CYSTIC DISEASES OF LIVER AND BILIARY TRACT (Part One)

Introduction

Cystic lesions of the bile ducts and liver can result from a variety of pathologic processes. They may be solitary or multiple.

• Cystic abnormalities occurring within the liver parenchyma, which are not in continuity with the biliary tree, are referred to as liver cysts.
  
• Cystic lesions which are in direct continuity with the intra- or extrahepatic bile ducts are considered as biliary cysts.
  

• Cystic lesions of the liver with an infectious origin (e.g. echinococcus or hydatid cysts, liver abscesses) and pseudocysts will not be discussed in this topic.

Cysts of the liver and bile ducts can occur as single entities, but are frequently found in various combinations of intra- or extrahepatic cystic abnormalities.

• Although the exact mechanisms underlying the origin of liver cysts are unknown, mutations in four distinct genes have been linked to various types of polycystic liver disease.
  
• Cystic abnormalities of the intra- and extrahepatic bile ducts have been historically classified as acquired entities; however, it is likely that other factors (i.e. genetic factors) also play a role in the pathogenesis of cystic diseases of the bile duct.
  
• In general, true or epithelialized liver and biliary cysts can be divided into two groups:

1. Neoplastic and
2. Non-neoplastic group.
   

• The neoplastic group primarily comprises:
  

1. Biliary cystadenoma and
   
2. Cystadenocarcinoma,

• The non-neoplastic group can be subdivided into:
  

1. Simple liver cysts,
   
2. Polycystic liver diseases,and
   
3. Bile duct-related cystic diseases.

Simple liver cysts

Simple hepatic cysts are also known as benign, nonparasitic, or solitary cysts, the latter being a poor name, since they are multiple in 50% of the cases.

• Although these cysts were traditionally considered as rare lesions, by the wider application of imaging modalities, such as the computed tomography (CT) scan, we now know that these cysts can be found rather commonly in asymptomatic patients.
  
• The exact pathogenesis of simple hepatic cysts is unknown, but it has been suggested that they develop from biliary microhamartoma or aberrant bile ducts, which have lost contact with other parts of the biliary system during the early embryological stages.
  

• Although simple hepatic cysts are not in direct continuity with the biliary tree, their presumed biliary origin, and the differential diagnosis with other types of hepatic and biliary cystic disorders, justifies a discussion of simple hepatic cysts in this topic

Simple cysts can be found at all ages, although the prevalence increases with increasing age and women are more often affected than men.

• Most cysts have a round or oval shape on cross-section and can vary in size from a few mm to more than 30 cm.
  
• They are usually asymptomatic and are found coincidentally during ultrasound or CT examination of the abdomen for unrelated symptoms or conditions.
  
• Occasionally, large cysts cause vague upper abdominal complaints or symptoms of partial bowel, secondary to compression of the gastrointestinal tract.
  
• Large cysts located in the hepatic hilum can cause obstructive jaundice or portal hypertension due to compression of the hepatic duct or portal vein.
  
• Compression of the inferior vena cava is a very rare complication, but it may lead to an inferior vena cava syndrome, characterized by symptoms related to venous congestion of the lower part of the body.
• Acute abdominal pain may result from rupture or bleeding into the cyst.
  
• Depending on the size and location within the liver, cysts can sometimes be found on physical examination.
• Serum values of the hepatic enzymes may be increased, but are usually within the normal range.

Histologically, the inner cystic lining is formed by a single layer of cuboidal or columnar epithelium that resembles biliary epithelium.

• The cystic fluid is usually clear yellow and serous, but may appear bloody or purulent under given circumstances.
  
• The presence of numerous microhamartomas in the surrounding liver, or the combination of multiple cysts should raise the possibility of autosomal dominant polycystic disease.
  
• Malignant degeneration, either to squamous cell carcinoma, adenocarcinoma, or a mixed type, is a rare but serious complication.

The diagnosis of simple cysts is usually made by ultrasonography or computed tomography .

• Differentiation with abscess, hematoma, and solid tumors is not difficult when using these radiological techniques.
  
• The differentiation between simple cysts and echinococcal (hydatid) cysts can be somewhat more difficult.
  
• Depending on the local prevalence of echinococcal infections, hydatid liver cysts may be mistaken for a simple liver cyst in up to 5% of the cases.
  
• Although simple cysts are always unilocular and never have calcifications, echinococcal cysts are usually septated and frequently have calcifications in the wall.

Serological studies will be helpful in discriminating the two conditions from each other.

Cysts with irregularities of the cystic wall or papillary projections into the cystic cavity should raise a very high suspicion for cystadenoma or cystadenocarcinoma.

• In these cases, carbohydrate antigen 19-9 (CA 19-9) or carcinoembryonic antigen (CEA) serum concentrations are usually elevated, where as this is not the case in simple cysts.
  
• Occasionally, metastasis from other tumors can present as cystic lesions due to central necrosis and cavity formation.

Treatment is not indicated in case of asymptomatic simple cysts.

For symptomatic cysts different approaches have been described.

Simple percutaneous puncture and aspiration of the cystic content is not effective and is immediately followed by refilling of the cysts.

• Percutaneous aspiration of the cyst followed by the injection of a sclerosing agent (95% alcohol or minocycline) has a higher success rate of up to 70%.
  
• However, for a long-term success, repeated procedures are usually required, which carry the risk of infection or sclerosing cholangitis.
  
• The use of alcohol can be complicated by pain, fever, or alcoholic intoxication.
  

Laparoscopic unroofing of the external part of the cyst, followed by transposition of an omental flap into the remaining cyst cavity, is currently considered to be the treatment of choice for symptomatic cysts.

Open surgery is indicated when cysts cannot be approached laparoscopically (e.g. the posterior segments VI and VII, and segment IVa), or when a potentially malignant disease cannot be excluded.

• If aspiration of the cystic contents, with precautions to avoid contamination of the abdominal cavity, provides evidence for a malignancy, a partial liver resection is indicated.
  
• Also, the incidental finding of a cystadenoma during or after laparoscopic fenestration of a liver cyst requires an open or laparoscopic enucleation of the cyst and in some cases hepatic resection.

Polycystic diseases of the liver

Multiple liver cysts can be identified in three different types of diseases:

1. Autosomal dominant polycystic kidney disease,
   
2. Autosomal dominant liver disease, and
   
3. Autosomal recessive polycystic liver disease (also known as congenital hepatic fibrosis).
   

The hepatic abnormalities in the first two types of polycystic liver disease are phenotypically similar, but mutations in distinct genes have been linked to these disorders.

Disease presentation in autosomal recessive polycystic liver disease is highly variable and may vary from biliary dysgenesis, resulting in congenital hepatic fibrosis, to intrahepatic bile duct dilatations.

Autosomal dominant polycystic diseases

The group of autosomal dominant polycystic diseases consists of genetically heterogeneous disorders with identified mutations in four distinct genes.

In the most common form, cystic manifestations are most prominent in the kidneys, and

• this disease is called autosomal dominant polycystic kidney disease (AD-PKD).
  
• Mutations in two different genes have been linked to AD-PKD: PKD1 and PKD2.
  
• Mutations in the PKD1 gene account for 85 to 90% of mutations in ADPKDfamilies; the remaining 10 to 15% are due to mutations in PKD2.
  
• PKD1 and 2 encode for proteins called polycystin-1 (PC-1) and polycystin-2 (PC-2), which have been characterized as membrane-bound proteins involved in cell–cell and cell–matrix interactions.
  
• Moreover, recent evidence demonstrates that PC-1 and PC-2 form the core of a mechanotransduction signaling complex within ciliated epithelium cells.

The three forms of polycystic liver disease are all characterized by the development of multiple liver cysts and are phenotypically indistinguishable.

The overall prevalence at autopsy studies is about 0.13%.

The natural history of the autosomal dominant forms of polycystic liver disease is strikingly similar, despite the variations in molecular and genetic background.

• Hepatic cysts are rarely observed before puberty.
  
• They tend to appear with increasing age, more commonly in women, especially after multiple pregnancies or the use of drugs containing sex hormones.
  
• In addition to liver and kidney cysts, patients with AD-PKD may also develop cysts in other organs, including the pancreas, spleen, ovaries, uterus, testes, thyroid, and mesenterium.
  
• Other associated disorders are colonic diverticula, vascular aneurysms, and inguinal hernias.
  
• Polycystic liver disease is considered to result from progressive dilatation of abnormal ducts in microhamartomas or von Meyenburg complexes, at the level of the small intrahepatic bile ducts.
  
• Apart from the initial gene mutation (“first hit”), a second loss-of-function muation in the functional gene copy (“second hit”) is believed to be responsible for initiation of cell proliferation and cyst formation.
  
• Expanding cysts detach from the intrahepatic bile duct, which explains the noncommunicating nature of the cysts in polycystic liver disease.
  
• On histological examination the cysts are very similar to simple hepatic cysts.
  
• The inner wall is formed by a single layer of more or less cuboidal epithelium, resembling biliary epithelium and they are surrounded by a thin fibrous wall.

Polycystic liver disease is usually asymptomatic and an incidental finding.

• Symptoms occur in 10 to 20% of the patients and usually not before the third decade.
  
• Most symptoms center around the massive hepatomegaly and include upper abdominal pain and discomfort, abdominal distention, and dyspnea.
  
• Hepatic function is well preserved in most cases and serum levels of liver enzymes are either normal or only slightly elevated.
  
• In symptomatic patients the liver can usually be felt on physical examination and may extend downwards into the pelvis.
  
• Complications may occur from infection, compression, bleeding, or rupture of the cysts.
  
• Infection of hepatic cysts occurs in up to 3% of patients with autosomal dominant polycystic disease who have end stage renal failure, but in less than 1% of such patients before end-stage renal failure.
  
• Compression of the bile ducts may result in jaundice.
  
• Isolated cases with compression of the inferior vena cava vein or portal vein, resulting in an inferior vena cava syndrome or portal hypertension, have been reported.
  
• Malignant degeneration is extremely rare and has been described only in a few case reports.
  
• Modern radiologic studies, such as ultrasonography, computed tomography, or magnetic resonance imaging (MRI) can be helpful in making the diagnosis or defining the cause of complications.

Diagnostic puncture and aspiration of the cyst content will facilitate in making the diagnosis when infection
of a cyst is suspected.

Most patients with polycystic liver disease do not require treatment.

• When kidney disorders are present, the abnormalities in kidney function, rather than the liver disease, define the long-term prognosis.
  
• Treatment of liver cysts is indicated in cases with serious complaints of pain or consequences of compression and/or infection.
  
• There is currently no specific medical treatment for polycystic liver disease.
  
• As with simple liver cysts, decompressing puncture alone does not provide long-term relief of symptoms.
  
• Chemical ablation is only indicated when one or two dominant cysts can be held responsible for the symptoms.
  

The indication for surgical interventions is less evident than for simple cysts.

Possible options are laparoscopic or open fenestration, partial liver resection, and liver transplantation.

• Relief of symptoms is often transient and the long-term effect of most surgical interventions is disappointing.
  
• Selected patients with severe symptomatic polycystic liver disease and favorable anatomy benefit from liver resection and open or laparoscopic fenestration with acceptable morbidity and mortality.
  
• The extent of hepatic resection and fenestration is important for the long-term effectiveness of this procedure.
  
• Some highly symptomatic patients with massive polycystic liver disease may benefit from combined hepatic resection and fenestration with acceptable risk.
  
• In general, the indication for surgical interventions in polycystic liver disease is limited and it should always be viewed in relationship with the risk of postoperative complications, such as infection or massive ascites production.
  
• In selected cases with diffuse bilobar polycystic disease and massive hepatomegaly, liver transplantation with or without combined kidney transplantation should be considered.

Autosomal recessive polycystic disease/congenital hepatic fibrosis

Autosomal recessive polycystic disease, also known as infantile polycystic disease, and congenital hepatic fibrosis are often seen in combination, and it has debated whether these entities are a different expression of the same underlying developmental disorder at the level of the intermediate or small intrahepatic bile ducts, rather than two distinct disorders.

• Both conditions are frequently associated with other liver malformations, such a Caroli’s disease and von Meyenburg complexes, but also with renal dysgenesis, such as polycystic renal disease, renal dysplasia, or nephronophthisis.
  
• The exact prevalence of autosomal recessive polycystic disease is not known, but estimates have suggested a frequency of 1 : 20,000 live births.
  
• Liver abnormalities are characterized by fibrous enlargements of the portal tracts containing numerous abnormally shaped and ectatic bile ducts.
  
• Macroscopically visible cysts are usually not present in the liver.
  
• Which term is used in an individual patient is mostly dependent on the amount of renal involvement, with the term autosomal recessive polycystic kidney disease preserved for those cases with renal involvement as the most prominent feature.
  
• Autosomal recessive polycystic kidney disease has been linked to mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene, encoding for fibrocystin, and located on chromosome 6p.
  
• Fibrocystin is a large protein and may have a receptor function.
  
• Recent evidence has linked the protein to the primary cilium of biliary epithelium cells.
  
• This localization is in common with that of other proteins that have been associated with other types of polycystic diseases.
  
• Cystic dilatations are not the main feature of these conditions.
• However, high mortality rates associated with this disorder make it an important cause of pediatric death.