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Revista Española de Enfermedades Digestivas

Print version ISSN 1130-0108

Rev. esp. enferm. dig. vol.106 n.4 Madrid Apr. 2014




Polycystic liver in the adult (PLA) in Spain: Analysis of a structured survey analysing the experience and attitude of gastroenterologists in Spain

La poliquistosis hepática del adulto (PHA) en España: análisis de una encuesta estructurada analizando la experiencia y actitud de los especialistas de digestivo españoles



Javier Ampuero1, Jesús M. Bañales2, Germán Soriano3, Javier Crespo4, José Luis Olcoz5, Moisés Diago6, José Luis Calleja7 and Manuel Romero-Gómez1

1Med-Surg Management Unit for Gastrointestinal Diseases and CIBERehd. Hospital Universitario de Valme. Universidad de Sevilla. Sevilla, Spain
2Instituto de Investigación Sanitaria Biodonostia. Hospital Universitario Donostia. Department of Liver and Gastrointestinal Diseases. IKERBASQUE. Universidad del País Vasco (UPV, EHU). CIBERehd. San Sebastián, Guipúzcoa. Spain
3Hepatology and CIBERehd Unit. Hospital de la Santa Creu i Sant Pau. Universitat Autònoma de Barcelona. Barcelona, Spain
4Gastrointestinal Service. Hospital Marqués de Valdecilla. Santander, Spain
5Gastrointestinal Service. Hospital de León. León, Spain
6Hepatology Section. Hospital General Universitario de Valencia. Valencia, Spain
7Hepatology and CIBERehd Unit. Hospital Puerta de Hierro. Majadahonda, Madrid. Spain

The authors would like to thank Ipsen Pharma Spain for their financial backing and logistical support of the Nationwide Survey and the SEPD [Sociedad Española de Patología Digestiva] Board of Directors for its scientific endorsement of this initiative.





Background: Polycystic liver in the adult (PLA) is a rare disease characterized by chronic liver enlargement.
Objective: To analyse gastroenterologists' involvement in, experience with, and attitude toward diagnosing, monitoring, and treating patients with PLA in Spain.
Methods: Each of seven study coordinators contacted 15 specialists in their geographic area about participating in the study via an online structured survey.
Results: Of the 105 clinics contacted, 88 completed the questionnaire, with a mean of 3 patients being followed per practice, although 6 clinics were following more than 20 patients with PLA. Patients were being followed mainly by the Department of Hepatology (81 %) and/or the Department of Gastroenterology (33 %). The majority of patients were diagnosed (98 %) and monitored (97 %) using liver ultrasound. When diagnosed, 76 % of patients were under 50 years of age, females predominating. The primary treatment objective for the patients was symptomatic management. Pharmacotherapy was prescribed by 28 % of physicians: Somatostatin analogues, primarily, followed by mTOR inhibitors. One-third of the clinics indicated that they had patients who had undergone liver transplant and/or surgery.
Conclusions: Ultrasound is the diagnosing and monitoring method of choice. Among the clinics using pharmacotherapy for symptomatic management, somatostatin analogues were the drugs of choice. These clinics' infrequent use of invasive procedures suggests that they perceive the various invasive techniques as not very effective.

Key words: Multiple hepatic cysts. Polycystic kidney disease. Polycystic liver disease. Somatostatin analogues. mTOR inhibitors. Liver transplant. Fenestration via laparotomy or laparoscopy. Autosomal-dominant polycistic liver-disease (PCLD). Autosomal-dominant polycistic kidney disease (PCKD)


Antecedentes: la poliquistosis hepática del adulto (PHA) es una enfermedad rara caracterizada por el engrandecimiento crónico del hígado.
Objetivo: analizar la implicación, experiencia y actitud de los especialistas españoles en el diagnóstico, seguimiento y tratamiento de los pacientes con PHA.
Métodos: siete coordinadores del estudio contactaron cada uno con 15 especialistas de su entorno geográfico para participar en el estudio a través de una encuesta estructurada online.
Resultados: de los 105 clínicos contactados, 88 completaron el cuestionario, siguiendo una mediana de 3 pacientes por consulta, aunque 6 clínicos realizan seguimiento a > 20 pacientes con PHA. El seguimiento se realiza mayoritariamente en el departamento de hepatología (81 %) y/o gastroenterología (33 %). La ecografía hepática se usa para el diagnóstico (98 %) y seguimiento (97 %) de la mayoría de los pacientes. En el momento del diagnóstico, 76 % de los pacientes tenían < 50 años predominando las mujeres. El objetivo principal del manejo de los pacientes es el control sintomático. Un 28 % de los médicos prescriben tratamiento farmacológico, principalmente análogos de somatostatina, seguidos por inhibidores de mTOR. Un tercio de los clínicos indicó que tenían pacientes que habían recibido trasplante hepático y/o cirugía.
Conclusiones: la ecografía es la técnica de elección para el diagnóstico y seguimiento. Entre los clínicos que administran tratamiento farmacológico para el control sintomático, los análogos de somatostatina son los fármacos de elección. El uso poco frecuente de técnicas invasivas sugiere que los clínicos tienen una percepción bastante pobre de la utilidad de las distintas técnicas invasivas.

Palabras clave: Poliquistosis hepática. Enfermedad poliquística renal. Enfermedad poliquística hepática. Análogos somatostatina. Inhibidores mTOR. Trasplante hepático. Fenestración laparotómica o laparoscópica. Enfermedad poliquística hepática autosómica dominante (PCLD). Enfermedad poliquística renal autosómica dominante (PCKD).



Multiple hepatic cysts in the adult (MHCA) is an autosomal-dominant hereditary disease characterized by the presence of multiple cystic lesions of biliary origin over more than 50 % of the liver parenchyma, ranging from large masses of 20-30 cm to small microscopic nodules (1,2). It is an uncommon disease with an estimated incidence of less than 0.01 % (3) and a prevalence of 0.05 %-0.53 %, although the prevalence of the mutations affects 1:600 (4). The liver cysts often present for the first time in the fourth decade of life; however, the natural history of the disease suggests a continuous growth, for the number and size of the cysts steadily increases with age (5). On the other hand, there is an autosomal-recessive variant, ARPKD (autosomal-recessive polycystic kidney disease), characterized by non-obstructive fusiform dilatations of the renal collecting tubules and malformations of the biliary tract, with bile duct ectasia and periportal fibrosis.

PLA is a disease common to two autosomal-dominant hereditary disorders. It is associated primarily with polycystic kidney disease, which is known as autosomal-dominant polycystic kidney disease (PCKD) (2,6). It may also present as an isolated condition not associated with PCKD, a disease known as autosomal-dominant polycystic liver disease (PCLD). PLA may also be associated with multiple cysts in other organs, such as the pancreas or lung, but in a much lower percentage.

Although various articles have been published on clinical cases of patients and families with PLA in Spain (7-20), the epidemiology has not been well defined, nor are there well-developed protocols for managing patients with PLA in our country. The objective of this study, backed by the Sociedad Española de Patología Digestiva, was to analyse gastroenterologists' involvement in and experience with diagnosing, monitoring, and treating patients with PLA in Spain, with the aim of defining how these patients are managed in Spain and determining whether this could be improved and/or a consensus could be reached.


Patients and methods

Information on the attitude and experience of gastroenterologists in Spain with regard to managing multiple hepatic cysts was obtained via a structured survey that took approximately 15 minutes to complete online. The 49-question survey was divided into 6 sections with several questions in each section. The section on incidence, prevalence, and patient referrals consisted of 12 questions about patients with PLA treated in the surveyee's practice to estimate the number of patients and how the different specialists managed them. The patient profiles section consisted of 10 questions designed to elicit further detail on patients with PLA in Spain; these questions asked for characterization of the PLA and its associated symptomatology. The section on surgical treatment of polycystic liver, with its 4 questions, asked about the surveyee's experience with different surgical techniques in the treatment of PLA. The pharmacotherapy in polycystic liver cysts section had 7 questions for describing the surveyee's familiarity with the available pharmacotherapies, including new therapies. The last two sections, sources of information and classification information, with 5 and 11 questions, respectively, were designed to categorize the surveyees. The survey was conducted by 7 coordinators, each of whom contacted 15 physicians in their geographic area. The survey itself is included as an Annex to this article.




Almost all of the 105 clinics contacted (104; 99 %) agreed to participate, and 88 of them (85 %) completed the survey. Half of the surveyees identified themselves as hepatologists (45; 51 %); the rest were gastroenterologists (34; 39 %) and internists, surgeons, or specialists in other areas (9; 10 %). Approximately half of the surveyees had been treating liver diseases for more than 15 years, and 31 % of them had more than 20 years in this practice. Study participants represented most of the Autonomous Communities, the strongest participation being physicians from the province of Barcelona, followed by the provinces of Sevilla and Valencia (Fig. 1).



Of the 88 clinics surveyed, 72 were following patients with PLA in their practice. A median of 3 patients per practice were being followed, although 6 of the 88 clinics were following more than 20 patients with PLA. Of the specialists surveyed, 28 % saw 1 new patient per year; 16 % saw 2 new patients per year; and 15 % saw more than 2 new patients per year. The percentage of patients with PCLD was 44 % compared to 56 % with PCKD. PLA was usually diagnosed prior to 50 years of age, two-thirds (65 %) of patients being female, with no difference in age at diagnosis between patients with PCLD and patients with PCKD. Few patients had an immediate family member with a clinical history of PLA. The most common phenotype was multiple small cysts. Among the hepatologists, 18 % reported that, in the last 10 years, fewer than 5 patients had died from the disease or PLA-related complications. The remaining 82 % reported no PLA-related deaths.

Patient flow

Patients with PLA usually came to the hepatologist, already diagnosed (73 % of cases), as referrals from other clinical departments -primarily from nephrology (35 %), primary care centres (33 %), and the Department of Gastroenterology (17 %). In 75 % of cases, patients who were diagnosed with PLA by the hepatologist were not referred to any other specialist for disease management. The majority of patients diagnosed with PCLD also were followed clinically by the hepatology unit (81 %) and/or gastroenterology unit (33 %). It was less clear how patients with PCKD are followed clinically, but in 28 % of cases, they were followed by both the nephrology and hepatology services. It is also worth mentioning that 23 % of the patients with PCKD were being seen only by the nephrology service (Table I).



Back pain, abdominal distension and discomfort constituted the most common symptomatology (73 %), followed by complications such as bleeding, infections, biliary obstructions, and cyst rupture (26 % of cases). Most of the clinics (82.3 %) had not experienced any of their patients dying of PLA-related complications (Table II).


Diagnosis and monitoring techniques

The technique of choice for diagnosing and monitoring patients with PLA was liver ultrasound, used for diagnosis in 98 % of cases and, for monitoring, in 97 %. Other techniques included computerized tomography (CT), used for diagnosing in 89 % and, for monitoring, in 49 % and, less commonly, magnetic resonance imaging (MRI), used for diagnosing in 58 % and, for monitoring, in 30 %.


Overall, the primary treatment objective for patients with PLA was symptomatic management (78 %), followed by improvement in quality of life (12 %), and hepatic volume reduction (6.8 %) and stabilization (3.4 %).


As with surgical treatment, one of the primary objectives of pharmacotherapy is symptomatic management (Table III). In the last year, 28 % of the clinics had used pharmacotherapy, the most common therapy being somatostatin analogues, followed by mammalian target of rapamycin (mTOR) inhibitors. Although some clinics had not prescribed any drugs, they still recognized that treatment with octreotide, lanreotide, everolimus, and sirolimus could be of value in the management of patients with PCLD. Of the 18 % of clinics that had no direct experience with pharmacotherapy, 40 % reported that they did not believe it was appropriate to prescribe drug treatment for their patients with PLA because of the significant number of adverse effects, and 30 % stated, as the reason for not recommending drug treatment, that their patients were currently asymptomatic.


Surgical treatment

At 40 % of the clinics reporting, their patients with PLA had undergone an orthotopic liver transplant (OLT) within the last 10 years. End-stage liver disease was the primary reason for these patients undergoing OLT in the context of PLA. At 14.8 % of the clinics, one patient from their practice had undergone a transplant, while at 4.9 % of the clinics it was two patients and, at 16.4 %, it was more than two. One-third (33.8 %) of the clinics indicated that they had patients under their care who had been treated surgically; 13.1 % of the clinics had one patient, 14.8 % had two patients, and 4.9 % had more than two patients who had undergone surgery. Laparoscopic fenestration was the invasive technique most commonly reported (75 %), this being perceived as the technique with the best risk/benefit ratio (Table IV).



In Spain, PLA is perceived as a rare disease, with the majority of hepatologists and gastroenterologists treating fewer than 5 patients with this pathology. This fact lends great importance to the survey conducted, for it reflects the reality and daily clinical practice of physicians in Spain. It is important to bear in mind, however, that these results are an approximation -not derived from a national registry of patients- and that the majority of surveyees were from the provinces of Barcelona, Sevilla, and Valencia.

Females have a greater predisposition than males to developing massive PLA (> 15 cysts) and to having larger cysts. There is a hormonal component to the disease being more prevalent in females: pregnancy and the number of pregnancies correlates with a more severe phenotype (6), and the use of oestrogen therapies in postmenopausal women is associated with an increase in liver volume (21). PLA is a disease common to two autosomal-dominant hereditary disorders: PCKD and PCLD. PCKD has its origin in mutations of two genes: PKD1 (85 % of cases) and PKD2 (15 % of cases) (22), which code for two proteins called polycystine 1 and 2, respectively. These genes are located on chromosomes 16 and 4 (23). In PCKD, the most common extrarenal manifestation is a polycystic liver. The prevalence of PLA in patients with PCKD is 58 % in patients 15-24 years old, 85 % in patients 25-34 years old, and 94 % in patients 35-46 years old (24). The mutations associated with PCLD are unknown in 80 % of patients, and in the remaining 20 %, they have their origin in the mutation of two other genes: PRKSCH and SEC63. The first gene codes for a protein called hepatocystine, which is expressed in the endoplasmic reticulum (25-27). In our study, there were similar percentages of patients with PCLD and patients with PCKD. In Spain, the specialist who treats most of the patients with PCLD is the hepatologist, whereas patients with PCKD are treated by various services -nephrology and hepatology, in particular- who work together on the majority of cases. Most patients come to the hepatologist already diagnosed, as referrals from the nephrologist or the patient's primary care physician. The diagnosis is made using imaging studies, such as ultrasound, CT (which best defines the extent of liver disease and the involvement of adjacent organs), and MRI -ultrasound being the technique of choice for diagnosis and monitoring.

The majority of patients are asymptomatic with normal liver function (both its synthesis and its excretion functions); thus, the diagnosis is usually a chance finding. Generally, the cysts cause no symptoms unless they become large or are complicated by bleeding, infection, rupture, or malignity (28). When hepatic cysts do become symptomatic, the clinical picture is characterized by painful hepatomegaly, abdominal distension, a feeling of fullness, or lumbar pain (13). In our study, the predominant symptoms (73 %) were those stemming from the cysts compressing adjacent hepatic parenchyma and neighbouring structures: back pain and abdominal distension and discomfort.

The primary objective of pharmacotherapy was symptomatic management, although the total number of patients receiving this was rather low. Only about one-third of the physicians surveyed for this study recommended pharmacotherapy for their patients, somatostatin analogues being the drug of choice. In patients with PCKD and PCLD, it has been shown that the renal and hepatic cysts grow in response to cAMP and that reducing cAMP levels limits the progression of nephropathy and hepatopathy, which suggests that inhibiting these mechanisms could be an effective therapy. The somatostatin analogues (such as octreotide and lanreotide) reduce intracellular cAMP and could limit fluid accumulation in hepatic cysts (29,30). In a recent study with 54 symptomatic patients with PCLD and PCKD, 6 months of lanreotide therapy resulted in a significant reduction in liver volume of 2.9 %, compared to a 1.6 % increase in patients who received a placebo (31). Despite this evidence, many of the physicians surveyed do not prescribe these drugs because of the side effects. On the other hand, the interaction between mTOR and the secretion of VEGF mediated by HIF-1 suggests that the use of mTOR inhibitors could be effective in the treatment of PCKD (32). Furthermore, the hepatic cyst epithelium expresses high levels of mTOR, which suggests that mTOR inhibitors could be effective in limiting the growth of hepatic cysts (33). Studies of multiple renal cysts conducted with numerous experimental models have shown that rapamycin and everolimus (mTOR inhibitors) slow cyst growth and protect renal function (33,34). A recent meta-analysis of the efficacy and safety of mTOR inhibitor therapy in patients with PCKD concluded that it may decrease renal volume with no great improvement in renal function (35); in patients with PLA, however, there was no effect on liver volume. In this survey, mTOR inhibitors were second to somatostatin analogues, in terms of the types of drugs recognized and administered by the surveyees.

As for surgical treatment of patients with PLA, the various invasive surgical techniques were perceived as not very effective, mainly because the benefits are transitory. Even so, one-third of the clinics surveyed indicated that their patients had undergone liver transplant and/or surgical treatment. In PLA, the objective of treatment is to reduce the size of the cysts without compromising liver function and to keep the patient asymptomatic for as long as possible (3). Treatment of these patients consists of reducing cyst volume using a percutaneous approach (aspiration and alcoholisation) or a surgical approach (fenestration via laparotomy or laparoscopy and/or hepatic resection) (36,37). Generally speaking, an attempt is made to reserve surgery for those cases where medical treatment has not been effective, although it appears that surgical intervention is the treatment of choice in our country. Partial hepatic resection with cyst fenestration is somewhat successful in certain patients with massive symptomatic cysts (30). Even though several research projects have recently been conducted, the results so far do not indicate whether laparotomy or laparoscopy is the best choice for fenestration (3). These treatments are aggressive, expensive, and only partially effective, however, because the symptoms usually recur due to the growth of new cysts or of the cysts already treated. Sometimes, in the most severe cases, a liver transplant or combined liver and kidney transplant must be done (36). The survival rate -for both transplanted organ and patient- is very high in patients with PCLD who have undergone liver transplant (38).

In conclusion -and acknowledging the possible limitations of the survey- PLA is an uncommon pathology in our country, which means there is little clinical experience. Moreover, because of its association with other organs, management of the disease would be shared by various specialists, with the hepatologist playing the leading role. The objective to be achieved with these patients is monitoring cyst size (ultrasound being the technique of choice) and keeping them asymptomatic. To do this, various pharmacotherapies, such as the somatostatin analogues and mTOR inhibitors, are used, while surgery is an option for patients who are refractory to medical treatment.



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Manuel Romero-Gómez
Medical-Surgical Management Unit for
Gastrointestinal Diseases and CIBERehd
Hospital Universitario de Valme
Avda. de Bellavista, s/n
41014 Sevilla, Spain

Received 02-09-2013
Accepted 21-01-2014

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