Intrahepatic stone disease

Overview

Hepatolithiasis (intrahepatic stones) is defined as the presence of gallstones in the bile ducts peripheral to the confluence of the right and left hepatic ducts. These intrahepatic stones can simultaneously be present with stones in the common bile duct (CBD) and/or gallbladder. Hepatolithiasis, which is most prevalent in East Asia, is characterized by recurrent bouts of cholangitis and can lead to sepsis, biliary cirrhosis, and even death if not properly treated (see Chapters 43 and 44 ). Hepatolithiasis is also associated with intrahepatic cholangiocarcinoma (ICC; see Chapter 50 ). Although the incidence of primary hepatolithiasis has decreased as a result of urbanization in endemic areas, the prevalence of secondary hepatolithiasis associated with past biliary surgery has increased with recent increases in hepatobiliary surgery and increased long-term survival.

Hepatolithiasis can be diagnosed by ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). Direct cholangiography and three-dimensional CT are useful in deciding treatment strategies (see Chapter 16 ).

Treatment for hepatolithiasis can be divided broadly into partial hepatectomy and endoscopic treatment. Treatment must be tailored to each patient, depending on performance status, liver function, stone location, and liver atrophy. With liver resection, bile duct strictures can also be eliminated, so stone recurrence rates are generally lower. Although satisfactory stone removal rates can be achieved with endoscopic treatment, rates of clinical failure are higher if bile duct strictures are not completely resolved, which can lead to recurrent cholangitis and subsequent ICC. Hepatectomy can be performed when the disease is limited to the right or left hemiliver with ipsilateral atrophy. In patients with multiple bile duct strictures in both hemilivers, percutaneous transhepatic cholangioscopic lithotomy (PTCSL) with balloon dilation is generally applied to remove stones and treat biliary strictures (see Chapters 20 and 31 ). Bilateral hepatic resections may offer better stone clearance and a reduced risk of ICC because of effective clearance of the affected liver in selected patients. Hepatolithiasis requires careful management for the possible presence of ICC, even after stone clearance. Long-term follow-up for at least 10 years is recommended.

Epidemiology

Hepatolithiasis is commonly seen in East Asian patients, but the incidence varies, even among Asian countries ( Table 39.1 ). In Japan, the Ministry of Health, Labour, and Welfare organized a research group to evaluate the epidemiology of hepatolithiasis and improve outcomes. This research group has conducted nationwide surveys seven times in the past 40 years. Their studies revealed that the incidence of hepatolithiasis among all patients with gallstone disease has decreased from 3% to 1.8%. Although hepatolithiasis has largely been limited to Asia, the incidence has increased in Western countries as a result of more common worldwide travel and increasing Asian immigration.

Etiology

The etiology of hepatolithiasis is unknown in about 70% to 80% of cases. Intrahepatic stones are classified by composition into calcium bilirubinate or cholesterol stones (see Chapter 8 ). Calcium bilirubinate stones are predominant, representing about 75% of cases, whereas stones formed within the gallbladder are composed mainly of cholesterol, suggesting differences in the lithogenic mechanism of gallbladder stones.

Hepatolithiasis is thought to be generated by four factors: infection, bile metabolism changes, anatomic abnormalities, and bile stasis. ^, The higher incidence of hepatolithiasis in rural compared with urban areas also suggests that poor nutrition and environmental factors play additional roles. ^, In Japan, as the urbanization of society has advanced, the chance of bacterial contamination decreased, which may also explain the decreasing incidence of bile pigment stones. In fact, a decrease in the presence of bactibilia, from 92.1% in 1913 to 67.3% in 1961, has been documented. A survey conducted in the town of Kamigoto in Nagasaki Prefecture, an area in Japan with a high incidence of hepatolithiasis (about 30% of all gallstone diseases), reported that the expression of specific human leukocyte antigens—A26, B44, BW54, CW7, and DR6—was higher in patients with than in those without intrahepatic stones. However, the etiologic role of these genetic factors remains undefined.

Infection of the biliary tree has long been regarded as a cause of bile pigment stones. Maki and colleagues found increased β-glucuronidase activity in bile harboring bile pigment stones. ^, It has been suggested that the increased activity of β-glucuronidase caused by bacterial contamination may be an important factor in lithogenicity. Glucuronic acid–conjugated bilirubin, the major component of bile bilirubin, is water soluble. However, it converts to unconjugated bilirubin, which is less soluble, when hydrolyzed by β-glucuronidase, which may be derived from bacteria. It is thought that unconjugated bilirubin combines with a calcium ion in bile before being deposited as bilirubin calcium. Despite reports of an association between Escherichia coli and CBD stones in Western Europe, the incidence of intrahepatic stones remains very low, and therefore biliary infection alone is an unlikely cause of hepatolithiasis.

The presence of chronic biliary inflammation has been shown to accelerate stone formation via increased secretion of mucin core proteins (MUCs). In addition, in biliary tract infection, pathogen-associated molecular patterns, such as increased bacterial lipopolysaccharide and lipoteichoic acid, bind to Toll-like receptors on bile duct epithelial cell membranes. The production of inflammatory cytokines from biliary epithelium is also increased. This activates intracellular signal molecules and increases the expression of protein kinase, nuclear factor kappa B (NF-κB), MUC2, and MUC5. Tian et al. reported that neutrophil elastase can stimulate MUC5AC expression in human biliary epithelial cells. The increased secretion of mucin induces gel formation of bile and may accelerate bile stasis, leading to crystallization. Therefore these factors are considered to be associated with stone formation and chronic proliferative cholangitis (CPC).

This disease entity includes recurrent pyogenic cholangitis (see Chapter 44 ), which is endemic in Southeast Asia, as first reported by Digby and colleagues at Hong Kong University. Clonorchiasis (Clonorchis sinensis) , ascariasis (Ascaris lumbricoides) , and fascioliasis ( Fasciola spp.; see Chapter 45 ) can lead to inflammation of the biliary epithelium. Patients with clonorchiasis (C. sinensis) are usually asymptomatic when the number of flukes is small, but bile duct obstruction, suppurative cholangitis, and intrahepatic stones usually occur when 500 to 1000 flukes (hepatic distomiasis) are present because the parasite’s fragments or eggs can act as a nidus for stone formation. Fluke eggs in the feces or bile and peripheral blood eosinophilia are important diagnostic findings for this disease. The presence of hepatolithiasis in regions without endemic parasitic infection supports the concept that biliary parasites may not be regarded as a primary cause of hepatolithiasis.

In regard to bile metabolic changes, a feature of intrahepatic calcium bilirubinate stones is that, compared with calcium bilirubinate stones in the gallbladder and CBD, a relatively high cholesterol content has been reported. ^, Cholesterol in hepatic bile may result from relative cholesterol supersaturation because of increased cholesterol secretion from hepatocytes or to relatively decreased bile phospholipids and acids. Specifically, decreased phospholipid secretion leads to reduced cholesterol dissolution and easier formation of lithogenic bile.

Transporter proteins in the bile canalicular membrane are involved in secretion and thus may also be a factor leading to changes in bile composition (see Chapter 8 ). Multidrug resistance-associated protein 3 (MRP3), encoded by the ABCB4 gene, is involved in phospholipid secretion. MRP2, encoded by the ABCC2 gene, is involved in bilirubin excretion, and bile salt export pump protein (BSEP), encoded by the ABCB11 gene, is involved in bile acid secretion. Therefore the role these transport proteins play as membrane proteins leading to changes in bile composition and the development of hepatolithiasis has received increasing attention. Recent studies have revealed that a single nucleotide polymorphism of the ABCB4 and ABCB11 genes might affect the expression of pertinent transporter proteins. ^, Gan et al. (2019) reported that rs497692 and rs118109635 mutations affected translation of the ABCB11 gene, resulting in the downregulation of BSEP expression. Dysregulation of these transporter proteins may change the composition of bile and lead to cholestasis and cholelithiasis. These genetic changes could explain the different racial and regional distributions of hepatolithiasis.

Whether simple anatomic bile stenosis or bile stasis alone can cause stone formation remains unclear; however, biliary stenosis and bile stasis usually co-exist, and can cause a high rate of stone formation. Indeed, numerous studies have reported that biliary stricture and stasis are strong predictors of stone recurrence and cholangitis after treatment for hepatolithiasis.

Secondary hepatolithiasis

Secondary hepatolithiasis associated with past biliary surgery or congenital biliary malformation is an example of a case in which the etiology can be presumed. With recent increases in hepatobiliary surgery and long-term survival, secondary hepatolithiasis because of bilioenteric stenosis or duct-to-duct biliary anastomoses has increased ^, (see Chapters 32 and 42 ).

Congenital choledochal cysts (CCs), including those in Caroli syndrome, are well known for their anatomic features, which include dilation and strictures of the intrahepatic and extrahepatic biliary tract (see Chapter 46 ). Congenital CCs are associated with intrahepatic stones (12%–17% of adult patients), as well as a high incidence of biliary tract carcinoma (10.6%–20.3%). ^, Hepatolithiasis occurs in 3.5% to 23.5% of patients after flow-diversion surgery for congenital CCs. Bile contamination and anastomotic strictures resulting from hepaticojejunal (Roux-en-Y) anastomosis may be contributing factors, but much remains unknown about the mechanisms of onset. Type IV-A cysts are most commonly associated with cholangitis and intrahepatic stone formation. ^, Aota et al. (2018) reported a higher postoperative incidence of hepatolithiasis in Type IV-A than in Type I cysts (7/20 [35%] vs. 1/20 [5.0%], respectively). Because complete resection of the dilated left and right hepatic ducts is difficult in Type IV-A cysts, part of the dilated ducts often remains, possibly leading to bile stasis. In such instances, creating a wide anastomosis by extending the incision along the lateral wall of both hepatic ducts by common hepatic duct-plasty is often attempted to obtain a wide hepaticoenterostomy at the hepatic hilum.

In addition to the possible carcinogenesis related to long-term stimulation of the biliary mucosa by pancreatic juices, bilioenteric anastomosis itself may accelerate carcinogenesis as a result of irritation from contaminated bile, even in benign conditions (see Chapter 51 ). The risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital CCs has been reported to be 0.7% to 5.4%. ^, Indeed, the risk of biliary malignancy remains elevated, even more than 15 years after CC excision. Therefore long-term surveillance is important after hepaticojejunostomy for congenital biliary cysts because the risk of cancer is suspected to be doubled.

Bile duct stones, sludge, and casts, which represent bile duct filling defects, occur in approximately 5% of patients after living donor liver transplantation (LDLT), with the majority of such defects caused by stones (see Chapter 111 ). Because the anastomotic site is more peripheral to that in orthotopic liver transplantation, hepatic ducts at the anastomotic site are usually small and thin walled. Therefore anastomotic stricture is likely to occur more frequently in LDLT than in deceased donor liver transplantation. Persistent cholangitis caused by small stones is sometimes difficult to discriminate from T-cell–mediated rejection and drug-induced liver dysfunction. Because delayed diagnosis and treatments may affect both long-term graft and patient survival, early recognition and prompt treatment of intrahepatic stones after liver transplantation is essential.

Cholangiocarcinoma

The development of cholangiocarcinoma (CCA) in patients with hepatolithiasis is associated with poor outcomes (see Chapters 50 and 51 ). The incidence of CCA in patients with hepatolithiasis reported from Asian centers ranges from 2.1% to 15.6% ( Table 39.2 ). By contrast, hepatolithiasis is uncommon in Western countries, with a reported incidence of only 2.4%. ^{, , ,} Vetrone and colleagues (2006) found only one case with intramucosal adenocarcinoma of the extrahepatic bile duct out of 22 patients with hepatolithiasis who underwent surgical therapy. On the other hand, Tabrizian and colleagues (2012) reported a much higher incidence of concomitant CCA (7/30 [23.3%]) during a 14-year follow-up period. In addition, Al-Sukhni and colleagues (2008) reported identifying CCA in 5 (12%) of 42 patients during a 20-year study period. Guglielmi and colleagues (2014) prospectively collected a cohort of 161 patients with hepatolithiasis from five Italian tertiary hepatobiliary centers. From their database, 23 (14.3%) patients with concomitant ICC were identified. From the aforementioned reports, although the overall incidence of hepatolithiasis is low in Western countries, the incidence of CCA arising in conjunction with hepatolithiasis is similar when comparing Eastern and Western countries. Therefore hepatolithiasis needs to be carefully evaluated for the possible presence of ICC, even in Western countries.

Although the association between hepatolithiasis and CCA is well recognized, the exact mechanism of carcinogenesis remains unclear. Persistent inflammation because of cholangitis can cause repeated tissue damage and regeneration; this recurrent inflammatory process may lead to carcinogenesis. Hyperplastic epithelial cells often show a papillomatous or adenomatous pattern, which is frequently associated with the presence of stones. Ohta and colleagues (1991) reported that various degrees of hyperplastic biliary epithelium exist around impacted stones and are associated with CPC. Mucosal dysplasia accompanied by MUC and cytokeratin expression may be a precursor to CCA. Recent studies have suggested that multiple factors, including NF-κB, epidermal growth factor receptor, prostaglandin E ₂ , c-Met, and p16, are associated with cell proliferation, inflammation, and carcinogenesis.

However, no clear symptoms or clinical presentations have been reported to be associated with the presence of CCA in patients with hepatolithiasis. Therefore the possibility of co-existing CCA should be considered in all cases but especially in unusual presentations, such as weight loss, anemia, and intractable pain.

Some risk factors for ICC concomitant with hepatolithiasis have been reported ( Box 39.1 ). ^{, ,} Atrophic liver segments with persistent cholangitis are well-accepted risk factors. CCA is likely to be found in atrophic liver with obliterated portal flow. Therefore hepatectomy of an atrophic liver with intrahepatic stones and biliary strictures may reduce the risk of CCA.

Concomitant CCA has been reported to be a strong negative predictive factor for overall survival after hepatectomy for hepatolithiasis. Zhu et al. (2014) found that 107 of 2056 patients who had undergone surgical treatment for hepatolithiasis had CCA. Overall, the 5-year survival rate was 20.2%, and a subgroup of patients who had undergone potentially curative resection showed good 5-year survival (50.0%). However, only about 40% (38/97) of patients underwent curative resection; the other 60% underwent either palliative resection, radiofrequency ablation, or were not resected. Zhang et al. (2018) reported that patients with hepatolithiasis-associated CCA had worse long-term outcomes than those with conventional ICC. Five-year overall survival among patients with hepatolithiasis-associated ICC was 18.3% compared with 38.0% for those with conventional ICC.

It should be noted that subsequent ICC may occur even after primary treatment for hepatolithiasis. Chijiiwa and colleagues (1995) reported that among 85 patients with hepatolithiasis, 6 (7%) died of subsequent CCA during a mean follow-up period of 6 years. Cheon et al. (2009) also reported that the rate of late development of CCA in patients with intrahepatic stones during follow-up was 4.8% (11/225). More recently, Kim et al. (2018) analyzed Korean National Health Insurance data. Among the 7419 patients who had undergone liver resection for hepatolithiasis, subsequent ICC developed in 107 (1.98%). Table 39.3 shows the incidence of subsequent ICC (approximately 0.3%–9.1%) among patients with hepatolithiasis. ^{, , , , , ,} The mean interval from initial treatment to the development of CCA was 10.7 years (range, 6.6–19.7 years). Half of those patients developed CCA at a site different from the initial site of hepatolithiasis.

Regarding the risk factors for subsequent ICC, age older than 65 years and stone removal only as the initial treatment were significant risk factors for the subsequent development of CCA. Further, the study revealed that age older than 65 years and the presence of biliary strictures were significant risk factors for the development of CCA in patients with a history of bilioenteric anastomosis. On the other hand, in patients without a history of a bilioenteric anastomosis, left lobe location and stone recurrence were significant risk factors for the development of subsequent CCA. Although partial hepatectomy as the initial treatment was associated with a reduced risk of CCA, it did not reach the level of statistical significance ( P = .066). On the other hand, Kim et al. (2015) reported that subsequent CCA occurred with similar rates in patients treated with and without hepatic resection (6.3% vs. 7.1%, respectively). They emphasized that the presence of residual stones was the most significant risk factor for subsequent CCA regardless of the initial treatment; therefore hepatic resection is considered to have limited value in preventing CCA. Meng et al. (2017) reported that the presence of stone-affected remaining liver segments after initial hepatic resection was also a predictive factor for subsequent CCA.

Long-term outcomes of patients with subsequent CCA after treatment for hepatolithiasis are extremely poor. The mean interval from diagnosis of CCA to disease-related death has been reported to be 4 months, compared with 41 months for patients with concomitant CCA at the time of initial diagnosis. Based on a Korean national database, patients with subsequent CCA had very poor survival outcomes compared with those with concomitant CCA, with a median survival time of 0.9 years. Intensive follow-up is therefore mandatory, especially in patients with risk factors for subsequent CCA, such as residual stones, hepaticojejunostomy, and a remaining stone-affected liver segment.

Symptoms

Charcot’s triad of symptoms—abdominal pain, fever, and jaundice—occur in about 60% of patients with hepatolithiasis (see Chapter 43 ). These pyogenic cholangitis-related symptoms tend to recur over the long term. Severe cholangitis is sometimes concomitant with liver abscess and septic shock. Patients with septic shock often develop disseminated intravascular cholangiopathy. On the other hand, some patients with hepatolithiasis present without any symptoms. According to a Japanese survey, 20% of patients with hepatolithiasis showed no symptoms. In another study, 14 (11.5%) of 122 patients with asymptomatic hepatolithiasis developed symptoms during long-term follow-up. In difficult-to-treat cases, when stones cannot be completely removed or bile duct strictures are not eliminated, hepatolithiasis is likely to recur. Symptoms occur in patients with biliary cirrhosis because of chronic recurrent cholangitis; this often progresses to liver failure. Patients in whom CCA develops during follow-up often present with an abdominal mass, bloating because of ascites, and weight loss.