Recurrent Pyogenic Cholangitis

Etiology

At the crux of this disease process is primary hepatolithiasis - the formation of multiple intraductal calculi without extrahepatic biliary obstruction. These are primarily brown-pigmented stones formed from calcium bilirubin, a product of increased rates of bilirubin deconjugation.[4] The exact etiology of this disequilibrium is unclear, and several mechanisms may play a part. Severe malnutrition is thought to result in deficiencies in enzymes such as D-Glucaro(1,4)lactone, an important beta-glucuronidase inhibitor responsible for inhibiting bilirubin deconjugation. With inhibition relatively unopposed, unconjugated bilirubin levels increase, leading to an increased propensity for calcium bilirubinate formation. Additionally, postulated is the role of helminthic infection.[5][6] 

Chronic infection with common helminths such as Clonorchis sinensis and Ascaris lumbricoides are thought to induce biliary epithelial inflammation, reduce host immune response, and subsequently increase susceptibility to ascending infection from translocating gut pathogens such as E.coli, Proteus, and Klebsiella.[7][8] Indeed, Ascaris ova have been observed at the center of calculi, suggesting a role in nidus formation. Both malnutrition and helminthic infection likely contribute to the strong association of RPC with low socio-economic status. An association is increasingly less relevant as prevalent regions in East Asia improve their economies and access to healthcare. In summary, RPC occurs due to hepatolithiasis, which stimulates a vicious cycle of recurrent bacterial infection, chronic epithelial damage, and ongoing biliary inflammation.[3]

Epidemiology

Specific statistics on worldwide rates of RPC are scarce. It is rare in the United States and West (prevalence < 2%), and the incidence is highest in immigrant populations from East and Southeast Asia. Disease prevalence is reported as high as 30% in East Asian and Southeast Asian regions with endemic helminthic infection.[9] This has likely decreased in the 21st century with higher access to healthcare, improved hygiene standards, and Westernization of diets. This disease affects women more than men, with increasing age beyond 50 years a risk factor. In one Korean study, the mean age of a patient at diagnosis was 59 years, with 71% of patients being female and 29% being men. Intrahepatic duct stones were present in 82% of cases in this study.[10] Data from Taiwan suggest that intrahepatic bile duct stones could be higher than 50%.[11] In 70% of those cases, there was the coexistence of intra and extrahepatic stones. These stones, made primarily of calcium bilirubinate, are responsible for developing RPC.[12]

Pathophysiology

RPC is primarily characterized by hepatolithiasis within the intrahepatic and extrahepatic bile ducts. These calculi, formed mostly by calcium bilirubinate, do not necessarily cause biliary obstruction (unlike cholesterol stones implicated in biliary colic) but initiate a cycle of inflammation and biliary stricture formation within a dilated biliary tree. This in itself exposes the biliary tree to ascending translocation of mainly coliform bacteria from the gut (such as E.coli), the process of which is responsible for the acute-on-chronic cholangitis presentation that RPC is known. The role of helminthic infection is unclear, but it is thought that chronic infection with trematodes such as Clonorchis sinensis and nematodes such as Ascaris lumbricoides aid the inflammatory process and dampen the immune response, allowing for further bacterial translocation, epithelial fibrosis and scarring, and subsequent stricture formation.[13]

Histopathology

One study examining autopsy findings of 46 patients who died of RPC showed the presence of either biliary sludge or brown pigment stones in every case. 80% showed evidence of liver abscesses, a common complication of chronic pyogenic cholangitis. Early histological findings included portal inflammation and pylephlebitis, whereas later findings included periductal fibrosis and stricturing.[14] The occasionally observed presence of liver fluke ova within brown pigment stones suggests that helminthic infestation may play a role in lithogenesis.[5]

History and Physical

Patients with RPC typically present on a spectrum of severity, ranging from mild symptoms in primary care to fulminant abdominal sepsis in the emergency department. Patients most often present with acute cholangitis, the symptoms of which include fevers, rigors, jaundice, vomiting, generalized abdominal pain, malaise, and pruritus. Charcot’s triad of fever, jaundice, and right upper quadrant pain is common but not always seen in its entirety. Recurrent similar presentations of acute cholangitis may be apparent, and patients may report a history of past biliary drainage procedures or endoscopic retrograde cholangiopancreatography (ERCP). Patients may also report being from or having lived in Southeast and East Asian endemic regions, such as Taiwan, Hong Kong, or Japan. Therefore, it is important to take a careful social history. 

During the later stages of the disease, patients may present with symptoms associated with complications of pyogenic cholangitis. For example, acute pancreatitis results in central rather than right upper quadrant pain, and bile duct perforation may result in an acute, peritonitic abdomen. In the case of cholangiocarcinoma, patients might present cachectic and malaised, reporting a history of weight loss and other constitutional symptoms.

Evaluation

A range of routine and specialized tests should aid clinicians in diagnosing RPC. These should be supported with careful history taking and comprehensive patient examination. Bloodwork should include a complete blood count, renal and liver function, coagulation studies, serum lipase, and peripheral blood cultures. The complete blood count may reveal microcytic anemia of chronic disease and neutrophilia. Raised urea and creatinine may be seen in more unwell, septic patients. Importantly, liver function tests are likely deranged with values consistent with obstructive pathology, namely raised gamma-glutamyl transferase, alkaline phosphatase, and bilirubin.[15] Blood cultures may grow common gut pathogens such as E.coli. Imaging has a major role in disease evaluation. Ultrasonography is the first-line bedside investigation of choice. Abdominal ultrasound in patients with PRC may show intrahepatic and extrahepatic biliary tree dilatation, more prominent in central than peripheral zones. Intraductal calculi may be visible; however, echogenicity is variable. Associated periportal echogenicity is often present.[16] Ultrasound is also useful for evaluating other findings consistent with more common diagnoses, such as a thickened gallbladder wall more consistent with acute cholecystitis, making diagnosing RPC less likely. However, a confusing picture can be seen with intrahepatic ductal dilatation but no extrahepatic ductal dilatation.

Abdominal computed tomography provides information similar to ultrasound, with the added benefit of less user dependence and more clearly visualizing other abdominal structures and associated potential pathologies. Computed tomography findings include intrahepatic and extrahepatic biliary tree dilatation (central > peripheral zones), hyperdense intraductal calculi (especially on unenhanced scans), biliary wall thickening, biliary stricture, and, in rarer cases, pneumobilia. Patients with later-stage disease may demonstrate hepatic parenchymal atrophy, most commonly in the left lateral segment. Magnetic resonance cholangiopancreatography is the gold standard non-invasive imaging modality for diagnosing RPC.[17] In addition to picking up the aforementioned findings, magnetic resonance cholangiopancreatography is superior to computed tomography or sonography in the visualization of intraductal calculi and bile duct strictures characteristic of pyogenic cholangitis. The “arrowhead sign” refers to a finding of reduced arborization of the peripheral biliary tree. A subtle cholangiocarcinoma could also be appreciated. Endoscopic retrograde cholangiopancreatography is an invasive procedure useful in diagnosing and managing RPC. It is covered under “Treatment/Management.”

Treatment / Management

The management of RPC requires a multidisciplinary approach involving emergency physicians, interventional radiologists, gastroenterologists, surgeons (general or hepatobiliary), and allied health professionals at each stage of treatment. Patients presenting acutely should be managed using a resuscitative A to E approach. This likely involves oxygen therapy, fluid resuscitation, correction of potential coagulopathy, and initiation of broad-spectrum antibiotics. Critical care support in fulminant sepsis should be utilized. Definitive treatment of RPC for those who do not respond to medical management comes in the form of biliary decompression. Initially, endoscopic retrograde cholangiopancreatography is used both to characterize the extent of disease (biliary tree ‘mapping’ for future procedures) and to provide therapy eg stone removal, sphincterotomy, or stent insertion for visible and accessible strictures for more distal obstructions. Percutaneous transhepatic cholangiography (PTC) is better for more peripherally obstructed ducts.[18] This decompression can buy time while further definitive management is planned, as it alone may not be sufficient due to extensive stone burden and stricture formation. If the disease is anatomically limited (typically to the left lobe), surgical resection of the involved liver, as well as the extrahepatic bile with reconstruction, should be undertaken.

Decompressive procedures may be required multiple times, and endoscopic ultrasound-guided drainage may be warranted, especially in those with concomitant hepatic abscesses, if surgical resection is not able to be performed.[19] Therefore, in patients with extensive common bile duct and common hepatic duct stricture formation, surgical anastomoses such as choledochoduodenostomy or hepaticojejunostomy may be indicated with the creation of an access loop for future biliary procedures. In severe cases where extensive hepatic parenchymal destruction or multiple abscesses are present or in the presence of cholangiocarcinoma, a partial hepatectomy may be considered. In these cases, cholecystectomy is often performed. One single-center study in India examined surgical outcomes in 94 patients with RPC.[20] Eighty-three percent of those who underwent primary surgery were deemed stone-free, with 81% remaining stone-free at a 3-year follow-up. Eleven percent of patients had disease recurrence. Another retrospective North American study of 42 patients with RPC over twenty years showed a reduced disease recurrence in patients who had undergone surgery (hepatectomies or bile duct explorations with or without access loop formation) when compared with nonoperative patients (15% compared to 36% respectively).[21] Major abdominal surgery is high-risk, and decisions about whether to operate should be taken using an interprofessional approach. Additionally, in very rare cases, a liver transplant could be considered in a case of diffuse bilateral disease.[18](B2)

Differential Diagnosis

The differential diagnoses for recurrent pyogenic cholangitis include the following:

• Cholangitis (acute ascending cholangitis) 
• Primary sclerosing cholangitis 
• Cholecystitis 
• Choledocholithiasis 
• Liver abscess (or pyogenic liver abscess) 
• Pancreatitis 
• Acute hepatitis
• Decompensated liver failure
• Cholangiocarcinoma 
• Biliary helminthiasis 
• Anastomotic stricture after biliary tract surgery

Surgical Oncology

Cholangiocarcinoma is a recognized complication of RPC. One retrospective study from Hong Kong sought to explore whether a cholangiocarcinoma diagnosis on an RPC background carried a worse prognostic outcome than cholangiocarcinoma without associated RPC.[22] Propensity score matching was used to compare post-hepatectomy outcomes in cholangiocarcinoma patients with and without a diagnosis of pyogenic cholangitis (n=143). It was found that a history of pyogenic cholangitis carried a significantly worse outcome for both disease-free survival and overall survival in this patient group.

Prognosis

Retrospective studies suggest that disease recurrence is common despite attempts at definitive treatment.[23] Some of the best outcomes for RPC are in patients who underwent hepatectomy as part of their treatment.[24] One study observed stone recurrence in long-term follow-ups in 31% of patients, and cholangiocarcinoma was observed in 5%.[25] Twenty percent of patients may eventually die from RPC and its associated complications, some of which are often terminal.

Complications

The complications that can manifest with RPC are as follows:

• Pancreatitis
• Acute kidney injury
• Septicemia 
• Disease recurrence 
• Liver abscess (pyogenic) 
• Portal hypertension
• Secondary biliary cirrhosis 
• Chronic liver disease 
• Cholangiocarcinoma