Liver Involvement in Autosomal-Dominant Polycystic Kidney Disease

Liver involvement is the most frequent extrarenal manifestation in autosomal-dominant polycystic kidney disease (ADPKD). Liver cysts are responsible for most hepatic complications, but other liver changes may occasionally be encountered, including congenital hepatic fibrosis and segmental dilation of the biliary tract. Both molecular and cellular changes implicated in liver cystogenesis have recently been enlightened by advances in genetics of ADPKD and the development of genetically modified animal models. Although most patients with ADPKD report no liver symptoms, some experience chronic manifestations related to progressive increase of the polycystic liver. Ultimately, disability may severely affect their quality of life. In addition, a few develop acute complications that follow a life-threatening course. An armamentarium of surgical procedures may now be offered to the most disabled patients, including liver resection or transplantation. Because early complications and mortality after either procedure remain frequent, the hazards of surgery have to be balanced against benefits; therefore, selection of the optimum therapy still remains a challenge. This article focuses on ADPKD patients with symptomatic liver involvement and provides guidelines for therapy in polycystic liver disease (PLD). Epidemiology In the general population, the prevalence of simple liver cysts detected by ultrasonography increases with age, reaching 4% at approximately 70 yr of age. Paralleling findings on simple cysts in the kidney, most liver cysts are solitary, but two or three cysts are found in one fourth of the patients with simple nonparasitic hepatic cysts. Polycystic liver as an isolated disease may be sporadic or dominantly inherited. Because no large systematic screening for liver and renal cysts has been performed in relatives of the patients with PLD, the respective prevalence of the hereditary and sporadic forms is not known. In most cases, PLD is related to ADPKD and is linked either to PKD1 (the main locus responsible for the disease) or to PKD2. The isolated form of autosomal dominant PLD has been firmly established as a distinct inherited disorder unlinked to PKD1 or PKD2 (1). Risk Factors In ADPKD, liver cysts seem to develop later than renal cysts. Cross-sectional studies by ultrasonography or enhanced computed tomography (CT) scan demonstrate a steady increase in frequency with advancing age. Although liver cysts are very rare for people younger than 20 yr, their prevalence increases from 20% in the third to 70% in the seventh decade of life, reaching a plateau beyond this threshold (2). Why liver cysts do not develop in some elderly ADPKD patients remains unknown. It is interesting that CT scan quantitation in PLD has demonstrated no decrease in liver parenchymal volume but rather an increase in liver cyst volume (3). Whether subtle differences regarding liver phenotype, such as age at onset or prevalence, exist among PKD1 and PKD2 families warrants further investigation. Women are more prone to liver cystic involvement than are men. Liver cysts are not only recognized earlier but also are more numerous and larger in females than in males. In the United States, it was found that the number of pregnancies correlates with the number of hepatic cysts. In addition, previous use of estrogens was identified as a risk factor for harboring liver cysts. In postmenopausal women, a case-control study documented that a 1-yr course of Premarin is associated with a 7% increase in liver volume resulting from parallel changes of cystic and parenchymal volumes in the treatment group versus a -2% change in the control group (4). Whether use of nonequine estrogens, as is currently practiced in most European countries, carries a similar risk is not known. A minority of ADPKD patients develop massive cystic involvement of the liver. Most are women. Familial aggregation for massive liver cystic disease is rare. Symptomatic PLD may occur in very young women and contrast with the mildness of renal involvement. For instance, in our experience, summarized in 1997 and based on 37 ADPKD patients with massive hepatomegaly, 35 were females and only 1 of 110 ADPKD relatives had experienced symptomatic PLD (5). Median age at first hospitalization for liver symptoms was 46 yr (range, 23 to 64 yr), and renal involvement was extremely heterogeneous; 47% of the patients had serum creatinine below 120 μmol/L, 22% had moderate to severe renal failure, and 21% were on regular dialysis. In contrast to the North American data, we found that numerous pregnancies or use of estrogen-containing contraceptives as not a prerequisite for massive liver disease because four women (11%) had never used contraceptives and seven (20%) had never been pregnant. In summary, epidemiologic evidence suggests that a specific mutation is not implicated in the liver phenotype in most cases but that the latter is strongly influenced by the hormonal environment. Pathogenesis Before identification of the primary molecular mechanism of cystogenesis (see below), PLD was regarded as a disorder of the development of small intralobular bile ducts. Embryologic studies suggest an abnormality of remodeling of the ductal plate. Actually, liver cysts in ADPKD patients arise from two different structures. Intrahepatic cysts originate from biliary microhamartomas. The latter represent overgrowth of bile ductules. While growing, they become disconnected from the bile ducts from which they derive, although the epithelial lining retains the distinctive characteristics of biliary epithelia. These cysts are mostly located in the peripheral portions of the liver, exhibiting an intraparenchymatous location on contrast-enhanced CT. Their diameter varies from less than 5 mm to more than 10 cm. It is surprising that peribiliary glands that surround large intrahepatic bile ducts also undergo cystic dilation in polycystic patients (6). The corresponding cysts typically are tiny and are located in the hepatic hilum or surround the larger portal tract. Clonality in Liver Cysts and Lessons From Knockout Mice Basic research has generated relevant techniques and information regarding liver cyst formation and progression. Immortalized epithelial cell lines from normal human intrahepatic biliary epithelium and from ADPKD liver cysts is a valuable tool to determine how the function of the biliary epithelium is altered in ADPKD and how pharmacologic agents may prevent cyst development (7). The pattern of expression of polycystin-1 and polycystin-2 in liver cysts and kidney cysts is very similar. Most liver cysts stained positive, and there was a striking coincidence of expression of the two polycystins; for example, each polycystin-2—negative cyst in a PKD2 patient also lacked polycystin-1 (8). Inactivating somatic mutations have been found in liver cyst epithelia, like in renal cysts, supporting the “two-hit” model as a unifying mechanism of cystogenesis (9). Heterozygous mice with targeted mutations in Pkd1 (10) or Pkd2 (11) develop liver cysts that are indistinguishable from those found in ADPKD patients. In contrast, homozygous mice that die in utero or early in the postnatal period have a normal biliary system and no liver cysts, suggesting that Pkd1 and Pkd2 are required in the maintenance but not in the formation of biliary ducts. These homozygous mice have renal (and pancreatic) cysts, showing that as in human disease, liver cysts develop later in life than do kidney cysts. These results suggest that Pkd1± or Pkd2± mice provide a relevant model of the pathophysiology of ADPKD. Clinical Manifestations The risk of suffering a complication related to PLD is ill-defined. No accurate assessment of its prevalence is available. Fifteen years ago, in the predialysis era, very little attention was paid to liver complications, apart from sporadic complications mentioned in case reports. In a first attempt to delineate liver lesions in ADPKD patients on renal replacement therapy, we were impressed by the severity of hepatic complications. Hepatic cyst infection or cholangiocarcinoma was responsible for 10% of deaths, most occurring in patients on regular dialysis (12). In the most recent period, it was shown that liver complications have a limited impact on outcome and are less frequent on renal replacement therapy than expected on the basis of these early observations (2). A large experience in the management of massive PLD has accumulated in several surgical series. We have documented a trend toward earlier liver morbidity, as exemplified by younger age at hospitalization for liver complications (19 to 64 yr) and less severe renal involvement, with a 21% rate of patients on renal replacement therapy. Although recruitment bias may account for this trend, it is also possible that changes in the exposure to estrogens have modified the natural history of PLD. Acute Complications of PLD While most patients with polycystic liver have a “huge, silent, and durable liver” (12), those with PLD mostly complain of pain. Acute pain usually denotes acute complication (see Table 1). Right abdominal pain and fever in the ADPKD patient should prompt the physician to rule out infection of the right kidney and to consider infection of a liver cyst. Concurrent elevation of liver enzymes is often found in the latter. Approximately 50% of the infections are nosocomial and complicate percutaneous liver cyst fluid aspiration (5). Spontaneous infection predominantly affects patients on dialysis. Localization of the infected cyst(s) may be difficult. The physician has to rely on imaging techniques. The causative microorganism should be identified by blood culture or puncture of the suspected cyst. The physician should use a combination of antibiotics, relying on drugs with proven penetration in cysts, such as ciprofloxacin (13) or amikacin (5), and possibly ceftriaxone, which is concentrated in bile. Drainage is not a prerequisite, but if treatment with antibiotics fails, percutaneous drainage or hepatic resection should be considered (2, 13). Severe hemorrhage of liver cysts may present with symptoms that mimic those of an infected liver, but this complication occurs less frequently in our experience. Magnetic resonance imaging differentiates best the hemorrhagic liver cyst from the cyst with other complications, because it is associated with a hyperintense signal in T-1 and T-2 images. On very rare occasions, acute pain is associated with torsion or rupture of massive liver cyst with hemoperitoneum (14).Table 1: Liver complications in autosomal-dominant polycystic kidney diseaseChronic Complications: PLD and the Massive Polycystic Liver Chronic symptoms related to huge polycystic liver include abdominal heaviness or distension, and intermittent or continuous pain. Mechanical compression displaces adjacent organs, including gut, diaphragm, and abdominal wall, and is responsible for early satiety, dyspnea, abdominal hernias, and uterine prolapse. At the end of the spectrum, extreme disability, malnutrition, and physical exhaustion may be present. In contrast to progressive deterioration of renal function over decades, hepatic function remains unaffected whatever the size of the liver. This is ascribed to the preservation of liver parenchyma. Symptoms of liver failure should prompt investigation for a diagnosis other than PLD. However, in massive PLD, moderate increases in serum γ-glutamyl transferase or alkaline phosphatase ranging between 2 and 5 times the upper limit of normal range are noted in two thirds and half of the patients, respectively. Serum levels of aminotransferase or bilirubin are elevated in fewer than 20% of the cases. In addition, a poor nutritional status is not rare in these patients, as assessed by serum albumin and total cholesterol (5, 15). Complications Superimposed on Massive PLD Ascites and variceal bleeding are uncommon in the polycystic patient. The initial workup should include routine analysis of the ascitic fluid, when present, to rule out an infective process and endoscopic examination of the upper gastrointestinal tract. If portal hypertension is diagnosed, then three diagnoses should be considered (16). First, when few or no liver cysts are demonstrable in the patients before 30 yr of age, congenital hepatic fibrosis (see below) or liver cirrhosis should be suspected. Second, mechanical compression of portal venous flow by liver cysts may affect the main portal vein or intrahepatic portal radicles causing portal hypertension. In rare cases, variceal bleeding was the presenting symptom. Finally, when a huge cystic liver is present (Figure 1), hepatic venous outflow obstruction (HVOO) is the most likely diagnosis. In that case, obstruction is due to compression of hepatic veins or of the inferior vena cava or both by one or multiple cysts. At least 30 patients with PLD and HVOO have been reported, most of them in three series (5, 17, 18). Twenty-seven of them had polycystic kidneys. Ascites is exudative and intractable. The high protein content of the ascitic fluid has been ascribed to high permeability of the dilated sinusoidal walls to proteins. In rare cases, hepatic vein thrombosis may be superimposed. Histologically, extensive sinusoidal dilation is found. In addition, the lumen of small supralobular branches of the hepatic veins may be narrowed or occluded by organized thrombi (18).Figure 1: Contrast-enhanced computed tomography (CT) scan showing massive polycystic liver disease (PLD) with diffuse small cysts but a single large cyst and ascites in a 57-yr-old female ADPKD patient. Only the caudate lobe was spared. Serum creatinine was 105 μmol/l.How can one diagnose hepatic venous outflow obstruction? Doppler ultrasound and CT easily show compression of hepatic veins and the inferior vena cava by voluminous cysts in posterior location. Evidence of hepatic venous outflow obstruction can be obtained (1) by hemodynamic studies showing a pressure gradient across the site of obstruction, (2) by cavography demonstrating compression and collateral circulation (16), (3) or by evidence of hepatic vein occlusion. Magnetic resonance imaging assessment of and flow in the hepatic or portal veins as as the inferior vena cava in PLD patients is rare and suggests bile compression in the with the may be related to blood flow in the inferior vena cava as the of compression by a cyst. Acute hepatic vein thrombosis and have been after or in ADPKD patients hepatic failure has also been but the mechanism remains Complications to Liver Cysts Hepatic hepatic fibrosis is a of the form of has now been recognized in more than 20 patients with ADPKD. cases PKD1 families In contrast to renal cystic disease, of liver involvement was not in these but some were The molecular mechanism of such has not been In portal hypertension may be present in early or before yr of age. and variceal bleeding are If present, ascites is Liver cysts were detected in only two cases of may be associated with or diffuse cystic dilation of the segmental bile ducts which is by or Magnetic resonance treatment of portal including is in these patients. A few cases of cholangiocarcinoma have been identified (12). An of liver cysts and has been in two with ADPKD of Massive PLD advances in liver surgery and have been but the selection of the remains a challenge. It has become to liver size in the most severely patients, but surgery carries a is no the selection of the patients, the and the best of therapy. should the patient for the of and physical related to liver liver complications, and renal and physical should be Finally, and complications of surgery be with the patient. of aspiration should be with or to as a of fluid by the cyst is in half of the patients, and a attempt is in half of those with primary infection and or biliary of are the of the should be considered if a limited number than of large cysts have to be (Figure It usually Contrast-enhanced CT scan before and after of two liver cysts responsible for the In patients, may flow and pressure gradient as a of cyst compression in the portal or the portal venous and were used in two patients had to liver surgery and had variceal bleeding and respectively. vena cava has also been used (Figure showing compression of the inferior vena cava by a liver cyst at the of the hepatic A pressure gradient of was documented across the by the cyst. of the vena cava and of or of the cyst has been the treatment of symptomatic PLD It is mostly used for cysts. cysts in or location a of their (Figure In contrast, resection or is not for small cysts the which little of their For instance, 5 of patients by had multiple small cysts and experienced results ascites is the most of the cysts, fluid is the but it is Ascites occurs if the rate of the of the approximately in patients with normal renal of ascites is in patients with chronic renal failure, in ascites may follow a course. are to because they can may be is often suggest that or may be of by fluid from complications also include to blood or bile ducts adjacent to the of the cysts. For experienced liver is a therapy. in the symptoms in 23 to of cases has been performed in PLD include and fewer In the of patients experienced initial but symptoms in of them to later in patients in large cysts Contrast-enhanced CT scan of the showing few massive cysts in the right lobe of the liver in a female ADPKD patient with renal involvement. of the two cysts should be performed in symptomatic patients with few large cysts in size in posterior and with moderate renal failure creatinine of symptoms is usually is but is the the is because it and can be Liver Liver resection is more because cysts the of the liver. to the most cystic as assessed by CT An of three to four liver are usually by or resection has also been recently in cases in which cysts are located in the is then with of cysts. of cystic is by or in the of experienced liver liver resection in PLD carries a from series including at least patients suggest a mortality rate of to was in 37 to of cases, including biliary more or acute function is usually not by the surgical Liver function remains Most symptoms related to and in as as nutritional status ascites related to hepatic venous outflow obstruction may and ascites is frequent, in patients with severe renal failure or on In three of our patients, ascites only after with of the ascitic fluid in the venous the dialysis or after renal of liver resection in polycystic liver the patients experience (Figure early complications. In the series liver volume as by CT scan from to after liver resection liver volume in patients. However, we have of the liver in a as a of of cysts that required a resection yr after an initial was also in the of the patients on at the massive polycystic by small cysts is by liver resection than by patients with severe renal failure seem to be at risk of severe complications, we liver resection when serum creatinine is still below CT before and one after liver resection in a female ADPKD patient. For diagnoses other than PLD, and after liver and 70% in most renal failure before affects the quality of life is for most In the can be in a minority of patients. Liver is a for the of symptoms in massive PLD. It has been used in the treatment of PLD, because patients typically present with series of PLD patients by liver are patients, most had cystic were Before liver had PLD with severe of normal and half of the patients had cyst aspiration surgical A single patient with liver failure to chronic was performed in patients of was yr (range, to the patients, the 1-yr mortality rate was Most early 2 after and liver and was the of severe infections in patients was poor before patients and after transplantation. The rate as a of surgical complications was It was in patients in surgical procedures had been performed before of liver in autosomal-dominant polycystic kidney disease patients with polycystic liver a than the course of renal function after isolated liver in seven ADPKD patients in two and in patients. The decrease in rate was to 37 and three patients required to 5 The rate of was than expected in ADPKD patients These are with an early in rate that is found in liver do not have ADPKD, to 50% as early as after In the of ADPKD patients with accurate of renal function at is in only three were on regular and the patients had moderate to severe renal The for renal in PLD patients before renal failure has been was the that of A or the of renal function and the for dialysis In addition, kidney is in as with kidney as the liver the kidney from acute this an for in patients with PLD and renal It is to the renal after kidney are still present. the diagnosis of acute or thrombosis has been in such patients several against renal in PLD patients, at least when renal failure is still to liver should be considered in ADPKD patients with PLD when patients have diffuse cystic involvement and portal hypertension or poor liver function or when liver resection has or be used (Figure it should be performed before patients are in poor physical should be to patients with renal Contrast-enhanced CT scan of the in a female patient with ADPKD and massive polycystic liver disease with portal hypertension. compression and of the inferior vena cava but only renal cystic Liver was in symptomatic the and natural history of PLD in patients with ADPKD have been the 2 In the identification of and increase of the development and of liver cysts and to patients are at risk for an extreme liver In the for patient with massive liver cystic disease, it is to develop guidelines to the for liver resection and liver as as their