Continuing Education Activity

Recurrent pyogenic cholangitis describes a chronic infective process of the biliary tree, presenting primarily with recurrent attacks of acute bacterial cholangitis. This is a disease traditionally prevalent in South East Asia; however, due in part to global population migration, it can also be seen in North America and Europe. Due to its significant clinical overlap with other, more common types of cholangitis, it must be considered as a differential diagnosis where relevant. This activity outlines the evaluation and treatment of recurrent pyogenic cholangitis and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Explain the pathophysiology of recurrent pyogenic cholangitis.
• Describe typical presentation of a patient with recurrent pyogenic cholangitis.
• Summarize management considerations for a patient with recurrent pyogenic cholangitis.
• Review common complications of recurrent pyogenic cholangitis.

Introduction

Recurrent pyogenic cholangitis is a condition resulting from repeated infections of the biliary tree (cholangitis) first described in Hong Kong in 1930.[1] It can also be referred to as Oriental cholangiohepatitis, Hong Kong disease, Oriental infestation cholangitis, or hepatolithiasis.[2] Endemic to South East Asia, this disease is now seen worldwide due in part to increased population mobility and international travel. It is characterized by the presence of multiple intraductal calculi causing subsequent biliary tree dilatation and stricture.[3] 

Patients typically present with repeating episodes of acute cholangitis and beyond immediate management, are at greater risk of complications than more common types of cholangitis due to the chronicity of the disease. Given its significant overlap in clinical presentation with other causes of cholangitis, diagnosis of recurrent pyogenic cholangitis is challenging. It requires a multidisciplinary approach, including the emergency physician, gastroenterologist, surgeon, interventional radiologist, and histopathology amongst other specialists. This article seeks to review the etiology, epidemiology, pathophysiology, and outline the evaluation and treatment of pyogenic cholangitis and its potential complications and risks, as well as highlight the role of the healthcare team in managing patients with this condition.

Etiology

At the crux of this disease process is primary hepatolithiasis - the formation of multiple intraductal calculi in the absence of 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. It is thought that severe malnutrition results in deficiencies in enzymes such as D-Glucaro(1,4)lactone, an important beta-glucuronidase inhibitor responsible for the inhibition of 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 recurrent pyogenic cholangitis 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, recurrent pyogenic cholangitis 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 recurrent pyogenic cholangitis 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 the presence of 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 the development of recurrent pyogenic cholangitis.[12]

Pathophysiology

Recurrent pyogenic cholangitis is characterized primarily by hepatolithiasis both within the intrahepatic and extrahepatic bile ducts. These calculi, formed for the most part 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 cholangitic presentation that recurrent pyogenic cholangitis is known for.

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 recurrent pyogenic cholangitis 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 recurrent pyogenic cholangitis 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 (RUQ) 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 ERCPs. Patients may also report being from or having lived in endemic regions in Southeast and East Asia such as Taiwan, Hong Kong, or Japan, and it is therefore important to take a careful social history. 

During later stages of the disease, patients may present with symptoms associated with complications of pyogenic cholangitis. For example, acute pancreatitis will result in central rather than RUQ 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 be utilized to aid clinicians in making a diagnosis of recurrent pyogenic cholangitis. These should be supported with careful history taking and comprehensive patient examination. Bloodwork should including 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 will likely be deranged with values consistent with obstructive pathology, namely raised gamma-glutamyl transferase (gamma-GT), alkaline phosphatase (ALP), 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 recurrent pyogenic cholangitis may show intrahepatic and extrahepatic biliary tree dilatation, more prominent in central zones 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 that are consistent with more common diagnoses such as a thickened gallbladder wall more consistent with acute cholecystitis, making a diagnosis of recurrent pyogenic cholangitis less likely.  However, a confusing picture can be seen with intrahepatic ductal dilatation but no extrahepatic ductal dilatation.

Abdominal computed tomography (CT) provides similar information to ultrasound with the added benefit of less user dependence and more clearly visualizing other abdominal structures and associated potential pathologies. CT 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  (MRCP) is the gold standard non-invasive imaging modality for the diagnosis of recurrent pyogenic cholangitis.[17] As well as picking up the aforementioned findings, MRCP is superior to CT or sonography at 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 (ERCP) is an invasive procedure useful in both diagnosis and management of recurrent pyogenic cholangitis. ERCP will be covered under “Treatment/Management.”

Treatment / Management

The management of recurrent pyogenic cholangitis requires a multidisciplinary approach, involving the emergency physicians, interventional radiologists, gastroenterologists, and surgeons (general and/or hepatobiliary), as well as allied health professionals at each stage of treatment. In patients presenting acutely, they should be managed using a resuscitative A to E approach. This will likely involve 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 recurrent pyogenic cholangitis for those who do not respond to medical management comes in the form of biliary decompression. Initially, ERCP is used both to characterize the extent of disease (biliary tree ‘mapping’ for future procedures) and to provide therapy e.g. 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 (EUS) 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 looked at surgical outcomes in 94 patients with recurrent pyogenic cholangitis.[20] 

Eighty-three percent of those who underwent primary surgery were deemed to be stone-free as a result, 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 recurrent pyogenic cholangitis over a twenty-year period 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]

Differential Diagnosis

• 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 recurrent pyogenic cholangitis. One retrospective study from Hong-Kong sought to explore whether a diagnosis of cholangiocarcinoma on a background of recurrent pyogenic cholangitis carried a worse prognostic outcome than cholangiocarcinoma without associated recurrent pyogenic cholangitis.[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 recurrent pyogenic cholangitis are in patients who underwent hepatectomy as part of their treatment.[24] In one study, stone recurrence was observed in long term follow up in 31% of patients and cholangiocarcinoma in 5%.[25] Twenty percent of patients may eventually die from recurrent pyogenic cholangitis and its associated complications, some of which are often terminal.

Complications

Here are some of the complications:

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

Deterrence and Patient Education

Knowledge of risk factors is important to reduce the risk of recurrent pyogenic cholangitis. Those patients from endemic regions should be educated as to the symptoms and minimize modifiable risk factors, such as eating a nutritious and balanced diet to maintain a healthy weight. Liver fluke infections should be treated with antihelminthic drugs where appropriate to reduce the risk of chronic infection. Finally, those patients diagnosed with recurrent pyogenic cholangitis should seek medical assistance early to avoid severe disease sequelae.

Pearls and Other Issues

A recurrent pyogenic cholangitis is a rare form of cholangitis that presents very similarly to the more common acute ascending cholangitis. A careful history and attention to patient risk factors are critical to distinguish the two. Histopathology and nuances in advanced imaging results will also reveal valuable information that aids the diagnosis of this uncommon disease.

Enhancing Healthcare Team Outcomes

Recurrent pyogenic cholangitis, although rare, can present acutely with symptoms in keeping with acute ascending cholangitis. When severe, patients can present in a life-threatening condition. Specific guidelines for the management of acute recurrent pyogenic cholangitis do not exist per se, but guidelines for initial management of acute ascending cholangitis remain relevant given the clinical overlap. Management bundles such as these facilitate a standard approach to the disease across sites, encourage optimized local protocols, and provide a framework within which a clinician can provide excellent patient care. 

The Tokyo Guidelines (2018) are a series of management bundles for acute cholangitis and cholecystitis. They include a helpful stepwise approach to the management of acute cholangitis, taking into account the severity of presentation, as well as providing guidance on when to consider drainage procedures and transfer to more specialist centers. Frameworks such as the Tokyo Guidelines can improve patient prognosis if used appropriately. Still, it is important to be aware that advanced management of pyogenic cholangitis does differ from acute ascending cholangitis, so these guidelines should be used with care and by appropriately trained clinicians.[26][27]