Advances in management of polycystic liver disease

The focus of this review is polycystic liver disease, a genetic disorder characterized by multiple macroscopic liver cysts that initially bud from biliary epithelium but subsequently lack communication with the biliary tree. There are two main clinical presentations: polycystic liver associated with autosomal dominant polycystic kidney disease and isolated polycystic liver disease. Both of these forms of polycystic liver disease exhibit an autosomal dominant pattern of inheritance. Clinical manifestations of polycystic liver disease are related to either mass effect of the volume of hepatic cysts or to complications arising within the cysts. Polycystic liver disease rarely progresses to hepatic failure or clinical complications of portal hypertension. Management is directed at counseling patients and families, treating complications and reducing cyst load by surgical techniques: cyst fenestration, hepatic resection or, rarely, hepatic transplantation. Recent research suggests that blockade of cyst secretion or inhibition of epithelial cells might be useful in halting progression of disease – these observations are discussed in this review.     

Association between pancreatic cystadenocarcinoma, malignant liver cysts, and polycystic disease of the kidney

Polycystic kidney disease is an autosomal dominant disease that may be associated with cystic disease of the liver. In women, the cysts may develop early and be more troublesome than in men. Cystadenocarcinoma of the pancreas is uncommon, comprising 1% of primary pancreatic malignancies. This case report is the first to describe a familial association between polycystic kidney disease and cystadenocarcinoma of the pancreas and liver in the English medical literature. A patient with autosomal dominant polycystic kidney disease (ADPKD) and multiple hepatic cysts developed cystadenocarcinoma of the pancreas with multiple malignant liver cysts. The patient's mother, sister, and niece had ADPKD, and the patient's sister also died of pancreatic cystadenocarcinoma. We believe that the development of these two disease entities in which the primary pathology is cyst formation has a genetic association. (Gastroenterology 1997 Jun;112(6):2104-7)     

Polycystic liver disease without autosomal dominant polycystic kidney disease

Polycystic liver disease is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. The natural history and clinical manifestations of polycystic liver disease are based on the disease as it manifests in patients with autosomal dominant polycystic kidney disease (ADPKD). The occurrence of polycystic liver disease independently from polycystic kidney disease has been known for a long time. More recently, a gene for autosomal dominant polycystic liver disease has been identified on chromosome 19p 13.2-13.1. Isolated polycystic liver disease is underdiagnosed and genetically distinct from polycystic liver disease associated with ADPKD but with similar pathogenesis and clinical manifestations. We report here two men with polycystic liver disease no associated with ADPKD. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively.     

Liver cysts in patients with autosomal dominant polycystic kidney disease

Liver cysts were found in 46 (29 per cent) of 158 patients over 10 years of age with documented autosomal dominant-type polycystic kidney disease (PKD) from 62 unrelated families. Hepatic cysts were not found in any patient at risk for PKD in whom renal cysts were not detected. The prevalence of liver cysts increased with advancing age and with declining rate of glomerular filtration. Results of clinical and laboratory studies indicate that polycystic liver disease in patients with autosomal dominant-type PKD is a benign condition, rarely, if ever, causing impaired liver function or portal hypertension.     

Polycystic liver disease: a clinical review

Polycystic liver disease rarely occurs in isolation as part of autosomal dominant polycystic liver disease, but more commonly, it exists as an extra-renal manifestation of autosomal dominant polycystic kidney disease. The pathogenesis of polycystic liver disease involves defects in the primary cilium of the cholangiocyte, with genetic mutations that impair key proteins integral to the complex functioning of cilia. While most patients are asymptomatic and require no intervention aside from reassurance and genetic counseling, in a minority of patients, polycystic liver disease creates a myriad of symptoms from the compressive effects of enlarged cysts, and can even cause malnutrition and liver decompensation in the severest of cases. In patients with symptomatic disease, a variety of interventional radiology or surgical techniques can be considered, including aspiration with sclerotherapy of a dominant cyst, fenestration, segmental hepatic resection, and even liver transplantation. Although there are no curative medical options for polycystic liver disease, somatostatin analogs hold promise and have shown minimal efficacy in human studies. However, further research is needed to develop more efficacious medical treatments.     

Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation

Polycystic liver disease (PLD) is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. PLD can manifest itself in patients with severe autosomal dominant polycystic kidney disease (ADPKD). Isolated autosomal dominant polycystic liver disease (ADPLD) is genetically distinct from PLD associated with ADPKD, although it may have similar pathogenesis and clinical manifestations. Recently, mutations in two causative genes for ADPLD, independently from ADPKD, have been identified. We report here a family (a mother and her daughter) with a severe form of ADPLD not associated with ADPKD produced by a novel missense protein kinase C substrate 80K-H (PRKCSH) mutation (R281W). This mutation causes a severe phenotype, since the two affected subjects manifested signs of portal hypertension. Doppler sonography, computed tomography (CT) and magnetic resonance (MR) imaging are effective in documenting the underlying lesions in a non-invasive way.     

Polycystic liver disease: quantitation of parenchymal and cyst volumes from computed tomography images and clinical correlates of hepatic cysts

Polycystic liver disease is a common manifestation of autosomal dominant polycystic kidney disease. However, factors that regulate hepatic cystogenesis have not been defined, and the effect of cyst formation on hepatic parenchymal mass has not been studied. We validated computed tomographic methods for measuring volumes from computed tomographic images using plastic-agar models and demonstrated that measured volumes were within 10% of actual volumes. The validated methods were used to measure hepatic parenchymal, hepatic cyst and kidney volumes in 25 subjects with polycystic liver disease and nine controls without autosomal dominant polycystic kidney disease. Hepatic cyst volume varied considerably in the 25 subjects with polycystic liver disease (20 to 7,148 ml), but hepatic parenchymal volume was not altered by hepatic cysts and was similar to that of controls (polycystic liver disease vs. controls: 1,357 +/- 185 vs. 1,319 + 340 ml). Total liver volume increased linearly as cyst volume increased (slope = 1.02 +/- 0.05, r = 0.994). Nine of 18 women with polycystic liver disease had massive hepatic cysts (cyst: parenchymal volume greater than 1; range of cyst volumes from 1,354 to 7,148 ml), and the other nine had cyst volumes (20 to 399 ml) similar to men with polycystic liver disease (25 to 1,107 ml). Total kidney volume, a measure of renal cystic disease, did not correlate with either total liver volume or the volume of hepatic cysts. The data indicate that hepatic parenchymal volume is preserved in polycystic liver disease despite massive cystic involvement and that women are uniquely susceptible to massive hepatic cystic disease.     

Successful living donor liver transplantation for polycystic liver in a patient with autosomal-dominant polycystic kidney disease

Orthotopic liver transplantation has been recommended for patients with disabling polycystic liver disease (PCLD). Because of the shortage of cadaveric donors, living donor liver transplantation (LDLT) has been developed as an alternative. We describe the case of a woman with PCLD as an extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD) who was successfully palliated by LDLT. The patient was a 48-year-old woman with abdominal distention. Computed tomography showed a massively enlarged liver containing innumerable cysts, as well as bilateral kidney cysts. Hepatic and renal functions were well preserved. Genetic analysis of the family did not exclude linkage to the PKD1 locus. Two and a half years after the first examination, the patient reported severely disabling symptoms caused by the PCLD. Living donor liver transplantation was performed using a right-lobe graft. The recipient and donor were both well 8 months after the transplantation. The excised liver weighed 7.4 kg, and the histopathology revealed multiple cysts and von Meyenburg complexes in the portal areas.     

Polycystic kidney disease associated with cervical arteriovenous shunt and bilateral jugular vein occlusion

A 59-year-old man with abnormal vascular features (intracranial aneurysm, a cervical arteriovenous shunt, bilateral internal jugular vein occlusions, and left transverse sinus hypoplasia), as well as left optic atrophy was suspected to have familial polycystic kidney disease. The possibility of autosomal dominant polycystic kidney disease complicated by Ehlers-Danlos syndrome type IV due to the coexistence of vasculopathy and polycystic kidneys was considered. However, the negative results of a skin fibroblast culture rendered the diagnosis of Ehlers-Danlos syndrome type IV unlikely. The cause of left optic atrophy in our patient remains unclear although it was suspected to be a secondary consequence of papilledema, which was caused by intracranial hypertension.     

Evaluation of hepatic cystic lesions

Hepatic cysts are increasingly found as a mere coincidence on abdominal imaging techniques, such as ultrasonography (USG), computed tomography (CT) and magnetic resonance imaging (MRI). These cysts often present a diagnostic challenge. Therefore, we performed a review of the recent literature and developed an evidence-based diagnostic algorithm to guide clinicians in characterising these lesions. Simple cysts are the most common cystic liver disease, and diagnosis is based on typical USG characteristics. Serodiagnostic tests and microbubble contrast-enhanced ultrasound (CEUS) are invaluable in differentiating complicated cysts, echinococcosis and cystadenoma/cystadenocarcinoma when USG, CT and MRI show ambiguous findings. Therefore, serodiagnostic tests and CEUS reduce the need for invasive procedures. Polycystic liver disease (PLD) is arbitrarily defined as the presence of > 20 liver cysts and can present as two distinct genetic disorders: autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (PCLD). Although genetic testing for ADPKD and PCLD is possible, it is rarely performed because it does not affect the therapeutic management of PLD. USG screening of the liver and both kidneys combined with extensive family history taking are the cornerstone of diagnostic decision making in PLD. In conclusion, an amalgamation of these recent advances results in a diagnostic algorithm that facilitates evidence-based clinical decision making.     

Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease

Hepatic cysts are a major manifestation of autosomal dominant polycystic kidney disease. This study examined 239 autosomal dominant polycystic kidney disease patients and 189 unaffected family members to define the factors that influence the presence and severity of hepatic cysts. Autosomal dominant polycystic kidney disease patients with hepatic cysts were older than autosomal dominant polycystic kidney disease patients without such cysts (44.6 +/- 1.1 yr vs. 32.9 +/- 1.1 yr; p less than 0.0001). The number of hepatic cysts increased with age (r = 0.43; p less than 0.0001). Women were more likely to have massive hepatic cystic disease (greater than 15 cysts) than men (p less than 0.04). Women also had larger maximal cyst size (4.2 +/- 0.4 cm vs. 2.7 +/- 0.3 cm; p less than 0.004). Women with hepatic cysts were more likely to have been pregnant (p less than 0.001) and to have had more pregnancies (2.9 +/- 0.3 pregnancies vs. 1.6 +/- 0.2 pregnancies; p less than 0.0009). Kidney volume (p less than 0.0001), number of cysts (p less than 0.004), percentage of cystic parenchyma (p less than 0.001) and predominant cyst size (p less than 0.001) were greater and creatinine clearance was lower (64.5 +/- 3.1 ml/min/1.73 m2 vs. 94.5 +/- 3.4 ml/min/1.73 m2; p less than 0.001) in autosomal dominant polycystic kidney disease patients with hepatic cysts. By logistic regression, the frequency of hepatic cysts was related to increased age, increased severity of renal cystic disease and decreased creatinine clearance. Number and size of hepatic cysts correlated with the occurrence of pregnancy, female gender, increased age and severity of the renal lesion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Polycystic liver disease: Classification,diagnosis, treatment process,and clinical management

Polycystic liver disease(PLD) is a rare hereditary disease that independently exists in isolated PLD, or as an accompanying symptom of autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease with complicated mechanisms. PLD currently lacks a unified diagnostic standard. The diagnosis of PLD is usually made when the number of hepatic cysts is more than 20. Gigot classification and Schnelldorfer classification are now commonly used to define severity in PLD. Most PLD patients have no clinical symptoms, and minority with severe complications need treatments. Somatostatin analogues,mammalian target of rapamycin inhibitor, ursodeoxycholic acid and vasopressin-2 receptor antagonist are the potentially effective medical therapies, while cyst aspiration and sclerosis, transcatheter arterial embolization, fenestration, hepatic resection and liver transplantation are the options of invasion therapies.However, the effectiveness of these therapies except liver transplantation are still uncertain. Furthermore, there is no unified strategy to treat PLD between medical centers at present. In order to better understand recent study progresses on PLD for clinical practice and obtain potential directions for future researches, this review mainly focuses on the recent progress in PLD classification, clinical manifestation, diagnosis and treatment. For information, we also provided medical treatment processes of PLD in our medical center.     

Massive inferior vena cava thrombosis in a patient with autosomal dominant polycystic hepatorenal disease

We report a 68-year-old man with autosomal dominant polycystic kidney disease, who developed multiple venous thromboses (inferior vena cava, left renal vein and iliofemoral veins) caused by local compression of the intrahepatic inferior vena cava by hepatic cysts. To our knowledge this is the first reported case of inferior vena cava thrombosis caused by hepatic cysts compression. Doppler ultrasound, computed tomography, and magnetic resonance imaging were effective in documenting the venous thromboses and the underlying lesions non-invasively. Long-term anticoagulation was an efficient and safe treatment.     

Hepatic venous outflow obstruction in patients with polycystic liver disease: pathogenesis and treatment.

Polycystic liver disease is commonly asymptomatic but may present with hepatomegaly, abdominal distension, and dull abdominal pain. Transudative ascites is a rare manifestation in these patients but may occur when portal hypertension is present resulting from associated hepatic fibrosis or after deroofing procedure of a cyst. Exudative ascites might suggest hepatic venous outflow obstruction. Four cases are described where hepatic venous outflow obstruction occurred in patients with polycystic liver disease. Three patients had orthotopic liver transplantation and one had a mesocaval shunt. Of the two patients that survived orthotopic liver transplantation both have shown considerable improvement in their symptoms. None of the patients had any confirmed procoagulant disorder. The mechanism of hepatic venous outflow obstruction in these patients seems to be mechanical compression of hepatic veins by the cysts and associated formation of thrombi in small hepatic vein tributaries. Patients with severe polycystic kidney/liver disease are at risk of hepatic venous outflow obstruction and the onset of this complication is heralded by tender hepatomegaly and presence of exudative ascites.     

Multiple cysts in the liver autosomal dominant polycystic liver disease

A 45-year-old woman was admitted because of abdominal pain and a feeling of fullness. Ultrasound and CT scan of the abdomen showed a massively enlarged liver with hundreds of cysts and displacement of the right kidney. There were no cysts in the kidneys. Because several members of her family also had multiple cysts in the liver, the diagnosis of autosomal dominant polycystic liver disease (PCLD) was made. Genetic analysis demonstrated a protein kinase C substrate 80 K-H (PR KCSH) gene mutation (1338-2A>G) and confirmed the clinical diagnosis. A brief review of the genetics and possible treatments is given.     

Chronic obstructive pancreatitis due to a pancreatic cyst in a patient with autosomal dominant polycystic kidney disease

Background—Autosomal dominant polycystic kidneydisease, the most frequent inherited polycystic disease, is a systemicdisorder characterised by the development of numerous and bilateralkidney cysts leading to chronic renal failure. Extrarenal cysts arelocated mainly in the liver but also in various organs including thepancreas. To our knowledge, complications of pancreatic cysts in thisdisease have never been reported.
Patient—The first case of painful chronicobstructive pancreatitis due to a true pancreatic cyst in a patientwith autosomal dominant polycystic kidney disease is reported.Abdominal transparietal and endoscopic ultrasonography, computedtomography, and endoscopic retrograde cholangiopancreatography showed acystic lesion in the body of the pancreas associated with upstreamdilatation of the main pancreatic duct. Intraoperative ultrasonographybefore and after cyst fluid aspiration, and pancreatography andpathological examination of the resected distal pancreas confirmed thatboth main pancreatic duct enlargement and chronic pancreatitis were caused by a benign cyst.
Conclusion—Chronic obstructive pancreatitisshould be added to the extrarenal complications of autosomal dominantpolycystic kidney disease.

Keywords:chronic obstructive pancreatitis; pancreatic cyst; autosomal dominant polycystic kidney disease; distal pancreatectomy

     

Functional similarities of hepatic cystic and biliary epithelium: studies of fluid constituents and in vivo secretion in response to secretin

Hepatic cysts are a frequent manifestation of autosomal dominant polycystic kidney disease, but little is known about their functional characteristics. The goals of our study were to define the composition of hepatic cyst fluid and to determine whether hepatic cysts secrete in response to intravenously administered secretin. We percutaneously punctured five hepatic cysts and one proximal renal cyst from six subjects with autosomal dominant polycystic kidney disease and one solitary hepatic cyst from a subject without autosomal dominant polycystic kidney disease. Most fluids had an electrolyte composition similar to serum. Fluid from all hepatic cysts had glutamyltranspeptidase concentrations above those found in serum [( cyst]/[serum] = 4.93 +/- 5.92), contained secretory component (the epithelial receptor for polymeric IgA) and had glucose concentrations less than 15 mg/dl. Fluid from both hepatic and renal cysts of subjects with autosomal dominant polycystic kidney disease, but not from the subject with the solitary hepatic cyst, demonstrated extensive changes in the electrophoretic mobility of several serum proteins. Initial intracystic pressures ranged from 16 to 40 cm H2O, were reduced 57% to 97% after aspiration of a portion of cyst fluid and were held constant during the secretion study. Within 8 min of the intravenous administration of secretin, secretion of fluid increased in two of three hepatic cysts and in the renal cyst. The electrolyte composition of cyst fluids was not altered by secretin. These data suggest that hepatic cystic epithelium has functional characteristics of biliary epithelium and that secretion by both hepatic and renal cysts may be hormonally regulated.     

Surgical treatment for an extrahepatic portosystemic shunt: a case report

An extrahepatic portosystemic shunt that has neither liver cirrhosis nor portal hypertension is rare. A 60-year-old Japanese woman who had been suffering chronic liver disease and anemia with mild disorientation was admitted to investigate general fatigue with dizziness and disorientation. The laboratory data revealed mild pancytopenia and liver dysfunction including hyperammoniemia, an increased Indocyanine Green 15-min retention rate, and a decreased Fischer's ratio. Color Doppler ultrasonography, computed tomography, and arterial portography revealed an extrahepatic portosystemic shunt that extended tortuously from the superior mesenteric vein into the inferior vena cava, and decreased blood flow in the main portal vein. Judging from intraoperative measurement of portal pressure and intraoperative portography, shunt ligations were performed at both the efferent portion of shunt from the superior mesenteric vein and the afferent portion of the shunt into the inferior vena cava, and resection of the spleen was also performed. On the postoperative laboratory data, pancytopenia disappeared, and liver function improved. Postoperative abdominal imaging showed increased blood flow in the main portal vein and disappearance of the shunt vessel. Moreover, symptoms present before surgery also disappeared. In conclusion, surgical treatment of extrahepatic portosystemic shunts may result in better postoperative quality of life if it is performed in carefully selected patients.     

Surgical management of polycystic liver disease

Adult polycystic liver disease (PCLD) is an autosomal dominant condition commonly associated with autosomal dominant polycystic kidney disease (ADPKD). However in the last decade, it has been recognized that there is a distinct form of autosomal dominant PCLD that arises without concomitant ADPKD. Early knowledge of the pathogenesis was gained from the study of hepatic cysts in patients with ADPKD. Bile duct overgrowth after embryogenesis results in cystic hepatic dilatations that are known as biliary microhamartomas or von Meyenburg complexes. Further dilatation arises from cellular proliferation and fluid secretion into these cysts. There is a variable, broad spectrum of manifestations of PCLD. Although PCLD is most often asymptomatic, massive hepatomegaly can lead to disabling symptoms of abdominal pain, early satiety, persistent nausea, dyspnea, ascites, biliary obstruction, and lower body edema. Complications of PCLD include cyst rupture and cyst infection. Also, there are associated medical problems, especially intracranial aneurysms and valvular heart disease, which clinicians need to be aware of and evaluate in patients with PCLD. In asymptomatic patients, no treatment is indicated for PCLD. In the symptomatic patient, surgical therapy is the mainstay of treatment tailored to the extent of disease for each patient. Management options include cyst aspiration and sclerosis, open or laparoscopic fenestration, liver resection with fenestration, and liver transplantation. The surgical literature discussing treatment of PCLD, including techniques, outcomes, and complication rates, are summarized in this review.     

Isolated Polycystic Liver Disease Not Linked to Polycystic Kidney Disease 1 and 2

Autosomal dominant polycystic liver diseaseoccurs commonly in association with autosomal dominantpolycystic kidney disease, types 1 and 2. It may alsoexist as a separate entity, genetically distinct from autosomal dominant polycystic kidneydisease types 1 and 2, as has been recently establishedto exist in a Belgian family. We report here a largeArgentinian family of Spanish-Belgian ancestry with autosomal dominant polycystic liver disease,where proximal and distal markers for both polycystickidney disease 1 and 2 failed to demonstrate geneticlinkage. The data support the notion that polycystic liver disease and autosomal dominant polycystickidney disease may have separate chromosomalloci.