Liver transplantation indications and strategies in polycystic liver disease: A European survey

Young Women With Polycystic Liver Disease Respond Best to Somatostatin Analogues: A Pooled Analysis of Individual Patient Data

Polycystic Liver Disease: The Benefits of Targeting cAMP.

The goal of this study was to compare the clinical features of patients with isolated polycystic liver disease (PCLD) with those of patients with polycystic liver and autosomal dominant polycystic kidney disease (ADPKD). Cases were identified from clinical records at the University of Colorado Hospital in Denver (USA) and at the Radboud University Hospital in Nijmegen (the Netherlands) by ICD-10 codes. To be included in this analysis, patients had to have an initial diagnosis of PCLD within six years of presentation to our clinics. Medical records were reviewed for demographic information, medical history, physical examination, symptoms, complications, laboratory and imaging results, therapy and outcomes. Out of a total of 94, 53 patients met our criteria for entering this study, 19 with PCLD and 34 with ADPKD. The mean time interval from diagnosis of PCLD to presentation in our clinics was 1.21 years for PCLD and 2.76 years for ADPKD (P=NS). PCLD was associated with female gender in both PCLD and ADPKD. Patients with PCLD had greater numbers (P=0.031), and larger sizes of liver cysts (P=0.0051), but had less associated morbidities than patients with ADPKD. Liver cyst decompressions were performed more frequently in PCLD patients (57.9 vs. 23.5%, P=0.012). However, serious hepatic complications, sufficient to require consideration of liver transplantation, were more frequent in patients with ADPKD (0/19 vs. 6/34, P<0.0001). Although PCLD in patients with PCLD is characterized by larger and greater number of hepatic cysts, the clinical course is relatively benign compared with ADPKD.

There are no proven, effective therapies for polycystic kidney disease (PKD) or polycystic liver disease (PLD). We enrolled 42 patients with severe PLD resulting from autosomal dominant PKD (ADPKD) or autosomal dominant PLD (ADPLD) in a randomized, double-blind, placebo-controlled trial of octreotide, a long-acting somatostatin analogue. We randomly assigned 42 patients in a 2:1 ratio to octreotide LAR depot (up to 40 mg every 28+/-5 days) or placebo for 1 year. The primary end point was percent change in liver volume from baseline to 1 year, measured by MRI. Secondary end points were changes in total kidney volume, GFR, quality of life, safety, vital signs, and clinical laboratory tests. Thirty-four patients had ADPKD, and eight had ADPLD. Liver volume decreased by 4.95%+/-6.77% in the octreotide group but remained practically unchanged (+0.92%+/-8.33%) in the placebo group (P=0.048). Among patients with ADPKD, total kidney volume remained practically unchanged (+0.25%+/-7.53%) in the octreotide group but increased by 8.61%+/-10.07% in the placebo group (P=0.045). Changes in GFR were similar in both groups. Octreotide was well tolerated; treated individuals reported an improved perception of bodily pain and physical activity. In summary, octreotide slowed the progressive increase in liver volume and total kidney volume, improved health perception among patients with PLD, and had an acceptable side effect profile.

Somatostatin, Estrogen, and Polycystic Liver Disease

We describe a new surgical approach for simultaneous liver and kidney transplant in which we utilized the same reverse L incision used for liver transplant to perform ipsilateral native nephrectomy and kidney transplant. The 48-year-old male patient had auto-somal dominant polycystic kidney and significant polycystic liver disease. He underwent multidisciplinary assessment and was listed for simultaneous liver and kidney transplant. The liver and kidney graft were donated from a donor after neurological determination of death. After hepatectomy and orthotopic liver transplant, a right native nephrectomy was performed followed by kidney transplant using the same incision. The transplanted kidney was placed on the right-hand side, with renal artery anastomosed to the external iliac artery, the renal vein anastomosed to the external iliac vein, and the ureter anastomosed to the end of the retained distal native ureter (ureteroureterostomy). Both liver and kidney graft had immediate function after transplant. This case highlights the feasibility and efficiency of a single reverse L incision approach for simultaneous liver and kidney transplant combined with a right-side nephrectomy.

Environmental Contribution to Pathogenesis of Cyst Formation in Autosomal-Dominant Polycystic Liver Diseases

Polycystic liver disease, a hereditary pathology, usually manifests as autosomal dominant polycystic kidney disease. The many cysts in the liver cause massive hepatomegaly, majorly affecting the patient's quality of life. In cases of refractory symptoms, liver transplantation is the only treatment choice. A 43-year-old woman was followed up as a hepatology outpatient in August 2020, with a progressive increase in abdominal volume, lower limb edema, and cachexia. The patient was diagnosed with polycystic renal and liver disease with massive hepatomegaly in March 2021, a combined kidney-liver transplant. Liver size represented 13% of the patient's corporal composition, weighing 8.6kg. The patient was discharged on the 7th postoperative day with no complications. Only 10-20% of patients with polycystic liver disease have clinical manifestations, most of which result from hepatomegaly. An increase in liver volume deteriorates liver function until the condition becomes end-stage liver disease, as kidney function is already compromised; liver-kidney transplantation remains the only treatment choice. The case described drew significant attention to the massive hepatomegaly presented in the patient, with the liver representing over 10% of the patient's body weight, approximately five to six times larger than a normal-sized liver.

Bacterial Cholangitis in Autosomal Dominant Polycystic Kidney and Liver Disease.

Polycystic liver disease (PLD) is commonly associated with polycystic kidney disease, but is unaccompanied by renal cysts in 10% of cases. Symptomatic PLD is mainly limited to adults and rarely, if ever, presents in childhood. There is currently no effective medical therapy for PLD. Most patients who have PLD require no medical or surgical intervention. Patients with PLD rarely, if ever, experience biochemical hepatic deterioration, and classic symptoms of hepatic failure such as ascites, variceal hemorrhage, or encephalopathy are unusual.1-3 Although there is a typical lowering of the quality of life in these patients, to date, quality of life (although not well studied) has not been associated with decreased survival. Serious, life-threatening complications related to multiple hepatic cysts may occur, including cyst infection, hepatic vein outflow obstruction, portal hypertension, refractory ascites after cyst fenestration, cyst carcinoma, cholangiocarcinoma, and most importantly, pain and/or chronic wasting with malnutrition.2-4 Symptomatic PLD only occurs in patients with massive hepatic cystic disease in which the total cyst:parenchyma ratio is >1.5 Patients with PLD on hemodialysis are at greatest risk of life-threatening complications due to hepatic cysts complicated by infection, hemorrhage, and carcinoma. In one center, 10% of the mortality in patients with PLD on hemodialysis was attributed to these complications. However, this observation has not been confirmed by other centers. Nontransplant interventions that can relieve symptoms of massive hepatic cystic disease include percutaneous cyst puncture and sclerotherapy, laparoscopic cyst decompression, open laparotomy with fenestration, and liver resection.3, 6-10 These interventions can provide temporary or prolonged relief of symptoms but may be associated with significant morbidity and even mortality. Open surgical decompression is associated with a very low mortality rate but is associated with substantial morbidity. Laparoscopic decompression reduces hospital length of stay but is also associated significant morbidity.6 Liver resection is indicated only in highly selected patients and is associated with the potential for frequent morbidity and significant mortality. Liver transplantation (LT), the ultimate treatment for PLD, eliminates the disease and its complications and provides long-lasting relief of symptoms.11-14 Approximately 40% of those undergoing LT will require simultaneous kidney transplantation. Five-year survival after LT or liver-kidney transplantation is approximately 70 to 75%, and much of the mortality is in the first year. LT with or without kidney transplantation should be avoided in severely malnourished or debilitated patients. Patients with PLD may be candidates for living-donor LT. Patients with PLD generally have preserved liver function and normal Model for End-Stage Liver Disease (MELD) scores if they do not have renal involvement. Satisfy criteria for massive PLD (total cyst:parenchyma ratio >1) and have a complication of the PLD that is likely to resolve after LT. Are not candidates for, or have disease that has failed to respond to, nontransplant interventions for relief of symptoms; malnutrition may be considered a primary contraindication to nontransplant surgery. Have clinically significant manifestations of liver disease that can be attributed to massive PLD, which may include cachexia, ascites, portal hypertension (variceal bleeding), hepatic venous outflow obstruction, biliary obstruction, cholestasis, or recurrent cyst infection. Have severe malnutrition (assessment made on the basis of hypoalbuminemia or decreased lean body mass). Have serum albumin <2.2 mg/dL. Have lean body mass reflected by decreased midarm circumference, measured in the nondominant arm midway between the acromion and the olecranon process: <23.1 cm in female patients and <23.8 cm in male patients. PLD, polycystic liver disease; LT, liver transplantation; MELD, Model for End-Stage Liver Disease. There are insufficient data to justify automatic priority for patients with PLD. Patients without renal insufficiency may receive a MELD score of 15. The score may be increased by an additional 3 points every 3 months upon reapplication with submission of current clinical data. Patients with renal insufficiency (defined as glomerular filtration rate or creatinine clearance < 30 mL/min) may receive a MELD score of 20. The score may be increased by an additional 3 points every 3 months upon reapplication. Clinical data that need to prospectively collected and be submitted to the Regional Review Boards include documentation of recurrent cyst infection by culture reports, and weight of the explant liver and the ratio of the liver weight to patient height to determine whether these parameters correlate with patient outcome. In addition, the Regional Review Boards may require vascular studies (full reports with computed tomographic scans, magnetic resonance imaging, or angiography) to document cases of vascular occlusion.

Clinical characteristics Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral renal cysts, liver cysts, and an increased risk of intracranial aneurysms. Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane; dilatation of the aortic root and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias. Renal manifestations include hypertension, renal pain, and renal insufficiency. Approximately 50% of individuals with ADPKD have end-stage renal disease (ESRD) by age 60 years. The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD). Overall the prevalence of intracranial aneurysms is fivefold higher than in the general population and further increased in those with a positive family history of aneurysms or subarachnoid hemorrhage. There is substantial variability in the severity of renal disease and other extrarenal manifestations even within the same family. Diagnosis/testing The diagnosis of ADPKD is established in a proband with age-specific renal imaging criteria and an affected first-degree relative with ADPKD or identification of a heterozygous pathogenic variant in PKD1, PKD2, GANAB, or DNAJB11. Management Treatment of manifestations: Vasopressin V2 receptor antagonists (e.g., tolvaptan) to slow disease progression. Treatment for hypertension may include ACE inhibitors or angiotensin II receptor blockers and diet modification. Conservative treatment of flank pain includes nonopioid agents, tricyclic antidepressants, narcotic analgesics, and splanchnic nerve blockade. More aggressive treatments include cyst decompression with cyst aspiration and sclerosis, laparoscopic or surgical cyst fenestration, renal denervation, and nephrectomy. Cyst hemorrhage and/or gross hematuria is usually self-limiting. Treatment of nephrolithiasis is standard. Treatment of cyst infections is difficult, with a high failure rate. Therapeutic agents of choice may include trimethoprim-sulfamethoxazole, fluoroquinolones, clindamycin, vancomycin, and metronidazole. The diagnosis of malignancy requires a high index of suspicion. Therapeutic interventions aimed at slowing the progression of ESRD in ADPKD include control of hypertension and hyperlipidemia, dietary protein restriction, control of acidosis, and prevention of hyperphosphatemia. Most individuals with PLD have no symptoms and require no treatment, but rare severe cases may require surgical resection or even liver transplantation. The mainstay of therapy for ruptured or symptomatic intracranial aneurysm is surgical clipping of the ruptured aneurysm at its neck; however, for some individuals, endovascular treatment with detachable platinum coils may be indicated. Thoracic aortic replacement is indicated when the aortic root diameter exceeds established size. Prevention of secondary manifestations (lifestyle and therapeutic factors that may modulate disease): Maintain appropriate blood pressure and urine osmolarity; low osmolar intake (e.g., moderate sodium and protein); increase hydration by moderate water intake; maintain sodium bicarbonate ≥22 mEq/L; moderate dietary phosphorus intake; moderate caloric intake to maintain normal BMI; low-impact exercise; lipid control; tolvaptan therapy. Surveillance: Early blood pressure monitoring starting in childhood; MRI screening for intracranial aneurysms in those determined to be at high risk; screening echocardiography in those with a heart murmur and those with a family history of a first-degree relative with a thoracic aortic dissection. Agents/circumstances to avoid: Long-term administration of nephrotoxic agents, high levels of caffeine, use of estrogens and possibly progestogens by individuals with severe PLD, smoking, and obesity. Evaluation of relatives at risk: Testing of adult relatives at risk permits early detection and treatment of complications and associated disorders. Pregnancy management: Pregnant women with ADPKD should be monitored for the development of hypertension, urinary tract infections, oligohydramnios, and preeclampsia; the fetus should be monitored for intrauterine fetal growth restriction, oligohydramnios, and fetal kidney anomalies including cysts, enlarged size, and atypical echogenicity. Genetic counseling ADPKD is inherited in an autosomal dominant manner. About 95% of individuals with ADPKD have an affected parent, but at least 10% of families can be traced to a de novo pathogenic variant. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for ADPKD are possible.

BackgroundPolycystic liver disease is a clinical feature of autosomal dominant polycystic kidney disease, and it can sometimes cause health damage more serious than polycystic kidney. Dialysis therapy can be used for renal failure, but liver transplantation is the only method available for liver failure. Thus, giant and multiple hepatic cysts may affect mortality. However, liver transplantation is not indicated in many cases because of the preserved liver function.Case presentationA 54-year-old Japanese woman with polycystic liver disease was transferred back to our hospital for abdominal pain caused by liver cyst infection with abdominal wall herniation. She had been diagnosed with polycystic liver disease associated with sporadic autosomal dominant polycystic kidney disease 25 years earlier. Although she had several surgical interventions to reduce her liver volume, including right hepatic lobectomy and fenestration for liver cysts in another hospital, she needed further repair of the recurrent incisional herniation with patch graft surgery using fascia lata to cover the herniation site. However, new herniation sites reemerged in the fragile abdominal wall area around the patch, and therefore, she reduced the recurrent abdominal wall herniation by herself. Recurrent intestinal obstructions were luckily released by fasting with decompression treatment via nasogastric tube insertion, but multiple skin ulcers around the enlarged hernia sac gradually developed, and ascites was extremely difficult to control with any medication. At final admission, her abdominal wall was even more prominent, causing shortness of breath, and it spontaneously ruptured many times, which was accompanied by discharge of around 5 liters of ascites each time. She died from sepsis caused by drug-resistant Enterococcus.ConclusionsWe report a case of autosomal dominant polycystic kidney disease with ruptured abdominal wall resulting from a hepatic cyst enlargement despite multiple laparotomy operations. Throughout the entire disease course, her liver volume increased rapidly, and her quality of life was severely impaired, but she could not undergo liver transplantation after readmission to our hospital. We will discuss the therapeutic strategy for this patient, including the timing and indication for liver transplantation.

Background: Polycystic liver disease(PLD) is the most common extra-renal manifestation in autosomal dominant polycystic kidney disease(ADPKD). Patients with PLD suffer from hepatomegaly leading to pain, dyspnea and caval obstruction. Interventions for symptomatic PLD include transcatheter arterial embolization(TAE), partial hepatic resection and liver transplantation(LT). We compared outcomes of each treatment modality. Methods: We retrospectively analyzed 29 patients who had undergone TAE, partial hepatectomy, or LT in ADPKD patients in a single center. Results: Six and seven patients underwent LT and partial hepatectomy, respectively, while sixteen patients underwent TAE. Living donor LT was performed for intractable hepatomegaly-related symptoms despite TAE in 2 patients, and for uncontrolled ascites in a patient. Deceased donor(DD) LT was performed in 2 patients for hepatic failure or uncontrolled ascites after TAE. Another patient underwent DDLT for hepatic failure after partial hepatectomy. The most common complications were ascites and pleural effusion. Two patients were under hemodialysis at LT, and acute kidney injury resulted in kidney failure in 1 DDLT patient. All patients had maintained good liver function at a median follow-up of 15.5 months, although subclinical acute cellular rejection was found in 2 patients. Causes of partial hepatectomy were recurrent cyst infection and hepatomegaly-related symptoms. One patient underwent partial hepatectomy, because multiple TAE had failed to control symptoms. Preoperative CTP score was lower in the partial hepatectomy group than in the LT group. A few serious infectious complications occurred, and antibiotic treatment cured them without mortality. Eleven patients received single TAE, and five patients underwent TAE twice. Two patients died of obstructive jaundice and cyst infection. Five patients (31.3%) in the TAE group needed LT or partial hepatectomy to relieve symptoms or rescue hepatic failure. Conclusion: LT is more effective and tolerable treatment option for symptomatic PLD in ADPKD patients compared to partial hepatectomy and TAE.

An increased understanding of the genetic, molecular and cellular mechanisms responsible for the development of polycystic kidney disease has laid out the foundation for the development of rational therapies. Many animal models where these therapies can be tested are currently available. This review summarizes the rationale for these treatments, the results of preclinical trials and the prospects for clinical trials, some already in early phases of implementation.

Autosomal dominant polycystic liver and kidney disease is a spectrum of hereditary diseases, which display disturbed function of primary cilia leading to cyst formation. In autosomal dominant polycystic kidney disease a genetic cause can be determined in almost all cases. However, in isolated polycystic liver disease (PLD) about half of all cases remain genetically unsolved, suggesting more, so far unidentified genes to be implicated in this disease. Customized next-generation sequencing was used to identify the underlying pathogenesis in two related patients with PLD. A variant identified in SEC61A1 was further analysed in immortalized patients' urine sediment cells and in an epithelial cell model. In both patients, a heterozygous missense change (c.706C>T/p.Arg236Cys) was found in SEC61A1, which encodes for a subunit of the translocation machinery of protein biosynthesis at the endoplasmic reticulum (ER). While kidney disease is absent in the proposita, her mother displays an atypical polycystic kidney phenotype with severe renal failure. In immortalized urine sediment cells, mutant SEC61A1 is expressed at reduced levels, resulting in decreased levels of polycystin-2 (PC2). In an epithelial cell culture model, we found the proteasomal degradation of mutant SEC61A1 to be increased, whereas its localization to the ER is not affected. Our data expand the allelic and clinical spectrum for SEC61A1, adding PLD as a new and the major phenotypic trait in the family described. We further demonstrate that mutant SEC61A1 results in enhanced proteasomal degradation and impaired biosynthesis of PC2.