The etiology of primary hepatolithiasis remains not fully understood, but genetic, dietary, and environmental factors are thought contributing factors.

In Western countries PIL is strictly related to congenital bile duct dilatation with intrahepatic-only localization corresponding to Todani type V [4]. This entity was first described by Caroli et al. [5] in 1958 and later classified by Guntz et al. [6] according to the morphology and the extent of intrahepatic bile duct dilatations. A recent multicenter study conducted by the French Association of Surgery [7] has shown that prevalence of intrahepatic lithiasis in patients with Caroli’s disease is above 50 %, whereas in Eastern patients, it seems mainly related to biliary infestations and infections [8].

Typically there are two types of intrahepatic stones : calcium bilirubinate stones (brown pigment stones) and cholesterol stones. Calcium bilirubinate stones, mainly composed of bilirubin, cholesterol, fatty acids, and calcium, represent the majority of intrahepatic stones, whereas cholesterol stones comprise 5.8–13.1 % of all intrahepatic stones [2]. Pathogenesis of intrahepatic stones involves not only the precipitation of calcium bilirubinate, but also an altered cholesterol metabolism.

In addition bile duct stricture , either congenital or acquired, and infection with β-glucuronidase-producing bacteria play a key role in bilirubin precipitation and formation of calcium bilirubinate stones, which are mostly observed in Eastern countries [1, 2, 9]. Lower socioeconomic status and poor hygiene may be involved in the development of intrahepatic stones [10].

Recently, Shoda et al. [11] has shown that pathogenesis of intrahepatic cholesterol stones formation is based upon the dual defects of upregulation of cholesterol synthesis and downregulation of bile-acid synthesis in the liver, possibly in association with defective secretion of phospholipid by its canalicular transporter, multidrug resistance protein (MDR3). Metabolic factors, either acquired or congenital, act synergistically in the development of these intrahepatic stones [1, 12].

Some investigators have reported that anatomic variations of intrahepatic bile ducts can cause hepatolithiasis. Notably, hepatolithiasis is more frequent in the left than in the right lobe, and the acute angle which the left hepatic duct forms at the junction with the common bile duct (CBD), which tends to induce bile stasis when associated with biliary strictures, has been advocated as a key point for this higher rate [1] (Fig. 10.2). In the right lobe the duct of segment 6 alone or of the posterior sector seems the most frequently involved, and also in this case the anatomy of the junction of the ducts of these segment or sector could play a major role (Fig. 10.3). Furthermore, it was reported [13] that confluence of the right posterior bile duct into the left hepatic duct (Norman’s anomaly [14]) may also play a role in the development of PIL. However, in a recent comparative study between patients with PIL in Taiwan and Japan, anatomic variations of intrahepatic segmental bile ducts did not seem to play any important role in the pathogenesis of PIL [15]. Therefore, the role of anatomic variations of intrahepatic bile ducts in hepatolithiasis remains unclear, although in clinical practice in Western countries anatomic variations of intrahepatic bile ducts are frequently observed in patients with intrahepatic lithiasis (Fig. 10.4).

Abdominal pain , either in the right upper quadrant or in the upper abdomen, generally is the most frequent initial symptom. Symptoms of hepatolithiasis include cholangitis , jaundice, and acute pancreatitis. Other abdominal complaints, including abdominal discomfort and vomiting, may be observed. In asymptomatic patients hepatolithiasis may be an incidental finding on abdominal imaging; this occurs with increasing frequency due to the advances in diagnostic imaging modalities and the popularization of routine medical examination.

Most patients have a long history of previous biliary operative and nonoperative treatments and tend to have consequent recurrent pyogenic cholangitis as the most common clinical sign. Pyogenic cholangitis may cause further septic complications such as hepatic abscess and may ultimately result in limited parenchymal atrophy or secondary sclerosing cholangitis. Indeed, the most frequently observed clinical history of patients with PIL includes several endoscopic treatments by endoscopic retrograde cholangiography (ERC) for recurrent stones of CBD. Patients usually first undergo cholecystectomy and then present with recurrent CBD stones misdiagnosed as residual stones that migrated from the gallbladder. For this reason they usually undergo several endoscopic treatments of the CBD stones, frequently without any further complete investigation of all the intrahepatic biliary tree. Patients usually develop recurrent cholangitis which can evolve into intrahepatic abscesses. It is important to consider that after multiple endoscopic or percutaneous treatments and recurrent episodes of cholangitis and medical treatments, it is likely to find multiresistant bacteria into the bile ducts, which strongly influence subsequent clinical history of these patients and the results of treatment. This fact should be strongly emphasized and microbiological cultures of bile should be performed whenever possible from external biliary drainages (percutaneous biliary drainage, naso-biliary drainage).

The Hepatolithiasis Research Group in Japan has proposed a clinical grade classification to quantify the severity of hepatolithiasis [16]: Grade 1, absence of symptoms; Grade 2, abdominal pain; Grade 3, transient jaundice or cholangitis; and Grade 4, persistent jaundice, sepsis, or cholangiocarcinoma.

Late complications of hepatolithiasis include liver abscesses, pyogenic sepsis, parenchymal atrophy, persistent liver dysfunction resulting in secondary biliary cirrhosis, and cholangiocarcinoma . The latter two represent, therefore, the major risks in patients with intrahepatic lithiasis. It is presumed that chronic inflammation of the bile ducts by bile stasis, stones, and infestation with parasites can lead to adenomatous hyperplasia of the epithelium and subsequently to cholangiocarcinoma.

Hepatolithiasis is an established risk factor for intrahepatic cholangiocarcinoma (ICC) in Asian countries, with 2–10 % of patients with hepatolithiasis developing ICC [17]. The Korean, hospital-based, case–control study by Lee et al. found a strong association between hepatolithiasis and ICC, with an OR of 50.0 (95 % CI = 21.2–117.3) [18]. A Chinese, hospital-based, case–control study by Zhou et al. also showed a significant association, with the OR at 5.8 (95 % CI = 1.97–16.9) [19]. There are less data on the relationship between hepatolithiasis and ICC in Western countries, but a recent Italian multicenter study showed that prevalence of ICC in patients who underwent liver resection for intrahepatic lithiasis was 14.3 % [20].

Previous reports showed that bilirubin stones [21], irregular ductal stricture or obstruction, age over 40 years, a long history of hepatolithiasis with weight loss, high level of serum alkaline phosphatase, low level of serum albumin, high level of the serum carcinoembryonic antigen, and/or hepatolithiasis in the right or both lobes [22] were predictive factors for cholangiocarcinoma associated with hepatolithiasis. In a recent Japanese multicenter study, the authors showed that previous choledocoenterostomy and liver atrophy may increase the risk of developing cholangiocarcinoma [23].

Despite the high number of suspected risk factors, preoperative diagnosis of cholangiocarcinoma in these patients is usually difficult because hepatolithiasis and related periductal inflammation hinder clear visualization of bile ducts by imaging techniques; therefore, especially in patients with biliary strictures in whom is very difficult to rule out a malignant stricture with certainty, liver resection should always be considered, and the possibility to find a cholangiocarcinoma should always be kept in mind. Indeed the multicenter Italian study [20] showed that a preoperative suspected diagnosis of ICC was obtained in only 39.1 % of the patients initially evaluated for resection for intrahepatic lithiasis; in the other cases diagnosis of ICC was performed intraoperatively and postoperatively in 26.1 and 34.8 %, respectively. Therefore, the risk of the presence of cholangiocarcinoma in patients with longstanding PIL and of development of cholangiocarcinoma in young patients with PIL, or in patients treated for a long period of time by nonsurgical treatments (Fig. 10.5), should always be considered when choosing the treatment. In case of postoperative diagnosis at pathology of unsuspected cholangiocarcinoma, reoperation to perform more radical procedure (more extended parenchymal resection, resection of main biliary confluence, lymphadenectomy) if necessary should be also considered [24]. Furthermore, development of cholangiocarcinoma has been reported also in patients with previous liver resection for hepatolithiasis; therefore, patients resected for PIL should be carefully followed up for early detection of cholangiocarcinoma [25].

Treatment of PIL still remains particularly difficult and controversial. Several surgical, endoscopic, and percutaneous procedures have been reported in the literature, but high recurrence rates are often reported.