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Fibrocystic Liver Diseases
Abbreviations
ADPKD
autosomal dominant polycystic kidney disease
ADPLD
autosomal dominant polycystic liver disease
ARPKD
autosomal recessive polycystic kidney disease
CD
Caroli disease
CHF
congenital hepatic fibrosis
K
a Although the prefix CK is widely used in surgical pathology to designate human cytokeratins, consensus nomenclature recommends the replacement of “cytokeratin” with “keratin” and the prefix “CK” with “K.” (Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins. J Cell Biol . 2006;174[2]:169–174.)
keratin
MRCP
magnetic resonance cholangiopancreatography
PRKCSH
protein kinase C substrate 80K-H
Fibrocystic diseases of the liver ( Table 25.1 ) are a group of conditions characterized by variable degrees of intrahepatic bile duct dilatation and hepatic fibrosis. Believed to result from abnormal or arrested development and modeling of the embryologic ductal plate, they characteristically show persistence of elements of the ductal plate and are also referred to as ductal plate malformations. Fibrocystic diseases of the liver are frequently associated with developmental renal cysts and renal disease; therefore the encompassing term fibrocystic hepatorenal diseases is often used. The recognition in recent years that several of these disorders result from mutations in genes encoding proteins associated with primary cilia has introduced the term ciliopathies to the lexicon. Biliary and renal epithelial cilia function as sensors of mechanical, chemical, and osmotic changes of intraluminal content. Abnormalities of cilia may disrupt this sensory function and predispose to fluid accumulation; cholangiocyte proliferation; and epithelial-mesenchymal interactions, which lead to hepatic fibrosis. The hepatorenal ciliopathies include autosomal dominant polycystic kidney disease (ADPKD); autosomal recessive polycystic kidney disease (ARPKD); and other rare syndromes such as Joubert syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome, and nephronophthisis.
Table 25.1
Fibrocystic Diseases of the Liver
| Disease | OMIM Number | Gene Mutated | Clinical Presentation | Pathology |
|---|---|---|---|---|
| Autosomal dominant polycystic kidney disease | 173900, 601313, 173910 | PKD1 encoding for polycystin1 PKD2 encoding for polycystin 2 |
Adult, renal symptoms prevail (eg, hypertension, pyelonephritis, hematuria) Extrarenal manifestations include intracranial/aortic aneurysm Liver cysts cause abdominal distention and discomfort, symptoms of compression, rupture, hemorrhage, and infection of cysts |
Kidney and liver with variable number of cysts; cystic effacement of parenchyma not uncommon ( eSlide 25.2 ) Intracranial/aortic aneurysm, colon diverticulosis, hernia |
| Autosomal recessive polycystic kidney disease | 263200 | PKHD1 encoding for fibrocystin/polyductin | Perineonatal-infantile: usually renal dysfunction and pulmonary insufficiency | Massive kidneys with cystic dilatation of collecting ducts ( eSlide 25.3B ) |
| Liver with ductal plate malformation ( eSlide 25.3A ) | ||||
| Older children, adolescents, adults: more likely liver manifestations with portal hypertension (bleeding varices, hypersplenism) or cholangitis | Congenital hepatic fibrosis ( eSlide 25.4 , eSlide 25.5 ) Caroli disease ( eSlide 25.6 ) |
|||
| Autosomal dominant polycystic liver disease | 174050 | PRKCSH encoding for hepatocystin SEC63 encoding for SEC63 LRP5 encoding for low-density lipoprotein receptor-related protein 5 |
May be asymptomatic Liver cysts cause abdominal distention and discomfort, symptoms of compression, rupture, hemorrhage, and infection of cysts Risk of intracranial aneurysm to be defined Mitral valve abnormalities described |
Similar to autosomal dominant polycystic kidney disease, liver with variable number of cysts; cystic effacement may occur |
| Miscellaneous hepatorenal ciliopathies | 216360/612285 | JBTS | Cerebellar vermis hypoplasia, oligophrenia, congenital ataxia, ocular coloboma, and hepatic fibrosis syndrome (Joubert syndrome) | |
| 208540 | NPHP3 | Ivemark syndrome (renal-hepatic-pancreatic dysplasia) | ||
| 256100 | NPHP1 | Nephronophthisis: tubulointerstitial disease with polydipsia, polyuria, anemia, cerebellar and midbrain, and ocular disorders | ||
| Renal cysts, encephalocele polydactyly (Meckel-Gruber syndrome) | ||||
| 249000 | MKS | Same as NPHP1 | ||
| 209900 | BBS | Retinal dystrophy, polydactyly, mental retardation, and mild obesity (Bardet-Biedl syndrome) | ||
OMIM , Online Mendelian Inheritance in Man.
The morphologic spectrum of fibrocystic diseases of the liver includes polycystic liver, congenital hepatic fibrosis (CHF), Caroli disease (CD), and other undefined patterns of ductal plate malformation; these may coexist in the same individual. Furthermore, choledochal cysts may be associated with fibrocystic diseases of the liver, in particular with CD. Finally, von Meyenburg complexes, which are believed to represent localized malformation of the ductal plate, are far more common and more numerous in individuals with fibrocystic diseases.
CD and choledochal cysts, which represent dilatation of intrahepatic and extrahepatic bile ducts, respectively, are sometimes grouped together as congenital dilatation of bile ducts. Dilatation of intrahepatic and extrahepatic bile ducts may coexist; although some consider this condition to represent coexistence of CD and choledochal cysts, others consider it to be a variant of a choledochal cyst (types IVa and V; see later discussion).
Ductal Plate
Liver development begins in the third week of gestation when a bud of endodermal tissue, the hepatic diverticulum, arises from the anterior foregut, proximal to the yolk sac. While the caudal portion of the hepatic diverticulum forms the extrahepatic bile ducts and gallbladder, the cranial portion develops into the liver and intrahepatic bile ducts. The cranial portion grows up toward the septum transversum, a plate of mesodermal tissue that lies between pericardial and peritoneal cavities. It proliferates to form hepatoblasts, which grow in between a simultaneously expanding network of endothelium-lined spaces within the septum transversum that arises from the capillary plexus of the vitelline veins; the blueprint for the approximation of liver cells to sinusoidal vessels is thus established at a very early stage of development. Early hepatoblasts are positive for keratins K8, K18, and K19.
Development of the intrahepatic bile ducts begins in the eighth week of gestation; it does not occur concurrently throughout the liver but begins around the large venous branches of the developing portal vein and proceeds centrifugally in concert with arborization of the portal vein into progressively smaller branches ( Fig. 25.1A ). The earliest event is enhanced expression of K19 by the layer of hepatoblasts surrounding the mesenchyme around the veins, which form a plate of distinctive cells, the ductal plate ( Fig. 25.2A ; see also Fig. 25.1B ). This is followed by similar expression of K19 by the layer of cells immediately adjacent to the first layer, thereby forming a double layer of cells expressing K19 (see Fig. 25.1C ). Beginning in the twelfth week, lumina appear in portions of this double layer to form a wreath of tubular or cylindrical structures around the vein. Further modeling involves outgrowth of mesenchyme, which separates the ductal plate from the limiting plate of hepatocytes and incorporates the definitive intrahepatic ducts into the portal tracts (see Figs. 25.1D and 25.2B ). Excess ductal structures are absorbed, whereas hepatoblasts not involved in the formation of the ductal plate lose their K19 positivity while retaining that for K8 and K18. Expression of K7, the second biliary keratin, begins in large bile ducts at 20 weeks’ gestation and progresses subsequently to the smaller ducts at the periphery; expression in the entire biliary tree is not complete until about 1 month after birth. The mesenchyme plays a crucial role in the development of intrahepatic ducts by inducing formation of the ductal plate and influencing its modeling.
Ductal Plate Malformation
Ductal plate malformation is a term used for improper or arrested modeling of the ductal plate and is seen morphologically as remnants of the embryonic ductal plate. It is often associated with abnormalities of development of the portal veins, testifying to the influence of the vascular system and mesenchyme in development of the ductal plate. However, the role of ciliary proteins, genes for which are often mutated in fibrocystic diseases, in development and modeling of the ductal plate has not been elucidated.
Histologically, ductal plate malformation may be seen as a circular lumen with a central fibrovascular core ( Fig. 25.3A ), multiple interrupted lumina around a central fibrovascular core (see Fig. 25.3B ), a dilated duct containing polypoid fibrovascular projections (see Fig. 25.3C ), a von Meyenburg complex, or a variety of other patterns reminiscent of the developing ductal plate. The pathologic differences among fibrocystic diseases are believed to reflect the stage at which development of the ductal plate is affected.
von Meyenburg Complex (Microhamartoma, Biliary Hamartoma)
von Meyenburg complexes are considered to represent a localized form of ductal plate malformation. They are present in otherwise normal livers, in livers affected by polycystic diseases as well as other nonmalformative, nondevelopmental conditions. They may be single or multiple but are usually more numerous in individuals with fibrocystic diseases.
The lesions consist of an enlarged portal tract containing a cluster of small, variably shaped, and often dilated bile ducts surrounded by fibrous stroma ( Fig. 25.4 ). The ducts are lined by flat or cuboidal and sometimes columnar epithelium ( eSlide 25.1, eSlide 25.2 ). The lumina may be empty or may contain bile or an eosinophilic material. von Meyenburg complexes are often found below the liver capsule where they appear as tiny white spots, raising suspicion of metastatic deposits during abdominal surgery. Rare cases of cholangiocarcinoma associated with von Meyenburg complexes have been reported.
Polycystic Liver
Polycystic liver is characterized by the presence of numerous (but varying in number) smooth-lined cysts containing serous fluid. Molecular studies have identified two distinct clinical forms. In ADPKD, a multisystem disorder, cystic enlargement of the kidneys overshadows that of the liver. In autosomal dominant polycystic liver disease (ADPLD), a polycystic liver occurs without involvement of other organs.
Autosomal Dominant Polycystic Kidney Disease
ADPKD is an autosomal dominant multisystem disorder. Anomalies include cysts in the kidney, liver, pancreas, and seminal vesicles; diverticulosis; intracranial and aortic aneurysms; and cardiac valvular disease; these conditions occur in variable combinations in individual patients. ADPKD occurs worldwide, with a prevalence ranging from 1 in 400 to 1 in 4000. The disease is associated with mutations of PKD1 or PKD2 , located on chromosome 16 (16p13) or chromosome 4 (4q21), respectively; mutations in PKD1 account for 85% of all cases of ADPKD. PKD1 and PKD2 encode for polycystin 1 and polycystin 2, respectively, which are transmembrane proteins localized on primary cilia of several organs and involved in Ca + signaling, cell cycle control, and cell–cell interactions. Complex genetic and environmental factors contribute to the highly variable phenotypic expression of the disease among individuals, even within the same family. Mutations in PKD1 are associated with greater disease severity with larger kidneys and cysts, which may be detectable before birth. Although polycystic liver is the most frequent hepatic manifestation of ADPKD, rare cases of ADPKD may manifest as CHF or CD in the liver. Portal hypertension may be the main clinical manifestation in these cases.
Autosomal Dominant Polycystic Liver Disease
ADPLD has isolated liver involvement without kidney disease. However, the clinical manifestations and morphologic appearance of the hepatic disease are similar to ADPKD. The incidence of ADPLD is not known, but it is estimated to be 1 in 100,000.
ADPLD is genetically distinct from ADPKD and is not associated with mutations in PKD1 or PKD2. Instead, ADPLD is associated with mutations in protein kinase C substrate 80K-H ( PRKCSH ) and SEC63 , located on chromosome 19 (19p13) and chromosome 6 (6q21), respectively. PRKCSH and SEC63 encode for hepatocystin and SEC63 protein, respectively, both of which are localized to the endoplasmic reticulum; the former is associated with glucosidase II and the latter is involved in oligosaccharide processing of newly synthesized glycoproteins. Whole-exome sequencing revealed mutations in the low-density lipoprotein receptor-related protein 5 ( LRP5 ) gene in four unrelated families with polycystic liver disease. Additional and as yet unrecognized mutations cannot be excluded. ADPLD is less penetrant in the liver than ADPKD is in the kidney.
Clinical Manifestations
Liver disease is overshadowed by kidney disease in patients with ADPKD, who usually present with systemic hypertension, pyelonephritis, hematuria, or renal insufficiency. However, the age and severity of presentation, as well as the rate of progression to end-stage renal failure, vary widely, even among families. As with renal disease, the severity and age at presentation of extrarenal manifestations also vary among individuals, even within the same family. Liver involvement is seen in more than 80% of patients and in both genotypes ( PKD1 and PKD2 mutations).
Both liver and kidney cysts increase in number and size with age. In a study of individuals who were shown to have mutations for ADPKD by linkage analysis, all subjects older than 30 years of age had renal cysts on ultrasound, whereas 40% of those younger than 30 years of age did not. Hepatic cysts were found in 58%, 85%, and 94% of patients with ADPKD in the 15-year to 24-year, 25-year to 34-year, and 35-year to 46-year age groups, respectively. A number of patients with ADPKD and ADPLD may be diagnosed by imaging during family screening of a proband, and almost one-third of those with ADPKD have treatable complications at diagnosis.
Despite being genetically distinct, the liver disease is clinically similar in both ADPKD and ADPLD. Because cysts increase in number and size with age, liver disease presents most often in adulthood and symptoms progress with age. Cysts are more prevalent and larger in women than in men. Postmenopausal estrogen therapy is associated with selective hepatic enlargement. Hepatomegaly appears to be not just due to cyst formation; hepatocyte hyperplasia and/or hypertrophy appears to play a role and there is upregulation of cytokines and growth factors that are implicated in hepatic regeneration.
The clinical features of polycystic liver arise from the presence of and compression from large cysts rather than from liver dysfunction. Therefore patients present with an enlarging abdomen and abdominal pain or discomfort; liver function is maintained; portal hypertension is usually absent; and liver tests are either normal or show minimal elevations of alkaline phosphatase and bilirubin. Abdominal enlargement results in dyspnea, gastroesophageal reflux, early satiety, and low back pain. Imaging demonstrates an enlarged and distorted liver, replaced by multiple cysts of varying sizes containing fluid ( Fig. 25.5 ).
Complications result from compression of vital structures and rupture, hemorrhage, or infection of cysts. Exudative ascites and tender hepatomegaly may occur when venous outflow is obstructed by compression from large cysts. Resolution of obstructive jaundice, ascites, and esophageal varices with decompression has been reported. Hemorrhage and rupture cause acute, severe pain; rupture of cysts is also accompanied by ascites. Posthemorrhagic changes in a cyst may mimic cystadenocarcinoma. Infection of cysts presents as an acute or subacute febrile illness associated with tenderness in the right upper quadrant, leukocytosis, and increased erythrocyte sedimentation rate. Minor abnormalities in liver function may be present, and microbial cultures of blood and cyst contents are positive.
Liver cysts, unlike renal cysts, continue to grow and appear de novo after institution of renal replacement therapy. Liver disease may contribute to significant morbidity and mortality in patients who have undergone renal transplantation for kidney disease.
Macroscopic Pathology
Liver involvement is characterized by the presence of multiple smooth-walled cysts, ranging in number from a few cysts ( Fig. 25.6A ) to innumerable cysts that enlarge and distort the liver (see Fig. 25.6B ). In some cases, involvement may be limited to one lobe. The cysts range from less than 1 cm to more than 10 cm in size. They contain clear, serous fluid unless there has been bleeding or infection, when the contents may be bloody or purulent, respectively. The cysts in ADPKD do not communicate with the biliary tree.
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