Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management

Abstract

Polycystic liver disease (PLD) is the result of embryonic ductal plate malformation of the intrahepatic biliary tree. The phenotype consists of numerous cysts spread throughout the liver parenchyma. Cystic bile duct malformations originating from the peripheral biliary tree are called Von Meyenburg complexes (VMC). In these patients embryonic remnants develop into small hepatic cysts and usually remain silent during life. Symptomatic PLD occurs mainly in the context of isolated polycystic liver disease (PCLD) and autosomal dominant polycystic kidney disease (ADPKD). In advanced stages, PCLD and ADPKD patients have massively enlarged livers which cause a spectrum of clinical features and complications. Major complaints include abdominal pain, abdominal distension and atypical symptoms because of voluminous cysts resulting in compression of adjacent tissue or failure of the affected organ. Renal failure due to polycystic kidneys and non-renal extra-hepatic features are common in ADPKD in contrast to VMC and PCLD. In general, liver function remains prolonged preserved in PLD. Ultrasonography is the first instrument to assess liver phenotype. Indeed, PCLD and ADPKD diagnostic criteria rely on detection of hepatorenal cystogenesis, and secondly a positive family history compatible with an autosomal dominant inheritance pattern. Ambiguous imaging or screening may be assisted by genetic counseling and molecular diagnostics. Screening mutations of the genes causing PCLD (PRKCSH and SEC63) or ADPKD (PKD1 and PKD2) confirm the clinical diagnosis. Genetic studies showed that accumulation of somatic hits in cyst epithelium determine the rate-limiting step for cyst formation. Management of adult PLD is based on liver phenotype, severity of clinical features and quality of life. Conservative treatment is recommended for the majority of PLD patients. The primary aim is to halt cyst growth to allow abdominal decompression and ameliorate symptoms. Invasive procedures are required in a selective patient group with advanced PCLD, ADPKD or liver failure. Pharmacological therapy by somatostatin analogues lead to beneficial outcome of PLD in terms of symptom relief and liver volume reduction.

Figure 1

Abdominal MRI and CT in patients with PLD. (A) Axial T1-weighted and (B) coronal T2-weighted MRI present 1 large cyst and numerous cystic nodules scattered at peripheral bile ducts. (C-D) CT-scanning in a PCLD patient presents multiple cysts originating from medium-sized bile ducts. (E-F) Co-occurrence of polycystic kidneys exists in ADPKD. Both PRKCSH and PKD2 gene mutations were predicted to be pathogenic (GRCh37-hg19; HGMD). Hepatic cysts are indicated by white arrows. (G) Diffuse VMC present numerous small-sized hepatic cysts located at peripheral branches of the biliary tree (in green). (H) The PLD phenotypes are arbitrarily staged and indicate disease progression. The disease course is progressive in a subset of severely affected PLD patients.

Figure 2

Comprehensive algorithm for diagnosis, management and genetic counseling in PCLD and ADPKD. The diagnostic criteria for PCLD and ADPKD compromises family history and age-related liver or kidney phenotype respectively [64,66]. PLD therapy is individually decided according to number, distribution and size of hepatic cysts [78]. Genetic counseling has an important role in symptomatic individuals with a positive family history for hepatic and/or renal cystogenesis in order to differentiate PLD and clinical management.

Figure 3

Intra-familial clinical heterogeneity in PCLD. Description of the data: (A) Pedigree of a PCLD family with PRKCSH gene mutation c.374_375delAG in affected individuals. The index patient (*) has 4 members with symptomatic PLD. Although the family history is positive, family members frequently are asymptomatic carriers or the liver phenotype remains unknown. (B) Axial CT-scanning, abdominal ultrasonography or MRI in 4 PCLD patients presented a variably number of hepatic cysts without renal disease.

Figure 4

Indications and considerations for treatment strategies in symptomatic PLD. Schematic overview of relevant indications and considerations in PLD management. Patient characteristics and liver phenotype such as severity of clinical symptoms, age, (surgical) history, degree of hepatomegaly, and number, size and location of hepatic cysts are essential parameters for this decision. In general, the choice of procedure is an individual process in consultation with the patient. Severely affected individuals are patients with massive hepatomegaly, refractory symptoms, PLD-related complications and/or end-stage liver failure. Care and follow-up of these patients should be managed with caution. *Notification: Results about treatment efficacy of prolonged or long-term somatostatin analogue use is unknown. **Arbitrary total liver volume (TLV), because this outcome measurement is related to other parameters such as height, total body surface and sex. ***For example: recurrent hepatic cyst infection, HVOO.