RARE DISEASE
Isolated polycystic liver disease
Isolated polycystic liver disease
Isolated polycystic liver disease
Synonyms: ADPCLD, Autosomal dominant polycystic liver disease, PCLD
Synonyms: ADPCLD, Autosomal dominant polycystic liver disease, PCLD
Synonyms: ADPCLD, Autosomal dominant polycystic liver disease, PCLD
Drug discovery
5
drugs
With orphan designations
Overview
Isolated polycystic liver disease (PCLD) is an autosomal dominant disorder caused by mutations in PRKCSH, SEC63, or other genes regulating endoplasmic reticulum protein processing. It manifests as ≥20 hepatic cysts without clinically significant kidney involvement. Symptoms like abdominal distension, pain, or early satiety typically arise after age 40, often requiring imaging for diagnosis. Liver function remains normal, but complications like cyst hemorrhage/infection occur. Management prioritizes symptom relief, with somatostatin analogs (lanreotide/octreotide) reducing liver volume by ~4% annually [1][4][9].
Burden
Therapies
Approach | Indications | Efficacy/Notes |
|---|---|---|
**Somatostatin analogs** | Symptomatic patients with massive hepatomegaly | 3-5% liver volume reduction at 6-12 months; prevents growth [3][4][12] |
**Cyst-directed interventions** | Dominant cysts >5 cm | Percutaneous sclerotherapy (72-100% symptom relief), fenestration (22-24% recurrence) [2][4] |
**Liver transplantation** | Refractory malnutrition/compression | Curative but rare (<1%); MELD exception criteria apply [4][12] |
Categories: rare genetic diseases, rare hepatic diseases, rare transplant-related disorders
Research Papers
321 drug discovery papers about Isolated polycystic liver disease, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
321 drug discovery papers about Isolated polycystic liver disease, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-12-20 | The evolving role of liver transplantation in managing polycystic liver disease
Polycystic liver disease (PLD) is a rare genetic condition characterised by the presence of numerous cysts throughout the liver (1). PLD was initially described in 1856 as a diseased state connected to polycystic kidney disease (PKD), and in 1925, it was suggested that PLD might exist independently of PKD. Most patients remain asymptomatic; however, some may develop clinical symptoms. The expansion of the liver and its strain on the surrounding organs cause PLD symptoms. Common symptoms of PLD include early satiety, postprandial fullness, gastroesophageal reflux, and digestive intolerance and due to these symptoms, the patient may decide to cut back on meals, which could result in severe malnutrition and weight loss (2). In extreme cases, venous drainage blockage can cause portal hypertension, along with associated symptoms such as jaundice, ascites, splenomegaly, oesophageal varices, and encephalopathy. Three types of primary therapeutic approaches are available for PLD: drug therapy, radiological or percutaneous intervention and surgery. Somatostatin analogues are recommended by the European Association for the Study of the Liver (EASL) decision-making flowchart for PLD patients who have a large number of dispersed small-to-medium-sized cysts (3). For percutaneous therapy, cyst aspiration and sclerosis are performed for patients with a single giant cyst while transcatheter arterial embolization is to embolize the branches of arteries that supply blood to cysts resulting in control of disease progression (1). Surgical procedures that include liver resection and liver transplantation, are usually considered for advanced cases. Some recent studies have brought attention to the role of liver transplantation in PLD, especially given the challenges in therapy and the requirement for successful long-term results. In this context, the results of a recent retrospective study done by Moein M et al. are worth considering. The study compared post-transplant outcomes of liver transplant recipients between 2000 and 2023, dividing the population into two subgroups. The findings highlight a notable improvement in the results of liver transplantation for PLD during the previous ten years, particularly in the 2011–2023 cohort. The prognosis shown by the graft and patient survival rates suggests that this therapeutic strategy has become a more viable course of treatment (4). Additionally, a case report by Niibek M et al. describes a patient with a large polycystic liver who underwent successful liver transplantation. The liver weighed 14,75 kg and measured 53 x 37 x 39 x 16 cm. ---Continue
2025-04-11 | Pure living donor liver transplant for liver and polycystic kidney disease, outcomes and experiences from an Asian transplant unit
• This study presents one of the largest single-center case series of isolated LDLT for PLD associated with polycystic kidney disease (PCKD). • LDLT offers excellent long-term survival (5-year survival of 88.9 %) with acceptable perioperative morbidity in patients with PLD. • Pre-existing chronic kidney disease (CKD) was associated with early post-transplant renal deterioration and need for renal replacement therapy (RRT). • No major complications or mortality were observed among living liver donors, supporting the safety of LDLT in this context. • The study highlights the importance of tailored surgical strategies, including caval reconstruction, in managing massive polycystic livers. Adult polycystic liver disease (PLD) is a rare genetic disorder. In instances of intractable symptoms from mass effect or recurrent cyst-related complications, liver transplant affords the best therapeutic solution. This is a retrospective case series of patients who underwent isolated pure living donor liver transplantation (LDLT) for adult polycystic kidney disease (PCKD) associated PLD from 2012- 2022. Short-term peri‑operative outcomes including renal sequelae and long-term survival were analysed. From 2012–2022, a total of 9 patients underwent LDLT for PLD. The median explanted liver weight was 6950 g (IQR 5653–7700) with a median blood loss of was 5450mls (IQR 2400–9875). There was 1 mortality due to acute antibody-mediated rejection (11.1 %). Of the four patients with existing chronic kidney disease (CKD), 2 (50 %) developed end-stage renal failure and was renal replacement therapy (RRT) dependent at 3 months. The median overall survival in our series was 63.9 months with a 5-year survival of 88.9 %. Despite its technical challenges, LDLT affords an excellent long-term prognosis with acceptable major morbidity. Pre-operative CKD appears to be a risk factor for early renal deterioration.
2024-05-23 | Liver transplantation for polycystic liver disease: How feasible is this option?
Polycystic liver disease is a rare hereditary disease that can occur as an isolated disease. Because of its benign nature, polycystic liver disease rarely needs treatment. If treatment is needed, there are no standard guidelines, but usually, a liver resection or medical therapy is performed. A liver transplant is the last resort when all other possibilities have been exhausted, or complications arise. However, the risks and benefits must be carefully weighed. A retrospective registry analysis of the SRTR database was done for liver transplants performed in the United States from January 2001 to May 2023. The analysis of the data indicated a notable improvement in 5-year graft survival rates between the 2001-2010 group (mean of 92%) and the 2011-2023 group (mean of 97%) (P<0.001). The 2011-2023 group had a higher proportion of simultaneous kidney and liver transplants, more than 3 times, from 106 cases to 374 cases (57.7% vs. 42.3%, P= .001). The type of transplant was also considered when analyzing the 5-year survival of grafts. Patients who underwent both kidney and liver transplants simultaneously had a slightly better outcome. It was found that the only hazard affecting LT graft survival in the cohort was the cold ischemic time (HR: 2.80, P=.03). With all the surgical techniques and post-operation improvements, a liver transplant can be a feasible option for polycystic liver disease when the medical treatments are not sufficient to eliminate the symptoms.
2023-09-01 | Liver transplantation for polycystic liver disease: a case report
A 57-year-old man complained about abdominal distension and pain, constant feeling of early satiety. He was diagnosed with polycystic kidneys at the age of 24 and liver cysts discovered at the age of 38. The CT scan revealed 33 x 21 x 27 cm polycystic liver with cysts up to 7 cm in diameter. In 2009-2019 the patient was repeatedly punctured for liver cysts. Considering the continued enlargement of the liver and the worsening of complaints, the patient was put on the waiting list for a liver transplant in the spring of 2019. The patient went through liver transplantation on 11th of July 2022, the liver measures were 53 x 37 x 39 x 16 cm and weight 14,75 kg. The postoperative course was uneventful. Liver transplantation can be very effective treatment method that significantly improves the quality of life in PLD patients.
2023-06-12 | Liver Only Living Donor Transplantation for Polycystic Disease in a Patient on Chronic Hemodialysis: Case Report.
Polycystic liver disease (PLD) is characterized by the progressive development of polycystic lesions in the kidney and the liver, possibly resulting in dual organ failure. We indicated living donor liver transplantation (LDLT) for a patient with end-stage liver and kidney disease (ELKD) due to PLD on uncomplicated chronic hemodialysis. A 63-year-old man with ELKD and uncontrolled massive ascites due to PLD and hepatitis B on uncomplicated chronic hemodialysis was referred to us with a single possible 47-year-old female living donor. Because of the necessity of right lobe liver procurement from this small middle-aged donor and uncomplicated hemodialysis on this recipient, we considered LDLT, rather than dual organ transplantation, could be the most well-balanced option to save the life of this recipient with acceptable risk limits for this donor. A right lobe graft with 0.91 for graft recipient weight ratio was implanted with an uneventful operative procedure under intra- and postoperative continuous hemodiafiltration. The recipient was rescheduled on routine hemodialysis on day 6 after transplantation and recovered with a gradual decrease in ascites output. He was discharged on day 56. He continues to have a very good liver function and quality of life without ascites and uncomplicated routine hemodialysis 1 year after transplantation. The living donor was discharged 3 weeks after surgery and is also doing well. Although combined liver-kidney transplantation from a deceased donor could be the best option for ELKD due to PLD, LDLT can also be an acceptable option for ELKD with uncomplicated hemodialysis, considering the double equipoise theory for both lifesaving of the recipient and acceptable donor risk.
small molecules
2026-09-06 | Scoping Review on Polycystic Liver Disease in PKD1/PKD2 Gene Carriers: Genetic Aspects, Pathophysiology, and Therapeutic Approaches.
Polycystic liver disease (PLD) comprises hereditary disorders characterized by the progressive cystic replacement of liver parenchyma, leading to variable degrees of hepatomegaly and potential liver dysfunction. Depending on the affected gene, it may appear as isolated autosomal dominant polycystic liver disease (ADPLD) or in association with renal cysts as autosomal dominant or recessive polycystic kidney disease (ADPKD/ARPKD). This scoping review analyzed the genetic, pathophysiological, and therapeutic aspects of PLD in PKD1 and PKD2 mutation carriers, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and including 29 relevant studies published between 2014 and 2024. Several included studies suggested an association between PKD1 and PKD2 mutations and differences in disease severity and hepatic cyst burden, confirming their central role in the molecular pathogenesis of PLD. Current therapeutic strategies primarily rely on somatostatin analogs, which have demonstrated benefits in reducing liver volume and symptom burden in selected patients, whereas mechanistic target of rapamycin (mTOR) inhibitors have shown variable and modest results and remain under continued investigation. Surgical interventions, such as cyst fenestration, hepatic resection, or transplantation, are reserved for advanced cases. Emerging therapies targeting molecular pathways and personalized approaches show promise for future clinical application. Advances in genetics and molecular biology have enhanced the understanding of hepatic cystogenesis and provide the basis for the development of precision treatments and standardized clinical management protocols for patients with PLD.
2026-07-21 | Comparative Efficacy and Safety of Octreotide, Lanreotide, and Pasireotide in ADPKD and PLD: A Network Meta-analysis with Real-world Evidence from the FAERS Database.
Somatostatin analogs were the primary treatment for autosomal dominant polycystic kidney disease (ADPKD) or polycystic liver disease (PLD), including octreotide, lanreotide, and pasireotide. We compared the effects and safety of octreotide, lanreotide, and pasireotide on total kidney volume (TKV), total liver volume (TLV), and kidney function (eGFR) in patients with ADPKD or PLD using network meta-analysis and FDA Adverse Event Reporting System (FAERS) data. Pooled estimates from limited available trials suggested that, at 6 months or 1 year, octreotide (MD: -3.7, 95%CI: -4.3 to -3.2) and pasireotide (-5.0, -8.2 to -1.8) were associated with preliminary evidence of TKV reduction compared with placebo. However, lanreotide (-7.8, -10.2 to -5.4) obviously manifested a decrease in the TKV after more than 2 years. TLV analyses showed early directional effects of octreotide (-7.7, -12.1 to -3.3) and pasireotide (-9.0, -13.7 to -4.3) at 1 year, and for lanreotide (-5.0, -6.3 to -3.9) after more than 2 years. Lanreotide demonstrated inferior efficacy in reducing the TLV growth rate compared to octreotide (10.0, 2.7 to 18.0) following a 2-3 year administration period. Cholelithiasis is the most common biliary adverse event in three somatostatin analogs. Cox regression identified age (HR: 0.966, 95% CI: 0.949 to 0.982, P < 0.001) and drug (HR: 2.168, 95% CI: 1.411 to 3.332, P < 0.001) as independent predictors of cholelithiasis. The onset time of TKV/TLV reduction differs among the three somatostatin analogs. Age and drug were independent predictors of cholelithiasis. Younger patients or those receiving pasireotide are at higher risk of cholelithiasis.
2026-07-14 | Halting cyst progression in ADPKD using long-term ketogenic metabolic therapy and supplementation with exogenous ketones and alkaline citrate-a case series.
ADPKD is a progressive cystic disorder characterized by increasing total kidney volume (TKV), declining kidney function, and limited disease-modifying options. Emerging preclinical and clinical evidence suggests metabolic interventions may influence cyst growth, but longitudinal imaging data in humans remain limited. We conducted a retrospective case series of four self-referred individuals (ages 33-71) with genetically confirmed truncating PKD1 variants who independently implemented metabolic interventions of varying duration and intensity, including carbohydrate restriction, intermittent fasting, and supplementation with a ketone- and citrate-based medical food (KetoCitra®). Intervention periods ranged from 6 months to approximately 4 years and followed prior phases of documented kidney volume enlargement. Serial abdominal imaging obtained during routine clinical care was re-analyzed using standardized volumetric software to assess TKV, liver volume, and Mayo imaging classification trajectories. Across all four cases, stabilization or reduction in TKV relative to prior growth trends was observed during intervention periods, accompanied by preserved kidney function. One participant transitioned from Mayo Class 1C to 1B, while the remaining three demonstrated downward shifts in Mayo imaging trajectory within their existing classifications. Reductions or attenuated increases in liver volume were also observed in cases with polycystic liver disease. Interventions were reported to be feasible and well tolerated, with no serious adverse events. These observations align with emerging preclinical and clinical evidence suggesting metabolic interventions may attenuate TKV progression in ADPKD. While limited by sample size and intervention heterogeneity, this case series provides hypothesis-generating data to inform prospective controlled trials.
2026-02-10 | Statins halt polycystic liver disease by reprogramming metabolism and normalizing mitochondrial bioenergetics in cystic cholangiocytes.
Polycystic liver disease (PLD) is a hereditary disorder characterized by the progressive development and enlargement of intrahepatic biliary cysts, which can lead to significant morbidity. Liver transplantation remains the only curative treatment. Mutations in endoplasmic reticulum (ER)-related genes contribute to ER stress in cystic cholangiocytes, promoting disease progression. Given the functional interplay between ER and mitochondria, we investigated mitochondrial dynamics and metabolism in cystic cholangiocytes from both PLD patients and Pkhd1mut rats to identify novel therapeutic targets. Cystic cholangiocytes exhibited increased mitochondrial mass, membrane potential, and superoxide levels, along with enhanced bioenergetic capacity and ATP production compared with normal cholangiocytes. These alterations were linked to the upregulation of electron transport chain protein complexes. Metabolic reprogramming involved enhanced oxidation of glucose, glutamine, and/or fatty acids, as well as increased denovo cholesterol synthesis and accumulation. Chronic treatment with pravastatin, a cholesterol synthesis inhibitor, significantly reduced hepatomegaly, cyst volume, and fibrosis in Pkhd1mut rats. It also normalized mitochondrial hyperactivity and reduced the proliferation of cystic cholangiocytes in culture, effects that were similarly observed with other statins such as atorvastatin and simvastatin. Importantly, a case-control study in PLD patients showed that statin use was associated with reduced liver growth, further supporting its potential therapeutic role. Mitochondrial and metabolic dysregulation are central to the pathogenesis of PLD. Targeting cholesterol metabolism with statins represents a promising therapeutic strategy to slow disease progression and reduce cyst burden.
2026-02-09 | Dual Monogenic Cystic Disease Case Report: Autosomal Dominant Polycystic Kidney Disease and Autosomal Dominant Polycystic Liver Disease.
Autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD) are inherited cystic conditions with overlapping features but distinct genetic causes and clinical courses. Here, we report a case of a 50-year-old woman with a clinical diagnosis of ADPKD, hypertension, preserved kidney function, significant abdominal distention consistent with hepatomegaly, and innumerable kidney and hepatic cysts. Family history was remarkable for ADPKD clinical diagnosis in the patient's mother, maternal grandmother, and the grandmother's siblings. Genetic testing with a 385-gene NGS-based kidney disease panel (the Renasight test) identified heterozygous truncating pathogenic variants in PKD1: c.3957_3994dup p.(Asp1332Glyfs*27)) (ClinVar ID VCV003376509.1) and PRKCSH: c.374_375del p.(Glu125fs)) (ClinVarID VCV001048653.34). To our knowledge, this is the first reported case of dual monogenic drivers of ADPKD and ADPLD in a single individual. This report highlights the importance of using unbiased genetic testing in cystic disease evaluation, even when family history suggests a single condition, to inform prognosis, reproductive risk, and accurate cascade testing in relatives.
proteins
2021-12-31 | Deletion of Sox9 in the liver leads to hepatic cystogenesis in mice by transcriptionally downregulating Sec63.
Hepatic cysts are found in heterogeneous disorders with different pathogeneses, of which simple hepatic cysts and polycystic liver diseases are two major types. The process of hepatic cytogenesis for these two diseases is caused by defects in remodelling of the ductal plate during biliary tract development, which is called ductal plate malformation. SOX9 is a transcription factor participating in the process of bile duct development, and thus, its dysregulation may play important roles in hepatic cystogenesis. SEC63 encodes an endoplasmic reticulum membrane protein that is mutated in human autosomal dominant polycystic liver disease. However, the transcriptional regulation of SEC63 is largely unknown. In the present study, a liver-specific Sox9 knockout (Sox9LKO ) mouse was generated to investigate the roles and underlying mechanism of SOX9 in hepatic cystogenesis. We found that hepatic cysts began to be observed in Sox9LKO mice at 6 months of age. The number and size of cysts increased with age in Sox9LKO mice. In addition, the characteristics of hepatic cytogenesis, including the activation of proliferation, absence of primary cilium, and disorder of polarity in biliary epithelial cells, were detected in the livers of Sox9LKO mice. RNAi silencing of SOX9 in human intrahepatic biliary epithelial cells (HIBEpic) resulted in increased proliferation and reduced formation of the primary cilium. Moreover, Sec63 was downregulated in primary biliary epithelial cells from Sox9LKO mice and SEC63 in HIBEpic transfected with siSOX9. Chromatin immunoprecipitation assays and luciferase reporter assays further demonstrated that SOX9 transcriptionally regulated the expression of SEC63 in biliary epithelial cells. Importantly, the overexpression of SEC63 in HIBEpic partially reversed the effects of SOX9 depletion on the formation of primary cilia and cell proliferation. These findings highlight the biological significance of SOX9 in hepatic cytogenesis and elucidate a novel molecular mechanism underlying hepatic cytogenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
2019-02-11 | Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts
Significance Statement CKD of various etiologies manifests with declining kidney function in the setting of progressive interstitial inflammation, with increased myofibroblasts and collagen deposition. In this study, the authors developed a novel genetic model, demonstrating that impairment of protein homeostatic mechanisms in the endoplasmic reticulum of collecting duct cells is sufficient to produce interstitial inflammation, fibrosis, and impaired kidney function. In this model, genes encoding both Sec63, a resident protein in the endoplasmic reticulum membrane, and Xbp1, a transcription factor that is central to the unfolded protein response, were inactivated in the collecting ducts of neonatal mice. The result was progressive macrophage and myofibroblast expansion within 5 weeks and significant progressive kidney dysfunction thereafter. The Sec63-Xbp1 collecting duct knockout mouse offers a novel genetic model for studying chronic tubulointerstitial kidney injury. Background SEC63 encodes a resident protein in the endoplasmic reticulum membrane that, when mutated, causes human autosomal dominant polycystic liver disease. Selective inactivation of Sec63 in all distal nephron segments in embryonic mouse kidney results in polycystin-1–mediated polycystic kidney disease (PKD). It also activates the Ire1 α -Xbp1 branch of the unfolded protein response, producing Xbp1s, the active transcription factor promoting expression of specific genes to alleviate endoplasmic reticulum stress. Simultaneous inactivation of Xbp1 and Sec63 worsens PKD in this model. Methods We explored the renal effects of postnatal inactivation of Sec63 alone or with concomitant inactivation of Xbp1 or Ire1α , specifically in the collecting ducts of neonatal mice. Results The later onset of inactivation of Sec63 restricted to the collecting duct does not result in overt activation of the Ire1 α -Xbp1 pathway or cause polycystin-1–dependent PKD. Inactivating Sec63 along with either Xbp1 or Ire1α in this model causes interstitial inflammation and associated fibrosis with decline in kidney function over several months. Re-expression of XBP1s in vivo completely rescues the chronic kidney injury observed after inactivation of Sec63 with either Xbp1 or Ire1α . Conclusions In the absence of Sec63 , basal levels of Xbp1s activity in collecting ducts is both necessary and sufficient to maintain proteostasis (protein homeostasis) and protect against inflammation, myofibroblast activation, and kidney functional decline. The Sec63-Xbp1 double knockout mouse offers a novel genetic model of chronic tubulointerstitial kidney injury, using collecting duct proteostasis defects as a platform for discovery of signals that may underlie CKD of disparate etiologies.
2015-04-05 | Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity
The HSP40 cochaperone SEC63 is associated with the SEC61 translocon complex in the ER. Mutations in the gene encoding SEC63 cause polycystic liver disease in humans; however, it is not clear how altered SEC63 influences disease manifestations. In mice, loss of SEC63 induces cyst formation both in liver and kidney as the result of reduced polycystin-1 (PC1). Here we report that inactivation of SEC63 induces an unfolded protein response (UPR) pathway that is protective against cyst formation. Specifically, using murine genetic models, we determined that SEC63 deficiency selectively activates the IRE1α-XBP1 branch of UPR and that SEC63 exists in a complex with PC1. Concomitant inactivation of both SEC63 and XBP1 exacerbated the polycystic kidney phenotype in mice by markedly suppressing cleavage at the G protein–coupled receptor proteolysis site (GPS) in PC1. Enforced expression of spliced XBP1 (XBP1s) enhanced GPS cleavage of PC1 in SEC63-deficient cells, and XBP1 overexpression in vivo ameliorated cystic disease in a murine model with reduced PC1 function that is unrelated to SEC63 inactivation. Collectively, the findings show that SEC63 function regulates IRE1α/XBP1 activation, SEC63 and XBP1 are required for GPS cleavage and maturation of PC1, and activation of XBP1 can protect against polycystic disease in the setting of impaired biogenesis of PC1.
cell therapies
2025-12-20 | The evolving role of liver transplantation in managing polycystic liver disease
Polycystic liver disease (PLD) is a rare genetic condition characterised by the presence of numerous cysts throughout the liver (1). PLD was initially described in 1856 as a diseased state connected to polycystic kidney disease (PKD), and in 1925, it was suggested that PLD might exist independently of PKD. Most patients remain asymptomatic; however, some may develop clinical symptoms. The expansion of the liver and its strain on the surrounding organs cause PLD symptoms. Common symptoms of PLD include early satiety, postprandial fullness, gastroesophageal reflux, and digestive intolerance and due to these symptoms, the patient may decide to cut back on meals, which could result in severe malnutrition and weight loss (2). In extreme cases, venous drainage blockage can cause portal hypertension, along with associated symptoms such as jaundice, ascites, splenomegaly, oesophageal varices, and encephalopathy. Three types of primary therapeutic approaches are available for PLD: drug therapy, radiological or percutaneous intervention and surgery. Somatostatin analogues are recommended by the European Association for the Study of the Liver (EASL) decision-making flowchart for PLD patients who have a large number of dispersed small-to-medium-sized cysts (3). For percutaneous therapy, cyst aspiration and sclerosis are performed for patients with a single giant cyst while transcatheter arterial embolization is to embolize the branches of arteries that supply blood to cysts resulting in control of disease progression (1). Surgical procedures that include liver resection and liver transplantation, are usually considered for advanced cases. Some recent studies have brought attention to the role of liver transplantation in PLD, especially given the challenges in therapy and the requirement for successful long-term results. In this context, the results of a recent retrospective study done by Moein M et al. are worth considering. The study compared post-transplant outcomes of liver transplant recipients between 2000 and 2023, dividing the population into two subgroups. The findings highlight a notable improvement in the results of liver transplantation for PLD during the previous ten years, particularly in the 2011–2023 cohort. The prognosis shown by the graft and patient survival rates suggests that this therapeutic strategy has become a more viable course of treatment (4). Additionally, a case report by Niibek M et al. describes a patient with a large polycystic liver who underwent successful liver transplantation. The liver weighed 14,75 kg and measured 53 x 37 x 39 x 16 cm. ---Continue
2025-04-11 | Pure living donor liver transplant for liver and polycystic kidney disease, outcomes and experiences from an Asian transplant unit
• This study presents one of the largest single-center case series of isolated LDLT for PLD associated with polycystic kidney disease (PCKD). • LDLT offers excellent long-term survival (5-year survival of 88.9 %) with acceptable perioperative morbidity in patients with PLD. • Pre-existing chronic kidney disease (CKD) was associated with early post-transplant renal deterioration and need for renal replacement therapy (RRT). • No major complications or mortality were observed among living liver donors, supporting the safety of LDLT in this context. • The study highlights the importance of tailored surgical strategies, including caval reconstruction, in managing massive polycystic livers. Adult polycystic liver disease (PLD) is a rare genetic disorder. In instances of intractable symptoms from mass effect or recurrent cyst-related complications, liver transplant affords the best therapeutic solution. This is a retrospective case series of patients who underwent isolated pure living donor liver transplantation (LDLT) for adult polycystic kidney disease (PCKD) associated PLD from 2012- 2022. Short-term peri‑operative outcomes including renal sequelae and long-term survival were analysed. From 2012–2022, a total of 9 patients underwent LDLT for PLD. The median explanted liver weight was 6950 g (IQR 5653–7700) with a median blood loss of was 5450mls (IQR 2400–9875). There was 1 mortality due to acute antibody-mediated rejection (11.1 %). Of the four patients with existing chronic kidney disease (CKD), 2 (50 %) developed end-stage renal failure and was renal replacement therapy (RRT) dependent at 3 months. The median overall survival in our series was 63.9 months with a 5-year survival of 88.9 %. Despite its technical challenges, LDLT affords an excellent long-term prognosis with acceptable major morbidity. Pre-operative CKD appears to be a risk factor for early renal deterioration.
2024-05-23 | Liver transplantation for polycystic liver disease: How feasible is this option?
Polycystic liver disease is a rare hereditary disease that can occur as an isolated disease. Because of its benign nature, polycystic liver disease rarely needs treatment. If treatment is needed, there are no standard guidelines, but usually, a liver resection or medical therapy is performed. A liver transplant is the last resort when all other possibilities have been exhausted, or complications arise. However, the risks and benefits must be carefully weighed. A retrospective registry analysis of the SRTR database was done for liver transplants performed in the United States from January 2001 to May 2023. The analysis of the data indicated a notable improvement in 5-year graft survival rates between the 2001-2010 group (mean of 92%) and the 2011-2023 group (mean of 97%) (P<0.001). The 2011-2023 group had a higher proportion of simultaneous kidney and liver transplants, more than 3 times, from 106 cases to 374 cases (57.7% vs. 42.3%, P= .001). The type of transplant was also considered when analyzing the 5-year survival of grafts. Patients who underwent both kidney and liver transplants simultaneously had a slightly better outcome. It was found that the only hazard affecting LT graft survival in the cohort was the cold ischemic time (HR: 2.80, P=.03). With all the surgical techniques and post-operation improvements, a liver transplant can be a feasible option for polycystic liver disease when the medical treatments are not sufficient to eliminate the symptoms.
2023-09-01 | Liver transplantation for polycystic liver disease: a case report
A 57-year-old man complained about abdominal distension and pain, constant feeling of early satiety. He was diagnosed with polycystic kidneys at the age of 24 and liver cysts discovered at the age of 38. The CT scan revealed 33 x 21 x 27 cm polycystic liver with cysts up to 7 cm in diameter. In 2009-2019 the patient was repeatedly punctured for liver cysts. Considering the continued enlargement of the liver and the worsening of complaints, the patient was put on the waiting list for a liver transplant in the spring of 2019. The patient went through liver transplantation on 11th of July 2022, the liver measures were 53 x 37 x 39 x 16 cm and weight 14,75 kg. The postoperative course was uneventful. Liver transplantation can be very effective treatment method that significantly improves the quality of life in PLD patients.
2023-06-12 | Liver Only Living Donor Transplantation for Polycystic Disease in a Patient on Chronic Hemodialysis: Case Report.
Polycystic liver disease (PLD) is characterized by the progressive development of polycystic lesions in the kidney and the liver, possibly resulting in dual organ failure. We indicated living donor liver transplantation (LDLT) for a patient with end-stage liver and kidney disease (ELKD) due to PLD on uncomplicated chronic hemodialysis. A 63-year-old man with ELKD and uncontrolled massive ascites due to PLD and hepatitis B on uncomplicated chronic hemodialysis was referred to us with a single possible 47-year-old female living donor. Because of the necessity of right lobe liver procurement from this small middle-aged donor and uncomplicated hemodialysis on this recipient, we considered LDLT, rather than dual organ transplantation, could be the most well-balanced option to save the life of this recipient with acceptable risk limits for this donor. A right lobe graft with 0.91 for graft recipient weight ratio was implanted with an uneventful operative procedure under intra- and postoperative continuous hemodiafiltration. The recipient was rescheduled on routine hemodialysis on day 6 after transplantation and recovered with a gradual decrease in ascites output. He was discharged on day 56. He continues to have a very good liver function and quality of life without ascites and uncomplicated routine hemodialysis 1 year after transplantation. The living donor was discharged 3 weeks after surgery and is also doing well. Although combined liver-kidney transplantation from a deceased donor could be the best option for ELKD due to PLD, LDLT can also be an acceptable option for ELKD with uncomplicated hemodialysis, considering the double equipoise theory for both lifesaving of the recipient and acceptable donor risk.
small molecules
2026-09-06 | Scoping Review on Polycystic Liver Disease in PKD1/PKD2 Gene Carriers: Genetic Aspects, Pathophysiology, and Therapeutic Approaches.
Polycystic liver disease (PLD) comprises hereditary disorders characterized by the progressive cystic replacement of liver parenchyma, leading to variable degrees of hepatomegaly and potential liver dysfunction. Depending on the affected gene, it may appear as isolated autosomal dominant polycystic liver disease (ADPLD) or in association with renal cysts as autosomal dominant or recessive polycystic kidney disease (ADPKD/ARPKD). This scoping review analyzed the genetic, pathophysiological, and therapeutic aspects of PLD in PKD1 and PKD2 mutation carriers, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and including 29 relevant studies published between 2014 and 2024. Several included studies suggested an association between PKD1 and PKD2 mutations and differences in disease severity and hepatic cyst burden, confirming their central role in the molecular pathogenesis of PLD. Current therapeutic strategies primarily rely on somatostatin analogs, which have demonstrated benefits in reducing liver volume and symptom burden in selected patients, whereas mechanistic target of rapamycin (mTOR) inhibitors have shown variable and modest results and remain under continued investigation. Surgical interventions, such as cyst fenestration, hepatic resection, or transplantation, are reserved for advanced cases. Emerging therapies targeting molecular pathways and personalized approaches show promise for future clinical application. Advances in genetics and molecular biology have enhanced the understanding of hepatic cystogenesis and provide the basis for the development of precision treatments and standardized clinical management protocols for patients with PLD.
2026-07-21 | Comparative Efficacy and Safety of Octreotide, Lanreotide, and Pasireotide in ADPKD and PLD: A Network Meta-analysis with Real-world Evidence from the FAERS Database.
Somatostatin analogs were the primary treatment for autosomal dominant polycystic kidney disease (ADPKD) or polycystic liver disease (PLD), including octreotide, lanreotide, and pasireotide. We compared the effects and safety of octreotide, lanreotide, and pasireotide on total kidney volume (TKV), total liver volume (TLV), and kidney function (eGFR) in patients with ADPKD or PLD using network meta-analysis and FDA Adverse Event Reporting System (FAERS) data. Pooled estimates from limited available trials suggested that, at 6 months or 1 year, octreotide (MD: -3.7, 95%CI: -4.3 to -3.2) and pasireotide (-5.0, -8.2 to -1.8) were associated with preliminary evidence of TKV reduction compared with placebo. However, lanreotide (-7.8, -10.2 to -5.4) obviously manifested a decrease in the TKV after more than 2 years. TLV analyses showed early directional effects of octreotide (-7.7, -12.1 to -3.3) and pasireotide (-9.0, -13.7 to -4.3) at 1 year, and for lanreotide (-5.0, -6.3 to -3.9) after more than 2 years. Lanreotide demonstrated inferior efficacy in reducing the TLV growth rate compared to octreotide (10.0, 2.7 to 18.0) following a 2-3 year administration period. Cholelithiasis is the most common biliary adverse event in three somatostatin analogs. Cox regression identified age (HR: 0.966, 95% CI: 0.949 to 0.982, P < 0.001) and drug (HR: 2.168, 95% CI: 1.411 to 3.332, P < 0.001) as independent predictors of cholelithiasis. The onset time of TKV/TLV reduction differs among the three somatostatin analogs. Age and drug were independent predictors of cholelithiasis. Younger patients or those receiving pasireotide are at higher risk of cholelithiasis.
2026-07-14 | Halting cyst progression in ADPKD using long-term ketogenic metabolic therapy and supplementation with exogenous ketones and alkaline citrate-a case series.
ADPKD is a progressive cystic disorder characterized by increasing total kidney volume (TKV), declining kidney function, and limited disease-modifying options. Emerging preclinical and clinical evidence suggests metabolic interventions may influence cyst growth, but longitudinal imaging data in humans remain limited. We conducted a retrospective case series of four self-referred individuals (ages 33-71) with genetically confirmed truncating PKD1 variants who independently implemented metabolic interventions of varying duration and intensity, including carbohydrate restriction, intermittent fasting, and supplementation with a ketone- and citrate-based medical food (KetoCitra®). Intervention periods ranged from 6 months to approximately 4 years and followed prior phases of documented kidney volume enlargement. Serial abdominal imaging obtained during routine clinical care was re-analyzed using standardized volumetric software to assess TKV, liver volume, and Mayo imaging classification trajectories. Across all four cases, stabilization or reduction in TKV relative to prior growth trends was observed during intervention periods, accompanied by preserved kidney function. One participant transitioned from Mayo Class 1C to 1B, while the remaining three demonstrated downward shifts in Mayo imaging trajectory within their existing classifications. Reductions or attenuated increases in liver volume were also observed in cases with polycystic liver disease. Interventions were reported to be feasible and well tolerated, with no serious adverse events. These observations align with emerging preclinical and clinical evidence suggesting metabolic interventions may attenuate TKV progression in ADPKD. While limited by sample size and intervention heterogeneity, this case series provides hypothesis-generating data to inform prospective controlled trials.
2026-02-10 | Statins halt polycystic liver disease by reprogramming metabolism and normalizing mitochondrial bioenergetics in cystic cholangiocytes.
Polycystic liver disease (PLD) is a hereditary disorder characterized by the progressive development and enlargement of intrahepatic biliary cysts, which can lead to significant morbidity. Liver transplantation remains the only curative treatment. Mutations in endoplasmic reticulum (ER)-related genes contribute to ER stress in cystic cholangiocytes, promoting disease progression. Given the functional interplay between ER and mitochondria, we investigated mitochondrial dynamics and metabolism in cystic cholangiocytes from both PLD patients and Pkhd1mut rats to identify novel therapeutic targets. Cystic cholangiocytes exhibited increased mitochondrial mass, membrane potential, and superoxide levels, along with enhanced bioenergetic capacity and ATP production compared with normal cholangiocytes. These alterations were linked to the upregulation of electron transport chain protein complexes. Metabolic reprogramming involved enhanced oxidation of glucose, glutamine, and/or fatty acids, as well as increased denovo cholesterol synthesis and accumulation. Chronic treatment with pravastatin, a cholesterol synthesis inhibitor, significantly reduced hepatomegaly, cyst volume, and fibrosis in Pkhd1mut rats. It also normalized mitochondrial hyperactivity and reduced the proliferation of cystic cholangiocytes in culture, effects that were similarly observed with other statins such as atorvastatin and simvastatin. Importantly, a case-control study in PLD patients showed that statin use was associated with reduced liver growth, further supporting its potential therapeutic role. Mitochondrial and metabolic dysregulation are central to the pathogenesis of PLD. Targeting cholesterol metabolism with statins represents a promising therapeutic strategy to slow disease progression and reduce cyst burden.
2026-02-09 | Dual Monogenic Cystic Disease Case Report: Autosomal Dominant Polycystic Kidney Disease and Autosomal Dominant Polycystic Liver Disease.
Autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD) are inherited cystic conditions with overlapping features but distinct genetic causes and clinical courses. Here, we report a case of a 50-year-old woman with a clinical diagnosis of ADPKD, hypertension, preserved kidney function, significant abdominal distention consistent with hepatomegaly, and innumerable kidney and hepatic cysts. Family history was remarkable for ADPKD clinical diagnosis in the patient's mother, maternal grandmother, and the grandmother's siblings. Genetic testing with a 385-gene NGS-based kidney disease panel (the Renasight test) identified heterozygous truncating pathogenic variants in PKD1: c.3957_3994dup p.(Asp1332Glyfs*27)) (ClinVar ID VCV003376509.1) and PRKCSH: c.374_375del p.(Glu125fs)) (ClinVarID VCV001048653.34). To our knowledge, this is the first reported case of dual monogenic drivers of ADPKD and ADPLD in a single individual. This report highlights the importance of using unbiased genetic testing in cystic disease evaluation, even when family history suggests a single condition, to inform prognosis, reproductive risk, and accurate cascade testing in relatives.
proteins
2021-12-31 | Deletion of Sox9 in the liver leads to hepatic cystogenesis in mice by transcriptionally downregulating Sec63.
Hepatic cysts are found in heterogeneous disorders with different pathogeneses, of which simple hepatic cysts and polycystic liver diseases are two major types. The process of hepatic cytogenesis for these two diseases is caused by defects in remodelling of the ductal plate during biliary tract development, which is called ductal plate malformation. SOX9 is a transcription factor participating in the process of bile duct development, and thus, its dysregulation may play important roles in hepatic cystogenesis. SEC63 encodes an endoplasmic reticulum membrane protein that is mutated in human autosomal dominant polycystic liver disease. However, the transcriptional regulation of SEC63 is largely unknown. In the present study, a liver-specific Sox9 knockout (Sox9LKO ) mouse was generated to investigate the roles and underlying mechanism of SOX9 in hepatic cystogenesis. We found that hepatic cysts began to be observed in Sox9LKO mice at 6 months of age. The number and size of cysts increased with age in Sox9LKO mice. In addition, the characteristics of hepatic cytogenesis, including the activation of proliferation, absence of primary cilium, and disorder of polarity in biliary epithelial cells, were detected in the livers of Sox9LKO mice. RNAi silencing of SOX9 in human intrahepatic biliary epithelial cells (HIBEpic) resulted in increased proliferation and reduced formation of the primary cilium. Moreover, Sec63 was downregulated in primary biliary epithelial cells from Sox9LKO mice and SEC63 in HIBEpic transfected with siSOX9. Chromatin immunoprecipitation assays and luciferase reporter assays further demonstrated that SOX9 transcriptionally regulated the expression of SEC63 in biliary epithelial cells. Importantly, the overexpression of SEC63 in HIBEpic partially reversed the effects of SOX9 depletion on the formation of primary cilia and cell proliferation. These findings highlight the biological significance of SOX9 in hepatic cytogenesis and elucidate a novel molecular mechanism underlying hepatic cytogenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
2019-02-11 | Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts
Significance Statement CKD of various etiologies manifests with declining kidney function in the setting of progressive interstitial inflammation, with increased myofibroblasts and collagen deposition. In this study, the authors developed a novel genetic model, demonstrating that impairment of protein homeostatic mechanisms in the endoplasmic reticulum of collecting duct cells is sufficient to produce interstitial inflammation, fibrosis, and impaired kidney function. In this model, genes encoding both Sec63, a resident protein in the endoplasmic reticulum membrane, and Xbp1, a transcription factor that is central to the unfolded protein response, were inactivated in the collecting ducts of neonatal mice. The result was progressive macrophage and myofibroblast expansion within 5 weeks and significant progressive kidney dysfunction thereafter. The Sec63-Xbp1 collecting duct knockout mouse offers a novel genetic model for studying chronic tubulointerstitial kidney injury. Background SEC63 encodes a resident protein in the endoplasmic reticulum membrane that, when mutated, causes human autosomal dominant polycystic liver disease. Selective inactivation of Sec63 in all distal nephron segments in embryonic mouse kidney results in polycystin-1–mediated polycystic kidney disease (PKD). It also activates the Ire1 α -Xbp1 branch of the unfolded protein response, producing Xbp1s, the active transcription factor promoting expression of specific genes to alleviate endoplasmic reticulum stress. Simultaneous inactivation of Xbp1 and Sec63 worsens PKD in this model. Methods We explored the renal effects of postnatal inactivation of Sec63 alone or with concomitant inactivation of Xbp1 or Ire1α , specifically in the collecting ducts of neonatal mice. Results The later onset of inactivation of Sec63 restricted to the collecting duct does not result in overt activation of the Ire1 α -Xbp1 pathway or cause polycystin-1–dependent PKD. Inactivating Sec63 along with either Xbp1 or Ire1α in this model causes interstitial inflammation and associated fibrosis with decline in kidney function over several months. Re-expression of XBP1s in vivo completely rescues the chronic kidney injury observed after inactivation of Sec63 with either Xbp1 or Ire1α . Conclusions In the absence of Sec63 , basal levels of Xbp1s activity in collecting ducts is both necessary and sufficient to maintain proteostasis (protein homeostasis) and protect against inflammation, myofibroblast activation, and kidney functional decline. The Sec63-Xbp1 double knockout mouse offers a novel genetic model of chronic tubulointerstitial kidney injury, using collecting duct proteostasis defects as a platform for discovery of signals that may underlie CKD of disparate etiologies.
2015-04-05 | Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity
The HSP40 cochaperone SEC63 is associated with the SEC61 translocon complex in the ER. Mutations in the gene encoding SEC63 cause polycystic liver disease in humans; however, it is not clear how altered SEC63 influences disease manifestations. In mice, loss of SEC63 induces cyst formation both in liver and kidney as the result of reduced polycystin-1 (PC1). Here we report that inactivation of SEC63 induces an unfolded protein response (UPR) pathway that is protective against cyst formation. Specifically, using murine genetic models, we determined that SEC63 deficiency selectively activates the IRE1α-XBP1 branch of UPR and that SEC63 exists in a complex with PC1. Concomitant inactivation of both SEC63 and XBP1 exacerbated the polycystic kidney phenotype in mice by markedly suppressing cleavage at the G protein–coupled receptor proteolysis site (GPS) in PC1. Enforced expression of spliced XBP1 (XBP1s) enhanced GPS cleavage of PC1 in SEC63-deficient cells, and XBP1 overexpression in vivo ameliorated cystic disease in a murine model with reduced PC1 function that is unrelated to SEC63 inactivation. Collectively, the findings show that SEC63 function regulates IRE1α/XBP1 activation, SEC63 and XBP1 are required for GPS cleavage and maturation of PC1, and activation of XBP1 can protect against polycystic disease in the setting of impaired biogenesis of PC1.
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Drug Discovery Landscape
5 orphan drug designations for Isolated polycystic liver disease.
5 orphan drug designations for Isolated polycystic liver disease.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Octreotide hydrochloride | peptides | EMA | Camurus AB | |
octreotide | peptides | FDA | Camurus AB | |
Sodium ascorbate and menadione sodium bisulfite | small molecules | EMA | — | MCA Regulatory Limited |
menadione sodium bisulfite | peptides | FDA | — | IC-MedTech Corporation |
sodium ascorbate and menadione sodium bisulfite | small molecules | FDA | — | IC-Medtech Corporation |
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