Patients with a variety of systemic diseases may present with clinical indications of biliary tract disorders. This article describes a group of systemic conditions associated with bile duct abnormalities and the role of endoscopic therapy in their diagnosis and management.
Key points
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Systemic illnesses can cause bile duct injuries and biliary tract disease.
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Biliary tract disease accompanying systemic illnesses is most often characterized by cholestasis, with or without clinical jaundice and mild liver enzyme abnormalities.
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Bile duct changes caused by immunoglobulin 4 cholangiopathy must be distinguished from pancreatic cancer and cholangiocarcinoma.
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Critical illness, regardless of cause, can cause bile duct injury mimicking sclerosing cholangitis.
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Acquired immune deficiency syndrome cholangiopathy is a bile duct disease of diminishing importance in the era of highly active antiretroviral therapy therapy.
Introduction
Biliary manifestations of systemic disease are common. Cholestasis causing clinical jaundice, hyperbilirubinemia, and nonspecific liver enzyme abnormalities are common sequels to systemic inflammatory and infectious conditions. Less often, but importantly, systemic illnesses cause more direct injury to the biliary tract ( Box 1 ). Endoscopic evaluations of these biliary tract involvements that complicate systemic illnesses are sometimes indicated and of proven therapeutic benefit.
Immunoglobulin G4 (IgG4) cholangiopathy
Sclerosing cholangitis in critically Ill patients (SC-CIP)
Acquired immune deficiency syndrome (AIDS) cholangiopathy
Cystic fibrosis
Sarcoidosis
Sickle cell disease
Graft-versus-host disease (GVHD)
Mycobacterium tuberculosis
Lymphoma
Histiocytosis X
Introduction
Biliary manifestations of systemic disease are common. Cholestasis causing clinical jaundice, hyperbilirubinemia, and nonspecific liver enzyme abnormalities are common sequels to systemic inflammatory and infectious conditions. Less often, but importantly, systemic illnesses cause more direct injury to the biliary tract ( Box 1 ). Endoscopic evaluations of these biliary tract involvements that complicate systemic illnesses are sometimes indicated and of proven therapeutic benefit.
Immunoglobulin G4 (IgG4) cholangiopathy
Sclerosing cholangitis in critically Ill patients (SC-CIP)
Acquired immune deficiency syndrome (AIDS) cholangiopathy
Cystic fibrosis
Sarcoidosis
Sickle cell disease
Graft-versus-host disease (GVHD)
Mycobacterium tuberculosis
Lymphoma
Histiocytosis X
IgG4-associated cholangitis
IgG4-related systemic disease (ISD) is a recently recognized, multisystem, fibroinflammatory condition characterized by IgG4-rich lymphoplasmacytic infiltration of affected organs and increased serum IgG4. Of the disease variants, autoimmune pancreatitis is the best studied. In 2001, increased serum IgG4 was described in patients with autoimmune pancreatitis (AIP). IgG4-related systemic disease has since been associated with effects in multiple organs. IgG4-associated cholangitis (IAC) is the biliary manifestation of ISD. Cases of biliary strictures that were previously reported in autoimmune pancreatitis and steroid-responsive biliary strictures were probably IAC related.
IgG4-associated cholangitis can resemble primary sclerosing cholangitis (PSC), cholangiocarcinoma, or pancreatic cancer and needs to be distinguished from these conditions so that unnecessary surgery can be avoided and appropriate medical therapy can be initiated. Patients with IAC are usually men in their sixth decade presenting with obstructive jaundice, weight loss, and mild abdominal discomfort. Coexisting inflammatory bowel disease should suggest the diagnosis of PSC rather than IAC. Alkaline phosphatase levels are usually 4 to 5 times the upper limit of normal (ULN) and are accompanied by increased total bilirubin and mild aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increases. Carbohydrate antigen (CA) 19-9 levels of more than 100 IU/mL usually indicate cases of cholangiocarcinoma rather than IAC.
Increased serum IgG4 is present at diagnosis in most (75%), but not all, patients with IAC. In contrast, less specific IgG4 increases can occur in patients with biliary strictures from other causes including PSC and cholangiocarcinoma. Increased IgG4 values (>140 mg/dL) are 64% to 78% sensitive and 88% specific in discriminating IAC from cholangiocarcinoma. Increasing the IgG4 cutoff value to more than 280 mg/dL decreases sensitivity to 34% to 50% and increases the specificity for the diagnosis of IAC to 97%.
The nonspecific cholangiogram findings in IgG4-associated cholangitis are shown by the results of cholangiography in a series of 53 patients described by Ghazale :
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Intrapancreatic biliary strictures resembling those seen pancreatic cancer (51%)
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Proximal extrahepatic biliary strictures resembling cholangiocarcinoma (9%)
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Intrahepatic biliary strictures resembling those seen in PSC (8%)
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Multifocal strictures with combinations of the first 3 findings (32%)
Findings from endoscopic transpapillary intraductal ultrasound that better distinguish IAC from cholangiocarcinoma include smooth outer and inner margins of imaged strictures and homogeneous internal echoes. The measured bile duct thickness in areas of normal-appearing (uninvolved) bile ducts seen by cholangiography can be of additional clinical importance. A duct wall thickness of 0.8 mm was 95% sensitive and 90.9% specific in differentiating IAC from cholangiocarcinoma, and a wall thickness of 1 mm was 85% sensitive and 100% specific for IAC.
The diagnosis of IgG4 cholangiopathy cannot be established by endoscopic retrograde cholangiopancreatography (ERCP) alone. The occasional finding of IgG4-positive cells in cases of PSC and cholangiocarcinoma limits this finding’s ability to establish or confirm a diagnosis of IAC. In IAC cases, ERCP serves an adjunctive and complimentary role to other diagnostic methods. Ampulla of Vater and transpapillary bile duct biopsies in patients with IAC often do not show classic histologic findings. The presence of IgG4 immunostained cells (>10 stained cells/high-power field) and absence of malignant cells support a suspected diagnosis of IAC. Biopsies from both the ampulla and bile duct increase the probability of finding IgG4-positive cells. Kawakami and colleagues showed that 21 of 29 (72%) patients had more than 10 IgG4-positive cells in at least 1 biopsy specimen.
An algorithm has been suggested for diagnosing and managing IAC using the HISORt (histology, imaging, serology, other organ involvement, response to steroid therapy) criteria ( Table 1 ). Patients with unexplained biliary strictures are considered to have IAC when core biopsies or surgical specimens from biliary or pancreatic tissues show features of IAC or AIP. Unexplained biliary strictures with classic imaging findings of AIP plus increased IgG4 results also confirm a diagnosis of IAC. The diagnosis of IAC is probable in patients with unexplained biliary strictures when 2 or more of the following conditions are present: (1) increased serum IgG4, (2) pancreatic imaging suggesting AIP, (3) the presence of other organ involvement with IgG4-related disease, or (4) bile duct biopsy showing more than 10 IgG4-positive cells/high-power field. In this group of patients, the diagnosis of IAC is confirmed by response to steroid therapy.
| Feature | Characteristic |
|---|---|
| Histology of the bile duct | Lymphoplasmacytic infiltrate with >10 IgG4-positive cells/hpf within and around the bile ducts with associated obliterative phlebitis and storiform fibrosis. See text regarding bile duct biopsy specimens |
| Imaging of the bile duct | One or more strictures involving intrahepatic, proximal extrahepatic, or intrapancreatic bile ducts |
| Fleeting/migrating biliary strictures | |
| Serology | Increased IgG4 |
| Other organ involvement | Pancreas: imaging or histology consistent with AIP or suggesting AIP |
| Retroperitoneal fibrosis | |
| Renal involvement | |
| Salivary/lacrimal gland enlargement | |
| IgG4 immunostaining of involved organs shows ≥10 IgG4-positive cells/hpf | |
| The presence of IBD suggests PSC rather than IAC | |
| Response to steroid therapy | Improvement of liver tests and biliary strictures |
Clinical response, indicated by lessening of bile duct strictures, is expected in patients with IAC treated with steroids ( Fig. 1 ). Nonresponse in patients with suspected IAC indicates the possibility of a different diagnosis that most often includes pancreatic or biliary malignancy. Biliary stent placement before steroid therapy can lead to more rapid resolution of symptoms and allow ERCP with possible stent removal after 6 to 8 weeks of steroid treatment. Relapse of disease can occur with steroid withdrawal and is more common in patients with proximal strictures. Maintenance therapies with azathioprine and mycophenolate mofetil have been described. Overall, the prognosis for treated patients with IAC seems to be good, although long-term studies proving efficacy are lacking.
Sclerosing cholangitis in critically ill patients
Sclerosing cholangitis in critically ill patients (SC-CIP) is a secondary sclerosing cholangitis seen in severely ill patients without biliary obstruction, PSC, or other preexisting biliary diseases. A wide array of underlying disease processes in the critically ill are associated with this condition, including severe pneumonia, bacterial sepsis, polytrauma, and burn injuries. Affected patients, regardless of the type of critical illness, commonly require prolonged intensive care unit confinements, mechanical ventilation, and vasopressor support. There are no specific patient demographics with regard to age or sex associated with SC-CIP; in one report, patients with SC-CIP ranged in age from 16 to 73 years.
The pathogenesis of biliary duct damage in SC-CIP is thought to be secondary to ischemic injury. The intrahepatic bile ducts receive blood exclusively from the peribiliary vascular plexus and are highly sensitive to ischemic injury. Arterial hypoperfusion related to severity of illness may cause ischemic injury of the bile duct epithelium, which in turn may lead to biliary cast formation ( Fig. 2 ) and SC-CIP. Gelbamann and colleagues performed chemical analyses on biliary casts from patients with SC-CIP, and protein, presumably from necrotic biliary epithelium, was the main component.
Cholestasis of SC-CIP is generally noticed within the first 1 to 2 weeks after the initial physiologic insult and injury. Early in development, SC-CIP can be difficult to differentiate from sepsis-associated cholestasis. SC-CIP is a progressive disorder, whereas sepsis-associated cholestasis typically resolves with recovery from the underlying condition. Marked increase of serum alkaline phosphatase is the most prominent laboratory abnormality in this condition, with levels commonly more than 1000 U/L and usually associated with clinical and laboratory evidence of jaundice. Mild increases 2 to 3 times the ULN of AST and ALT are typical.
In patients with SC-CIP, ultrasound with Doppler should be performed to evaluate patency of the hepatic artery and to exclude hepatic or portal vein thrombosis. Ultrasound examinations are otherwise not helpful in diagnosing SC-CIP. Bile duct obstruction causing dilatation in SC-CIP is unusual. Magnetic resonance cholangiopancreatography (MRCP) showed intrahepatic strictures in a small series of SC-CIP cases.
ERCP plays a key role in diagnosing SC-CIP. Dynamic cholangiogram findings can worsen with disease progression ( Box 2 ).
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Intrahepatic bile duct cast formation leading to intraductal filling defects early in disease course
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Multiple irregular intrahepatic biliary strictures of variable degree occurring several weeks after onset of cholestasis
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Advancing rarefaction of small bile ducts and progressive sclerosis several months after onset of cholestasis
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Dominant strictures of the right or left hepatic ducts
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Common bile duct (CBD) is generally unremarkable except in cases of filling defects from biliary casts migration
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Biliary casts resembling intrahepatic ductal system
ERCP also has a therapeutic role for patients with SC-CIP, allowing dilation and stenting of strictures. Multiple sessions of ERCP are sometimes required. Extracting biliary casts ( Fig. 3 ) and debris by balloon catheter or Dormia basket results in clinical and biochemical improvements with decreasing bilirubin and alkaline phosphatase. Nasobiliary drainage and saline lavage do not remove biliary casts from smaller intrahepatic ducts inaccessible to endoscopic intervention.
Failure of endoscopic therapies to improve SC-CIP predicts poor outcomes. In long-term follow-up of 29 patients with SC-CIP, 19 patients died, 3 patients required orthotropic liver transplantation, 4 patients were registered for transplantation, and 3 patients showed signs of severe cholestasis. Ursodeoxycholic acid (UDCA) used in combination with endoscopic treatments may transiently improve the clinical course but does not seem to affect progression. Prescription of UDCA in 16 of the 29 patients followed longitudinally was thought to be of limited efficacy.
AIDS cholangiopathy
Biliary manifestations in patients with AIDS were first described before the advent of highly active antiretroviral therapy (HAART). The associated type of secondary sclerosing cholangitis was initially classified as AIDS-related sclerosing cholangitis and later as AIDS cholangiopathy. In a report of 3 patients with AIDS and biochemical evidence of cholestatic liver disease, all 3 patients had stenosis of the distal CBD and irregularity of the intrahepatic bile ducts. A larger series later described variable ERCP findings in 26 patients with AIDS and suspected biliary tract disease.
In contemporary patients, the diagnosis of AIDS cholangiopathy should be considered in untreated human immunodeficiency virus (HIV) disease and unexplained cholestasis. HIV-infected patients with AIDS cholangiopathy usually have low cluster of differentiation 4 (CD4) counts and evidence of opportunistic infection. CD4 counts are typically less than 200 × 10 6 /L and most patients have a CD4 count less than 50 ×10 6 /L. Multiple opportunistic infections, most commonly by Cryptosporidium and cytomegalovirus species, are implicated as causes of AIDS-associated cholangiopathy.
Patients with AIDS cholangiopathy present with complaints of right upper quadrant and epigastric pain. Fever is present in approximately one-half of patients. Liver profiles reflect cholestasis but clinical jaundice is rare. The most striking laboratory abnormality is a marked increase of serum alkaline phosphatase to 6 or 7 times the ULN. Serum transaminases are typically increased only 2 to 3 times the ULN.
Noninvasive imaging by ultrasound is the initial study of choice in evaluating patients with AIDS and suspected bile duct injury. Ultrasound findings include minimal to marked dilatation of the intrahepatic and extrahepatic bile ducts, and thickening of the CBD wall. A normal transabdominal ultrasound should not, however, preclude further imaging and diagnostic considerations in patients with suspected bile duct disease, because ultrasound examination fails to show biliary abnormalities in 11% to 28% of cases. MRCP and endoscopic ultrasound (EUS) were not available during the early descriptions of AIDS cholangiopathy so reports of MRCP and EUS findings in these patients are lacking.
Since the early reports of the disease, ERCP has been the predominate mode of bile duct study used to confirm a diagnosis of AIDS cholangiopathy. Cholangiogram results can be categorized into 4 major findings, described in Box 3 . Papillary stenosis with intrahepatic ductal irregularities resembling sclerosing cholangitis is the most common finding, occurring in approximately 50% to 70% of cases ( Fig. 4 ).
Related posts:
Endoscopic Advances in Biliary Disease
Pre-ERCP Imaging of the Bile Duct and Gallbladder
Endoscopic Evaluation of Bile Duct Strictures
Endoscopic Management of Benign Bile Duct Strictures
Endoscopic Ultrasonographic Access and Drainage of the Common Bile Duct
Endoscopic Management of Acute Cholecystitis
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