Brief Introduction to the Polycystic Liver Disorders
A hepatic cyst is a fluid-filled, epithelial lined cavity which varies in size from a few milliliters to several liters. Unlike single cysts, polycystic liver, which is arbitrarily defined when >20 cysts are present, is a rare condition and is part of the phenotype of two inherited disorders. In autosomal dominant polycystic kidney disease (ADPKD), patients have polycystic kidneys and may eventually develop polycystic liver disease (PLD). 1 In autosomal dominant polycystic liver disease (PCLD), multiple hepatic cysts are the primary presentation, whereas polycystic kidneys are absent. 2 Traditionally, treatment consists of physical removal or emptying of cysts by a range of invasive techniques. 3 However, there has been considerable progress in the development of new medical modalities over the last few years. Therefore, it is timely to review recent advances focused on promising novel therapies for this disease.
Clinical Presentation and Epidemiology
ADPKD is the most prevalent inherited renal disorder, with a prevalence of 0.1%-0.2%. 1,3 The prevalence of PCLD is not known, but it is likely underre-cognized. 2 Although PCLD and ADPKD are distinct at the genetic level, both disorders have polycystic livers in common. The clinical presentation of ADPKD is well known, but the clinical profile of PCLD is poorly defined, and much of the information available so far stems from extrapolation of studies in ADPKD. The common thinking is that the natural history of PLD is compatible with a continuous growth in number and size of cysts. Data from three recent trials [4][5][6] indicate that the annual growth of polycystic livers is $0.9%-3.2% (Fig. 5). The prevalence of hepatic cysts in ADPKD is high (67%-83%), and is likely age-dependent. 7,8 Risk factors for cyst growth are age, female sex, and renal cyst volume. 8 In addition, severity of renal cystic disease, prior pregnancies, and estrogen use predict increase of polycystic liver size in ADPKD. 7,9 Indeed, 1 year of estrogen use in postmenopausal ADPKD patients selectively increases total liver volume by 7%, whereas total kidney volume remains unaffected. 2,10 Symptoms in PLD are probably secondary to the increased total liver volume. 10 As polycystic livers can grow up to 10 times their normal size, they compress adjacent abdominal and thoracic organs. Patients with massively enlarged polycystic livers suffer from epigastric pain, abdominal distension, early satiety, nausea, or vomiting. Typically, dress size increases, and patients are unable to see their feet, cut toenails, and bend over. Patients with grossly enlarged livers develop abdominal wall herniation and may report shortness of breath. Other complications are infection, hemorrhage or rupture of a cyst, compression of the inferior cava, hepatic veins, or bile ducts, but these occur less frequently. 2
Pathogenesis of Cyst Formation
Both ADPKD and PCLD are autosomal dominant disorders. Two gene mutations account for almost all ADPKD cases: PKD1, which encodes polycystin-1, accounts for 85% of cases, whereas PKD2, encoding polycystin-2, is responsible for the remainder. PCLD is caused by PRKCSH or SEC63 mutations, although in Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; cAMP, 3 0 -5 0 -cyclic adenosine monophosphate; mTOR, mammalian target of rapamycin; PCLD, polycystic liver disease; TAE, transcatheter arterial embolization; VEGF, vascular endothelial growth factor.