NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and Joost PH Drenth, MD, PhD, Professor of Gastroenterology and Hepatology, Head, Department of Gastroenterology and Hepatology, Radboud UMC, and Dr. Lucas Bernts, Radboud UMC, The Netherlands, for assistance in the preparation of this report.
Polycystic liver disease (PLD) is an inherited disorder estimated to affect around 1 in 100,000 people [1, 2]. It is characterized by the progressive growth of cysts of various sizes scattered throughout the liver. People affected by this condition tend to have more and larger cysts as they age and usually start to have symptoms around age 50, although symptoms can begin to occur earlier . However, many affected individuals do not have symptoms. Enlargement of the liver (hepatomegaly) can cause abdominal pain and discomfort, shortness of breath (dyspnea), early satiety and gastro-esophageal reflux. Rare complications are hepatic cyst hemorrhage, infection or rupture.[3-6]. Surgical and medical treatment is available to manage the symptoms, but the only definitive treatment for this condition is liver transplant [2, 7-10]. Most cases are inherited in an autosomal dominant pattern, but some cases seem to occur with no apparent cause (sporadically). Sometimes, cysts are found in the liver in association with the presence of autosomal dominant polycystic kidney disease (ADPKD). In fact, most people who have ADPKD have liver cysts [3, 11].
Polycystic liver disease is characterized by the growth of more than 10 cysts in the liver, ranging in size from a few millimeters to over 15 cm in diameter. Symptoms usually begin to show in people around 50 years old, as cysts grow in size and number with age . Some people begin to have symptoms in early adulthood and many affected individuals do not have symptoms. The growth and accumulation of cysts can cause enlargement of the liver (hepatomegaly) and compression of adjacent anatomical structures, leading to abdominal pain and discomfort, shortness of breath (dyspnea), indigestion (dyspepsia), gastro-esophageal reflux, and limited mobility [3-6]. More rarely, liver cysts can also compress the bile duct and lead to yellowing of the skin (jaundice). Compression of the blood vessels of the liver by cysts can lead to accumulation of fluid in the abdomen (ascites), bleeding, and high blood pressure in the blood flow from intestines to the liver (portal hypertension) [12-14]. In rare cases, patients can suffer from cyst bleeding (hepatic cyst hemorrhage), or a cyst can be infected by bacteria (hepatic cyst infection), causing pain and fever. Infrequently, large liver cysts may rupture, causing severe abdominal pain. (Van Aerts et al. 2017) Even with the presence of many cysts, the liver of individuals with polycystic liver disease functions normally.
Changes (mutations) in three genes, PRKCSH, LRP5 and SEC63, are linked to polycystic liver disease [15, 16]. These genes are not associated with AD-PKD. Individuals with mutations in SEC63 or PRKCSH tend to have more severe symptoms compared to individuals with polycystic liver disease without mutations in one of these two genes . However, less than 50% of individuals with polycystic liver disease have a mutation in one of these genes, so other genes may be involved in this condition [3, 13]. GANAB, ALG8 and SEC61B are three genes potentially involved in polycystic liver disease and are being investigated as possible causes of the disease [18-21].
Disease causing (pathogenic) mutations in SEC63 and PRKCSH lead to defects in processing, folding and translocation of newly synthesized glycoproteins. This is associated with embryological malformations which causes the formation of fluid-filled cysts throughout the liver. [4, 7, 13].
Most cases of polycystic liver disease are inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Polycystic liver disease affects around one in 100,000 people [1, 2]. Males and females are affected in equal numbers, but most patients with symptoms and with severe disease are women. The suggested cause of this difference is that female sex hormones, such as estrogen, contribute to growth of liver cysts [1, 3, 7, 13, 17, 22]. Oral contraceptives and estrogen replacement therapy are also associated with more severe disease [23-25]. Cysts can begin to grow at any age, but are rare in childhood and more common with age. The age at which symptoms begin to occur varies with individuals, but is usually around 50 years old.
Magnetic resonance imaging (MRI), computed tomography (CT) scan, and ultrasound (US) are used to take pictures of the liver to see if cysts are present. The images are used for diagnosis and monitoring of cysts growth. Molecular genetic testing is available to look for mutations in the SEC63, LRP5 and PRKCSH genes and may be particularly helpful in individuals that inherited the disease from one of their parents. It is also possible to test for blood levels of two markers of liver and bile duct disease: gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP). These two markers might be elevated in patients with severe polycystic liver disease .
Treatment may not be necessary in many cases of polycystic liver disease and is only indicated in severely affected or symptomatic patients. Large cysts (>5 cm) can be treated with aspiration sclerotherapy, which includes puncture of the cyst, removal of the fluid and treatment of the cyst wall with a chemical allowing tissues to harden, (sclerosing agent) such as ethanol. . When multiple large cysts are causing symptoms, keyhole surgery can be a treatment option. The surgeon punctures and then removes the ‘roof’ of the cysts. This procedure is called laparoscopic fenestration. It is also possible to remove parts of the liver (hepatic resection) to reduce symptoms related to hepatomegaly [7, 9]. The only definitive treatment of PLD, used in only the most severe cases, is liver transplant [2, 8, 33].
Medication to slow down cyst growth and fluid secretion in the liver (somatostatin analogs, namely octreotide and lanreotide) is also useful in reducing liver volume [7, 10]. Because they are very expensive, these medications are typically reserved for patients with moderate to severe disease with reduced quality of life. Referral to a specialized center is recommended. As estrogen promotes cysts growth, it is recommended for women diagnosed with polycystic liver disease to stop hormonal contraceptives or estrogen replacement therapy [3, 7, 22, 23, 25].
Genetic counseling is recommended for patients and their families.
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