Isolated Autosomal Dominant Polycystic Liver Disease

Adult-onset hepatobiliary disease with multiple cysts of biliary origin and kidneys without clinically significant disease; a genetically heterogeneous class (PRKCSH, SEC63, GANAB, ALG8, LRP5, SEC61B and genes of the polycystic kidney disease spectrum), with treatment shared with the polycystic liver disease of ADPKD.

Literature and regulatory information update: 28 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From polycystic kidney disease to an autonomous hepatic entity

For much of the twentieth century, the presence of numerous liver cysts in an adult was interpreted as an extrarenal manifestation of adult polycystic kidney disease. The hypothesis of an inherited polycystic liver disease independent of the kidneys arose from families in which several members had polycystic livers and kidneys without disease: a Finnish family studied by Sotaniemi and colleagues in 1979 and by Luoma and colleagues in 1980, and the family described by Berrebi and colleagues in 1982, in which two sisters and two daughters of one of them had polycystic liver disease, with only isolated or few renal cysts and, in one of the patients, numerous pancreatic microcysts [4]. In 1986, Karhunen and Tenhu analysed 33,700 medicolegal autopsies and identified 22 cases of polycystic disease of the liver or kidney; both organs were affected in the same individual in only one case, and cerebral haemorrhage occurred only in the renal disease, which reinforced the idea of two distinct entities [4].

Genetic proof came in 1996, when Pirson and colleagues described a family with isolated polycystic liver disease over three generations, without any renal cyst, in which linkage to the PKD1 and PKD2 loci was excluded [27]. In 2000, Reynolds and colleagues, using two extended families without renal cysts, mapped the first locus to 19p13.2–13.1, with a maximum LOD score (logarithm of the odds) of 10.3, and noted that the clinical and histological picture was indistinguishable from the liver disease of ADPKD [28]. In 2003, the same strategy led to the first gene: Drenth and colleagues, in four Dutch families, found a variant of the splicing acceptor site of exon 16 of PRKCSH (historical nomenclature 1138-2A>G) in three families and a donor-site variant (292+1G>C) in the fourth, with complete segregation, and named the protein hepatocystin [29]; in parallel, Li and colleagues narrowed the interval to about 3 Mb and identified truncating PRKCSH variants in several families, including the two studied by Reynolds, proposing a two-hit mechanism [30]. In the same year, the Mayo Clinic team published the first systematic characterisation of families with ADPLD, which showed that the disease was underdiagnosed among at-risk relatives [31].

1.2. Genetic heterogeneity and the polycystin-1 biogenesis pathway

In 2004, Davila and colleagues linked ADPLD to 6q21 in families without a PRKCSH variant and identified seven heterozygous SEC63 variants in eight families, including the Pirson family and three Finnish families; SEC63 was altered in 8 of 66 probands (about 12 %), and the two genes together explained less than one third of cases [6, 32]. The identification of a second gene without a direct ciliary function — SEC63 encodes a protein of the endoplasmic reticulum (ER) translocation machinery — shifted attention from the ciliary hypothesis to the cotranslational processing of membrane proteins [32].

The unifying model emerged in 2011, when Fedeles and colleagues showed in mice that glucosidase IIβ and Sec63p are required for expression of the functional polycystin-1–polycystin-2 complex and that the severity of cystic dilatation depends on the amount of functional polycystin-1 (PC1) [33]. In the same year, Janssen and colleagues demonstrated somatic loss of the wild-type PRKCSH allele in 76 % of liver cysts from heterozygous patients, establishing that the disease is recessive at the cellular level [34]. There followed LRP5, by exome sequencing in an extended Dutch family (Cnossen and colleagues, 2014) [35]; GANAB, which encodes the catalytic α subunit of glucosidase II and causes a spectrum ranging from mild polycystic kidney disease to severe PLD (Porath and colleagues, 2016) [36]; ALG8 and SEC61B, with enrichment of heterozygous PKHD1 variants in patients with PLD, in an exome study of 102 patients without variants in PRKCSH or SEC63 (Besse and colleagues, 2017) [37]; an intronic GANAB variant, initially discarded by exome algorithms, which explained the isolated PLD of a family with five affected siblings (Besse and colleagues, 2018) [38]; ALG9 (Besse and colleagues, 2019) [39]; and DNAJB11, a cofactor of the chaperone BiP, responsible for a phenotype intermediate between ADPKD and autosomal dominant tubulointerstitial kidney disease (Cornec-Le Gall and colleagues, 2018) [40]. In 2023, the Nijmegen group extended the ADPLD spectrum to ALG9, in a woman without renal cysts [41], and described eight novel ALG8 variants in 16 patients with PLD [42]; in 2025, Jawaid and colleagues characterised, in more than 3900 families, the phenotype of monoallelic ALG8 and ALG9 variants [43].

1.3. Nomenclature and reclassifications

Three naming systems coexist. OMIM groups the forms in phenotypic series PS174050, with types PCLD1 (PRKCSH), PCLD2 (SEC63), PCLD3 (ALG8) and PCLD4 (LRP5), all qualified as «with or without kidney cysts», whereas the GANAB phenotype was recorded as polycystic kidney disease type 3 with or without PLD (PKD3) and SEC61B remains an association pending confirmation [4, 14, 16]. Orphanet uses a single entity, ORPHA:2924, broader than each OMIM entry [1]. The KDIGO 2025 guideline introduced a gene–disease nomenclature that joins the clinical designation to the gene (for example, ADPLD-PRKCSH); it reserves the gene-specific designation for genes with definitive evidence (PRKCSH, SEC63 and, among the minor genes, only GANAB) and applies the ADPLD designation to the remaining genes only when the phenotype is consistent; moderate to severe PLD with very few or no renal cysts is classified as ADPLD even without genetic testing [2]. The phenotypic overlap has also led to GANAB, ALG9 and DNAJB11 being listed simultaneously as minor ADPKD genes, and to the ADPKD GeneReviews grouping ALG8, GANAB, LRP5, PRKCSH, SEC63 and SEC61B under the designation «polycystic liver disease 1» in the differential diagnosis [2, 17]. Saudubray includes PRKCSH and GANAB among the congenital disorders of glycosylation (PRKCSH-CDG and GANAB-CDG), with the phenotypic group «polycystic liver disease with or without polycystic kidney disease», in a classification centred on the biochemical pathway rather than on the mode of inheritance [44].

1.4. Scope of the article and definition of the entities

PLD is defined by the presence of more than 10 cysts of the liver parenchyma without communication with the biliary tree and arises in three contexts: in ADPKD (the most frequent extrarenal manifestation of this disease), in ADPLD, in which the patient does not meet the criteria for ADPKD and the cysts are typically confined to the liver, and, less frequently, in heterozygotes for genes of autosomal recessive polycystic kidney disease (ARPKD) [3, 45]. Some authors have used a threshold of more than 20 cysts, which shows the lack of a unified criterion [46]. This article covers ADPLD as a genetic class — PRKCSH, SEC63, GANAB, ALG8, LRP5, SEC61B and the genes of the overlapping spectrum (ALG9, DNAJB11, monoallelic PKHD1, ALG6) — and the treatment of PLD, which the guidelines formulate jointly for ADPLD and for the PLD of ADPKD, because the trials included both and the responses were similar [3, 23, 47].

2. Molecular Genetics and Pathophysiology

2.1. Origin of the cysts and the common polycystin-1 pathway

PLD cysts derive from the biliary epithelium. Progressive dilatation of biliary microhamartomas (von Meyenburg complexes) and of peribiliary glands, disconnected from the biliary tree, gives rise to the cysts, which grow through cholangiocyte proliferation and fluid secretion [6, 31]. Structural biliary abnormalities may be present from an early age and remain silent until adulthood, when cyst growth begins [6]. Growth depends on cyclic adenosine monophosphate (cAMP): secretin, an agonist of this pathway, promotes the insertion of transporters and fluid secretion, and somatostatin analogues, by lowering intracellular cAMP, reduce secretion and proliferation [23, 48].

The ADPLD genes encode ER proteins that take part in the synthesis, folding and quality control of membrane glycoproteins. Polycystin-1 is a large, heavily glycosylated membrane protein whose maturation and trafficking to the ciliary membrane are particularly sensitive to disturbances of this pathway; loss of any of these factors reduces the amount of mature PC1 available and indirectly reproduces the mechanism of ADPKD [17, 33, 37]. In orthologous mouse models, the severity of cystic dilatation after inactivation of Prkcsh or Sec63 tracks the levels of functional PC1, in a dose–response relationship; PC1 is the limiting component of the polycystin-1–polycystin-2 complex; reduced PC1 sensitises the kidney to cystogenesis induced by Pkhd1 variants; and proteasome inhibition increases PC1 in cells lacking glucosidase IIβ and reduces cystic disease in these models [33]. In murine epithelial cell lines, biallelic inactivation of Alg8 reduced PC1, its post-translational glycosylation and its trafficking to the cell surface, defects corrected by re-expression of the gene; inactivation of Sec61b made PC1 almost undetectable and activated the unfolded protein response [8, 16].

2.2. Somatic second hit and disease that is recessive at the cellular level

Inheritance is dominant at the level of the individual, but the cyst results from loss of both functional copies in the cholangiocyte. In 71 cysts obtained by laparoscopic fenestration from eight patients with a heterozygous germline PRKCSH variant (2 to 14 cysts per patient), there was loss of heterozygosity of the wild-type allele in 54 cysts (76 %); hepatocystin was absent from the epithelium with loss of heterozygosity and present in heterozygous epithelium; two of 12 cysts without loss of heterozygosity (17 %) had a somatic point mutation of PRKCSH, and no somatic SEC63 mutations in trans were found [34]. Each cyst develops independently, and the accumulation of somatic hits in the epithelium appears to determine the rate of cyst formation [6, 34]. This model explains the variability among relatives carrying the same variant and the absence of a congenital phenotype.

2.3. Genes, proteins and gene-by-gene mechanisms

PRKCSH (19p13.2; MANE Select reference transcript, Matched Annotation from NCBI and EMBL-EBI, NM_001289104.2) encodes hepatocystin, or 80K-H protein, the non-catalytic β subunit of ER glucosidase II, with a leader sequence, an LDLa domain, two EF-hand domains and a C-terminal HDEL ER-retention sequence [30, 49]. Glucosidase II sequentially removes the two inner α-1,3 glucoses from the N-glycan Glc2Man9GlcNAc2 of immature glycoproteins, a step that regulates entry into and exit from the calnexin–calreticulin quality-control cycle; the β subunit is required for efficient PC1 biogenesis and for its trafficking to the primary cilium [21]. The germline mechanism is heterozygous loss of function, and ClinGen assigns it the highest level of evidence for haploinsufficiency [21]. There is no clinical biochemical assay of glucosidase II [21].

SEC63 (6q21; MANE Select NM_007214.5) encodes ERdj2 (DNAJC23), an integral component of the ER translocon that acts with SEC62 and the chaperone BiP/HSPA5 in co- and post-translational translocation, mainly of proteins with short or apolar signal peptides, and in retrotranslocation [49, 50]. ClinGen classifies haploinsufficiency as having sufficient evidence (level 3) [50]. The gene is expressed in all tissues studied, although the cysts are practically confined to the liver [6].

GANAB (11q12.3; MANE Select NM_198334.3) encodes the catalytic α subunit of glucosidase II (glycosyl hydrolase family 31), the partner of hepatocystin in the same heterodimer [49, 51]. Its complete inactivation in human kidney cells abolished mature PC1, and heterozygous null cells had a 50 % reduction in mature PC1; three missense variants did not restore surface PC1 expression, indicating loss of function [14, 36]. It is unclear why GANAB variants cause more renal disease than PRKCSH variants, given that both proteins are subunits of the same enzyme [14].

ALG8 (11q14.1; MANE Select NM_024079.5) encodes the α-1,3-glucosyltransferase that adds the second of the three glucoses to the dolichol-linked precursor oligosaccharide (Glc1Man9GlcNAc2-PP-dolichol to Glc2Man9GlcNAc2-PP-dolichol, the substrate of ALG10) [10, 49]. The gene has 13 exons and encodes a protein of 526 to 532 amino acids, depending on the description, with 12 transmembrane domains and an ER-retention signal (KTKKQ) [9]. In the description of PCLD3, biallelic CRISPR/Cas9 inactivation of Alg8 in a mouse epithelial line reduced the amount of polycystin-1, its glycosylation and post-translational modification and its transport to the cell surface, defects corrected by re-expression of the wild-type gene; the patients' variants were not studied functionally [9, 37]. ALG9 (MANE Select NM_024740.2) encodes an α-1,2-mannosyltransferase of the same pathway, and ALG5 and ALG6 other glycosyltransferases of the dolichol precursor; PC1 maturation and trafficking are particularly sensitive to loss of DNAJB11, glucosidase IIα, ALG9 and ALG5 [17, 49].

SEC61B (9q22.33; MANE Select NM_006808.3) encodes the β subunit of the Sec61 complex, the core of the ER translocon, which associates with ribosomes or with the SEC62–SEC63 complex for co- or post-translational transport [16, 49]. DNAJB11 (MANE Select NM_016306.6) encodes a cofactor of BiP [40, 49].

LRP5 (11q13.2; MANE Select NM_002335.4) encodes a co-receptor of the Wnt/β-catenin pathway with the Frizzled receptors and stands apart from the other genes because it does not belong to the PC1 biogenesis pathway [13, 49]. The protein, of 1615 amino acids, belongs to the low-density lipoprotein receptor family, with four epidermal growth factor-like repeats, three LDL receptor-like repeats and a single transmembrane domain; the gene has 23 coding exons and is abundantly expressed in the liver, particularly in the bile duct epithelium, and the cyst epithelium of the Dutch proband showed intense immunohistochemical staining for LRP5 [12, 35]. In the families described, the variants reduced activation of the canonical Wnt pathway in response to Wnt3a [11, 35]. GeneGuidance considers the hepatic phenotype of LRP5 disputed, and KDIGO 2025 classifies the evidence as limited [2, 13].

2.4. Gene–disease validity and contribution of each gene

The known genes explain less than 40 % of ADPLD index cases in the exome cohort of Besse and colleagues and 30–45 % according to EASL; about half of families remain undiagnosed, indicating genes yet to be identified or variants outside the regions analysed [3, 37, 38]. The proportions in the KDIGO table refer to screened families with an identified cause and not to all patients with ADPLD.

2.5. Variant spectrum and nomenclature

The spectrum in PRKCSH and SEC63 is dominated by truncating and splicing variants, consistent with loss of function [21, 30, 32]. The variants in the original descriptions were published with historical numbering, without a reference transcript. The donor variant of Drenth and colleagues corresponds to NM_002743.3:c.292+1G>C, identical in the MANE transcript (NM_001289104.2:c.292+1G>C; NC_000019.10:g.11437972G>C), with protein effect p.? [29, 49]. The exon 16 acceptor variant, published as 1138-2A>G and recorded in OMIM as 177060.0001, does not validate in VariantValidator on NM_002743.3 (exon boundary error) nor as c.1338-2A>G (reference base mismatch), and is therefore retained only in the original nomenclature [5, 29, 49]. The remaining classic PRKCSH variants recorded in OMIM (Gln413Ter, Tyr422Ter, a 1-bp insertion with premature termination at codon 84 and a 2-bp deletion at the intron 16 donor with exon 16 skipping) and SEC63 variants (Trp58Ter, present in two probands from the central USA without known relationship; a 1-bp insertion, an intron 8 donor variant and the in-frame deletion Glu568del, in three distinct Finnish families) were described with historical numbering and have not been converted to the MANE transcript [5, 7]. In the Finnish families, each family had a different variant, which does not support a founder effect [6].

The variants used in this article with validated nomenclature are as follows. In SEC63, NM_007214.5:c.715C>T p.(Arg239Ter) (NC_000006.12:g.107908945G>A), from the case in section 10 [49, 52]. In LRP5, NM_002335.4:c.3562C>T p.(Arg1188Trp) (NC_000011.10:g.68426112C>T), which segregated with the disease in an extended Dutch family (LOD 4.62) and was absent in more than 1000 controls; the other three missense variants from the original description, confirmed in VariantValidator on the MANE transcript, are NM_002335.4:c.1360G>A p.(Val454Met) (NC_000011.10:g.68386660G>A), in an 86-year-old Dutch woman and her 49-year-old daughter, absent in 1000 Dutch controls; c.4587G>C p.(Arg1529Ser) (NC_000011.10:g.68448809G>C), in a Moroccan woman and her two adult daughters, without renal cysts, absent in 525 Moroccan controls; and c.4651G>A p.(Asp1551Asn) (NC_000011.10:g.68448873G>A), in a 65-year-old Dutch man with renal cysts and no family history [12, 35, 49]. The first two affect the extracellular domain and the last two the intracellular domain; p.(Arg1188Trp) and p.(Asp1551Asn) reduced Wnt pathway activation in response to Wnt3a, and the others were not studied functionally [12]. In ALG8, the variants from the PCLD3 description, confirmed in VariantValidator, are NM_024079.5:c.1090C>T p.(Arg364Ter) (NC_000011.10:g.78106895G>A), in three unrelated patients (two of European ancestry and one African American; ExAC frequency 4.5 × 10⁻⁵), c.535C>T p.(Arg179Ter) (NC_000011.10:g.78119193G>A), in a 63-year-old man and his 19-year-old daughter, and c.1038+1G>T (NC_000011.10:g.78109441C>A), a splicing site variant, in a 59-year-old Finnish woman without renal cysts [9, 49]. The same p.(Arg364Ter) has been described in compound heterozygosity, with p.(Thr47Pro), in a patient from the Austrian Tyrol with ALG8-CDG, which shows that an allele associated with PLD in the heterozygous state is also a cause of severe recessive disease [9]. In ALG9, NM_024740.2:c.677G>C p.(Gly226Ala) (NC_000011.10:g.111857626C>G), in a woman with ADPLD without renal cysts [41, 49]. In SEC61B, the two variants of Besse and colleagues (a 2-bp frameshift insertion, p.Arg34fs, and c.1A>G at the initiation codon) are classified in OMIM as variants of uncertain significance, because the association has not been confirmed [16].

In GANAB, the literature used transcript NM_198335 rather than MANE NM_198334.3, which changes the numbering; applying the published notation to the MANE transcript yields different variants (for example, NM_198334.3:c.1835G>C corresponds to p.(Gly612Ala), not to the published variant). The conversions made in VariantValidator from the genomic coordinate were as follows [49, 53]:

The GANAB variant that explained the isolated PLD of the family of Besse and colleagues (2018) is a 9-bp intronic deletion close to the exon 24 splicing donor, recorded in OMIM as NM_198335.3:c.2791+4_2791+12del (published numbering, = NM_198334.3:c.2725+4_2725+12del on the MANE transcript; NC_000011.10:g.62626053_62626061del); a minigene assay demonstrated exon 24 skipping in cell lines and in primary cholangiocytes [15, 38]. Large deletions including GANAB or SEC63 have also been described in patients with polycystic kidney and liver disease, invisible to sequencing without copy-number analysis [54].

2.6. Penetrance, expressivity and genotype–phenotype correlations

Penetrance is incomplete and age-dependent, and expressivity varies among relatives with the same genotype, from a few asymptomatic cysts to massive hepatomegaly [2, 3, 11]. Predicted pathogenic variants in ADPLD genes are much more frequent in the population (1 in 91 to 1 in 130 people in gnomAD) than ascertained disease, especially in LRP5 and ALG8, whose phenotypes are milder, indicating that many carriers never develop clinical disease [19]. In ALG8 carriers, penetrance for reduced estimated glomerular filtration rate (eGFR) is limited [43].

The relationship between gene and severity is a matter of disagreement between sources. EASL 2022 states that the ADPLD phenotype does not vary with the gene or with the type of variant [3]. In contrast, the largest genotyped cohort (265 patients with pathogenic variants in PRKCSH or SEC63, European and North American consortium) showed greater severity, measured by age at first hepatic event, in women and in PRKCSH carriers than in SEC63 carriers, and proposed a sex–gene score that distinguishes mild, moderate and severe disease; age-adjusted liver volume progression groups predicted events independently of sex and gene [55]. In a German cohort of 80 patients, carriers of a diagnostic variant had more severe disease (age at transplant listing and at first hospitalisation) than patients without a genetic diagnosis [56]. In the Dutch and Belgian cohort, carriers of PRKCSH or SEC63 variants were younger at diagnosis (median 39 years) and 95 % were symptomatic [20]. Renal cysts are more frequent with the GANAB and ALG8 genes, and severe liver disease is occasional with ALG8 and rare with ALG9 [36, 43].

2.7. Allelic disorders

Several genes of the class cause, in the biallelic state, distinct and more severe diseases, which has consequences for reproductive counselling (section 8).

2.8. Modifiers and dual diagnoses

The coexistence of variants in two genes of the pathway alters the phenotype. Patients have been described with ADPKD due to PKD1 and a pathogenic PRKCSH variant, two individuals with PKD1 and ALG8 variants in the series of Jawaid and colleagues, and the case in section 10, with a SEC63 variant and an IFT140 variant [17, 43, 52]. Variation in LRP5 has been proposed as a modifier of hepatic cystogenesis in PKD1 ADPKD; in a screen of 79 probands with polycystic kidney disease, four LRP5 missense variants did not segregate cleanly with the disease and two families also had PKD1 variants, so the association remains pending [11, 13]. Outside genetics, the most consistent modifying factor is oestrogen exposure (sections 3.5 and 7.2).

3. Clinical Spectrum and System-Specific Manifestations

3.1. Natural history: asymptomatic disease, symptomatic disease and determinants of progression

Most patients with PLD are asymptomatic and remain so; the cysts are found on ultrasound or CT scans requested for other reasons [3, 21]. Estimates of the proportion who develop symptomatic hepatomegaly differ by population: 2–5 % of patients with PLD according to EASL, about 20 % of patients with ADPKD according to the same guideline and the ERN RARE-LIVER position statement, and less than 5 % of patients with ADPKD according to KDIGO 2025 [2, 3, 23]. These proportions refer to different populations (PLD in general, ADPKD in referral centres, ADPKD in general) and are not interchangeable. In tertiary-centre cohorts, by contrast, most patients are already symptomatic when referred, which reflects selection bias.

Liver volume increases with age until the menopause. In a pooled analysis of trials, liver volume in untreated patients increased by 1.8 % over 6–12 months, and by 4.8 % in women under 48 years, with no growth in older women or in men [3, 47]. In the Leipzig cohort, hepatic growth and renal growth did not correlate within the same individual [56]. The main determinants of progression and of need for treatment are female sex, oestrogen exposure, liver volume and its age-adjusted growth rate and, in genotyped forms, the gene [55, 56, 59].

3.2. Liver: mass effect, complications and biochemistry

Symptoms result from liver volume and compression of neighbouring structures: abdominal fullness and distension, early satiety, acid reflux, nausea and vomiting, pain in the rib cage, flanks, abdomen or back, dyspnoea (especially when lying down), limited mobility (difficulty bending or lying prone), fatigue, involuntary weight loss, concern about abdominal size and difficulties with sexual relations [3, 23]. Malnutrition, which results from early satiety and gastric compression, is considered by EASL the most threatening complication of PLD and is an indication for referral for transplantation; weight loss is underestimated because the liver gains weight while muscle mass decreases [3]. Abdominal wall hernias occurred in 40.1 % (194/484) of the Nijmegen patients, mainly umbilical (25.8 %), and were associated with male sex, previous abdominal surgery, Gigot type 3 and hTLV [22].

Hepatic synthetic function remains preserved even with massive livers; the burden of disease is volume and symptoms [3, 21]. Gamma-glutamyltransferase (GGT) and alkaline phosphatase may be raised (median GGT 1.4 times the upper limit of normal in the Dutch and Belgian cohort), with normal bilirubin and albumin [20, 50]. Carbohydrate antigen 19-9 (CA 19-9) is produced by the cyst epithelium, is markedly raised in cyst fluid, increased in serum in up to half of patients and correlates with total cyst volume [3, 60].

Hepatic venous outflow obstruction by strategically located cysts may cause portal hypertension, ascites or hepatic hydrothorax; in 45 patients proposed for resection, 78 % had moderate and 22 % severe hepatic vein stenosis, but clinically apparent portal hypertension is very rare in the overall PLD population [3]. In a British centre, 42.7 % of 47 patients listed for transplantation had portal hypertension, with varices in about 2 % and ascites as the most frequent manifestation, which reflects selection of the most severe cases [61]. Compression of the inferior vena cava or of the bile ducts may cause lower limb oedema or jaundice [1, 17].

Intracystic haemorrhage is the most frequent complication of liver cysts, especially cysts larger than 8 cm; it presents with sudden, severe pain in 80 % of cases, without haemodynamic instability, resolves within days to weeks, rarely lowers haemoglobin and may leave mural calcification [3]. Cyst infection is caused mainly by Escherichia coli and other Enterobacterales, probably through bacterial translocation, and recurs mainly in immunosuppressed patients, such as patients with ADPKD after kidney transplantation; it occurs in about 5 % of patients with PLD and in 37 % of patients with ADPKD and liver cysts after kidney transplantation [3, 17, 61]. Spontaneous rupture is rare, occurs in large cysts (median size of more than 10 cm in case reports), may follow minor trauma, drains into the peritoneum and, rarely, into the pleura or duodenum, and is accompanied by haemorrhage in about half of cases; most patients recover, but deaths have occurred [3, 62].

3.3. Kidneys

By definition, patients with ADPLD do not have clinically significant polycystic kidney disease. A fraction of 28–35 % have renal cysts, usually incidental findings without functional consequence, according to the review by Cnossen and Drenth summarised in OMIM [4, 6]. In the Leipzig cohort, 65 % of patients with ADPLD had renal cysts, but none had more than 10 [56]. The frequency and number of renal cysts vary with the gene: PRKCSH and SEC63 are associated with no or very few cysts; ALG8 with renal cysts in 89 % of carriers with imaging in the Mayo Clinic Biobank, half with more than 10, but with limited renal enlargement; GANAB with a variable number of cysts, from fewer than 10 to more than 40 in the original series, including in patients referred for PLD, with mild renal disease, hypertension in less than half and no kidney failure [2, 14, 43]. Reduced eGFR and kidney failure are rare in ALG8 and ALG9 carriers [43]. Renal imaging and function are relevant mainly to distinguish ADPLD from ADPKD (sections 5 and 6).

3.4. Extrahepatic and extrarenal manifestations

In the Mayo Clinic cohort, structural abnormalities of the mitral valve leaflets were more frequent in the affected than in the unaffected, and a vascular phenotype, investigated with cerebral MR angiography, was found in 5.6 % of patients with ADPLD and in no unaffected relative [31]. EASL considers mitral valve malformations possible extrahepatic manifestations, of low clinical relevance, to be assessed only in the presence of signs or symptoms, and reserves screening for intracranial aneurysms for patients with ADPKD and a family history, according to KDIGO [3]. In the original GANAB series, two sisters had intracranial aneurysms and their father had an aneurysm rupture [14]. Pancreatic microcysts were described in one of the historical families [4]. Orphanet lists, as occasional (5–29 %), heart valve abnormalities, pancreatic abnormalities, cerebral artery dilatation, gastro-oesophageal reflux, gastrointestinal haemorrhage, respiratory failure, jaundice and foot oedema [1].

3.5. Sex, hormones, pregnancy and menopause

Women account for more than 80 % of patients in the large cohorts and more than 80 % of transplants for PLD, and the disease appears earlier and progresses faster in females [3, 20]. In a controlled trial, one year of oestrogens in 19 postmenopausal women with ADPKD increased hepatic cyst volume by 7 %, against a reduction of 2 % in the control group, with no renal effect [3]. In a survey of 287 patients with PLD, each year of use of oestrogen-containing oral contraceptives was associated, in premenopausal women, with a 1.45 % increase in hTLV (about 15.5 % per 10 years), with no association in postmenopausal women nor with the duration of pregnancies [63]. The effect of pregnancy is controversial; PLD is more severe in multiparous women with ADPKD, and medically assisted reproduction techniques expose women to oestradiol concentrations of 1000–4000 pg/mL for 2–6 weeks, which may accelerate growth [3, 17]. After the menopause, liver volume stabilises and severe PLD often regresses; oestrogen replacement therapy increases cyst size [3, 64, 65]. At the level of the treated population, the need for volume-reducing therapy is greater in women, and the relationship between liver volume and need for treatment differs between the sexes [59].

3.6. Gene-specific features

In PRKCSH ADPLD (PCLD1), the liver is the target organ, with proliferation of the biliary epithelium and connective tissue; renal cysts are incidental [4, 21]. A 49-year-old man was described with a truncating PRKCSH variant, PLD requiring liver resection and eight cysts in the left kidney, who underwent right nephrectomy for an atrophic cystic kidney with suspected neoplasm [4]. In SEC63 ADPLD (PCLD2), the course ranges from asymptomatic cysts to massive hepatomegaly with distension, pain in the right upper quadrant and flank, early satiety and limited mobility; in a three-generation family, the proband had highly symptomatic PLD diagnosed at 50 years, the mother had massive PLD and the proband's son had no cysts [6, 50]. SEC63 disease is, on average, less severe than PRKCSH disease [55].

In PCLD3 (ALG8), the five patients in the original description were aged 48 to 63 years; four had numerous liver cysts and one about 10; almost all had fewer than 10 renal cysts; one man required intervention, and the 19-year-old daughter of a carrier had eight renal cysts without liver cysts [8, 9]. In the Nijmegen series, ALG8 PLD ranged from mild to severe and fewer than five renal cysts without effect on renal function were common [42]. In the series of Jawaid and colleagues, 71 % of ALG8 carriers with imaging had liver cysts, 11 of 62 had a liver larger than 2 L and surgery was rare; in ALG9 carriers, renal cysts were frequent (78 %, 27 % with more than 10) and enlarged livers rare [43]. In PCLD4 (LRP5), a three-generation Dutch family had at least 16 affected members of variable severity and renal cysts in several members, without renal disease; a smaller Dutch family, a Moroccan family and a sporadic case were also described, with evidence of age-dependent incomplete penetrance [11, 35]. In the SEC61B form, the two patients described (a 42-year-old woman and a 51-year-old man) had numerous small liver cysts and one or no renal cyst [16]. In PKHD1 heterozygotes, liver cysts are common and may occur without renal cysts, but severe PLD is rare [2].

3.7. Children and adolescents

Liver cysts are rare in childhood, both in ADPLD and in ADPKD, and symptomatic disease is exceptional before adulthood; a boy in the original GANAB series became symptomatic at 9 years [14, 17]. In ADPKD, MRI in the CRISP study found liver cysts in 58 % of patients aged 15–24 years, 85 % of those aged 25–34 years and 94 % of those aged 35–46 years, frequencies that do not apply directly to ADPLD but show the age dependence [66]. In the HALT-PKD study, in 534 patients with early ADPKD, PLD severity correlated with biochemical and haematological abnormalities and with worse quality of life [67]. A cystic hepatic picture in a newborn or young child points to other entities (section 6).

4. Clinical Recognition and Warning Signs

4.1. When to suspect

ADPLD should be considered in an adult, especially a woman (median age at diagnosis of 47 years in a tertiary-centre cohort and of 39 years in carriers of a PRKCSH or SEC63 variant), with more than 10 liver cysts on ultrasound, CT or MRI, kidneys without cysts or with few cysts and normal renal function [2, 3, 20]. Suspicion is strengthened by a family history of liver cysts or of unspecified «polycystic disease», by palpable hepatomegaly and by complaints of mass effect (distension, early satiety, right upper quadrant pain, low back pain, dyspnoea when lying down) [3, 21]. The absence of a family history does not exclude the diagnosis: penetrance is incomplete, the disease is underdiagnosed among relatives and more than half of cases remain without a genetic cause [3, 31]. A single liver cyst or a few simple cysts do not constitute PLD; simple cysts occur in 2.5–18 % of the population [3].

4.2. Warning and emergency signs

Traumatic rupture of a cyst in a patient with massive PLD can be fatal, as in the case of a patient with isolated PLD who, weeks after being placed on the transplant waiting list, developed haemoperitoneum and abdominal compartment syndrome [62].

4.3. Newborn and population screening

There is no newborn screening. EASL recommends abdominal ultrasound to screen for PLD in all patients with ADPKD, but does not recommend genetic testing to screen for PLD nor searching for cysts in asymptomatic relatives of patients with PLD [3].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

The diagnosis of PLD is radiological: more than 10 cysts of the liver parenchyma without communication with the biliary tree [3, 61]. In ADPLD, cross-sectional imaging shows numerous cysts distributed throughout all liver segments, with absent or scarce renal cysts and normal renal function [50, 68]. The distinction between ADPLD and ADPKD is made by renal imaging: patients with ADPLD do not meet the criteria for ADPKD, and moderate to severe PLD with very few or no renal cysts is classified by KDIGO 2025 as ADPLD, even without genetic testing [2, 3]. There is no unified criterion for the number of cysts: besides the threshold of 10, some authors have used more than 20 cysts, and the Qian classification (section 5.3) grades the number of cysts [31, 46]. Age-dependent criteria applied to ADPLD in some reports derive from ADPKD criteria and have not been validated for ADPLD. The unified ultrasound criteria for ADPKD of Pei and colleagues were built in families with PKD1 and PKD2, and GANAB carriers may not meet them; normal or equivocal renal imaging does not exclude a GANAB variant [51].

Simple renal cysts increase with age in the general population: in kidney donors assessed by contrast-enhanced CT, 39 % of people aged 19–49 years and 63 % of those aged 50–75 years had at least one renal cyst of 2 mm or more, which limits the interpretation of a few renal cysts in a patient with PLD [17].

5.2. Imaging

Ultrasound has a sensitivity and specificity of about 90 % for hepatic cystic lesions; the simple cyst is anechoic with posterior enhancement, hypoattenuating without enhancement on CT and hyperintense on T2 and hypointense on T1 on MRI [3]. Contrast-enhanced ultrasound is indicated for complex cysts (vascularised septa or mural enhancement suggest malignancy), and the HASTE sequence (half-Fourier single-shot turbo spin echo) is the most useful on MRI [3]. In a patient with PLD without symptoms or complications, no further imaging is needed after ultrasound; CT or MRI serve to assess cyst distribution, compression of the hepatic and portal veins and the volume of unaffected parenchyma. MRI is preferable to CT, especially in kidney failure, and better detects the small cysts of young patients [3]. Imaging should always include the kidneys [2, 21].

Liver volumetry by manual contouring on CT or MRI is the reference standard, and automated deep-learning segmentation performs similarly [3]. Height-adjusted total liver volume (hTLV, in mL/m) is the measure used in trials and in treatment decisions; serial images should use the same modality, and MRI is preferable to unenhanced low-dose CT (2–5 mSv) [23]. A centre without volumetry should refer the patient before starting somatostatin analogues [23].

5.3. Severity and progression classifications

In the Leipzig cohort, no Kim I patient was considered for transplantation, in contrast with 39 % of Kim II and 74 % of Kim III; Kim stage III was associated with a 4.9-fold higher risk of a hepatic event than Kim I (95 % confidence interval, 95 % CI, 1.6–15.1) and female sex with a 10.4-fold higher risk (95 % CI 2.8–38.9) [56]. In that cohort, the median age at transplant listing was 42.9 years in PG III and 59.5 years in PG II, and was not reached in PG I; the median age at first hepatic event was 43.4, 56.2 and 67.9 years, respectively [56]. Purely radiological classifications did not separate severe from moderate courses, whereas grouping by age-adjusted volume progression discriminated risk [56]. In Gigot's series, extensive fenestration in 10 patients reduced mean liver volume from 7761 to 4596 cm³ (43 %), but in type III volume increased again in 40 % of patients [70].

5.4. Symptom questionnaires

EASL suggests using specific questionnaires when symptoms arise (level 3, weak, 95 %) and recommends them for assessing treatment efficacy (level 1, strong, 96 %) [3]. The Polycystic Liver Disease Questionnaire (PLD-Q) has 16 items with weekly recall, each with a severity or frequency question and an impact question, and a score from 0 to 100; it was validated in Dutch and North American patients, correlates with the EORTC symptom scale (r=0.788 and 0.811), does not correlate with liver volume and has a reproducibility of 0.94–0.96 [23, 73]. A threshold of 32 points distinguished treated from untreated patients with an area under the curve of 0.856, sensitivity of 85.0 %, specificity of 71.4 %, positive predictive value of 75.2 % and negative predictive value of 82.4 % [74]. The Polycystic Liver Disease Complaint-Specific Assessment (POLCA), validated in Belgium and available online, groups symptoms into four subscales (perception of enlarged liver volume, impact on intake, reflux and related complaints, perceived severity), with a severity index (SPI) from 0 to 35; an SPI below 7 makes the need for treatment unlikely [61, 75, 76]. In 198 symptomatic Belgian patients followed for 5 years, 35.9 % needed volume-reducing therapy; SPI ≥14 predicted this need and was proposed as the threshold for somatostatin analogues, and SPI ≥18 for transplantation [77]. EASL cites a POLCA threshold ≥16.5 to predict the need for transplantation (sensitivity 81.3 %, specificity 88.9 %) [3]. Generic questionnaires (SF-36, EQ-VAS) did not consistently capture the benefit of the analogues [23].

5.5. Biomarkers

5.6. Diagnosis of complications

Cyst infection is definite when the aspirate shows neutrophil debris or microorganisms (level 4, strong); it is probable, after exclusion of other sources, with the criteria in the following table [3]. KDIGO uses an algorithm adapted from Lantinga, with fever above 38.0 °C, abdominal pain, CRP ≥50 mg/L or leucocytes >11 × 10⁹/L, microbiology and imaging [2].

CT and MRI are useful but not very specific; 18F-FDG PET-CT is the most sensitive technique and superior to the others in doubtful cases; indium-111-labelled leucocyte scintigraphy is more specific, but not always conclusive [3, 17, 79]. Urinary tract infection and pneumonia should be excluded (urine culture and chest radiograph) [3]. In intracystic haemorrhage, ultrasound shows sediment or mobile septa and MRI a heterogeneous, high signal on T1 and T2, which may persist for months; CT is not recommended for this purpose (level 4, strong) [3]. Haemorrhagic cysts may cause fever and mimic cholecystitis or infection [17].

Suspicion of mucinous cystic neoplasm requires at least one major criterion (thick septation, nodularity) and one minor criterion (upstream biliary dilatation, thin septa, internal haemorrhage, perfusional change, fewer than three coexisting liver cysts) (level 3, weak); the combination had a specificity of 94–98 % in a series of 13 neoplasms and 71 simple cysts, and MRI is the characterisation technique (level 3, strong) [3]. Cysts complicated by haemorrhage or infection may mimic mucinous neoplasm, which justifies multidisciplinary discussion [3].

5.7. Genetic testing

Indications. EASL considers genetic testing of little use in the clinical practice of ADPLD, because the phenotype does not vary with the gene and the result does not change treatment; it recommends it mainly when there is diagnostic doubt between ADPLD and ADPKD, and does not recommend it for PLD screening (level 3, strong, 100 %) [3]. The American College of Gastroenterology (ACG) guideline on focal liver lesions (2024) also does not recommend testing in general, accepting it in young patients with few renal cysts who do not meet ADPKD criteria [80]. KDIGO 2025 uses the result for gene–disease nomenclature and for counselling [2]. Other contexts in which testing adds information include reproductive planning, identification of genes with a severe biallelic phenotype (ALG8, ALG9, PKHD1, DNAJB11) and investigation of dual diagnoses [2, 17, 52].

Method. The recommended test is a multigene panel including PRKCSH, SEC63, GANAB, ALG8, LRP5, SEC61B, ALG9, DNAJB11, PKHD1, PKD1, PKD2, ALG5, ALG6 and IFT140, with copy-number variant analysis, because large deletions of GANAB and SEC63 have been described [2, 17, 54]. In the Leipzig cohort, targeted next-generation sequencing combined with multiplex ligation-dependent probe amplification (MLPA) identified diagnostic monoallelic variants in 75 % of 80 patients with PLD, 48 % in ADPKD genes (PKD1, PKD2, GANAB) and 27 % in PRKCSH or SEC63, which shows that some patients referred for PLD in fact have ADPKD [56]. In the Dutch and Belgian cohort, 41 % of patients tested for PRKCSH and SEC63 had a variant [20].

Limitations. The known genes explain 30–45 % of ADPLD index cases, and about half of families remain undiagnosed [3, 38]. Deep intronic variants, such as the GANAB deletion of Besse and colleagues, escape exome algorithms, and large deletions are not detected without copy-number analysis [38, 54]. The proportion of detectable variants in a gene is not equivalent to the clinical sensitivity of the test, which depends on the fraction of patients explained by the set of genes. A negative result does not exclude ADPLD, and a positive result confirms but does not predict individual severity, because penetrance and expressivity vary [3]. Interpretation of variants in genes with limited evidence (LRP5, SEC61B, ALG8, PKHD1) is difficult, given the population frequency of predicted pathogenic variants (1 in 91 to 1 in 130) and low penetrance [2, 19]. ClinVar contained, for ALG8, 36 pathogenic, 50 likely pathogenic and 220 uncertain-significance submissions, a raw count that illustrates the weight of variants of uncertain significance [10]. ClinGen has no actionability assertion for PRKCSH or SEC63 [21].

Report and variants of uncertain significance. The report should state the gene, the versioned reference transcript (preferably MANE Select, see 2.3), the HGVS c. and p. nomenclature, zygosity, the classification according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and the method (sequencing and copy-number analysis), and flag historical notations from non-MANE transcripts (as in GANAB). A variant of uncertain significance should not guide decisions; segregation analysis in affected and unaffected relatives with liver imaging is the main route to reclassification, taking into account age-dependent penetrance [2, 11].

Prenatal and preimplantation diagnosis. See section 8.

5.8. Practical algorithm

6. Differential Diagnosis

The differential diagnosis is organised on three levels: other cystic lesions of the liver, which are not PLD; PLD associated with polycystic kidney disease, especially ADPKD; and syndromic or metabolic diseases with liver cysts, which present in childhood.

6.1. ADPLD versus ADPKD

The most frequent and most consequential distinction is between ADPLD and ADPKD with PLD. PLD in ADPKD is the most common extrarenal manifestation of this disease (liver cysts in more than 80 % of patients over 30 years), and the hepatic pictures are clinically and histologically indistinguishable [2, 28]. What separates the two entities is the kidney: in ADPKD, the kidneys enlarge with multiple bilateral cysts and renal function declines, whereas in ADPLD renal cysts, when present, are few (no patient with ADPLD had more than 10 in the Leipzig cohort) and renal function is maintained [17, 56]. The distinction has consequences: in ADPKD it is necessary to monitor blood pressure, renal function and, in selected groups, intracranial aneurysms, and to consider tolvaptan, whereas in ADPLD follow-up is hepatic. The genes of the overlapping spectrum (GANAB, ALG8, ALG9, PKHD1) may or may not meet the renal criteria, and genetic testing resolves the doubt in some cases; almost half of patients referred for PLD to a German centre had a variant in an ADPKD gene [51, 56].

6.2. Other cystic liver lesions

The number of cysts (more than 10) and their simple architecture distinguish PLD from simple cysts and from mucinous cystic neoplasm. The latter is rare but has malignant potential (transformation in up to 30 %), and 20–50 % of mucinous neoplasms are not identified before surgery; fenestration of a neoplasm mistaken for a simple cyst is associated with recurrence, so complete resection is the standard treatment (level 3, strong, 100 %) [3]. Biliary hamartomas and peribiliary cysts are lesions smaller than 1 cm that do not require follow-up when asymptomatic (level 3, strong, 96 %) [3]. Caroli disease is distinguished by communication with the biliary tree, visible on MR cholangiography, and by the central dot sign [3].

6.3. Paediatric differential diagnosis

Liver cysts in a newborn or young child do not suggest ADPLD, whose expression is adult. At that age, they point to ARPKD with congenital hepatic fibrosis, syndromic ciliopathies (Meckel, Joubert/COACH), the Zellweger spectrum, congenital disorders of glycosylation (ALG8-CDG, PMM2 with promoter variant) and, more rarely, very early-onset ADPKD [17, 44, 81, 82].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

PLD does not compromise liver function, and the aim of treatment is to relieve symptoms and improve quality of life, not to reduce volume as an end in itself (level 1, strong, 100 %) [3]. Only symptomatic patients should be treated (level 2, strong, 100 %); no volume-reducing strategy has a prophylactic role, and cyst infection or haemorrhage alone are not indications for volume-reducing treatment [3]. The choice is guided by symptoms and complications and by the hepatic phenotype (number, size and distribution of cysts, spared sectors, venous compression) (level 2, strong, 100 %), and patients with symptomatic PLD should be referred to reference centres (level 3, strong, 100 %) [2, 3]. Previous interventions complicate a future total hepatectomy for transplantation, through adhesions and involvement of the retrohepatic vena cava, which should weigh in the initial choice [3]. Treatment does not depend on the gene: the guidelines do not distinguish ADPLD from the PLD of ADPKD, and response rates to somatostatin analogues were similar in both groups [23, 47].

7.2. General measures, hormones and nutrition

Oestrogens. EASL recommends withdrawing exogenous oestrogens in women with PLD (level 3, strong, 100 %), and KDIGO recommends counselling women about the benefits and potential harms of sex hormone therapy [2, 3]. The ACG 2024 suggests withdrawal, as a conditional recommendation with very low evidence, and cites a cross-sectional study in which every 10 years of oestrogen-containing oral contraception in premenopausal women was associated with a 15.5 % higher height-adjusted liver volume [80]. The levonorgestrel intrauterine device is a contraceptive alternative, with systemic exposure of 4–13 % of that of oral contraceptives, although without data on its effect on PLD; there are no data or recommendations for progestogen-only oral pills, such as desogestrel [3]. GeneReviews recommends avoiding oestrogens and possibly progestogens in severe PLD [17]. Medically assisted reproduction techniques expose women to high oestradiol concentrations and should be discussed in that context [3]. In postmenopausal women with symptomatic PLD, oestrogen replacement therapy increases cyst size [17, 65].

Digestive symptoms. GeneReviews mentions H2 blockers or proton pump inhibitors for symptomatic relief of reflux in symptomatic PLD [17]. There are no specific diets that treat PLD [2].

Nutrition and sarcopenia. EASL suggests CT to assess sarcopenia in patients with massive hepatomegaly displacing organs (level 3, weak, 87 %) and recommends intensive nutritional and exercise rehabilitation, with a dietitian and physiotherapist, in patients with sarcopenia (level 5, strong, 100 %); it advises small, frequent meals and exercise several times a week [3]. KDIGO recommends assessing sarcopenia and malnutrition in symptomatic PLD and offering intensive nutritional counselling and physical rehabilitation [2]. It is not known whether somatostatin analogues prevent sarcopenia [3].

Hernias. Abdominal wall hernias occur in about 40 % of patients and are associated with liver volume; the sources consulted do not define a specific repair strategy for PLD [22].

7.3. Somatostatin analogues

Mechanism and evidence. Somatostatin analogues bind to cholangiocyte somatostatin receptors, reduce intracellular cAMP and, with it, fluid secretion and proliferation; octreotide inhibited hepatic cystogenesis in a rodent model by lowering cholangiocyte cAMP [23, 48]. They are the only medical option that has shown benefit in randomised trials; they reduce liver volume, with maximal effect in the first 6 months and sustained up to 4 years, slightly reduce kidney volume without effect on the decline in renal function, and the benefit is greatest in young women (under 48 years) with rapidly progressing disease [3, 23, 47]. About 60 % of patients respond with volume reduction, regardless of baseline factors except age and sex; the median liver volume reduction is 2–8 %, and treatment does not change the trajectory of the disease [23]. There is no evidence that they reduce severe hepatic outcomes [23]. KDIGO 2025 recommends long-acting analogues in people with ADPKD, markedly enlarged polycystic livers and severe volume-related symptoms (recommendation 1B), and EASL and ERN RARE-LIVER extend the indication to PLD in general, including ADPLD [2, 3, 23].

Eligibility. The ERN RARE-LIVER position statement, based on a Delphi process with strong consensus defined as ≥80 %, considers eligible patients with symptoms attributable to liver volume in non-localised disease, assessed with specific questions, total liver volume and, if available, the expected volume trajectory (strong consensus) [23]. Before starting, a validated questionnaire (PLD-Q or POLCA) and liver volume by CT or MRI volumetry should be recorded (strong consensus) [23]. The suggested thresholds for starting are POLCA ≥14, PLD-Q ≥32, progression group ≥2 or hTLV >1600 mL/m (Kim ≥2) (weak consensus); there is no cut-off that predicts response, and treatment may be considered with few symptoms when rapid growth is confidently predicted [23]. Asymptomatic patients should not be treated, and a patient with a slightly enlarged liver and symptoms should be investigated for another cause [23]. The analogues may be considered regardless of renal function, with limited experience below an eGFR of 30 mL/min/1.73 m², and in patients with a history of cyst infection or gallstones, with monitoring (weak consensus) [23]. Kidney transplant recipients on immunosuppression are less suitable candidates, because immunosuppression is a major risk factor for cyst infection [23].

Choice of drug and dose. Lanreotide and long-acting release octreotide are equivalent as a class effect; pasireotide has comparable efficacy but greater glucose intolerance and is not recommended first line [23]. The ERN RARE-LIVER position statement recommends starting at the full trial dose and adjusting for adverse effects, without escalating above those doses (strong consensus); subgroup analyses suggest a dose–response relationship [23]. In the survey of ERN experts, lanreotide was the drug of choice of seven of eight regular prescribers, with a target dose of 120 mg at monthly intervals [23]. All analogues are used off-label in PLD [23].

Administration. Lanreotide is given by slow deep subcutaneous injection (about 20 seconds) into the upper outer quadrant of the buttock, alternating sides, and may be self-administered after training; the Portuguese SmPC also allows the upper outer thigh, the site indicated for self-administration, with the needle fully inserted, perpendicular to the skin and without a skin fold [85]; octreotide LAR is given by intramuscular gluteal injection every 4 weeks, and intervals longer than 4 weeks are not recommended by the label [23, 84, 86].

Adverse effects and their management.

Serious adverse effects leading to discontinuation occur in less than 5 % of patients [3]. In DIPAK 1, only 34 % of patients tolerated the full dose of lanreotide, whereas more than 80 % tolerated 40 mg of octreotide in the extension of Hogan and colleagues [23, 92].

Response, duration and discontinuation. Response is assessed only after 6–12 months, with the questionnaire at 6 months or more and volumetry at 12 months or more; it is defined as symptomatic relief without progression of hTLV (strong consensus), and stabilisation of volume during a period of expected growth counts as response [23]. KDIGO recommends assessing the effect on symptoms or volume at 6–12 months and stopping if there is no benefit [2]. Lanreotide reduces volume in up to 60 % of patients, but about 30 % of patients on placebo also show a reduction, so there is no robust cut-off [23]. If symptoms improve without volume stabilisation, another cause or oestrogen exposure should be sought; if there is neither volume reduction nor symptomatic improvement with confirmed adherence, the drug should be stopped (strong consensus) [23]. Treatment is continued while the benefits outweigh the adverse effects, until the natural attenuation of progression is expected (strong consensus) [23]. Early discontinuation leads to regrowth of volume and symptoms within 3–4 months; reintroduction is effective [23]. In the International PLD Registry, in 34 patients with two courses separated by a pause, the initial effect was −2.6 % per 6 months and the effect after resumption −1.6 % per 6 months (p=0.510), and intermittent therapy in responders kept volume stable relative to baseline (−0.6 % after 46.5 months) [93]. In young women with rapid growth on the transplant waiting list, the analogue acts as a bridge and should not be stopped; after the menopause, the ERN suggests continuing for 3–5 years and attempting a trial discontinuation, made permanent if there is no rebound [23]. An abrupt fall in volume on treatment should raise suspicion of cyst rupture [23].

Pregnancy and breastfeeding. Somatostatin analogues should not be offered during pregnancy or breastfeeding, according to ERN RARE-LIVER [23]. The Portuguese octreotide SmPC describes fewer than 300 exposed pregnancies, with congenital anomalies in about 4 % without suspected causality, considers it preferable to avoid the drug in pregnancy and states that patients should not breastfeed; the Portuguese lanreotide SmPC likewise describes fewer than 300 exposed pregnancies, considers it preferable to avoid the drug in pregnancy, as a precaution, and contraindicates its use during breastfeeding; the FDA labels for octreotide and lanreotide consider the data insufficient to estimate the risk [84–87].

7.4. Percutaneous and surgical procedures

Aspiration with sclerotherapy. This is the treatment of choice for symptoms caused by one or a few dominant cysts [17]. Before instillation of the sclerosant, contrast is injected into the cyst to exclude biliary communication [17]. Aspiration alone invariably leads to recurrence; the agents used (100 % ethanol, 20 % saline, tetracycline, minocycline, polidocanol) have not shown superiority over one another [3, 17]. Volume reduction is slow (6 months or more), so reintervention should not take place before 6 months; series report volume reduction of 76–100 %, symptomatic relief of 72–100 % and cyst disappearance in 56–100 %, and complications (ethanol intoxication, pain) are associated with long sessions (more than 1 hour) and large volumes of ethanol [3]. GeneReviews reports success in 70 % after one treatment and in a further 20 % after repetition, inversely related to cyst size [17]. Adding pasireotide did not improve the result of ethanol sclerotherapy [3]. In PLD, sclerotherapy is possible for a large or strategically located cyst, but symptomatic recurrence is frequent [3]. In a retrospective Mayo Clinic series (2017–2021), sodium tetradecyl sulfate foam sclerotherapy in 77 patients (102 sessions) reduced the volume of the treated liver cysts by a median of 83.1 % (interquartile range, IQR, −93.5 to −52.9 %), with volumes close to zero after one year and stable in the following years, and improved the PLD-Q; a prospective study is under way (NCT04111692, expected completion November 2027) [94].

Transarterial hepatic embolisation. This is intended for highly symptomatic patients with diffuse cysts, at least one functioning segment and no surgical alternative; experience is limited [2, 3, 95]. Post-embolisation syndrome is universal [2].

Fenestration. Laparoscopic or open fenestration (deroofing) treats large superficial cysts, several in a single procedure, with lasting relief, but does not alter the natural history of PLD; the laparoscopic route is preferred, and recurrence is below 8 % for simple cysts [3]. In PLD, transient ascites occurs in about 40 % and results are often short-lived; fenestration does not help livers with many small and medium cysts [17]. Adhesions should be weighed against a future transplant [3].

Partial hepatectomy with fenestration. Indicated in the phenotype with cysts confined to some segments and at least one spared sector with patent vessels [2, 3]. In the Mayo Clinic series of 1985–2006 (141 operated patients, 122 women, age 51 years, 117 with polycystic kidney disease), 124 underwent partial hepatectomy with fenestration, 10 fenestration alone and 7 transplantation; 65 % had significant compression of the inferior vena cava or hepatic veins; morbidity was 58 %, mortality 4 % and Clavien III–V complications 30 %; survival was 90 % at 5 years and 78 % at 10 years, functional status normalised or improved in 75 % and 73 % returned to work, but symptoms recurred in 73 % during a follow-up of about 8 years [71]. For resection with fenestration in PLD, EASL reports perioperative mortality of up to 14 % and postoperative liver failure requiring transplantation in 2–3 % in series with mean follow-up of 6 and 8 years, and reserves it for severe symptoms without a transplant option [3]. Long-term results in severe PLD are favourable in specialised centres, and the procedure is often preferable to transplantation when there is spared parenchyma [17, 83]. Complications include ascites, biliary fistula, haemorrhage and pleural effusion [3, 17].

7.5. Liver transplantation

Transplantation is the only curative option and accounts for 1–1.5 % of patients on the waiting list [3]. EASL suggests referral for liver or liver–kidney transplantation based on clinical criteria, taking into account allocation rules, waiting lists and the risk of deterioration (level 3, weak, 100 %) [3]. The EASL exception criteria are: clinically apparent liver disease due to massive PLD severely affecting quality of life; massive PLD with complications treatable only by transplantation (severe malnutrition, hepatic venous outflow obstruction, ascites, portal hypertension, variceal haemorrhage, recurrent cyst infections); and failure or contraindication of non-transplant interventions [3]. KDIGO recommends referral for transplantation in massive PLD without contraindications or alternatives and proposing combined kidney–liver transplantation when there is a hepatic indication and eGFR <30 mL/min/1.73 m² [2]. A 2024 consensus considered recurrent cyst infection (more than two episodes in 6 months) an indication for transplantation [61].

Because liver function is preserved, the MELD score (Model for End-Stage Liver Disease) is low and does not reflect severity, which requires exception points [3, 17]. National criteria differ:

In Europe, only Spain, the United Kingdom, France and Eurotransplant have specific criteria for PLD [61]. Transplant outcomes are comparable to those of other indications: 5-year survival of 81.3 % in PLD against 76.5 % in other indications, and intraoperative mortality of 1 % against 0.4 % in a 7-year British registry [3, 61]. The technique requires initial hilar dissection, inflow control, a portocaval shunt or venovenous bypass and no traction on the liver [3]. In combined liver–kidney transplantation, early loss of the renal graft reaches 20 %; alternatives include hypothermic perfusion with delayed renal implantation from the same donor or a metachronous living-donor kidney [3]. In a European survey, 40.4 % of centres preferred simultaneous transplantation, 30.8 % liver first and 1.9 % kidney first; some series report survival above 90 % at 3 and 5 years with combined transplantation [61]. In highly selected patients, cava-preserving hepatectomy followed by living-donor transplantation is an alternative [96]. In Brazil, a series from the Unicamp university hospital (1994–2024) recorded 9 transplants for PLD among 1188 liver transplants (0.75 %), with 88.8 % women, mean age 47.3 years, mean waiting time 7.1 months, three retransplants for hepatic artery thrombosis and survival of 66.6 % at 30 days and 55.5 % at 5 years; the series is small, long and does not separate ADPLD from ADPKD [97].

The case of a patient with isolated PLD, initially considered «too well» for transplantation because of a low MELD, who progressed with weight loss, sarcopenia and functional decline and died weeks after listing from traumatic cyst rupture, illustrates the limitation of MELD; the North American exception guidance has since included malnutrition and sarcopenia [62].

7.6. Treatment of complications

Cyst infection. The guidelines recommend fluoroquinolones and third-generation cephalosporins as empirical first line (EASL: level 2, strong, 90 %), directed at Enterobacterales; KDIGO proposes an intravenous third-generation cephalosporin, with or without a fluoroquinolone, followed by an oral fluoroquinolone adjusted to cultures [2, 3]. Carbapenems and cefazolin penetrate cyst fluid poorly; co-trimoxazole penetrates renal cysts better, with no data for hepatic cysts; the combination of ciprofloxacin with a cephalosporin may be considered in severe cases; the dose should be adjusted to renal function and local resistance, and fungal infection should be suspected if there is no improvement [3]. Treatment failure reaches 70 % in a meta-analysis, especially with monotherapy [3]. Eradication is defined by resolution of fever, normalisation of CRP and at least two negative blood cultures [3]. Secondary prophylaxis is not recommended (level 5, strong, 92 %), and the evidence for selective digestive decontamination is insufficient [3]. KDIGO does not recommend empirical antibiotics for localised hepatic pain without fever, with normal leucocytes and CRP, a situation in which haemorrhage should be considered [2].

In PLD, drainage requires caution, because of the difficulty of identifying the infected cyst and the risk of spread to adjacent cysts [3]. In recurrent infections that severely compromise quality of life, liver transplantation may be considered [3].

Intracystic haemorrhage. Treatment is conservative, and aspiration or fenestration should be avoided during active haemorrhage [3]. EASL recommends temporary interruption of anticoagulants (level 5, strong, 96 %) and their resumption between 7 and 15 days after the onset of haemorrhage (level 5, weak, 100 %), earlier if thromboembolic risk is high; there is no role for vitamin K, prothrombin complex concentrate or plasma, except in haemodynamic instability; a supratherapeutic INR (international normalised ratio) is a risk factor; aspirin is withheld for 3 days and, with dual antiplatelet therapy, the P2Y12 inhibitor is continued; direct oral anticoagulants are managed like vitamin K antagonists [3].

Rupture. Most patients recover, but deaths have occurred, and traumatic rupture with haemoperitoneum may be complicated by abdominal compartment syndrome; the risk of rupture does not justify preventive volume-reducing treatment [3, 62].

Hepatic venous outflow obstruction. Primary hepatic vein stenting is the intervention of choice, with patency above 80 % [3].

7.7. Drugs without benefit and agents to avoid

7.8. Special populations, perioperative care and transition

Pregnancy. EASL recommends not advising against pregnancy (level 3, strong, 96 %); pregnancy success is similar to that of the general population [3]. Somatostatin analogues should be stopped [23]. The sources consulted do not define a protocol for hepatic monitoring during pregnancy in ADPLD.

Chronic kidney disease and kidney transplantation. Lanreotide has lower clearance and volume of distribution on haemodialysis; 90 mg was used with eGFR <30 mL/min/1.73 m² in DIPAK 1 [23]. The Portuguese SmPC describes an approximately 2-fold reduction in total serum clearance in severe renal impairment, but does not provide for dose adjustment [85]. Immunosuppression after kidney transplantation increases the risk of cyst infection [3, 23].

Perioperative care. Surgical interventions in PLD should be concentrated in specialised centres; the most frequent complications are transient ascites, biliary fistula, haemorrhage and pleural effusion; planning should consider a possible future transplant [3, 17]. Discontinuation of analogues before surgery is not addressed in the sources consulted; discontinuation is associated with biliary complications in patients with incident stones, which warrants attention during that period [90].

Transition. ADPLD manifests in adulthood; there is no indication to test asymptomatic children, and paediatric transition rarely arises [17].

7.9. Regulatory status

No drug has an approved indication for PLD in any jurisdiction; all somatostatin analogues are used off-label, on the basis of the trials and guidelines [21, 23].

7.10. Clinical trials

The analogue trials are small, last from 6 months to 3 years and use liver volume as a surrogate endpoint; symptom questionnaires improved inconsistently, and no trial assessed hard clinical outcomes such as transplantation or mortality [23, 111]. Most included patients with ADPKD and ADPLD together, with a predominance of women, and DIPAK 1 was open-label and designed for the kidney [23, 108]. Differences between trials in population, imaging (CT or MRI), baseline volume and duration preclude indirect comparisons between drugs; a relative reduction of a few percentage points should be read against natural growth (about 1.8 % in 6–12 months, 4.8 % in young women) and against the volume reduction also seen in about 30 % of patients on placebo [23, 47]. The negative trials (everolimus, ursodeoxycholic acid, leuprorelin) and the absence of an effect on the decline in renal function in ADPKD (DIPAK 1, ALADIN 2) delimit the role of these drugs [17, 98–100, 112]. In an Italian trial of octreotide LAR for 3 years in 75 patients with ADPKD, the smaller increase in kidney and liver volumes after 1 year was no longer significant at 3 years [17].

7.11. Developments in the last 12 months

In AGAINST-PLD, conducted in three Dutch university centres, the patients had hTLV above the 90th percentile for age or greater than 2.0 L/m and PLD-Q greater than 30; liver growth increased in half of the treated patients (3–7 % per year in 3 of 6), there was no improvement in PLD-Q or SF-36, adverse effects were more frequent with leuprorelin (38 against 9; p<0.001), with menopausal symptoms in 5 of 6 patients, and only 2 of the 14 participants wished to continue the drug after the monitoring committee recommended stopping [100]. The authors conclude that oestrogens do not appear to be the only driver of cyst growth [100]. For CAM2029, the secondary endpoints of POSITANO (symptoms) had no numerical results in the registry consulted, and no journal publication or marketing authorisation application for PLD was identified [109]. The ERN RARE-LIVER research agenda includes the natural history of aggressive subphenotypes, preventive treatment, arterial embolisation and radioembolisation [23].

7.12. Guideline recommendations and divergences

The ACG guideline on focal liver lesions (2024), graded with the GRADE system (Grading of Recommendations, Assessment, Development and Evaluation) and with a literature search up to September 2022, devotes a section to PLD [80]. It recommends suggesting withdrawal of exogenous oestrogens in women with PLD (conditional recommendation, very low evidence), whereas EASL formulates it as a strong recommendation [3, 80]. It recommends somatostatin analogues (strong recommendation, moderate evidence) in patients with numerous scattered small to medium cysts not amenable to resection, fenestration or aspiration with sclerotherapy, and in patients with symptomatic ADPKD and PLD [80]. The ACG key concepts, which are not graded, set as the goal symptomatic relief and preservation of quality of life, the choice between aspiration with sclerotherapy, fenestration and resection according to cyst characteristics, hepatic reserve and centre experience, and liver transplantation, with or without simultaneous kidney transplantation, as the curative option for refractory symptoms [80]. The ACG does not recommend imaging surveillance of cysts in asymptomatic patients, asks for an initial renal ultrasound to exclude ADPKD and considers that genetic testing is generally not recommended, except in young patients with few renal cysts who do not meet ADPKD criteria, a position close to that of EASL [3, 80]. There are three points of divergence with the European sources. The ACG frames ADPLD within the ciliopathy spectrum, whereas recent genetic sources place the ADPLD genes in polycystin-1 biogenesis in the ER (section 2) [37, 80]. It indicates simultaneous liver and kidney transplantation in patients on dialysis, with glomerular filtration rate <20 mL/min or who need a kidney transplant, a threshold different from the KDIGO eGFR <30 mL/min/1.73 m² [2, 80]. It describes the lanreotide of the reference trial as given intramuscularly, whereas the trial and the labels use deep subcutaneous injection [80, 84, 85]. The prevalence of 1–10 per million cited by the ACG for isolated PLD lies below the class assigned by Orphanet (1–9/100,000, i.e. 10–90 per million; section 9.1) [1, 80].

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

ADPLD is transmitted in an autosomal dominant manner: each child of a carrier has a 50 % probability of inheriting the variant [1, 3]. The probability of developing clinical disease is lower than that of inheriting the variant, because penetrance is incomplete and age-dependent, and expressivity varies widely among relatives with the same genotype, from a few cysts to massive hepatomegaly [3, 11]. The sex of the offspring modulates the risk of severe disease: symptomatic PLD is much more frequent in women [3, 20]. For genes with limited evidence and low penetrance (ALG8, LRP5, SEC61B, monoallelic PKHD1), the risk of clinical disease in a carrier offspring is even less predictable [2, 19]. In the absence of an identified variant, which is the situation of more than half of families, counselling is based on imaging and family history [3].

8.2. Preconception counselling and pregnancy

EASL recommends preconception counselling on the risk of transmission (level 4, strong, 96 %) and recommends not advising against pregnancy (level 3, strong, 96 %); genetic testing can confirm but not exclude the disease, more than half of cases have no identified gene and testing is not done routinely [3]. Pregnancy success is similar to that of the general population [3]. Counselling should address the potential effect of oestrogens on liver volume (contraception, medically assisted reproduction techniques and, in the future, hormone replacement therapy) and the need to stop somatostatin analogues during pregnancy and breastfeeding [3, 23].

8.3. Relatives, cascade testing and minors

EASL does not consider it necessary to screen relatives of patients with PLD for liver cysts, unless they have symptoms [3]. When the familial variant is known, adult relatives who wish to may undergo targeted testing; imaging remains the means of assessing disease expression [3, 51]. In relatives without an identified familial variant, a normal ultrasound in a young adult does not exclude the disease, given the age-dependent penetrance [11, 31]. Regarding minors, the ADPKD GeneReviews states that there is no indication to test asymptomatic children; for ADPLD, of adult expression and without preventive treatment, the same principle applies all the more [17]. For genes with a severe biallelic phenotype, testing the partner of a carrier is of value when there are reproductive plans [2, 10].

8.4. Prenatal and preimplantation diagnosis and mosaicism

When the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing are technically possible; the sources consulted do not describe their use in ADPLD, an adult-onset condition with preserved liver function and variable expressivity, nor are there specific guidelines on their acceptability [3]. In couples at risk of severe biallelic disease (for example, two ALG8 carriers), prenatal and preimplantation diagnosis is directed at the recessive disease and not at ADPLD [57]. The sources consulted do not describe cases of germline mosaicism or de novo variants in ADPLD; the absence of data does not prove that they do not occur.

8.5. Content of counselling

Counselling should cover: the benign nature of liver function and the fact that most patients do not need treatment; the 50 % transmission risk and the unpredictability of severity; the influence of sex and oestrogens; the symptoms that warrant review; the meaning and limits of genetic testing; and the existence of reference networks and patient organisations (section 9.4) [2, 3, 23].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The figures refer to different quantities: the prevalence of ascertained disease (Orphanet), the prevalence of PLD in general (EASL), the annual incidence of symptomatic patients treated in hospitals (Japan) and the frequency of genotypes in the population (gnomAD). The gap between genotype frequency and disease prevalence reflects incomplete penetrance and underdiagnosis.

9.2. Geography, ancestry and founder effect

The families that allowed the genes to be discovered were mainly Dutch, Finnish and North American: the PRKCSH variants of Drenth and colleagues were described in four Dutch families, the SEC63 variants in families from the central USA and Finland, and the LRP5 variants in Dutch families and one Moroccan family [7, 11, 29]. The ALG8 variants of the PCLD3 description were identified in patients of European ancestry, a Finnish woman and an African American patient, from an exome cohort of 102 patients [9]. One PRKCSH variant was shared by three of the four Dutch families of Drenth and colleagues, and the SEC63 variant Trp58Ter was found in two probands from the central USA without known relationship; the sources consulted do not demonstrate a formal founder effect [7, 29]. In Finland, three families had different SEC63 variants [6]. In gnomAD, predicted pathogenic variants in ADPLD genes were more frequent in admixed Americans (1/91), Finns (1/110) and Africans and African Americans (1/43) than in non-Finnish Europeans (1/187) (p<0.0001), differences that concern genotypes and not disease prevalence [19].

Most clinical data come from the Netherlands and Belgium (Nijmegen and Leuven registries), the USA (Mayo Clinic), Germany (Leipzig) and European and North American consortia [20, 31, 55, 56]. In Brazil, the Unicamp transplant series described 9 transplants for PLD among 1188 liver transplants (0.75 %) over 30 years [97]. The sources consulted do not include epidemiological studies from Portugal; two Portuguese centres (the Coimbra Liver Transplantation Unit and Hospital Curry Cabral, in Lisbon) took part in the ERN RARE-LIVER position statement [23]. The absence of national data in the sources consulted does not demonstrate that none exist.

9.3. Special populations

Women. They make up more than 80 % of patients with severe PLD and of transplants; the reproductive years and oestrogen exposure are the periods of greatest progression [3, 59]. Men. They have less frequent and less severe disease, but a higher risk of hernias, and the relationship between liver volume and need for treatment differs from that in women [22, 59]. Older people. After the menopause volume stabilises and severe PLD may regress [3, 64]. Kidney transplant recipients (ADPKD). Increased risk of liver cyst infection [23, 61]. Children. ADPLD is exceptional; liver cysts in childhood point to other diseases [17].

9.4. Reference networks and patient organisations

ERN RARE-LIVER (European Reference Network for rare liver diseases) is the relevant network for PLD and published the position statement on somatostatin analogues; ERKNet (European Reference Network for rare kidney diseases) covers the forms with renal involvement, and members of both networks co-authored the position statement [23, 25, 26]. The PKD Charity (United Kingdom) provides information on PLD [114]. In the USA, the PKD Foundation, founded in 1982, is mainly concerned with polycystic kidney disease: it funds research, maintains the ADPKD patient registry, a network of centres of excellence, a telephone helpline (Hope Line) and local communities; its home page has no content specific to ADPLD [115]. The POLCA questionnaire is available online at the Leuven university hospital [76]. Patient registries exist: the UK Polycystic Liver Disease Registry (NCT04645251, recruiting, expected completion December 2030, enrolling patients with more than 10 cysts) and the International PLD Registry in the Netherlands [93, 116].

10. Illustrative Clinical Case

10.1. SEC63 ADPLD with an IFT140 variant and renal cysts

Ortega-Macías and colleagues, from the University of New Mexico (USA), described in 2026 a 40-year-old woman with multiple liver cysts and a father with unspecified polycystic kidney disease [52]. The liver cysts had been diagnosed in 2015, during an emergency department visit for projectile vomiting; the patient was haemodynamically stable, with right upper quadrant tenderness on deep palpation, and imaging from another hospital suggested rupture of a cyst [52]. Ten years later, she was seen in a nephrology clinic with normal renal and liver function: creatinine 0.65 mg/dL (eGFR 114 mL/min/1.73 m²), aspartate aminotransferase (AST) 25 U/L, alanine aminotransferase (ALT) 21 U/L, alkaline phosphatase 71 U/L, total bilirubin 0.3 mg/dL and albumin 4 g/dL [52].

Abdominal MRI with and without contrast showed a slightly enlarged liver, without steatosis or iron overload, with numerous lobulated cysts hyperintense on T2, the largest measuring 12.9 × 10.8 cm in the right lobe, and multiple bilateral renal cysts, the largest measuring 5.2 × 3.3 cm, exophytic at the left upper pole, with haemorrhagic or proteinaceous content, without hydronephrosis; brain MRI showed no aneurysms [52]. Figure 1 of the article, consulted in PubMed Central (https://pmc.ncbi.nlm.nih.gov/articles/PMC13081031/figure/FIG1/), shows the T2-weighted MRI with the liver cyst of about 12 × 10 cm (white arrow, panel A) and the left renal cyst of about 5 × 3 cm (red arrow, panel B) [52].

Genetic testing on saliva identified two heterozygous variants classified as pathogenic: SEC63 NM_007214.5:c.715C>T p.(Arg239Ter), consistent with ADPLD type 2 (PCLD2), and IFT140 c.634G>A p.(Gly212Arg) (transcript not stated in the article), associated with IFT140 polycystic kidney disease [49, 52]. Management was conservative: tolvaptan was deferred because of preserved renal function, gastroenterology proposed ultrasound every 6 months to look for portal hypertension and monitoring of kidney volume was maintained; somatostatin analogues or sclerotherapy were reserved for recurrence of symptoms [52].

The authors interpret the picture as a combination of two diagnoses with additive effects on the same pathway, without functional validation or segregation analysis [52]. Three aspects deserve critical reading. First, the article attributes ciliary dysfunction to SEC63, whereas SEC63 is an ER translocation protein and its effect on PC1 is indirect (section 2.3) [32, 33]. Second, the age-dependent ADPLD criteria cited in the article derive from a reference on ADPKD and are not validated for ADPLD (section 5.1). Third, six-monthly ultrasound for portal hypertension does not correspond to a guideline recommendation: EASL does not recommend imaging surveillance of asymptomatic patients with PLD, and clinically apparent portal hypertension is very rare [3]. The case illustrates the value of a multigene panel when the renal burden seems disproportionate for ADPLD (section 5.7) and the coexistence of variants in ADPLD and ADPKD genes (section 2.8).

10.2. Limitation of MELD in isolated PLD

Vinton and colleagues described a patient with isolated PLD initially considered «too well» for transplantation because of a low MELD; the course with weight loss, sarcopenia and functional decline led to reassessment, listing and the award of exception points, but weeks later the patient suffered traumatic rupture of a cyst, with fatal haemoperitoneum and abdominal compartment syndrome [62]. The case, without a genotype, illustrates that the severity of PLD is not measured by liver function and that malnutrition and sarcopenia are indications for referral (section 7.5) [3, 62].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Hepatic synthetic function remains preserved, and liver failure is exceptional; the burden of disease is volume and symptoms [3, 21]. In the Dutch and Belgian cohort (137 patients, median follow-up 8.2 years), mortality was 8 %, and only 2 % of deaths were PLD-related; complications occurred in 10 % of untreated and in 51 % of treated patients, and 58 % were treated, at a median of 2 years after diagnosis [20]. In Japan, deaths from symptomatic PLD were due to cyst infection and liver failure, and mortality was highest in Gigot type III [18].

Individual prognosis is estimated from age-adjusted volume progression, sex and, in genotyped forms, the gene. In the progression groups of the Leipzig cohort, the median age at first hepatic event was 43.4 years in PG III, 56.2 years in PG II and 67.9 years in PG I, and the median age at transplant listing was 42.9 years in PG III and 59.5 years in PG II [56]. Female sex was associated with a 10.4-fold higher risk of a hepatic event and Kim stage III with a 4.9-fold higher risk than Kim I [56]. The combination of female sex, a PRKCSH variant and rapid volume progression identifies the highest-risk group [55]. In the Belgian cohort of symptomatic patients, 35.9 % needed volume-reducing therapy within 5 years [77]. After the menopause, progression slows, and severe PLD may regress [3, 64].

With treatment, the analogues reduce volume by 2–8 % without altering the natural trajectory; partial hepatectomy with fenestration has survival of 96 %, 93 %, 86 % and 78 % at 1, 5, 10 and 15 years; transplantation has a 5-year survival of 77–92 % (81.3 % in the series summarised by Perez-Prado and Suddle) [2, 23, 61]. Symptoms recur in up to 73 % of operated patients at long-term follow-up [71].

11.2. Surveillance

11.3. Referral

Referral to a centre with experience in PLD is warranted in the presence of symptoms affecting quality of life, need for volumetry before analogues, recurrent complications, malnutrition or sarcopenia, venous obstruction or suspected mucinous neoplasm [2, 3, 23]. Referral for transplantation follows the exception criteria (section 7.5).

12. Summary and Concluding Remarks

Isolated autosomal dominant polycystic liver disease is an adult-onset disease of the biliary epithelium, defined by more than 10 liver cysts in a patient who does not meet ADPKD criteria. The known genes — PRKCSH and SEC63, with definitive evidence, GANAB, and the limited-evidence genes ALG8, LRP5, SEC61B, ALG6 and monoallelic PKHD1 — converge on polycystin-1 biogenesis in the endoplasmic reticulum, with the exception of LRP5, and explain 30–45 % of cases. The cyst arises from a somatic second hit, which explains the variability among relatives. The KDIGO 2025 nomenclature (ADPLD-gene) and the OMIM phenotypic series (PCLD1–4) coexist, and GANAB, ALG8 and ALG9 bridge to ADPKD.

Most patients are asymptomatic and need neither treatment nor imaging surveillance. Symptomatic disease is concentrated in women of reproductive age, and oestrogen exposure aggravates it. Staging combines height-adjusted liver volume, age-adjusted progression and the PLD-Q and POLCA questionnaires. Diagnosis is radiological, ultrasound is the first-line modality, and renal assessment separates ADPLD from ADPKD; genetic testing, with copy-number analysis, is reserved for doubt between the two entities, for counselling and for suspected dual diagnosis, and a negative result does not exclude the disease.

Treatment is guided by symptoms and the hepatic phenotype: withdrawal of oestrogens, somatostatin analogues (lanreotide 120 mg or octreotide LAR 40 mg every 4 weeks, off-label, with assessment at 6–12 months), sclerotherapy for dominant cysts, fenestration, partial hepatectomy when there are spared sectors and liver transplantation, the only curative option, with exception criteria that recognise malnutrition and sarcopenia. Cyst infection, haemorrhage and rupture have their own management, and the EASL and KDIGO guidelines diverge in details of antibiotic therapy and drainage. Everolimus, ursodeoxycholic acid, tolvaptan and leuprorelin have no place in treatment. Under investigation are subcutaneous depot octreotide, with a positive phase 2/3 result, and statins, still at the preclinical and observational stage. Counselling rests on the 50 % transmission risk, incomplete penetrance and the unpredictability of severity, and should take into account the severe biallelic phenotypes of some genes of the class.

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