Biliary Strictures: Etiologies and Medical Management

Abstract

Biliary strictures have several etiologies that can broadly be classified into benign and malignant causes. The clinical presentation is variable with strictures identified incidentally on imaging or during the evaluation of routine laboratory abnormalities. Symptoms and cholangitis lead to imaging that can diagnose biliary strictures. The diagnosis and medical management of biliary strictures will be discussed in this article.

Biliary stricture is defined as an area of narrowing in the extrahepatic or intrahepatic biliary system resulting in obstruction of the antegrade flow of bile, upstream biliary dilation, and resultant pathologic sequelae of biliary obstruction. The clinical presentation is often variable; some patients present asymptomatically with strictures noted incidentally on imaging, while others present with symptoms such as jaundice and pruritus. Cholangitis can also occur and should be suspected in the setting of fever and abdominal pain.

Biochemical evaluation of biliary strictures classically shows a cholestatic pattern of liver injury with elevated alkaline phosphatase and total bilirubin, but in many cases liver chemistries can be unremarkable. The variability in presentation can make diagnosis of biliary stricture challenging, but as definitive treatment often entails major surgery, it is imperative for clinicians to recognize biliary strictures. In addition to making recognizing biliary strictures, it is equally important to identify the underlying etiology of biliary stricture ( Table 1 ). Biliary strictures have traditionally been classified as benign, malignant, or indeterminate, with malignant strictures being the most common (up to 70% of cases). ¹

Table 1. Etiologies of biliary strictures.

Malignant  Pancreatic adenocarcinoma  Cholangiocarcinoma  Ampullary cancer  Gallbladder cancer  Duodenal adenocarcinoma  Hepatocellular carcinoma  Lymphoma  Metastatic disease

Benign

Iatrogenic

Liver transplantation   Cholecystectomy   Pancreaticoduodenectomy   Radiation   Medications (chemotherapy)

Autoimmune

IgG4 sclerosing disease   Sarcoidosis   Eosinophilic cholangitis

Inflammatory

Chronic pancreatitis   Systemic mastocytosis   Langerhans cell histiocytosis

Infectious

Recurrent pyogenic cholangitis   AIDS cholangiopathy

Ischemia

Ischemic cholangiopathy   Vasculitis

Obstructive

Mirizzi syndrome   Portal cholangiopathy

Unknown

Primary sclerosing cholangitis

It is recommended that clinicians use a multifactorial approach in making the diagnosis, which involves reviewing biochemical results, imaging, and pathology findings. In this review, we will discuss the etiologies of biliary stricture, biochemical evaluation, and medical management.

Malignant Strictures

Malignant strictures are the most common, accounting for approximately 70% of all biliary strictures. ¹ Patients with malignant strictures typically present with nonspecific symptoms including weight loss, fatigue, night sweats, and abdominal pain. Given the high prevalence, it is important to thoroughly investigate for the presence of an underlying malignancy in any patient with a biliary stricture that cannot definitively be attributed to a benign cause.

Malignant biliary strictures can be caused by extrinsic bile duct compression from malignancy or can develop intrinsically, secondary to either a primary biliary duct malignancy or from metastases into the biliary ducts.

The most common cause of malignant biliary stricture is pancreatic ductal adenocarcinoma, a malignant epithelial tumor composed of mucin-producing glandular structures. Up to 70% of patients with pancreatic ductal adenocarcinoma have some degree of biliary stricturing at the time of diagnosis. ^{2 3} These patients typically present with jaundice, weight loss, and abdominal pain and frequently have a mass arising from the head of the pancreas that can be seen on magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), computed tomography (CT), or endoscopic ultrasound (EUS). ^{4 5} The classic radiographic appearance of pancreatic head tumors includes the “double duct sign,” which refers to the simultaneous dilation of both the pancreatic and common bile duct on imaging.

Cholangiocarcinoma, a highly proliferative malignant tumor originating from the bile duct epithelium, is the second most common cause of malignant biliary strictures. Due to the intrinsic nature of this malignancy, strictures occur in virtually all patients with cholangiocarcinoma. Cholangiocarcinoma is classified as intrahepatic, perihilar, or distal, of which perihilar accounts for 60 to 70% of cases. Perihilar cholangiocarcinoma can be further subclassified by location using the Bismuth–Corlette classification. ⁶ Patients with cholangiocarcinoma are usually asymptomatic in the early course of the disease and present later with jaundice, fatigue, and pruritus. Cholangiocarcinoma is common in the setting of primary sclerosing cholangitis (PSC) and often presents as a new dominant stricture. Up to 50% of patients with a diagnosis of cholangiocarcinoma will have had a new diagnosis of PSC within the preceding year. ^{7 8} Hence the level of suspicion for cholangiocarcinoma should be high in a patient with a recent diagnosis of PSC and a dominant stricture.

Other less common causes of malignant strictures include ampullary adenocarcinoma, gallbladder cancer, hepatocellular carcinoma (HCC), duodenal adenocarcinoma, or lymphadenopathy at the porta hepatis causing compression of extrahepatic biliary ducts, which can be seen in lymphoma or metastatic disease. ^{2 9 10} Metastatic disease can also cause stricturing by metastasis directly into the biliary ducts and is most frequently a consequence of gastric or colorectal cancers. ²

Benign Strictures

There are numerous causes of benign biliary strictures, most of which have subtle clinical presentations and are often incidentally identified on biochemical profiles or imaging. Etiologies of benign strictures can be subdivided into iatrogenic, autoimmune, inflammatory, infectious, obstructive, ischemic, or unknown causes.

Iatrogenic Strictures

Iatrogenic strictures are the most common, typically seen as a consequence of surgical manipulation of the biliary ducts during cholecystectomy, liver transplantation, or pancreaticoduodenectomy (Whipple procedure). They are often unrecognized until months to years postoperatively. ^{11 12} These strictures develop due to inadvertent biliary injury during the procedure, hepatic arterial compromise leading to ischemic cholangiopathy, or from stricturing at the anastomotic site. ^{13 14} Iatrogenic strictures can also develop as a consequence of prior radiation therapy or can be drug induced, commonly secondary to chemotherapy. ¹⁵ Chemotherapy-associated sclerosing cholangitis results from hepatic artery inflammation and typically involves the intrahepatic bile ducts. Culprit chemotherapeutic agents include 5-fluorouracil and bevacizumab.

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis is a progressive disease of unknown etiology that affects intrahepatic and extrahepatic biliary ducts and is characterized by inflammation and fibrosis that eventually leads to the development of biliary stricture and cirrhosis. Approximately 50% of patients are asymptomatic at the time of diagnosis. Up to 60 to 90% of patients with PSC are also found to have underlying inflammatory bowel disease such as ulcerative colitis. ¹⁶ Imaging shows multifocal intra- and extrahepatic biliary strictures with alternating areas of normal or minimally dilated segments, giving a “beaded” appearance on cholangiography. PSC also carries an increased risk of cholangiocarcinoma, with studies demonstrating a lifetime risk of anywhere from 10 to 15%. ^{17 18}

Chronic Pancreatitis

Chronic pancreatitis causing stricturing can account for up to 10% of all benign strictures and up to 5 to 46% of patients with chronic pancreatitis have biliary strictures. ^{19 20 21} Classically, the intrapancreatic portion of the common bile duct becomes fibrosed as a consequence of repeated episodes of pancreatic inflammation. Patients can be asymptomatic with stricturing incidentally noted on imaging or can present with cholestatic liver injury and right upper quadrant pain. However, it is thought that most strictures due to chronic pancreatitis are clinically insignificant. ^{19 22} EUS is necessary to rule out malignancy of the pancreatic head, however, especially if no lesion is seen on cross-sectional imaging.

IgG4-Related Sclerosing Cholangitis

IgG4-related sclerosing cholangitis is an immune-mediated disease characterized by lymphoplasmacytic infiltration of IgG4-positive plasma cells resulting in fibrosis and stricturing of the intra- and extrahepatic biliary ducts. ²³ Patients are typically older males who present with other manifestations of IgG4-related disease including autoimmune pancreatitis or salivary and lacrimal gland enlargement. Distal common bile duct stricturing is the most common biliary manifestation of the disease, and biopsies demonstrate IgG4-positive plasma cell infiltrate and periportal fibrosis. ^{23 24} Sarcoidosis and eosinophilic cholangitis are other rare causes of immune-mediated biliary strictures. ^{25 26}

Acquired Immunodeficiency Syndrome Cholangiopathy

Acquired immunodeficiency syndrome (AIDS) cholangiopathy was previously a common cause of benign biliary strictures; however, the incidence has decreased with the advent of antiviral therapy. ²⁷ It is typically seen in patients with a CD4 count less than 100 units and can be the presenting manifestation of AIDS. Cryptosporidium parvum is the most common isolated organism, accounting for 20 to 50% of cases. ^{28 29 30 31 32} Other opportunistic pathogens include cytomegalovirus, Cyclospora , Microsporidium , Histoplasma , Giardia , and Isospora . ^{29 30 31 32} Chronic inflammation from these pathogens leads to intra- and extrahepatic stricture formation.

Recurrent Pyogenic Cholangitis

Recurrent pyogenic cholangitis is another cause of biliary stricturing that is thought to be caused by infection. This disease is characterized by recurrent bacterial cholangitis caused by bile stasis and formation of stones within the intrahepatic bile ducts. The underlying pathophysiology is unknown but is believed to be due to malnutrition and biliary parasitosis from liver flukes or roundworms such as Ascaris . ^{33 34} Episodic inflammation from bacterial infection leads to scarring and fibrosis with resultant stricturing. Recurrent pyogenic cholangitis is more common in patients from South Asia and imaging demonstrates intra- and extrahepatic biliary dilatation and strictures with intraductal pigmented calculi, with the notable absence of gallbladder calculi. ³⁵

Ischemic Cholangiopathy

Ischemic injury to the bile ducts or ischemic cholangiopathy typically occurs due to hepatic artery compromise, as the hepatic artery is the sole blood supply to the major extrahepatic bile ducts. This commonly occurs post–liver transplantation but can also occur due to injury to vascular structures during bile duct surgeries or thrombosis due to a hypercoagulable state. ^{36 37} Prolonged ischemia results in the formation of biliary strictures and secondary obstructive cholestasis. A variant of ischemic cholangiopathy occurs in transplanted livers from organ donation after cardiac death (DCD). This can occur in up to 35% of DCD organ donor recipients and results in significant morbidity after liver transplant. ³⁸ Vasculitis can also cause stricturing through ischemia of bile ducts but is a rare cause of benign strictures. ³⁹

Mirizzi Syndrome

Mirizzi syndrome is a rare cause of biliary stricturing by secondary chronic inflammation that is caused by extrinsic compression of the hepatic duct from an impacted stone in the cystic duct or in the infundibulum of the gallbladder. ^{40 41} Patients typically present with right upper quadrant pain, fever, and cholestatic pattern of liver injury. A second obstructive cause of biliary strictures is portal cholangiopathy. This complication is typically seen with portal vein thrombosis and occurs when venous collaterals form as a consequence of portal hypertension and compress the large bile ducts leading to fibrinous and scarring. ^{42 43}

Indeterminate Strictures

Indeterminate strictures are defined as strictures without an associated mass on imaging that cannot be defined as benign or malignant after an endoscopic retrograde cholangiopancreatography (ERCP) with sampling has been performed. ⁴⁴ Given the prevalence of malignant strictures, indeterminate strictures must be closely monitored for features that may suggest a malignant etiology.

Evaluation

The evaluation of a suspected biliary stricture requires a stepwise approach that includes a combination of imaging and potentially endoscopic management. In addition to a basic laboratory evaluation, we suggest one such approach in Fig. 1 .

Fig. 1.

Proposed diagnostic workup of biliary stricture. EUS, endoscopic ultrasound; FNA, fine needle biopsy; MRI, magnetic resonance imaging; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; PTC, percutaneous transhepatic cholangiography. ^† Can include MRCP (magnetic resonance cholangiopancreatography), ERCP, or PTC. *Workup can include viral serologies, autoimmune markers, medication review, and liver biopsy.

Biliary strictures typically presents with a conjugated hyperbilirubinemia and elevated alkaline phosphatase. One of the major functions of the liver is bilirubin excretion. Within hepatocytes, unconjugated bilirubin is converted to conjugated bilirubin by uridine 5′-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase) and then transferred by a canalicular membrane transporter into bile. Consequently, obstruction of downstream bile ducts leads to increased serum levels of conjugated bilirubin and bile salts. The reabsorption of bile salts into the serum results in pruritus. Prolonged biliary obstruction with increased serum levels of conjugated bilirubin results in clinical jaundice. Relief of biliary obstruction often results in rapid resolution of pruritus; however, jaundice may persist for up to 14 days to covalent bonding of bilirubin to serum albumin. ⁴⁵

Alkaline phosphatase is an enzyme expressed throughout the body. A brief overview of elevated alkaline phosphatase is presented in Fig. 2 . In the hepatobiliary system, it is localized on the apical poles of hepatocytes and cholangiocytes. Under normal conditions, alkaline phosphatase is predominantly released from the apical membrane into bile, with smaller amounts being released from the basolateral membrane into plasma. When there is downstream obstruction of biliary ducts, there is increased enzyme synthesis by an unknown mechanism resulting in increased serum levels. In cases of diagnostic uncertainty regarding the origin of elevated serum levels, alkaline phosphatase isoenzymes can be checked to elucidate the source, as each specific site of alkaline phosphatase production has different carbohydrate and lipid side chains attached to the same amino acid backbone. Another approach to confirm the elevation of hepatobiliary origin is to measure gamma-glutamyl transpeptidase or 5′-nucleotidase, both of which rise along with hepatobiliary alkaline phosphatase. Serum alkaline phosphatase generally rises first in the setting of an evolving biliary obstructive process such as malignancy. ⁴⁶ As the degree of biliary obstruction increases, so will the serum bilirubin level. In the setting of acute or rapid biliary obstruction such as in choledocholithiasis, the serum bilirubin level will often rise first with a corresponding several-day delay in alkaline phosphatase. ⁴⁵

Fig. 2.

Workup of elevated alkaline phosphatase (Image courtesy of Ahsun Riaz, MD).

Aminotransferases such as aspartate aminotransferase (AST) can be markers of hepatocellular damage. Hepatocellular damage and elevated AST can occur due to severe cholestatic injury in the setting of biliary obstruction; however, this is thought to be mostly in the setting of obstructive stone disease rather than biliary strictures. ⁴⁷

Tumor markers, including carbohydrate antigen 19–9 (CA 19–9), carcinoembryonic antigen (CEA), and α-fetoprotein (AFP), are commonly used in the evaluation of suspected malignant strictures. CA 19–9 is a biomarker that is traditionally used for evaluation of pancreatic adenocarcinoma and has a 70 to 80% sensitivity and 82 to 92% specificity for pancreatic malignancy; however, it can also be used to evaluate for the presence of other malignancies including gallbladder cancer, cholangiocarcinoma, ampullary cancer, and hepatocellular cancer. ^{48 49 50 51} It should be noted that Ca 19–9 is increased in the setting of biliary obstruction regardless of etiology; hence, this result should not be considered in isolation. Other emerging biomarkers for pancreatic adenocarcinoma include CA 125, CA 50, macrophage inhibitory cytokine 1, and mucin 5AC (MUC5AC), which may be of use in the future as standalone markers or in combination with CA 19–9. ^{49 50 52 53}

CEA is another tumor marker that may be of utility in the evaluation of suspected metastatic malignant strictures. Typically used in the evaluation of colorectal malignancies, there may be some utility in evaluation of cholangiocarcinoma, particularly in those with PSC. An elevated CEA greater than 5.2 ng/mL had a sensitivity of 68% and a specificity of 82% in one study. ⁵⁴ Other studies have shown that CEA in combination with CA 19–9 may have a higher sensitivity and specificity for cholangiocarcinoma in patients with PSC. ⁵⁵

AFP can be used to evaluate for HCC, which is a less frequent causes of malignant strictures. An AFP cutoff of 20 ng/mL has a sensitivity of 41 to 65% with specificity from 80 to 94%. ⁵⁶ However, it should be noted that not all HCCs have an elevated AFP and an elevated AFP can be seen in pregnancy, tumors of gonadal origin, and chronic liver diseases such as acute or chronic viral hepatitis as it is released from hepatic progenitor cells.

There are several other emerging biomarkers under investigation, including mutations picked up in cell-free DNA, circulating proteins, and metabolites. These can be identified to aid in the diagnosis of malignant strictures, but results thus far have not been widely validated.

Medical Management

The treatment of both benign and malignant strictures mainly consists of mechanical alleviation of the stricture either through endoscopic or percutaneous approaches; however, there is a role for medications and other therapies in specific instances.

Ursodeoxycholic acid (UDCA), also known as ursodiol, has been a long-studied treatment of PSC. UDCA is a hydrophilic bile acid that naturally occurs in small amounts in human bile. The exact mechanism of action is not known and is likely multifactorial. Proposed mechanisms include stimulation of hepatobiliary secretion, inhibition of intestinal reabsorption of toxic bile salts, stabilization of hepatocytes against toxic bile salts, and inhibition of apoptosis and fibrosis. ^{57 58} In patients with PSC, doses of up to 15 mg/kg per day have been shown to significantly improve liver biochemical profiles but have not significantly shown mortality benefit or decreased need for liver transplantation. ^{59 60 61} High doses of UDCA ranging from 28 to 30 mg/kg per day also showed improved liver biochemical profiles but were associated with increased mortality and need for liver transplantation; the mechanism for these poor outcomes, however, is unclear. ⁶² Given the lack of data for UDCA slowing down the progression of disease, the American Association for the Study of Liver Diseases' practice guidelines recommend against the routine use of UDCA in the treatment of PSC. ⁶³

24- Nor ursodeoxycholic acid (norUDCA) is a side-chained reduced homolog of UDCA that is reabsorbed by cholangiocytes and concentrates in the liver. In an initial study, it has been shown to improve biochemical profiles, though further studies are ongoing. ⁶⁴

Among immunosuppressants, prednisone has shown to be of minor benefit in PSC. One study showed a decrease in pruritus and alkaline phosphatase, but no long-term benefit was shown. ⁶⁵ Methotrexate, a folate antagonist and adenosine agonist that inhibits cell proliferation and intracellular inflammatory pathways, has been shown to have a significant reduction in alkaline phosphatase in patients with PSC but showed no improvement in biliary stricturing or clinical outcomes. ⁶⁶ Tacrolimus, a calcineurin inhibitor, has also been shown to decrease alkaline phosphatase but showed no improvement in ERCP findings and was poorly tolerated in a more recent study. ^{67 68}

Finally, antibiotics may have a role in the treatment of PSC by altering the gut microbiome. Recent studies have shown improvement in alkaline phosphatase with courses of metronidazole in combination with UDCA in one trial and oral vancomycin alone in another; however, both had no effect on other clinical outcomes. ^{69 70}

Specific therapies for other causes of biliary strictures include both medications and other nonendoscopic therapies and can, in rare instances, reverse stricturing. Patients with severe ischemic cholangiopathy as a result of liver transplantation after cardiac death can be considered for retransplantation if meeting the following Organ Procurement and Transplantation Network (OPTN) guidelines within 12 months of transplantation: persistent cholestasis with a bilirubin greater than 2 mg/dL, two or more episodes of cholangitis with an associated episode of bacteremia requiring hospital admission, and evidence of nonanastomotic strictures that are nonresponsive to further treatment ⁷¹ In IgG4-related sclerosing cholangitis, a tapered course of corticosteroids can lead to reversal of stricturing and improvement in alkaline phosphatase. ^{72 73} Disease that is steroid dependent or refractory to steroids can show response to rituximab, a monoclonal antibody against CD20. ^{74 75} Mirizzi syndrome can be definitively managed by surgical exploration, cholecystectomy, and removal of the impacted stone. ⁷⁶ Portal cholangiopathy, which is defined as biliary obstruction due to biliary compression from the adjacent portal vein thrombosis and portal-systemic collaterals, has been managed by transjugular intrahepatic portosystemic shunt placement with portal vein recanalization. ^{77 78}

In addition to its use in PSC, UDCA is also indicated for the dissolution of cholelithiasis and is used in primary biliary cholangitis, intrahepatic cholestasis of pregnancy, liver involvement in cystic fibrosis, and progressive familial intrahepatic cholestasis. ^{58 79} Given that the proposed mechanism of action involves stabilization of hepatocytes against toxic bile salts and inhibition of apoptosis and fibrosis, UDCA is also used in the cholestatic period associated with both malignant and benign biliary strictures, as well as in the medical treatment of nonextractable choledocholithiasis. ⁸⁰ It should be noted, however, that UDCA is not approved for the treatment of biliary strictures and there are limited data on its efficacy outside of PSC.

Secondary Biliary Cirrhosis

Chronic obstruction of the biliary system from any cause can lead to the development of fibrosis within the liver and eventually cirrhosis. The obstruction of bile flow is associated with biliary interface activity and biliary necrosis resulting in portal inflammation which leads to fibrosis. ⁸¹ The time frame for development of cirrhosis can be highly variable depending on the etiology for biliary obstruction. Case series of unintended surgical ligation of the common bile duct demonstrates fibrotic changes within 1 month of ligation and cirrhosis at mean time of approximately 5 years. ⁸² Other causes for biliary obstruction have variable times to onset of cirrhosis with 7.1 years for common bile duct strictures, 4.6 years for choledocholithiasis, and 0.8 years for malignant biliary strictures. ⁸³

Conclusion

Biliary strictures pose diagnostic dilemmas to clinicians due to the wide variety of benign and malignant disease processes that can cause narrowing in the extrahepatic or intrahepatic biliary systems. It is important to take a stepwise diagnostic approach in patients presenting with jaundice and a cholestatic pattern of liver injury because most biliary strictures are malignant. While most biliary strictures are treated by mechanically alleviating the stricture by endoscopic or percutaneous means, medical management consists of treating the underlying disease process. Most medical options for managing biliary strictures exist for PSC and include UDCA, immunosuppressants, and antibiotics. Despite limited data, UDCA may have theoretical benefits in preventing hepatic injury in the setting of biliary obstruction.