Recurrent pyogenic cholangitis

INTRODUCTION — Recurrent pyogenic cholangitis is a disease characterized by intrabiliary pigment stone formation, resulting in stricturing of the biliary tree and biliary obstruction with recurrent bouts of cholangitis. Various other names have been used since the first description in 1930 [1]. The lack of a uniform nomenclature complicates direct comparison of studies.

EPIDEMIOLOGY — Recurrent pyogenic cholangitis is found almost exclusively in people who live or who have lived in East and Southeast Asia [2-7], with reported disease prevalence as high as 30 to 50 percent [8].

Although considered rare in the West, the incidence had been increasing due to the immigration of people from endemic countries. However, with improvements in access to quality healthcare and standards in hygiene, as well as westernization of the diet, the incidence of recurrent pyogenic cholangitis in the 21st century is decreasing [9].

It occurs in equal frequency in males and females, with a peak prevalence in the third and fourth decades of life, although it can also be seen in patients over the age of 60 [10-13]. It is more common in the rural population and in lower socioeconomic groups.

PATHOGENESIS — Recurrent pyogenic cholangitis is characterized by recurrent cholangitis caused by bile stasis and stone formation proximal to biliary strictures. The pathogenesis of the stone formation and biliary abnormalities is incompletely understood. Stone formation occurs de novo within the intrahepatic bile ducts in contrast with the more common pattern of stone formation within the gallbladder seen in patients with more common forms of gallstone-related disease.

Transient portal bacteremia is thought to introduce bacteria into the biliary ducts, initiating a cycle of infection and secondary stone formation which lead to further obstruction and infection. Common organisms cultured from bile include E. coli, Klebsiella, Pseudomonas, and Proteus species and, less frequently, anaerobes, although the culture of multiple organisms is common [10,14]. Abnormal phospholipid metabolism has also been implicated [15]. (See "Inherited disorders associated with conjugated hyperbilirubinemia".)

The bile ducts are markedly abnormal, characterized by extrahepatic and intrahepatic ductal dilatation with focal areas of stricturing in the intrahepatic biliary tree. The biliary wall is fibrotic with inflammatory cell infiltration. The bile is purulent and filled with debris composed of bile pigment, desquamated epithelial cells, bacteria, and pus.

The left hepatic duct, especially the left lateral segmental duct, is usually affected in the early course of the disease, although stones may be present in the right and left hepatic lobes and the extrahepatic biliary tree [16]. The reason why the left ductal system is more commonly involved is unknown. A possible explanation may be that the left hepatic ducts come off at a more acute angle compared with the right hepatic ducts, thus predisposing to stasis and stricture formation.

There are often innumerable stones of varying sizes. The stones are mainly composed of calcium bilirubinate or brown pigment in contrast to the cholesterol stones more commonly seen in patients with other gallstone-related diseases. (See "Gallstones: Epidemiology, risk factors and prevention".)

Other changes that may be seen include hypertrophy of the papilla of the sphincter of Oddi as the result of repeated passage of stones, and enlargement and scarring of the liver with multiple capsular adhesions or deep subcapsular abscesses. The liver may eventually atrophy because of multiple episodes of infection and inflammation, leaving segments containing nothing more than fibrous tissue and dilated ducts.

ETIOLOGY — The etiology of recurrent pyogenic cholangitis is unknown, although many theories have been proposed. The observation that the disease occurs mainly in southeast Asia and among the rural, lower socioeconomic population suggests that environmental factors have an important role.

Parasitic infection — Geographic clustering of recurrent pyogenic cholangitis in regions where biliary parasites are endemic has implicated biliary parasitosis (mainly liver flukes and the roundworm Ascaris) in its pathogenesis. The three major liver trematodes or flukes that infect humans are Clonorchis sinensis, Opisthorchis species, and Fasciola hepatica. These organisms can cause epithelial damage and biliary obstruction, possibly initiating the disease [17].

●C. sinensis, also known as the Chinese liver fluke, is endemic in the East, particularly in China, Japan, Taiwan, Vietnam, and Korea. (See "Liver flukes: Clonorchis, Opisthorchis, and Metorchis".)

●The two species that most frequently cause human opisthorchiasis are O. felineus and O. viverrini. O. felineus occurs in southeast Asia and in central and eastern Europe, particularly in Siberia and other parts of the former Soviet Union. (See "Liver flukes: Clonorchis, Opisthorchis, and Metorchis".)

●Fascioliasis is infection caused by one of two liver flukes, either Fasciola hepatica or Fasciola gigantica. F. hepatica is more common and has a worldwide distribution, while F. gigantica occurs predominantly in the tropics. (See "Liver flukes: Fascioliasis".)

Ascaris lumbricoides, an intestinal roundworm, has also been implicated [12,18]. It is one of the most common helminthic human infections worldwide, infecting more than 1.4 billion people or 25 percent of the world's population. (See "Ascariasis".)

Despite the epidemiologic association, evidence supporting the role of these infections in the pathogenesis of recurrent pyogenic cholangitis is inconclusive. While these infections can be demonstrated in 20 to 45 percent of patients with recurrent pyogenic cholangitis , they are not uniformly present [10,13,14,18]. Furthermore, recurrent pyogenic cholangitis is relatively common in some Asian countries in which these parasites are not endemic. Certain areas of China, Taiwan, and Japan where the recurrent pyogenic cholangitis is relatively common are virtually free of Clonorchis infection [19].

Two possible explanations may contribute to the variable detection of parasitic infection in patients with recurrent pyogenic cholangitis . First, the prevalence of infection depends upon the sensitivity of the diagnostic testing being performed; the rigor with which infection was sought was variable among studies. Second, the infection may have resolved after initiating the disease without leaving detectable footprints of the inciting cause. In support of this hypothesis are studies in which the analysis of stones has shown debris and ova, which may have served as a nidus for stone formation [11,12].

Bacterial infection — Pigment stones seen in patients with recurrent pyogenic cholangitis may be caused by the action of bacterial glucuronidases, which produce unconjugated bilirubin from bilirubin glucuronide in the bile ducts. Insoluble calcium bilirubinate stones form when the unconjugated bilirubin complexes with calcium. Once the stones have formed, they may lead to a cycle of persistent obstruction predisposing to stasis and recurrent infection with additional stone formation.

The source of entry of bacteria is unclear. Some studies suggest bacteremia from a portal source originating from the lower intestine. Others suggest that the bacteria gain entry to the biliary tree as a result of injury from a parasitic infection [17,20-23].

However, it is uncertain whether bacterial infection is a cause or the result of the formation of stones, although at least one study suggested that infection followed the formation of stones [24]. Furthermore, recurrent bacterial infection in the biliary tree seen in other disorders does not lead invariably to stone formation. One possible explanation may be that patients with recurrent pyogenic cholangitis lack an inhibitor of bacterial glucuronidases present in normal bile [12,13,19,25-29].

Stasis — As noted above, it is generally accepted that stasis, stricturing, and recurrent infection contribute to the pathogenesis of recurrent pyogenic cholangitis [12,30-32]. Stricture formation has generally been considered to be a secondary occurrence from the repeated episodes of inflammation and healing. However, it is also possible that stone formation and recurrent infection occur as a result of biliary stricture formation. Animal experiments in which an incomplete stricture was produced around the terminal common bile duct caused formation of stones in the gallbladder and intrahepatic ducts even without evidence of bile infection [33,34].

CLINICAL MANIFESTATIONS — Patients typically present with recurrent bouts of cholangitis, characterized by Charcot's triad of right upper quadrant or epigastric pain, fever with or without rigors, and jaundice (see "Acute cholangitis: Clinical manifestations, diagnosis, and management"). Other complications related to passage of biliary stones (such as pancreatitis) have also been described. In a study of 41 patients, the most common presenting features were cholangitis (44 percent), abdominal pain without overt cholangitis (32 percent), and pancreatitis (17 percent) [35].

The diagnosis is established in only 15 to 30 percent of patients after symptoms first develop. Many patients have a history of recurrent symptoms for which they have not sought medical attention. Repeated attacks can lead to progressive damage to the bile ducts and liver parenchyma, which can result in formation of liver abscesses or cirrhosis.

Some patients may have a more fulminant presentation with a variety of complications. The recurrent attacks of cholangitis can lead to sepsis and abscess formation at distant sites, including the lungs and the brain [13,14]. Other potential complications include rupture of obstructed pus-filled bile ducts into the peritoneum or formation of a fistula into the gastrointestinal tract or abdominal wall [10,13,35]. Fistulization can also occur into the pericardium or vascular structures. Portal vein thrombosis and hemobilia have also been reported [13,14].

On physical examination, patients may be jaundiced. Epigastric and right upper quadrant tenderness and hepatomegaly may be present. Other physical findings reflect the occurrence of the specific complications noted above.

DIAGNOSIS — The diagnosis of recurrent pyogenic cholangitis is established by imaging of the liver and biliary system in patients with a clinically compatible history.

●A right upper quadrant ultrasound is a useful initial test; ductal dilation and stones can be seen in 85 to 90 percent of patients [12,36]. Hepatic abscesses can also be seen.

●More detailed information can be obtained from a computed tomography (CT) scan, which also complements cholangiography since cholangiography may not fully visualize segments of the biliary tree that are obstructed due to stricturing [10,12]. A variety of CT findings have been described, including dilated central intrahepatic ducts, abrupt tapering of peripheral ducts, enhancement of the duct walls, hepatic abscesses, bilomas, and stones (image 1) [37]. CT can also demonstrate whether the disease is localized (usually to the left lobe) and whether atrophy has developed. These are important considerations in determining a treatment plan.

●Cholangiography can be obtained by endoscopic retrograde cholangiopancreatography (ERCP) (image 2), magnetic resonance cholangiopancreatography (MRCP), or percutaneously (PTC) [38-43]. (See "Overview of endoscopic retrograde cholangiopancreatography (ERCP) in adults" and "Percutaneous transhepatic cholangiography in adults".)

An advantage of MRCP is that it is noninvasive and can provide detailed visualization of the extent of biliary involvement (which may not always be possible with ERCP or PTC if dye cannot be introduced into extensively strictured or occluded segments). Its major disadvantage compared with ERCP and PTC is that it does not permit therapeutic intervention. PTC is typically reserved for patients in whom biliary imaging cannot be obtained by ERCP or MRCP or in whom therapeutic intervention through the percutaneous tract is planned. Patients undergoing PTC or ERCP should receive prophylactic antibiotics because of the risk of inciting cholangitis and/or sepsis following manipulation of the bile ducts [38,44].

Cholangiography may reveal a variety of abnormalities, including intra- and extrahepatic duct dilatation, straightened intrahepatic ducts with less acute or right-angled branching patterns (as a result of extensive periductal fibrosis), and decreased arborization and acute tapering of the peripheral ducts [38,39,45]. This produces a classic "arrowhead" sign [38,39]. There may be a "missing duct" sign where there is complete obstruction of a bile duct.

All patients with newly diagnosed recurrent pyogenic cholangitis should have their stools checked for ova and parasites. As a general rule, liver biopsies are not helpful for diagnosing recurrent pyogenic cholangitis or for finding evidence of parasitic infection.

MANAGEMENT — The management of patients with recurrent pyogenic cholangitis should involve a multidisciplinary approach since endoscopic, surgical, and radiologic interventions may be required. There are two general considerations in the care of patients: treatment of acute complications such as cholangitis, and long-term prevention of complications.

Acute complications — Patients presenting with complications such as cholangitis should be treated appropriately with fluid resuscitation, antibiotics, and biliary drainage (see "Acute cholangitis: Clinical manifestations, diagnosis, and management"). However, in contrast with patients who develop cholangitis as a result of an impacted common bile duct stone, it may be more difficult to achieve drainage in patients with recurrent pyogenic cholangitis since multiple intra- and extrahepatic stones may be present. Stricturing, intrahepatic duct stone impaction, and ductal angulation can add further challenge to endoscopic intervention [46,47]. Nevertheless, in skilled hands, it may be possible to clear sites of biliary obstruction and achieve adequate drainage until more definitive therapy can be accomplished [38,39,48,49]. Acutely ill patients in whom adequate drainage cannot be achieved during endoscopic retrograde cholangiopancreatography (ERCP) will require percutaneous or surgical drainage. Surgery often involves cholecystectomy with common bile duct exploration and T-tube drainage.

Prevention of long-term complications — There have been two general approaches to the prevention of long-term complications in patients with recurrent pyogenic cholangitis. The first involves attempting to remove as many stones as possible with regular surveillance and intervention for stone recurrence. The second involves surgical resection of the affected hepatobiliary segment with a biliary-enteric anastomosis. Optimal strategies have not been well established in large comparative studies. For many patients, a combination of approaches may be required.

Clearance of stones — A variety of methods for clearing intrahepatic stones has been described, including endoscopic, percutaneous, surgical, and combined techniques. The choice among these should be guided by specific anatomic considerations in individual patients and the availability of local expertise.

Stones and infected bile can be removed using a choledochoscope (a small caliber endoscope) passed either percutaneously through the T-tube tract [50-52], through a hepaticocutaneous jejunostomy site [53], or via the transpapillary route during ERCP [54]. Multiple sessions are usually required. These approaches also permit dilation of intrahepatic strictures, and the fragmentation of stones that are difficult to remove with conventional means with the addition of mechanical, electrohydraulic, or laser lithotripsy (see appropriate topic reviews.)

The efficacy of combined approaches was illustrated in a study that focused on 190 of 245 patients in whom surgical choledocholithotomy failed to remove stones completely [55]. Patients subsequently underwent biliary dilation and stenting, performed through the T-tube tract, and then underwent choledochoscopy and electrohydraulic lithotripsy. Complete stone removal was achieved in 88 percent of these patients. Stone clearance is often difficult to achieve with these techniques in patients with right-sided stone disease and in those with anatomic abnormalities, such as sharp angulation of the biliary tree [56].

Stones recur in more than 30 percent of patients, even in those in whom they can be cleared completely [56,57]. The rate with which this occurs is variable but is more likely in patients with an intrahepatic duct stricture [52]. As a general rule, most patients should undergo periodic surveillance to monitor for stone recurrence. We usually accomplish this by obtaining serial right upper quadrant ultrasound examinations every three to six months initially, then less often based on clinical indication. Patients who develop recurrent symptoms undergo an ERCP, possibly with therapeutic intervention [35].

Whether the risk of stone recurrence can be decreased with ursodeoxycholic acid (UDCA) or other prophylactic measures (such as courses of antibiotics) is unknown. UDCA will have no significant effect on dissolving existing stones in most patients since they are composed predominantly of calcium bilirubinate, not cholesterol (see "Overview of nonsurgical management of gallbladder stones"). However, case reports have suggested a possible benefit from UDCA in patients in whom analysis of stone composition revealed cholesterol stones [58]. Despite the limited data, we usually add UDCA (20 mg/kg body weight per day) because it may increase bile flow, make bile less viscous, and reduce the likelihood of stone formation. Ursodiol increases bicarbonate rich bile flow in animal studies, and probably in humans as well [59-61].

Hepatic resection — Resection of the hepatobiliary segments that are considered to be the main source of complications may be feasible in the minority of patients in whom the disease is localized (typically in the left hepatic ductal system) [57,62-74], although bilateral partial hepatectomy has also been described [75]. The goal of surgery is to resect the area of recurrent infection, biliary stasis, and hepatic atrophy.

There have been no large controlled trials comparing hepatic resection with other management strategies. Most studies have been retrospective reports of patients followed in major centers in Asia over many years. As a general rule, these reports have suggested higher rates of residual biliary strictures and more frequent stone recurrence in patients who underwent percutaneous transhepatic cholangioscopic lithotomy without hepatic resection, even with completed stone removal, compared to those who had left lobectomy with a biliary drainage procedure [76-78]. Better quality of life, lower rates of secondary biliary cirrhosis, cholangiocarcinoma, and mortality have also been suggested in patients treated surgically [57,67,69].

Patients frequently require a biliary-enteric anastomosis (such as a hepaticojejunostomy), although the efficacy and safety of this approach remain controversial. Standard biliary drainage procedures (such as choledochoduodenostomy, Roux-en-Y choledochojejunostomy, or sphincteroplasty) are generally contraindicated since residual strictured biliary segments may not be drained adequately [79]. Case series have reported patients who have undergone successful orthotopic liver transplantation for decompensated cirrhosis and recurrent cholangitis from recurrent pyogenic cholangitis [80-82]. Long-term biliary access has been achieved by creation of a cutaneous stoma from a roux limb of a hepaticojejunostomy in some case series [53,83]. The following examples illustrate the results in some of the largest, English-language surgical series with the longest follow-up [57,62].

●A study from Taiwan focused on 380 patients treated surgically and 47 patients treated with percutaneous transhepatic cholangioscopy who were followed for 4 to 10 years [57]. The overall rate of recurrent stone formation was 30 percent. A repeated operation was required in 19 percent of patients. Patients treated with hepatectomy were more likely to be symptom free, had a lower rate of stone recurrence and mortality, and were less likely to develop secondary biliary cirrhosis or cholangiocarcinoma.

●Another series focused on 159 patients who underwent surgical treatment during a 23-year period in Japan [62]. A hepatectomy was performed in 60 percent while 40 percent had liver-preserving surgery by means of intra- and postoperative endoscopic lithotripsy. An hepaticojejunostomy was created in 72 patients (45 percent). Residual stones were present in 30 percent of patients, 30 percent of whom developed recurrent cholangitis. The rate of cholangitis was higher in patients who had undergone a hepaticojejunostomy compared with those who did not undergo a biliary-enteric anastomosis.

●A third series of 136 patients combined hepatic resection with lithotripsy performed during choledochoscopy [75]. A subset of patients (n = 54) underwent bilateral hepatectomy. Immediate stone clearance rates after bilateral and unilateral hepatectomy were 82 and 66 percent, respectively. Hospital mortality rates were 5.6 and 0 percent, while overall complicate rates were 46 and 46 percent, respectively. These observations support the feasibility of partial hepatectomy in patients with bilateral hepatolithiasis.

PROGNOSIS — The most common causes of death in patients with recurrent pyogenic cholangitis are sepsis, liver failure, or complications from cirrhosis such as portal hypertension. Patients are also at increased risk for cholangiocarcinoma. In the study of 427 patients with hepatolithiasis described above [57], 7 percent developed secondary biliary cirrhosis and 3 percent developed cholangiocarcinoma. Overall, disease-related mortality was 10 percent. In another report, cholangiocarcinoma occurred in 55 of 1105 Taiwanese patients (annual incidence of 5 percent) with hepatolithiasis seen during a three-year period [84].

One retrospective cohort study from Korea evaluated the natural course and risk of cholangiocarcinoma in patients with recurrent pyogenic cholangitis [85].

Of the 310 patients diagnosed with recurrent pyogenic cholangitis, acute cholangitis requiring hospitalization occurred in 41 percent, while chronic complications from liver abscesses, biliary cirrhosis, and cholangiocarcinoma occurred in 19, 10, and 7 percent, respectively. The risk of cholangiocarcinoma was noted in patients with liver atrophy, and tumors were mainly located in atrophied lobes. For patients who underwent hepatectomy, cholangiocarcinoma did not recur in those who had complete remission after surgery. The study highlights the importance of pursuing surgical measures in patients with high risk factors to prevent cholangiocarcinoma, such as patients with liver atrophy.

Another retrospective study that included 143 patients evaluated whether a diagnosis of cholangiocarcinoma on the background of recurrent pyogenic cholangitis carried a worse prognosis than cholangiocarcinoma without associated recurrent pyogenic cholangitis. The study used propensity matching to compare post-hepatectomy outcomes between cholangiocarcinoma with and without recurrent pyogenic cholangitis. They found that among patients with cholangiocarcinoma, those with a history of recurrent pyogenic cholangitis carried a significantly worse outcome in both disease-free survival and overall survival as compared to those without recurrent pyogenic cholangitis [86].

Cholangiocarcinoma should be suspected in patients with clinical deterioration (such as worsening jaundice and weight loss) or with unexplained increases in liver cholestatic measures (such as alkaline phosphatase). Tumors frequently arise in the atrophied left lobe of the liver. The benefit of screening patients for cholangiocarcinoma has not been established. One could consider routinely performing cytology brushings at the time of endoscopic retrograde cholangiopancreatography, although the yield is disappointingly low. (See "Clinical manifestations and diagnosis of cholangiocarcinoma".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Biliary infection and obstruction".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Recurrent pyogenic cholangitis is a disease characterized by intrabiliary pigment stone formation, resulting in stricturing of the biliary tree and biliary obstruction with recurrent bouts of cholangitis. Recurrent pyogenic cholangitis is found almost exclusively in people who live or who have lived in Southeast Asia. (See 'Epidemiology' above.)

●Etiology – The etiology of recurrent pyogenic cholangitis is unknown, although many theories have been proposed. (See 'Etiology' above.)

●Clinical manifestations – Patients typically present with recurrent bouts of cholangitis, characterized by Charcot's triad of right upper quadrant or epigastric pain, fever with or without rigors, and jaundice (see "Acute cholangitis: Clinical manifestations, diagnosis, and management"). Other complications related to passage of biliary stones (such as pancreatitis) have been described. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis is established by imaging of the liver and biliary system in patients with a clinically compatible history. (See 'Diagnosis' above.)

●Management – The management of patients with recurrent pyogenic cholangitis should involve a multidisciplinary approach since endoscopic, surgical, and radiologic interventions may be required. There are two general considerations in the care of patients: treatment of acute complications such as cholangitis, and long-term prevention of complications. (See 'Management' above.)