.J.G.
      • Kievit W.
      • Koopmans L.
      • Nieboer T.E.
      • et al.
      Estrogen-containing oral contraceptives are associated with polycystic liver disease severity in premenopausal patients.
      There is a paucity of studies that investigate the effect of in vitro fertilisation on PLD. However, in vitro fertilisation involves exposure to very high oestradiol levels (<60 pg/ml at cycle baseline to 1,000-4,000 pg/ml during IVF) during a short (2-6 weeks) time frame. Clinicians should be aware that this may aggravate hepatic cyst growth. Pregnancy success is expected to be similar in patients with PLD compared to the general population.
      • Chapman A.B.
      Cystic disease in women: clinical characteristics and medical management.
      Collectively, epidemiological and experimental evidence supports a pivotal role for oestrogens as a driver of PLD. While there is no definitive proof that avoidance of external oestrogen use is beneficial, exogenous oestrogen use is probably deleterious and results in the recommendation to discourage prescribing oral contraceptives to female patients with PLD. Levonorgestrel-releasing intrauterine devices may be an alternative option as a contraceptive. With these devices the systemic exposure to levonorgestrel is 4%–13% of the levels seen with oral contraceptives.
      • Attia A.M.
      • Ibrahim M.M.
      • Abou-Setta A.M.
      Role of the levonorgestrel intrauterine system in effective contraception.
      However, data on the effect of these devices on PLD growth is unknown. Similarly, no reliable data is available on contraceptive options only containing gestagens (e.g., desogestrel) and no recommendation on the use of these contraceptives can be made.

      Which treatment should be administered in patients with PLD?

      Recommendations
      • Choice of treatment should be guided by symptoms and complications related to the presence of cysts, as listed in Table 5, in combination with liver phenotypes, displayed in Fig. 4 (LoE 2, strong recommendation, 100% consensus).
      • Treatment for PLD should be administered in symptom-atic patients exclusively (LoE 2, strong recommendation, 100% consensus).
      • Symptom relief and improvement in quality of life should be the primary goal of treatment in PLD (LoE 1, strong recommendation, 100% consensus).
      Since PLD does not compromise the functional capacity of the liver, the aim of treatment is to relieve symptoms and to improve quality of life. While symptoms drive the decision to treat, the choice of treatment option depends on the number, size and localisation of hepatic cysts in combination with the expertise of the treating centre.
      • D'Agnolo H.M.
      • Kievit W.
      • van Munster K.N.
      • van der Laan J.J.
      • Nevens F.
      • Drenth J.P.
      Center is an important indicator for choice of invasive therapy in polycystic liver disease.
      ,
      • van Aerts R.M.M.
      • van de Laarschot L.F.M.
      • Banales J.M.
      • Drenth J.P.H.
      Clinical management of polycystic liver disease.
      Cyst infection or haemorrhage are not an indication for volume-reducing therapy. None of the current available treatment strategies are used prophylactically (see question 4). Moreover, previous interventions such as these may make future total hepatectomy or liver transplantation more complex.
      • Pirenne J.
      • Aerts R.
      • Yoong K.
      • Gunson B.
      • Koshiba T.
      • Fourneau I.
      • et al.
      Surgical strategy in liver transplantation for polycystic liver disease.
      Liver transplantation for PLD is considered technically difficult from a surgical perspective due to the challenge of removing a (often) huge liver. Potential encasement of the retrohepatic inferior vena cava, traction to very fragile hepatic veins that span out thinly around massive cysts and adhesions due to previous interventions or surgery, may further complicate a liver transplant procedure and increase the risks of massive blood loss .
      Table 5Polycystic liver disease-related symptoms and complications.
      Polycystic liver disease-related symptomsPolycystic liver disease-related complications
      Abdominal fullnessJaundice
      Lack of appetite or early satietyHepatic venous outflow obstruction
      Acid refluxPortal hypertension
      Nausea and vomitingRecurrent cyst infection
      Pain in rib cage, sides, abdomen or backRecurrent cyst haemorrhage
      Shortness of breath
      Limited mobility
      Fatigue
      Anxiety about the future
      Concern or dissatisfaction with abdomen size
      Problems with intercourse
      Involuntary weight loss
      Figure thumbnail gr4
      Fig. 4Decision-making flowchart for treatment choice in polycystic liver disease.
      Adjusted from v. Aerts et al. Journal of Hepatology, 2018.

      Interventional (radiological) treatment

      When a large or strategically located cyst is the main cause of symptoms, percutaneous aspiration sclerotherapy can also be performed in the context of PLD. Recurrence of symptoms is frequent in the context of PLD
      • Moorthy K.
      • Mihssin N.
      • Houghton P.W.
      The management of simple hepatic cysts: sclerotherapy or laparoscopic fenestration.
      ,
      • van Aerts R.M.M.
      • van de Laarschot L.F.M.
      • Banales J.M.
      • Drenth J.P.H.
      Clinical management of polycystic liver disease.
      ,
      • van Keimpema L.
      • de Koning D.B.
      • Strijk S.P.
      • Drenth J.P.
      Aspiration-sclerotherapy results in effective control of liver volume in patients with liver cysts.
      (see question 4). Some series have demonstrated that transarterial embolisation of the hepatic arteries may reduce cyst volume in PLD but the experience with this intervention is limited.
      • Yan J.Y.
      • Zhang J.L.
      • Yuan K.
      • Fu J.X.
      • Wang Y.
      • Yuan B.
      • et al.
      Transarterial embolisation with bleomycin and N-butyl-2-cyanoacrylate -Lipiodol mixture for symptomatic polycystic liver disease: preliminary experience.

      Surgical treatment

      Cyst fenestration, also called deroofing, can be considered in patients with superficial large cysts. Multiple large cysts can be resected simultaneously with this procedure. It provides effective long-term reduction of cyst volume and symptomatic relief but does not change the natural course of the disease.
      • van Keimpema L.
      • Ruurda J.P.
      • Ernst M.F.
      • van Geffen H.J.
      • Drenth J.P.
      Laparoscopic fenestration of liver cysts in polycystic liver disease results in a median volume reduction of 12.5.
      ,
      • Bernts L.H.P.
      • Echternach S.G.
      • Kievit W.
      • Rosman C.
      • Drenth J.P.H.
      Clinical response after laparoscopic fenestration of symptomatic hepatic cysts: a systematic review and meta-analysis.
      The risk of a potential complicating effect of adhesions at the time of a future liver transplantation should be taken into account when considering cyst fenestration.
      A liver phenotype with small to medium sized cysts restricted to a few liver segments may be amenable to segmental hepatic resection. The intervention results in a substantial liver volume reduction and improves symptoms. Since surgical resection in PLD is associated with high morbidity, especially in the presence of vascular abnormalities and biliary dilatation, it is only indicated in patients with severe symptoms in whom liver transplantation is not an option. Several postoperative complications can occur (ascites, haemorrhage, pleural effusion) and mortality rates of more than 2% have been observed while the recurrence rate is high.
      • van Aerts R.M.M.
      • van de Laarschot L.F.M.
      • Banales J.M.
      • Drenth J.P.H.
      Clinical management of polycystic liver disease.
      ,
      • Temmerman F.
      • Missiaen L.
      • Bammens B.
      • Laleman W.
      • Cassiman D.
      • Verslype C.
      • et al.
      Systematic review: the pathophysiology and management of polycystic liver disease.
      ,
      • Aussilhou B.
      • Douflé G.
      • Hubert C.
      • Francoz C.
      • Paugam C.
      • Paradis V.
      • et al.
      Extended liver resection for polycystic liver disease can challenge liver transplantation.
      The only curative option for patients with PLD is liver transplantation (see question 19) 177.

      Pharmacological therapies

      Several clinical trials have provided evidence that somatostatin analogues e.g., lanreotide, octreotide or pasireotide can reduce the volume of the liver
      • van Keimpema L.
      • Nevens F.
      • Vanslembrouck R.
      • van Oijen M.G.
      • Hoffmann A.L.
      • Dekker H.M.
      • et al.
      Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.
      ,
      • Hogan M.C.
      • Masyuk T.V.
      • Page L.J.
      • Kubly V.J.
      • Bergstralh E.J.
      • Li X.
      • et al.
      Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.
      • Caroli A.
      • Antiga L.
      • Cafaro M.
      • Fasolini G.
      • Remuzzi A.
      • Remuzzi G.
      • et al.
      Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide.
      • Pisani A.
      • Sabbatini M.
      • Imbriaco M.
      • Riccio E.
      • Rubis N.
      • Prinster A.
      • et al.
      Long-term effects of octreotide on liver volume in patients with polycystic kidney and liver disease.
      • van Aerts R.M.M.
      • Kievit W.
      • D'Agnolo H.M.A.
      • Blijdorp C.J.
      • Casteleijn N.F.
      • Dekker S.E.I.
      • et al.
      Lanreotide reduces liver growth in patients with autosomal dominant polycystic liver and kidney disease.
      • Hogan M.C.
      • Chamberlin J.A.
      • Vaughan L.E.
      • Waits A.L.
      • Banks C.
      • Leistikow K.
      • et al.
      Pansomatostatin agonist pasireotide long-acting release for patients with autosomal dominant polycystic kidney or liver disease with severe liver involvement: a randomized clinical trial.
      (Table 6). They demonstrate a mild reduction in kidney volume but do not affect the rate of kidney function decline.
      • Meijer E.
      • Visser F.W.
      • van Aerts R.M.M.
      • Blijdorp C.J.
      • Casteleijn N.F.
      • D'Agnolo H.M.A.
      • et al.
      Effect of lanreotide on kidney function in patients with autosomal dominant polycystic kidney disease: the DIPAK 1 randomized clinical trial.
      The most important reduction in liver volume is observed in the first 6 months, but a sustained effect can be seen for up to 4 years of treatment.
      • Pisani A.
      • Sabbatini M.
      • Imbriaco M.
      • Riccio E.
      • Rubis N.
      • Prinster A.
      • et al.
      Long-term effects of octreotide on liver volume in patients with polycystic kidney and liver disease.
      ,
      • Hogan M.C.
      • Masyuk T.
      • Bergstralh E.
      • Li B.
      • Kremers W.K.
      • Vaughan L.E.
      • et al.
      Efficacy of 4 Years of octreotide long-acting release therapy in patients with severe polycystic liver disease.
      Several systematic reviews and meta-analyses have confirmed the beneficial effect of somatostatin analogues on liver volume and quality of life.
      • Griffiths J.
      • Mills M.T.
      • Ong A.C.
      Long-acting somatostatin analogue treatments in autosomal dominant polycystic kidney disease and polycystic liver disease: a systematic review and meta-analysis.
      • Suwabe T.
      • Barrera F.J.
      • Rodriguez-Gutierrez R.
      • Ubara Y.
      • Hogan M.C.
      Somatostatin analog therapy effectiveness on the progression of polycystic kidney and liver disease: a systematic review and meta-analysis of randomized clinical trials.
      • Neijenhuis M.K.
      • Gevers T.J.
      • Nevens F.
      • Hogan M.C.
      • Torres V.E.
      • Kievit W.
      • et al.
      Somatostatin analogues improve health-related quality of life in polycystic liver disease: a pooled analysis of two randomised, placebo-controlled trials.
      • Garofalo C.
      • Capuano I.
      • Pennino L.
      • De Gregorio I.
      • Riccio E.
      • Provenzano M.
      • et al.
      The effects of somatostatin analogues on liver volume and quality of life in polycystic liver disease: a meta-analysis of randomized controlled trials.
      The dosage of somatostatin analogues is balanced between efficacy and side effects. Lanreotide at a dose of 120 mg every 4 weeks is associated with greater reductions in liver volume, but more side effects, than a lower dose of 90 mg every 4 weeks.
      • Temmerman F.
      • Gevers T.
      • Ho T.A.
      • Vanslembrouck R.
      • Coudyzer W.
      • van Pelt J.
      • et al.
      Safety and efficacy of different lanreotide doses in the treatment of polycystic liver disease: pooled analysis of individual patient data.
      Patients who benefit most are young women (aged <48 years) who suffer from a rapidly progressive disease.
      • Gevers T.J.
      • Inthout J.
      • Caroli A.
      • Ruggenenti P.
      • Hogan M.C.
      • Torres V.E.
      • et al.
      Young women with polycystic liver disease respond best to somatostatin analogues: a pooled analysis of individual patient data.
      Therapy cessation after short-term treatment usually results in a relapse of liver growth, but patients who discontinued treatment can benefit from retreatment.
      • Sherstha R.
      • McKinley C.
      • Russ P.
      • Scherzinger A.
      • Bronner T.
      • Showalter R.
      • et al.
      Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease.
      The therapy is well tolerated and serious adverse events leading to withdrawal are infrequent (<5%). Most patients experience gastrointestinal discomfort (steatorrhea like symptoms) during the first injections which gradually fade over time. Other infrequent side effects of somatostatin analogues include cholelithiasis, hypo- and hyperglycaemia and alopecia.
      • Aapkes S.E.
      • de Haas R.J.
      • Bernts L.H.P.
      • Blijdorp C.J.
      • Dekker S.E.I.
      • van Gastel M.D.A.
      • et al.
      Incident gallstones during somatostatin analog treatment are associated with acute biliary complications especially after discontinuation.
      Hyperglycaemia and diabetes are most frequently observed with pasireotide.
      • Hogan M.C.
      • Chamberlin J.A.
      • Vaughan L.E.
      • Waits A.L.
      • Banks C.
      • Leistikow K.
      • et al.
      Pansomatostatin agonist pasireotide long-acting release for patients with autosomal dominant polycystic kidney or liver disease with severe liver involvement: a randomized clinical trial.
      Table 6Overview of the prospective clinical trials using somatostatin analogues in polycystic liver disease.
      StudyCountryNumber of patients (males)Treatment duration (months)Imaging modalityDrugEffect on liver volumep value
      van Keimpema et al. 2009

      LOCK CYST
      The Netherlands and Belgium54 (7)6CTLanreotide – LAR

      120 mg IM every 28 days
      −2.9% vs. + 1.6%<0.01
      Hogan et al. 2010USA42 (6)12MRIOctreotide- LAR

      40 mg IM every 28 days
      −4.95% vs. + 0.92%0.048
      Caroli et al. 2010

      Post hoc analysis
      Italy12 (9)6CTOctreotide – LAR

      40 mg IM every 28 days
      −17 ± 57 ml vs. + 14 ± 85 ml<0.05
      Pisani et al.2016Italy27 (10)36MRIOctreotide – LAR

      40 mg IM every 28 days
      −7.8% vs. + 6.1%0.004
      Van Aerts et al. 2019

      Post hoc analysis
      The Netherlands175 (74)30MRILanreotide – LAR

      120 mg IM every 28 days
      −1.99% vs. + 3.92%<0.01
      Pre-clinical data and observational studies in patients with ADPKD, who received a kidney transplantation and were treated with sirolimus, suggested that mammalian target of rapamycin inhibitors had a positive effect on liver volume.
      • Temmerman F.
      • Chen F.
      • Libbrecht L.
      • Vander Elst I.
      • Windmolders P.
      • Feng Y.
      • et al.
      Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver-disease.
      These data were not confirmed in a clinical trial, wherein everolimus, a mammalian target of rapamycin inhibitor, did not confer any beneficial effect. Due to the toxicity of these drugs, they should not be used in patients with PLD.
      • Chrispijn M.
      • Gevers T.J.
      • Hol J.C.
      • Monshouwer R.
      • Dekker H.M.
      • Drenth J.P.
      Everolimus does not further reduce polycystic liver volume when added to long acting octreotide: results from a randomized controlled trial.
      Based on pre-clinical data in rodents in which bile acid-induced hyperproliferation of cystic cholangiocytes was decreased with ursodeoxycholic acid, the drug was tested in a phase II study.
      • D'Agnolo H.M.
      • Kievit W.
      • Takkenberg R.B.
      • Riano I.
      • Bujanda L.
      • Neijenhuis M.K.
      • et al.
      Ursodeoxycholic acid in advanced polycystic liver disease: a phase 2 multicenter randomized controlled trial.
      No significant effect on liver volume was seen after 6 months. In a sub-group analysis restricted to patients with ADPKD, ursodeoxycholic acid appeared to reduce hepatic cyst volume, but these findings need corroborating. Currently, ursodeoxycholic acid treatment is not indicated for the treatment of PLD.

      Liver volume

      The primary endpoint in all pharmacological and some surgical trials is restricted to change in liver volume.
      • van Keimpema L.
      • Nevens F.
      • Vanslembrouck R.
      • van Oijen M.G.
      • Hoffmann A.L.
      • Dekker H.M.
      • et al.
      Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.
      ,
      • Bernts L.H.P.
      • Neijenhuis M.K.
      • Edwards M.E.
      • Sloan J.A.
      • Fischer J.
      • Smoot R.L.
      • et al.
      Symptom relief and quality of life after combined partial hepatectomy and cyst fenestration in highly symptomatic polycystic liver disease.
      ,
      • van Keimpema L.
      • Ruurda J.P.
      • Ernst M.F.
      • van Geffen H.J.
      • Drenth J.P.
      Laparoscopic fenestration of liver cysts in polycystic liver disease results in a median volume reduction of 12.5.
      ,
      • Hogan M.C.
      • Masyuk T.V.
      • Page L.J.
      • Kubly V.J.
      • Bergstralh E.J.
      • Li X.
      • et al.
      Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.
      • Caroli A.
      • Antiga L.
      • Cafaro M.
      • Fasolini G.
      • Remuzzi A.
      • Remuzzi G.
      • et al.
      Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide.
      • Pisani A.
      • Sabbatini M.
      • Imbriaco M.
      • Riccio E.
      • Rubis N.
      • Prinster A.
      • et al.
      Long-term effects of octreotide on liver volume in patients with polycystic kidney and liver disease.
      • van Aerts R.M.M.
      • Kievit W.
      • D'Agnolo H.M.A.
      • Blijdorp C.J.
      • Casteleijn N.F.
      • Dekker S.E.I.
      • et al.
      Lanreotide reduces liver growth in patients with autosomal dominant polycystic liver and kidney disease.
      • Hogan M.C.
      • Chamberlin J.A.
      • Vaughan L.E.
      • Waits A.L.
      • Banks C.
      • Leistikow K.
      • et al.
      Pansomatostatin agonist pasireotide long-acting release for patients with autosomal dominant polycystic kidney or liver disease with severe liver involvement: a randomized clinical trial.
      ,
      • Temmerman F.
      • Chen F.
      • Libbrecht L.
      • Vander Elst I.
      • Windmolders P.
      • Feng Y.
      • et al.
      Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver-disease.
      ,
      • D'Agnolo H.M.
      • Kievit W.
      • Takkenberg R.B.
      • Riano I.
      • Bujanda L.
      • Neijenhuis M.K.
      • et al.
      Ursodeoxycholic acid in advanced polycystic liver disease: a phase 2 multicenter randomized controlled trial.
      Therefore, accurate and sensitive measurements of liver volume are crucial to evaluate current treatment strategies and to explore new therapeutic options. Manual contouring of the liver by CT or MRI in patients with PLD is the current gold standard for liver volume measurements. This is a challenging and time-consuming endeavour because of the severely deformed liver anatomy in combination with massive hepatomegaly found in PLD. Automatic segmentation of polycystic livers using deep learning methods achieves much faster segmentation with similar performance and will probably find its way into routine clinical practice.
      • van Gastel M.D.A.
      • Edwards M.E.
      • Torres V.E.
      • Erickson B.J.
      • Gansevoort R.T.
      • Kline T.L.
      Automatic measurement of kidney and liver volumes from MR images of patients affected by autosomal dominant polycystic kidney disease.

      Which patients with PLD should be referred for liver or combined kidney-liver transplantation?

      Recommendation
      • Referral for liver transplantation or combined liver-kidney transplantation may be initiated based on the criteria listed in Box 2, taking into consideration local allocation systems, local waitlist criteria, anticipated waiting times and risk of deterioration while waiting for a liver graft (LoE 3, weak recommendation, 100% consensus).
      Liver transplantation is the only curative treatment for PLD and only the most severe cases with massive PLD are eligible. Allocation of scarce donor liver grafts in most allocation networks is based on a sickest-first principle or transplant benefit score, including incorporation of model of end-stage liver disease (MELD) score which is validated for patients with cirrhosis.
      • Wiesner R.
      • Edwards E.
      • Freeman R.
      • Harper A.
      • Kim R.
      • Kamath P.
      • et al.
      Model for end-stage liver disease (MELD) and allocation of donor livers.
      ,
      • Neuberger J.
      • Gimson A.
      • Davies M.
      • Akyol M.
      • O'Grady J.
      • Burroughs A.
      • et al.
      Selection of patients for liver transplantation and allocation of donated livers in the UK.
      For patients without end-stage liver failure related to cirrhosis, most allocation systems work with exception points or listing as variant syndromes. PLD represents about 1–1.5% of patients on the waitlist and donor allocation is based on exception points or listing as a variant syndrome because liver function remains preserved even in the most severe cases.

      Transplant NHSBa. Liver transplantation: selection criteria and recipient registration POLICY POL195/6. 2018.

      ,
      • Manuals E.
      Chapter 5: ET Liver Allocation System (ELAS).
      Criteria to refer polycystic liver disease patients for liver or combined liver-kidney transplantation.
      Several waitlist exception criteria are being used that have considerable overlap. The most important exception criteria for liver transplantation in PLD are: i) clinically apparent liver disease due to massive PLD severely affecting quality of life, ii) massive PLD and complications (e.g. severe malnutrition, hepato-venous outflow obstruction, ascites, portal hypertension, variceal haemorrhage, recurrent hepatic cyst infections), that can exclusively be treated by liver transplantation, iii) failure of non-transplant-related interventions and contraindications for non-transplant-related interventions. Referral for liver transplantation may be initiated based on these criteria, taking into account local allocation systems, local waitlist criteria, anticipated waiting times and risk of deterioration while waiting for a liver graft. Assessment for liver transplantation should be performed in multidisciplinary teams in transplant centres that include transplant surgeons, hepatologists and, in case of combined kidney-liver transplantation, nephrologists.
      Two studies compared waitlist outcomes between PLD- and non-PLD-initiated transplantations. Waitlist outcomes were determined using liver function-related adverse outcomes: waitlist death, too sick to transplant or deterioration of liver function measured by international normalised ratio or bilirubin. Unsurprisingly, chances of adverse outcomes using these parameters were lower in patients with PLD compared to patients listed based on a MELD-point based allocation.
      • Umgelter A.
      • Hapfelmeier A.
      • Kopp W.
      • van Rosmalen M.
      • Rogiers X.
      • Guba M.
      Disparities in Eurotransplant liver transplantation wait-list outcome between patients with and without model for end-stage liver disease exceptions.
      ,
      • Doshi S.D.
      • Bittermann T.
      • Schiano T.D.
      • Goldberg D.S.
      Waitlisted candidates with polycystic liver disease are more likely to be transplanted than those with chronic liver failure.
      Unfortunately, there is very limited data regarding which parameters adequately define waitlist outcomes for patients with PLD and outcomes are probably unrelated to portal hypertension.
      • Rajoriya N.
      • Tripathi D.
      • Leithead J.A.
      • Gunson B.K.
      • Lord S.
      • Ferguson J.W.
      • et al.
      Portal hypertension in polycystic liver disease patients does not affect wait-list or immediate post-liver transplantation outcomes.
      In general, liver transplant outcomes for PLD are excellent and comparable to other indications for liver transplantation.
      • van Keimpema L.
      • Nevens F.
      • Adam R.
      • Porte R.J.
      • Fikatas P.
      • Becker T.
      • et al.
      Excellent survival after liver transplantation for isolated polycystic liver disease: an European Liver Transplant Registry study.
      ,
      • Doshi S.D.
      • Bittermann T.
      • Schiano T.D.
      • Goldberg D.S.
      Waitlisted candidates with polycystic liver disease are more likely to be transplanted than those with chronic liver failure.
      ,
      • Gedaly R.
      • Guidry P.
      • Davenport D.
      • Daily M.
      • Ronsenau J.
      • Shah M.
      • et al.
      Peri-operative challenges and long-term outcomes in liver transplantation for polycystic liver disease.
      Because of the volume of livers with massive polycystic disease, manipulation of the liver for explantation and access to the suprahepatic vena cava and hepatic veins is considered difficult, with the risk of massive bleeding. It is generally advised not to make any attempt to control access to the inferior vena cava at the beginning of the dissection phase. Instead, the structures of the liver hilum are dissected first and some form of inflow control achieved.
      • Pirenne J.
      • Aerts R.
      • Yoong K.
      • Gunson B.
      • Koshiba T.
      • Fourneau I.
      • et al.
      Liver transplantation for polycystic liver disease.
      ,
      • Lerut J.
      • Ciccarelli O.
      • Rutgers M.
      • Orlando G.
      • Mathijs J.
      • Danse E.
      • et al.
      Liver transplantation with preservation of the inferior vena cava in case of symptomatic adult polycystic disease.
      After transection of the hepatic artery, other strategies include deviation of the portal venous inflow by preparing a porto-caval shunt or to place patients on full veno-venous bypass. Surgeons should avoid excessive traction on the liver downwards and to the left to prevent tearing of the fragile hepatic veins. The liver is then progressively mobilised, from below upwards or from left to right to avoid turning the liver to the left, until the suprahepatic vena cava can be safely controlled. Both, cava-sparing techniques and caval replacement have been described with good outcomes. Techniques describing liver explantation under total vascular exclusion have also been described.
      • Thieme F.
      • Fronek J.
      Sharp liver excision under hepatic vascular exclusion in case of liver transplant for large polycystic disease. Case report of a new surgical technique.
      In summary, surgeons should aim for a preferred strategy to prevent massive blood loss during the hepatectomy phase.
      There is some notion of superiority of combined liver-kidney transplantation over sequential procedures in patients with PLD that require both procedures, but robust evidence is lacking.
      • Coquillard C.
      • Berger J.
      • Daily M.
      • Shah M.
      • Mei X.
      • Marti F.
      • et al.
      Combined liver-kidney transplantation for polycystic liver and kidney disease: analysis from the United Network for Organ Sharing dataset.
      • Cerwenka H.
      Bile duct cyst in adults: interventional treatment, resection, or transplantation?.
      • Simpson N.
      • Cho Y.W.
      • Cicciarelli J.C.
      • Selby R.R.
      • Fong T.L.
      Comparison of renal allograft outcomes in combined liver-kidney transplantation versus subsequent kidney transplantation in liver transplant recipients: analysis of UNOS Database.
      In combined liver-kidney transplantation concerns have been raised about high rates of short-term kidney graft loss of up to 20%.
      • Lunsford K.E.
      • Bodzin A.S.
      • Markovic D.
      • Zarrinpar A.
      • Kaldas F.M.
      • Gritsch H.A.
      • et al.
      Avoiding futility in simultaneous liver-kidney transplantation: analysis of 331 consecutive patients listed for dual organ replacement.
      Delayed renal graft function and renal allograft failure in this setting has been attributed to major perioperative haemodynamic and metabolic instability associated with liver transplantation. Current approaches to balance the potential futility of kidney transplantation in the combined setting of end-stage hepatic and renal failure, include the use of hypothermic machine perfusion with delayed implantation of a kidney from the same donor,
      • Lunsford K.E.
      • Agopian V.G.
      • Yi S.G.
      • Nguyen D.T.M.
      • Graviss E.A.
      • Harlander-Locke M.P.
      • et al.
      Delayed implantation of pumped kidneys decreases renal allograft futility in combined liver-kidney transplantation.
      or metachronous living-donor kidney transplantation after recovery from liver-only transplantation which avoids subsequent long waiting times for a deceased organ. All approaches take into account: i) potential better survival rates with combined liver-kidney transplantation, ii) blunted immunological response/immunoprotection due to absorption of donor-specific antibodies by the liver allograft and use of the same donor, iii) increased risk of failure of kidney graft with combined liver-kidney transplantation, iv) anticipated waiting times given the availability or absence of a local allocation policy targeted at combined liver-kidney transplantation, and v) availability of a live kidney donor.

      Should preconception carrier screening be offered to patients with PLD and when?

      Recommendations
      • Patients with PLD should receive preconception counselling concerning the risk of passing on PLD to the newborn (LoE 4, strong recommendation, 96% consensus).
      • Patients with PLD should not be counselled against pregnancy (LoE 3, strong recommendation, 96% consensus).
      Patient with PLD, both in the context of ADPKD and ADPLD, should receive preconception counselling concerning the risk that their newborn will develop the disease. PLD is passed on in an autosomal dominant fashion, giving a 50% chance that the newborn inherits the mutation. Genetic testing for PLD is available, though screening mutations of the genes causing PLD can only confirm the genetic diagnosis and not exclude the disease. The genes responsible for PLD are different for ADPKD and ADPLD. ADPKD is mainly caused by 2 genes: PKD1 and PKD2. In contrast, ADPLD is caused by at least 6 different genes which combined do not even explain the disease development in over half of the affected population.
      • Boerrigter M.M.
      • Bongers E.
      • Lugtenberg D.
      • Nevens F.
      • Drenth J.P.H.
      Polycystic liver disease genes: practical considerations for genetic testing.
      Genetic testing is not routinely performed because knowledge about the genotype-phenotype correlation is currently limited and does not affect the therapeutic management of PLD. Incomplete penetrance and variable expressivity cause wide variation among family members with the same genotype.
      Oestrogen exposure is considered the most important driver of cyst growth and is further discussed in question 17. Controversy still exists regarding the fluctuations in oestrogen that occur during pregnancy and the effects of pregnancy on liver growth. Patients with PLD should not be counselled against pregnancy.

      How to differentiate between Caroli disease and Caroli syndrome?

      Recommendation
      • The finding of multiple segmental cystic or saccular dilatations of bile ducts should initiate a search for congenital hepatic fibrosis in order to differentiate Caroli disease from Caroli syndrome (LoE 4, strong recommendation, 100% consensus).
      Multifocal segmental dilatation of the intrahepatic ducts is present both in Caroli disease and Caroli syndrome. The cystic dilatation results from ductal plate malformation of the large intrahepatic bile ducts. This is a failure of proper remodelling and resorption of the ductal plate during foetal development and results in persistence of embryonic biliary structures. On imaging, these bile ducts appear as saccular or fusiform cystic dilatations that can grow up to 5 cm in diameter. These lesions are mainly located in the intrahepatic large sized bile ducts and correspond to type V choledochal cysts (part of the Todani classification). However, extrahepatic dilatations are commonly seen in Caroli disease and are thought to result from recurrent episodes of cholangitis and stone passage.
      Hepatic fibrosis is the key histological lesion that separates Caroli syndrome from Caroli disease. Caroli syndrome is likely part of the phenotypical spe