At this time, there is no established medical treatment for patients with PSC.
UDCA has been the best studied of a number of potential treatments. A study of 105 patients using the dose of UDCA appropriate for patients with primary biliary cirrhosis (13–15 mg/kg/day) did show biochemical improvement but lack of evidence of clinical improvement (25). Subsequently, somewhat higher doses were tested and potential benefit was identified (43, 44). A large trial, which was nevertheless under enrolled, was reported from Scandinavia using a dose of 17–23 mg/kg/day. Biochemical improvement and important trends in clinical improvement were seen (45). The study enrolled only 63% of patients planned by power calculations; thus, the results were inconclusive. Recently, a large trial using a high dose of UDCA of 28–30 mg/kg/day was tested (46). Unfortunately, in this study the patients receiving the drug fared worse when compared with placebo, with substantially more adverse clinically important outcomes such as the need for transplantation and the development of varices. More recently, high doses of UDCA have been associated with an increased risk of colonic neoplasia in the settings of PSC and ulcerative colitis. At this point, no indication exists for using the higher doses of 28–30 mg/kg/day of UDCA (42).
More recently, several studies have shown that patients with PSC, who normalize liver biochemistries, whether this occurs spontaneously or more often with UDCA therapy, have a better prognosis. This has led some to revisit the issue of UCDA treatment for PSC; many practitioners are using a dose of ˜20 mg/kg/day, although data from well-controlled clinical trials are lacking (47, 48, 49).
Other treatments that have been tested without any obvious proven clinical benefit or improvement of liver biochemistries include:
There are case series data and anecdotal reports that oral vancomycin has been associated with marked improvement in clinical symptoms and liver biochemistries in some patients, in particular in the pediatric age group (63). No randomized clinical trials of antibacterial therapy have been performed to date. This is a promising area for future study.
Biliary obstruction in PSC may develop at all levels of the biliary tree, from microscopic biliary ductules to the extrahepatic bile ducts, but endoscopic therapy is feasible only for the larger bile ducts. ERCP is reserved for patients with significant bile duct strictures localized to the extrahepatic and large intrahepatic bile ducts, which are described as dominant strictures. For selected patients with dominant strictures, endoscopic intervention relieves the complications of pruritus and cholangitis, allows early diagnosis of cholangiocarcinoma, and may lead to improved survival.
At cholangiography, dominant strictures are defined as stenoses measuring <1.5 mm in the common bile duct or <1.0 mm in the hepatic ducts (73). Dominant strictures are common at the initial clinical presentation of PSC and frequently will develop over the course of the disease. In a retrospective study of 125 patients, a dominant stricture was detected in 56/125 (45%) of patients at time of diagnosis (74). By following patients over a median of 7.1 years, another retrospective study demonstrated the development of new dominant strictures in 77/151 (51%) patients (75). Advancements in therapeutic endoscopy for PSC have focused on dominant strictures, because they are common and potentially amenable to endoscopic therapy by ERCP.
Endoscopic treatment of dominant strictures offers clinical benefit with diminished symptoms of pruritus or cholangitis, reduced cholestasis, and measureable improvement of strictures radiologically. The studies that reported these outcomes have been relatively small, uncontrolled, and retrospective, but their results have been generally favorable and reflect the experience of multiple academic centers managing almost 500 patients over several decades (64, 65). In a representative study from 1991, 35 patients with dominant strictures were treated by dilation with or without stent placement, and showed improvement in jaundice, reduced rates of hospitalization, and radiologic improvement of the strictures (66). Another retrospective study of 53 patients, published in 1995, also reported benefit from treatment of dominant strictures: 77% of patients had improvement in liver-related tests, symptoms, or cholangiograms after dilation, with or without stenting and stone extraction (67). In 2001, a report of 71 patients with dominant strictures treated endoscopically showed favorable results. This retrospective comparison of dilation alone vs. dilation with stenting showed a statistically significant lessening of jaundice in both treatment groups, and reduced fevers for those with dilation (68).
Endoscopic treatment of dominant strictures in PSC may be considered specifically for cholangitis. Cholangitis can be the initial presentation of PSC and occurs frequently during the course of disease (76). Recurrent cholangitis can contribute to progression of the disease. Dominant strictures are associated with biliary bacterial colonization and antibiotic therapy alone may not be sufficient to eradicate the bacteria (77). The persistence of this bacteriobilia may be clinically significant: greater numbers of bacterial isolates have been associated with a shorter interval to liver transplant (71). ERCP is employed routinely to treat cholangitis due to biliary obstruction in other clinical settings, such as biliary obstruction from stone disease or malignancy, and biliary decompression allows improved response to antibiotic treatment and prevention of recurrent cholangitis. Endoscopic treatment of dominant strictures in PSC similarly may allow more effective treatment of cholangitis. The increased risk of cholangitis as a complication of ERCP, however, does reduce the potential benefit of endoscopic therapy for this indication (78).
Endoscopic treatment of dominant strictures in PSC may improve prognosis. Chronic biliary obstruction leads to progressive hepatic fibrosis and cirrhosis, even in the absence of pre-existing liver disease. Dominant strictures in PSC contribute to bile outflow obstruction, and have been associated with reduced survival free of liver transplantation (79). Relief of biliary obstruction by endoscopic therapy can arrest and potentially reverse cholestatic injury to the liver (80). Endoscopic therapy for relief of biliary obstruction due to dominant strictures in PSC has not been evaluated by prospective studies, but two retrospective studies did show improved survival after endoscopic therapy as compared with survival predicted by the Mayo Risk Score. In the first study, 63 patients were treated by balloon dilation of dominant strictures and their 5-year observed survival was significantly greater than predicted survival (83% vs. 65%, respectively) (81). In the second study, 55 patients were treated with balloon dilation of dominant strictures, 5 patients were treated with stenting, and the outcomes were positive: the 5-year observed survival was significantly greater than predicted survival in the treated group (94% vs. 78%, respectively) (73). Endoscopic therapy for dominant strictures, however, is not uniformly supported. In a retrospective study of 125 patients with PSC, ERCP was performed without therapy, and there was no significant difference in cholestasis 1 year after cholangiography in the 56 patients with dominant strictures as compared with the 69 patients without dominant strictures (74). However, this study did not evaluate the potential benefit of endoscopic intervention for their patients with dominant strictures, but simply found that 1-year prognosis is not worse when dominant strictures were present (82).
Cholangiocarcinoma must be considered in every patient with PSC and a dominant stricture, although the majority of these strictures will prove to be benign (83). In a series of 128 patients with PSC, 80/128 (63%) of patients had dominant strictures and 21/80 (26%) of patients with dominant strictures developed cholangiocarcinoma (84). Evaluation of dominant strictures discovered soon after the diagnosis of PSC is particularly important: among patients with cholangiocarcinoma, almost half of the malignancies were diagnosed within the first 4 months after initial diagnosis of PSC (85).
Endoscopic techniques to detect malignancy in dominant strictures routinely include brushings for cytology and biopsies for pathology. The specificity of these methods in detecting cholangiocarcinoma is very high, but their sensitivity has been reported below 30%, which limits their negative predictive value (69). The poor sensitivity of conventional diagnostic tools has led to considerable effort to enhance the diagnostic yield by employing newer technologies. FISH increases sensitivity to 64% from one cytology specimen and the presence of polysomy on two sequential specimens increases the positive predictive value to 69% (69, 70). Cholangioscopy allows direct biliary visualization and directed biopsies of the dominant stricture, which has been reported to increase sensitivity and specificity to >90% (86). Confocal laser microscopy has a very high reported sensitivity (98%) and moderate specificity (67%) for indeterminate strictures in general, but has not been studied specifically in dominant strictures in PSC (87) Intraductal ultrasound also may offer improved diagnostic yield, although it has not been widely adopted since its initial report for diagnosis of indeterminate strictures (88).
Techniques employed for endoscopic treatment of dominant strictures in PSC are not well standardized. Case series support the benefit of dilation, stent placement, and combinations of these methods for treatment of dominant strictures. A review of multiple case series showed that stent placement can lead to more frequent complications of cholangitis than dilation alone, but stenting for short duration will reduce the risk of stent occlusion and may allow stenting without increased risk of cholangitis (68, 72). Bile duct stones frequently develop in PSC due to impaired bile outflow and bacterial overgrowth from biliary strictures. When intraductal stones are recognized, endoscopic dilation of obstructing strictures and stone extraction will reduce bile outflow obstruction. Cholangioscopy is used primarily to interrogate indeterminate strictures in an effort to enhance detection of cholangiocarcinoma, but has the additional benefit of detection of unrecognized bile duct stones (89).
Patients undergoing endoscopic therapy for PSC are at significantly increased risk of post-ERCP cholangitis (78). Cholangitis in PSC can be life-threatening due to inability to decompress intrahepatic areas of biliary obstruction and infection. Prophylactic antibiotic therapy is a rational precaution against post ERCP cholangitis. Preoperative antibiotics followed by a 3- to 5-day course post ERCP have been advised, using quinolones or cephalosporins, although no prospective studies have been performed to determine the best antibiotic choices (71).
Percutaneous cholangiography for treatment of dominant strictures can be performed in PSC patients with altered anatomy that prevents successful ERCP, such as Roux-en-Y choledochojejunostomy or gastric bypass, or as a rescue therapy after failed endoscopic access. Percutaneous cholangiography is generally the second line of treatment after ERCP because of the risk of complications, including hepatic arterial injury, hemobilia, and cholangitis (90, 91, 92). Percutaneous cholangiography also requires placement of a percutaneous drain, which can be uncomfortable or difficult for the patient to manage. Percutaneous cholangiography is the primary choice of treatment for intrahepatic strictures that cannot be accessed by the retrograde approach or for very tight strictures that cannot be traversed by endoscopically placed wires or dilators. When percutaneous treatment is undertaken, the dominant stricture must be dilated adequately to prevent retrograde biliary flow and percutaneous bile leakage.
Biliary reconstruction by biliary-enteric drainage allows prolonged clinical improvement, with resolution of jaundice and cholangitis, but has significant risk of cholangitis and increased rates of mortality (93). Post-operative scarring also increases the difficulty of liver transplantation. Surgical drainage procedures have largely been discontinued in favor of transplantation due to the superior outcomes of liver transplantation (94).
Liver transplantation is the definitive treatment for patients with decompensated cirrhosis. The natural history of PSC is extremely variable but, in the absence of effective medical therapy for PSC, the median time for progression of disease from diagnosis until death or liver transplantation is 10–12 years (34, 97). Liver transplantation for PSC with a deceased donor organ offers 5-year survival of 80–85% (95, 98).
Priority to receive a donor liver from the United Network for Organ Sharing is established by the MELD score. The MELD score is calculated from the patient’s bilirubin, international normalized ratio and creatinine, which together create an objective measure of liver dysfunction that can be compared across different etiologies of liver disease. Liver transplantation offers survival benefit for patients with MELD score >15; however, MELD scores in most United Network for Organ Sharing regions must be considerably higher to achieve liver transplant due to scarcity of donor organs (99). For patients listed for transplant, who seek an alternative to waiting for a progressive increase in MELD score until a deceased donor becomes available, transplantation from a living donor is a viable option: patients undergoing living donor transplant for PSC have long-term outcomes that are comparable or superior to those undergoing deceased donor transplant (100).
In specific clinical circumstances, patients with PSC may be offered additional MELD points, to improve their priority for receiving a donor organ for liver transplantation. MELD exception points can be approved by the United Network for Organ Sharing Regional Review Board for the following indications:
Recurrence of PSC after liver transplantation is relatively common, affecting as many as 20% of patients at 5 years after transplant (102). The majority of patients tolerate recurrent disease without significant morbidity or mortality, but progressive disease can occur in as many as one-third of patients with recurrent PSC (103).
The prevalence of IBD in PSC is much higher than previously thought and recent reviews have stated that up to 80% of patients with PSC have IBD (3). It is possible that the prevalence may have been underestimated given that the colonic mucosa may frequently appear normal on endoscopic examination, although biopsies may disclose evidence of histologic colitis. A preliminary study in which rectosigmoid biopsies were routinely performed and histology reviewed by an expert pathologist suggested that the prevalence may be as high as 90% (96).
The majority of patients with IBD and PSC have a known diagnosis of IBD before the diagnosis of PSC. However, PSC may be diagnosed after proctocolectomy for UC and IBD may be diagnosed after a liver transplant has been done for end-stage liver disease due to PSC (3). IBD in patients with PSC may frequently be asymptomatic and have a quiescent course. Therefore, a full colonoscopy with biopsies is recommended in patients with PSC regardless of the presence of symptoms. This recommendation is consistent with other PSC Practice Guidelines (3).
Based on these data, it is reasonable to recommend a full colonoscopy with random biopsies in patients with PSC, who do not already have a diagnosis of IBD. Biopsies should be obtained even if the colonic mucosa appears grossly normal. Some have advocated that colonoscopy with biopsy be repeated every 5 years, although there is no consensus on this approach.
The risk of colorectal dysplasia and cancer is significantly higher (approximately four- to fivefold) among patients with PSC and IBD compared with those with IBD without PSC (104). The mechanism for increased risk of colon cancer in PSC–IBD is unknown, but exposure of the colonic mucosa to toxic bile acids, namely secondary bile acids that may promote carcinogenesis such as deoxycholic acid, has been proposed (105). The possible favorable effect of low-dose UDCA in a few retrospective studies also has been thought to provide circumstantial evidence in support of the toxic bile acid hypothesis, although there are no prospective controlled trials demonstrating a benefit for UDCA for chemoprevention against colon dysplasia or neoplasia in IBD associated with PSC. A recent meta-analysis suggested a possible benefit for low-dose (8–13 mg/kg/day) UDCA but significant heterogeneity in the studies was notified, limiting the interpretation of the results (106). 5-Acetylsalicylic acid may also reduce the risk of colonic malignancy in this setting.
The differentiation of cholangiocarcinoma from a benign stricture arising a setting of PSC is difficult. CA 19-9 levels have been used and may be of value, although there are a number of patients with high CA 19-9 levels with no evidence of cholangiocarcinoma, whereas there are a number of patients with normal or low levels, who do have an underlying cholangiocarinoma; therefore, CA, 19-9 has limited predictive value (115, 116, 117). Brush cytology is specific but quite insensitive. Sensitivity ranges from 18% to 40% from the literature and this has been improved by the use of FISH as discussed earlier (70, 118). FISH is of particular importance in this setting. The role of positron emission tomography scanning is problematic and controversial, and is not a widely adapted diagnostic tool (119, 120). Screening for cholangiocarcinoma with regular (every 6–12 months) cross-sectional imaging with ultrasound or MR and serial CA 19-9 measures is recommended by experts in this area, for all patients with PSC (107, 108).
Patients with PSC have an increased risk of gallbladder cancer and gallstones themselves are found in a quarter of patients with PSC (109). The patients with PSC may also develop gallbladder polyps, and if these are >8 mm there is a risk of being or becoming malignant (121). At this point, cholecystectomy is typically recommended for lesions greater than >8 mm in diameter. It is recommended that surveillance of the gallbladder be done on at least an annual basis with ultrasound (109).
PSC and autoimmune hepatitis may co-exist in the same patient and the prevalence of autoimmune hepatitis in patients with PSC is ˜10%, but has ranged from 1.4% to 17% in various studies of patients with PSC (1, 3). Patients with autoimmune hepatitis and PSC overlap syndrome tend to be younger than 25 years of age and have serum biochemical tests and autoantibodies suggestive of autoimmune hepatitis (1, 3). One study suggested that a large proportion of children with autoimmune hepatitis subsequently developed cholangiographic evidence of PSC (122).
Based on these data, it is reasonable to recommend that further testing for autoimmune hepatitis is appropriate among younger patients with PSC or those with higher-than-expected levels of aminotransferases usually >5 × the upper limit of normal. Similarly, it appears reasonable to recommend MRCP among younger patients (i.e., <25 years of age) with autoimmune hepatitis, who have elevated serum ALP usually >2 × the upper limit of normal (1).
PSC appears to be much less common among children than adults, with an estimated prevalence 20% lower than in adults and is a rare indication for liver transplantation in this population (3). Furthermore, PSC in children is more often associated with higher serum aminotransferase levels and concomitant autoimmune hepatitis, and sclerosing cholangitis is a more common phenomenon, leading to the use of the term “autoimmune sclerosing cholangitis.” (1, 122) Serum ALP may be elevated in children due to bone growth; hence, suspected cholestasis should be confirmed by measurement of gamma-glutamyl transpeptidase levels. Cholangiocarcinoma appears to be rare in this population and surveillance for gallbladder cancer or cholangiocarcinoma is not recommended (3).
In summary, pediatric PSC may have a different clinical presentation than in adults and the workup should include efforts to identify concomitant autoimmune hepatitis, which may lead to a different therapeutic approach (i.e., corticosteroids or immunosuppressive medications). Current guidelines do not recommend routine surveillance for cholangiocarcinoma in children with PSC.
IgG4-associated pancreatitis and cholangitis is being increasingly recognized in patients who present with sclerosing cholangitis. IgG4-associated autoimmune pancreatitis is a clearly described entity characterized by strictures in the pancreatic duct, elevated IgG4 levels and response to immunosuppressive therapy (reference). This condition may be associated with biliary strictures and elevated plasma IgG4 levels, and liver biopsy may reveal a lymphoplasmacytic infiltrate (1, 3). In some cases, the biliary disease is predominant and features of autoimmune pancreatitis may or may not be present. A subset of patients with PSC have marked elevations of IgG4 levels (>140 mg/dl), although mild increases in IgG4 levels appear common in PSC (40). Patients with IgG4-associated sclerosing cholangitis appears to be less likely to have IBD and there may be differences in cholangiographic appearance between PSC and IgG4 cholangitis (41). Corticosteroids or other immunosuppressive agents are generally used in patients with IgG4 cholangitis, whereas they do not have a role in PSC (1). Combination of predizone and azathioprine are used to treat autoimmune hepatitis and has been used by some.
Measurement of IgG4 levels is reasonable in patients with PSC and consideration should be given to imaging for autoimmune pancreatitis and the presence of IgG4-associated cholangitis among those with markedly elevated IgG4 levels. Liver biopsy should be considered to identify the classical lymphoplasmacytic infiltrate and consideration of immunosuppression therapy may be useful in such patients, especially if they have higher-than-expected elevations of serum aminotransferase levels.
PSC causes progressive hepatic fibrosis and cirrhosis, which can lead to portal hypertension. The mechanisms of portal hypertension from PSC generally are not unique to this disease. Elevated portal pressure in cirrhosis is most commonly the result of increased resistance to portal blood flow combined with augmented portal inflow. Increased resistance to portal flow results from architectural distortion of the liver, associated with hepatic fibrosis and regenerative nodules. Evidence from rat models suggests that increased resistance to portal inflow may also result from active intrahepatic vasoconstriction due to decreased release of nitrous oxide (130). Portal venous inflow is increased in the rat model due to splanchnic vasodilation that is not adequately decompressed by porto-systemic collaterals (131).
In a small percentage of patients with PSC, portal hypertension may develop before cirrhosis due to pre-cirrhotic portal hypertension. Among 306 patients transplanted for PSC at 2 institutions, 11/306 (3.3%) patients had portal hypertension without cirrhosis due to nodular regenerative hyperplasia or obliterative venopathy (132). MELD exception points are not offered for patients with PSC and non-cirrhotic portal hypertension.
Complications of portal hypertension in PSC generally are not unique to this disease, and include gastroesophageal varices and variceal hemorrhage. Previous guidelines have addressed the management of gastroesophageal varices (133). Screening of patients with signs of advanced disease with platelet counts <150 × 103/dl is recommended (127).
However, patients with PSC and portal hypertension do sustain an increased rate of bleeding from peristomal varices. IBD associated with PSC may require proctocolectomy and peristomal varices develop in 25% of patients who have ileal stomas after colectomy (134). Peristomal varices can be avoided by ileal pouch–anal anastomosis in place of an ileal stoma. Hemorrhage from peristomal varices is treated effectively by decompression of the underlying portal hypertension with a transjugular intrahepatic portacaval shunt, portosystemic shunt surgery, or liver transplantation (135, 136, 137). Peristomal variceal hemorrhage may be treated by embolization of varices percutaneously or through balloon-occluded retrograde transvenous obliteration, as described in case reports (138, 139).
Fat-soluble vitamin deficiencies can occur in late stages of PSC when patient becomes jaundiced. Levels of vitamins A, E, and D should be assessed in patients with advanced disease (129).
Pruritus in patients with PSC is similar to that in other cholestatic liver diseases. It is often worse at night, in warm, humid climates, and may lead to excoriations from scratching, as well as other dermatologic complications (123). Pruritus may have a negative impact on quality of life and sometimes lead to suicidal ideation; pruritus may rarely be considered an indication for liver transplantation (140). In patients with PSC, who have a cholestatic pattern of liver test abnormalities, pruritus can generally be ascribed to cholestasis and empiric treatment is appropriate.
The management of pruritus should be directed to the underlying cause of cholestasis. In PSC, therapeutic intervention for patients with a dominant stricture should be considered. Medical management of pruritus is directed by the severity of the underlying pruritus. Mild pruritus may be treated with skin emollients and possibly antihistamines. More severe pruritus is best managed by bile acid sequestrants, such as cholestyramine. A total daily dose of cholestyramine of 4–16 g is needed to maintain symptom control (124). Second-line therapies include rifampin, at a dose of 150–300 mg twice daily (liver tests and serum bilirubin should be monitored during rifampin therapy to evaluate for hepatotoxicity), naltrexone (up to 50 mg/day), sertraline (75–100 mg per day) or phenobarbital (90 mg at bedtime) (125, 126).
Metabolic bone disease is a common complication of chronic liver disease, especially with chronic cholestasis. Osteoporosis has been reported in 13%–60% of patients with cholestatic liver disease (141). BMD in PSC is significantly lower than expected for age-matched controls (142). In a cohort of 237 patients monitored by serial BMD measurements over the course of 10 years, osteoporosis was diagnosed in 36/237 (15%) and osteopenia was found in 41% (128). The risk of osteoporosis increased with greater age, low body mass index, and longstanding IBD; three quarters of patients with all three of these risk factors had osteoporosis. Those patients with PSC, who underwent liver transplantation, have an additional risk of bone disease due to inactivity and dietary limitations, with a resultant increased risk of bone fractures and avascular necrosis (143).
The pathophysiology of bone disease in cholestatic liver disease is not known, and most studies have focused specifically on metabolic bone disorders in primary biliary cirrhosis rather than PSC. With these caveats, it is recognized that cholestatic liver disease predisposes to osteopenia and osteoporosis, which is associated with decreased bone formation, but there is not an increased risk of osteomalacia (144). Supplemental vitamin D and calcium has not been shown to reduce the risk of metabolic bone disease in this group of patients (145). The mechanism of decreased bone formation in cholestasis is uncertain. In theory, retained toxins from inadequate biliary excretion may predispose to bone disease, but treatment with UDCA has not offered benefit (146, 147).
Metabolic bone disease is diagnosed by low BMD as compared with age-matched controls. Dual-energy X-ray bone absorptiometry is applied to the lumbar vertebrae and femoral neck to measure BMD. By the World Health Organization scale, a BMD t-score of < −2.5 is diagnostic of osteoporosis and a t-score < −1.0 is diagnostic of osteopenia (negative t-scores indicate the number of s.d. below normal for age-matched controls) (148). The risk of fractures increases progressively with the decrease in t-scores: a decrease in t-score by one indicates a two- to threefold increased risk of fracture.
Treatment of metabolic bone disease in PSC is comparable to treatment for osteopenia and osteoporosis of any cause. Patients are advised to undergo weight-bearing exercise and take calcium and vitamin D supplementation. BMD is performed at diagnosis and every 2–4 years thereafter. The role of bisphosphonates for treatment of osteoporosis in PSC is not proven. However, in patients with osteopenia and primary biliary cirrhosis, alendronate treatment has resulted in significant improvement in BMD, both at the lumbar spine and the femoral neck, suggesting that alendronate may be useful for treatment of osteopenia and osteoporosis in patients with PSC (149).
This guideline was produced in collaboration with the Practice Parameters Committee of the American College of Gastroenterology. The Committee gives special thanks to Rishi Pawa, MD, who served as guideline monitor for this document.
1. Hirschfield GM, Karlsen TH, Lindor KD et al
. Primary sclerosing cholangitis. Lancet 2013;382:1587–1599.
2. Dave M, Elmunzer BJ, Dwamena BA et al
. Primary sclerosing cholangitis: meta-analysis of diagnostic performance of MR cholangiopancreatography. Radiology 2010;256:387–396.
3. Chapman R, Fevery J, Kalloo A et al
. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660–678.
4. Angulo P, Pearce DH, Johnson CD et al
. Magnetic resonance cholangiography in patients with biliary disease: Its role in primary sclerosing cholangitis. J Hepatol 2000;33:520–527.
5. Berstad AE, Aabakken L, Smith HJ et al
. Diagnostic accuracy of magnetic resonance and endoscopic retrograde cholangiography in primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2006;4:514–520.
6. Boonstra K, van Erpecum KJ, van Nieuwkerk KM et al
. Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease. Inflamm Bowel Dis 2012;18:2270–2276.
7. O'Toole A, Alakkari A, Keegan D et al
. Primary sclerosing cholangitis and disease distribution in inflammatory bowel disease. Clin Gastroenterol Hepatol 2012;10:439–441.
8. Halliday JS, Djordjevic J, Lust M et al
. A unique clinical phenotype of primary sclerosing cholangitis associated with crohn's disease. J Crohns Colitis 2012;6:174–181.
9. Olsson R, Danielsson A, Jarnerot G et al
. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology 1991;100:1319–1323.
10. Karlsen TH, Franke A, Melum E et al
. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology 2010;138:1102–1111.
11. Ellinghaus D, Folseraas T, Holm K et al
. Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology 2013;58:1074–1083.
12. Melum E, Franke A, Schramm C et al
. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nat Genet 2011;43:17–19.
13. Farrant JM, Doherty DG, Donaldson PT et al
. Amino acid substitutions at position 38 of the DR beta polypeptide confer susceptibility to and protection from primary sclerosing cholangitis. Hepatology 1992;16:390–395.
14. Mohamadnejad M, DeWitt JM, Sherman S et al
. Role of EUS for preoperative evaluation of cholangiocarcinoma: A large single-center experience. Gastrointest Endosc 2011;73:71–78.
15. Martin CR, Zaman MM, Ketwaroo GA et al
. CFTR dysfunction predisposes to fibrotic liver disease in a murine model. Am J Physiol Gastrointest Liver Physiol 2012;303:G474–G481.
16. Grant AJ, Lalor PF, Salmi M et al
. Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease. Lancet 2002;359:150–157.
17. Benhamou Y, Caumes E, Gerosa Y et al
. AIDS-related cholangiopathy. critical analysis of a prospective series of 26 patients. Dig Dis Sci 1993;38:1113–1118.
18. Grant AJ, Goddard S, Ahmed-Choudhury J et al
. Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease. Am J Pathol 2002;160:1445–1455.
19. Pol S, Romana CA, Richard S et al
. Microsporidia infection in patients with the human immunodeficiency virus and unexplained cholangitis. N Engl J Med 1993;328:95–99.
20. Talwalkar JA, Angulo P, Johnson CD et al
. Cost-minimization analysis of MRC versus ERCP for the diagnosis of primary sclerosing cholangitis. Hepatology 2004;40:39–45.
21. Burak KW, Angulo P, Lindor KD. Is there a role for liver biopsy in primary sclerosing cholangitis? Am J Gastroenterol 2003;98:1155–1158.
22. Bjornsson E, Olsson R, Bergquist A et al
. The natural history of small-duct primary sclerosing cholangitis. Gastroenterology 2008;134:975–980.
23. Angulo P, Maor-Kendler Y, Lindor KD. Small-duct primary sclerosing cholangitis: A long-term follow-up study. Hepatology 2002;35:1494–1500.
24. Bjornsson E, Boberg KM, Cullen S et al
. Patients with small duct primary sclerosing cholangitis have a favourable long term prognosis. Gut 2002;51:731–735.
25. Lindor KD. Ursodiol for primary sclerosing cholangitis. mayo primary sclerosing cholangitis-ursodeoxycholic acid study group. N Engl J Med 1997;336:691–695.
26. Mendes FD, Jorgensen R, Keach J et al
. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol 2006;101:2070–2075.
27. Bjornsson E, Chari ST, Smyrk TC et al
. Immunoglobulin G4 associated cholangitis: description of an emerging clinical entity based on review of the literature. Hepatology 2007;45:1547–1554.
28. Kamisawa T, Okamoto A. IgG4-related sclerosing disease. World J Gastroenterol 2008;14:3948–3955.
29. Boberg KM, Fausa O, Haaland T et al
. Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis. Hepatology 1996;23:1369–1376.
30. Portmann B, Zen Y. Inflammatory disease of the bile ducts-cholangiopathies: liver biopsy challenge and clinicopathological correlation. Histopathology 2012;60:236–248.
31. Chapman RW, Arborgh BA, Rhodes JM et al
. Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology. Gut 1980;21:870–877.
32. Bjornsson E, Chari S, Silveira M et al
. Primary sclerosing cholangitis associated with elevated immunoglobulin G4: Clinical characteristics and response to therapy. Am J Ther 2011;18:198–205.
33. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995;332:924–933.
34. Wiesner RH, Grambsch PM, Dickson ER et al
. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 1989;10:430–436.
35. Angulo P, Peter JB, Gershwin ME et al
. Serum autoantibodies in patients with primary sclerosing cholangitis. J Hepatol 2000;32:182–187.
36. Seibold F, Weber P, Klein R et al
. Clinical significance of antibodies against neutrophils in patients with inflammatory bowel disease and primary sclerosing cholangitis. Gut 1992;33:657–662.
37. Gossard AA, Angulo P, Lindor KD. Secondary sclerosing cholangitis: a comparison to primary sclerosing cholangitis. Am J Gastroenterol 2005;100:1330–1333.
38. Barnett KT, Malafa MP. Complications of hepatic artery infusion: a review of 4580 reported cases. Int J Gastrointest Cancer 2001;30:147–160.
39. Castellano G, Moreno-Sanchez D, Gutierrez J et al
. Caustic sclerosing cholangitis. report of four cases and a cumulative review of the literature. Hepatogastroenterology 1994;41:458–470.
40. Alswat K, Al-Harthy N, Mazrani W et al
. The spectrum of sclerosing cholangitis and the relevance of IgG4 elevations in routine practice. Am J Gastroenterol 2012;107:56–63.
41. Nakazawa T, Naitoh I, Hayashi K et al
. Diagnosis of IgG4-related sclerosing cholangitis. World J Gastroenterol 2013;19:7661–7670.
42. Eaton JE, Silveira MG, Pardi DS et al
. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol 2011;106:1638–1645.
43. Mitchell SA, Bansi DS, Hunt N et al
. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology 2001;121:900–907.
44. Harnois DM, Angulo P, Jorgensen RA et al
. High-dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis. Am J Gastroenterol 2001;96:1558–1562.
45. Olsson R, Boberg KM, de Muckadell OS et al
. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: A 5-year multicenter, randomized, controlled study. Gastroenterology 2005;129:1464–1472.
46. Lindor KD, Kowdley KV, Luketic VA et al
. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50:808–814.
47. Stanich PP, Bjornsson E, Gossard AA et al
. Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis. Dig Liver Dis 2011;43:309–313.
48. Al Mamari S, Djordjevic J, Halliday JS et al
. Improvement of serum alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 2013;58:329–334.
49. Lindstrom L, Hultcrantz R, Boberg KM et al
. Association between reduced levels of alkaline phosphatase and survival times of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2013;11:841–846.
50. Schramm C, Schirmacher P, Helmreich-Becker I et al
. Combined therapy with azathioprine, prednisolone, and ursodiol in patients with primary sclerosing cholangitis. a case series. Ann Intern Med 1999;131:943–946.
51. Angulo P, Batts KP, Jorgensen RA et al
. Oral budesonide in the treatment of primary sclerosing cholangitis. Am J Gastroenterol 2000;95:2333–2337.
52. Martin CR, Blanco PG, Keach JC et al
. The safety and efficacy of oral docosahexaenoic acid supplementation for the treatment of primary sclerosing cholangitis - a pilot study. Aliment Pharmacol Ther 2012;35:255–265.
53. Bach N, Bodian C, Bodenheimer H et al
. Methotrexate therapy for primary biliary cirrhosis. Am J Gastroenterol 2003;98:187–193.
54. Knox TA, Kaplan MM. A double-blind controlled trial of oral-pulse methotrexate therapy in the treatment of primary sclerosing cholangitis. Gastroenterology 1994;106:494–499.
55. Farkkila M, Karvonen AL, Nurmi H et al
. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: A randomized placebo-controlled trial. Hepatology 2004;40:1379–1386.
56. Silveira MG, Torok NJ, Gossard AA et al
. Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am J Gastroenterol 2009;104:83–88.
57. Talwalkar JA, Angulo P, Keach JC et al
. Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid. J Clin Gastroenterol 2005;39:168–171.
58. Angulo P, Bharucha AE, Jorgensen RA et al
. Oral nicotine in treatment of primary sclerosing cholangitis: a pilot study. Dig Dis Sci 1999;44:602–607.
59. Bharucha AE, Jorgensen R, Lichtman SN et al
. A pilot study of pentoxifylline for the treatment of primary sclerosing cholangitis. Am J Gastroenterol 2000;95:2338–2342.
60. Angulo P, MacCarty RL, Sylvestre PB et al
. Pirfenidone in the treatment of primary sclerosing cholangitis. Dig Dis Sci 2002;47:157–161.
61. Boberg KM, Egeland T, Schrumpf E. Long-term effect of corticosteroid treatment in primary sclerosing cholangitis patients. Scand J Gastroenterol 2003;38:991–995.
62. Talwalkar JA, Gossard AA, Keach JC et al
. Tacrolimus for the treatment of primary sclerosing cholangitis. Liver Int 2007;27:451–453.
63. Davies YK, Cox KM, Abdullah BA et al
. Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: an immunomodulating antibiotic. J Pediatr Gastroenterol Nutr 2008;47:61–67.
64. Stiehl A. Primary sclerosing cholangitis: the role of endoscopic therapy. Semin Liver Dis 2006;26:62–68.
65. Johnson GK, Saeian K, Geenen JE. Primary sclerosing cholangitis treated by endoscopic biliary dilation: review and long-term follow-up evaluation. Curr Gastroenterol Rep 2006;8:147–155.
66. Johnson GK, Geenen JE, Venu RP et al
. Endoscopic treatment of biliary tract strictures in sclerosing cholangitis: a larger series and recommendations for treatment. Gastrointest Endosc 1991;37:38–43.
67. Lee JG, Schutz SM, England RE et al
. Endoscopic therapy of sclerosing cholangitis. Hepatology 1995;21:661–667.
68. Kaya M, Petersen BT, Angulo P et al
. Balloon dilation compared to stenting of dominant strictures in primary sclerosing cholangitis. Am J Gastroenterol 2001;96:1059–1066.
69. Levy MJ, Baron TH, Clayton AC et al
. Prospective evaluation of advanced molecular markers and imaging techniques in patients with indeterminate bile duct strictures. Am J Gastroenterol 2008;103:1263–1273.
70. Barr Fritcher EG, Kipp BR, Voss JS et al
. Primary sclerosing cholangitis patients with serial polysomy fluorescence in situ
hybridization results are at increased risk of cholangiocarcinoma. Am J Gastroenterol 2011;106:2023–2028.
71. Olsson R, Bjornsson E, Backman L et al
. Bile duct bacterial isolates in primary sclerosing cholangitis: a study of explanted livers. J Hepatol 1998;28:426–432.
72. van Milligen de Wit AW, Rauws EA, van Bracht J et al
. Lack of complications following short-term stent therapy for extrahepatic bile duct strictures in primary sclerosing cholangitis. Gastrointest Endosc 1997;46:344–347.
73. Stiehl A, Rudolph G, Kloters-Plachky P et al
. Development of dominant bile duct stenoses in patients with primary sclerosing cholangitis treated with ursodeoxycholic acid: outcome after endoscopic treatment. J Hepatol 2002;36:151–156.
74. Bjornsson E, Lindqvist-Ottosson J, Asztely M et al
. Dominant strictures in patients with primary sclerosing cholangitis. Am J Gastroenterol 2004;99:502–508.
75. Gotthardt DN, Rudolph G, Kloters-Plachky P et al
. Endoscopic dilation of dominant stenoses in primary sclerosing cholangitis: outcome after long-term treatment. Gastrointest Endosc 2010;71:527–534.
76. Kaplan GG, Laupland KB, Butzner D et al
. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol 2007;102:1042–1049.
77. Pohl J, Ring A, Stremmel W et al
. The role of dominant stenoses in bacterial infections of bile ducts in primary sclerosing cholangitis. Eur J Gastroenterol Hepatol 2006;18:69–74.
78. Bangarulingam SY, Gossard AA, Petersen BT et al
. Complications of endoscopic retrograde cholangiopancreatography in primary sclerosing cholangitis. Am J Gastroenterol 2009;104:855–860.
79. Rudolph G, Gotthardt D, Kloters-Plachky P et al
. Influence of dominant bile duct stenoses and biliary infections on outcome in primary sclerosing cholangitis. J Hepatol 2009;51:149–155.
80. Hammel P, Couvelard A, O'Toole D et al
. Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med 2001;344:418–423.
81. Baluyut AR, Sherman S, Lehman GA et al
. Impact of endoscopic therapy on the survival of patients with primary sclerosing cholangitis. Gastrointest Endosc 2001;53:308–312.
82. Kozarek RA. Endoscopic therapy in primary sclerosing cholangitis. dominant strictures may not matter: does that mean that endotherapy does not work? Am J Gastroenterol 2004;99:509–510.
83. Lindberg B, Arnelo U, Bergquist A et al
. Diagnosis of biliary strictures in conjunction with endoscopic retrograde cholangiopancreaticography, with special reference to patients with primary sclerosing cholangitis. Endoscopy 2002;34:909–916.
84. Chapman MH, Webster GJ, Bannoo S et al
. Cholangiocarcinoma and dominant strictures in patients with primary sclerosing cholangitis: a 25-year single-centre experience. Eur J Gastroenterol Hepatol 2012;24:1051–1058.
85. Burak K, Angulo P, Pasha TM et al
. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol 2004;99:523–526.
86. Tischendorf JJ, Kruger M, Trautwein C et al
. Cholangioscopic characterization of dominant bile duct stenoses in patients with primary sclerosing cholangitis. Endoscopy 2006;38:665–669.
87. Meining A, Chen YK, Pleskow D et al
. Direct visualization of indeterminate pancreaticobiliary strictures with probe-based confocal laser endomicroscopy: a multicenter experience. Gastrointest Endosc 2011;74:961–968.
88. Farrell RJ, Agarwal B, Brandwein SL et al
. Intraductal US is a useful adjunct to ERCP for distinguishing malignant from benign biliary strictures. Gastrointest Endosc 2002;56:681–687.
89. Awadallah NS, Chen YK, Piraka C et al
. Is there a role for cholangioscopy in patients with primary sclerosing cholangitis? Am J Gastroenterol 2006;101:284–291.
90. Ginat D, Saad WE, Davies MG et al
. Incidence of cholangitis and sepsis associated with percutaneous transhepatic biliary drain cholangiography and exchange: a comparison between liver transplant and native liver patients. AJR Am J Roentgenol 2011;196:W73–W77.
91. Savader SJ, Trerotola SO, Merine DS et al
. Hemobilia after percutaneous transhepatic biliary drainage: treatment with transcatheter embolotherapy. J Vasc Interv Radiol 1992;3:345–352.
92. Choi SH, Gwon DI, Ko GY et al
. Hepatic arterial injuries in 3110 patients following percutaneous transhepatic biliary drainage. Radiology 2011;261:969–975.
93. Cameron JL, Pitt HA, Zinner MJ et al
. Resection of hepatic duct bifurcation and transhepatic stenting for sclerosing cholangitis. Ann Surg 1988;207:614–622.
94. Farges O, Malassagne B, Sebagh M et al
. Primary sclerosing cholangitis: liver transplantation or biliary surgery. Surgery 1995;117:146–155.
95. Graziadei IW, Wiesner RH, Marotta PJ et al
. Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis. Hepatology 1999;30:1121–1127.
96. Tung BY, Brentanall t, Kowdley KV et al
. Diagnosis and prevalence of ulcerative colitis in patients with sclerosing cholangitis (abstract). Hepatology 1996;24:169A.
97. Tischendorf JJ, Hecker H, Kruger M et al
. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol 2007;102:107–114.
98. Fosby B, Karlsen TH, Melum E. Recurrence and rejection in liver transplantation for primary sclerosing cholangitis. World J Gastroenterol 2012;18:1–15.
99. Merion RM, Schaubel DE, Dykstra DM et al
. The survival benefit of liver transplantation. Am J Transplant 2005;5:307–313.
100. Kashyap R, Safadjou S, Chen R et al
. Living donor and deceased donor liver transplantation for autoimmune and cholestatic liver diseases—an analysis of the UNOS database. J Gastrointest Surg 2010;14:1362–1369.
101. Goldberg D, Bittermann T, Makar G. Lack of standardization in exception points for patients with primary sclerosing cholangitis and bacterial cholangitis. Am J Transplant 2012;12:1603–1609.
102. Campsen J, Zimmerman MA, Trotter JF et al
. Clinically recurrent primary sclerosing cholangitis following liver transplantation: a time course. Liver Transpl 2008;14:181–185.
103. Charatcharoenwitthaya P, Lindor KD. Recurrence of primary sclerosing cholangitis: what do we learn from several transplant centers? Liver Transpl 2008;14:130–132.
104. Soetikno RM, Lin OS, Heidenreich PA et al
. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc 2002;56:48–54.
105. Tsaitas C, Semertzidou A, Sinakos E. Update on inflammatory bowel disease in patients with primary sclerosing cholangitis. World J Hepatol 2014;6:178–187.
106. Hansen JD, Kumar S, Lo WK et al
. Ursodiol and colorectal cancer or dysplasia risk in primary sclerosing cholangitis and inflammatory bowel disease: a meta-analysis. Dig Dis Sci 2013;58:3079–3087.
107. Charatcharoenwitthaya P, Enders FB, Halling KC et al
. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 2008;48:1106–1117.
108. Razumilava N, Gores GJ, Lindor KD. Cancer surveillance in patients with primary sclerosing cholangitis. Hepatology 2011;54:1842–1852.
109. Buckles DC, Lindor KD, Larusso NF et al
. In primary sclerosing cholangitis, gallbladder polyps are frequently malignant. Am J Gastroenterol 2002;97:1138–1142.
110. de Groen PC, Gores GJ, LaRusso NF et al
. Biliary tract cancers. N Engl J Med 1999;341:1368–1378.
111. Kornfeld D, Ekbom A, Ihre T. Survival and risk of cholangiocarcinoma in patients with primary sclerosing cholangitis. A population-based study. Scand J Gastroenterol 1997;32:1042–1045.
112. Harnois DM, Gores GJ, Ludwig J et al
. Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol 1997;27:512–516.
113. Zenouzi R, Weismuller TJ, Hubener P et al
. Low risk of hepatocellular carcinoma in patients with primary sclerosing cholangitis with cirrhosis. Clin Gastroenterol Hepatol 2014;12:1733–1738.
114. de Valle MB, Bjornsson E, Lindkvist B. Mortality and cancer risk related to primary sclerosing cholangitis in a swedish population-based cohort. Liver Int 2012;32:441–448.
115. Levy C, Lymp J, Angulo P et al
. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci 2005;50:1734–1740.
116. Boberg KM, Jebsen P, Clausen OP et al
. Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 2006;45:568–574.
117. Sinakos E, Saenger AK, Keach J et al
. Many patients with primary sclerosing cholangitis and increased serum levels of carbohydrate antigen 19-9 do not have cholangiocarcinoma. Clin Gastroenterol Hepatol 2011;9:434–439.
118. Bangarulingam SY, Bjornsson E, Enders F et al
. Long-term outcomes of positive fluorescence in situ
hybridization tests in primary sclerosing cholangitis. Hepatology 2010;51:174–180.
119. Keiding S, Hansen SB, Rasmussen HH et al
. Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography. Hepatology 1998;28:700–706.
120. Fevery J, Buchel O, Nevens F et al
. Positron emission tomography is not a reliable method for the early diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis. J Hepatol 2005;43:358–360.
121. Eaton JE, Thackeray EW, Lindor KD. Likelihood of malignancy in gallbladder polyps and outcomes following cholecystectomy in primary sclerosing cholangitis. Am J Gastroenterol 2012;107:431–439.
122. Gregorio GV, Portmann B, Karani J et al
. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: A 16-year prospective study. Hepatology 2001;33:544–553.
123. Bolier R, Oude Elferink RP, Beuers U. Advances in pathogenesis and treatment of pruritus. Clin Liver Dis 2013;17:319–329.
124. Bunchorntavakul C, Reddy KR. Pruritus in chronic cholestatic liver disease. Clin Liver Dis 2012;16:331–346.
125. Imam MH, Gossard AA, Sinakos E et al
. Pathogenesis and management of pruritus in cholestatic liver disease. J Gastroenterol Hepatol 2012;27:1150–1158.
126. Bloomer JR, Boyer JL. Phenobarbital effects in cholestatic liver diseases. Ann Intern Med 1975;82:310–317.
127. Zein CO, Lindor KD, Angulo P. Prevalence and predictors of esophageal varices in patients with primary sclerosing cholangitis. Hepatology 2004;39:204–210.
128. Angulo P, Grandison GA, Fong DG et al
. Bone disease in patients with primary sclerosing cholangitis. Gastroenterology 2011;140:180–188.
129. Jorgensen RA, Lindor KD, Sartin JS et al
. Serum lipid and fat-soluble vitamin levels in primary sclerosing cholangitis. J Clin Gastroenterol 1995;20:215–219.
130. Wiest R, Groszmann RJ. Nitric oxide and portal hypertension: its role in the regulation of intrahepatic and splanchnic vascular resistance. Semin Liver Dis 1999;19:411–426.
131. Sikuler E, Groszmann RJ. Interaction of flow and resistance in maintenance of portal hypertension in a rat model. Am J Physiol 1986;250:G205–G212.
132. Abraham SC, Kamath PS, Eghtesad B et al
. Liver transplantation in precirrhotic biliary tract disease: portal hypertension is frequently associated with nodular regenerative hyperplasia and obliterative portal venopathy. Am J Surg Pathol 2006;30:1454–1461.
133. Garcia-Tsao G, Sanyal AJ, Grace ND et al
. Practice Guidelines Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922–938.
134. Kartheuser AH, Dozois RR, LaRusso NF et al
. Comparison of surgical treatment of ulcerative colitis associated with primary sclerosing cholangitis: Ileal pouch-anal anastomosis versus brooke ileostomy. Mayo Clin Proc 1996;71:748–756.
135. Lagier E, Rousseau H, Maquin P et al
. Treatment of bleeding stomal varices using transjugular intrahepatic portosystemic shunt. J Pediatr Gastroenterol Nutr 1994;18:501–503.
136. Adson MA, Fulton RE. The ileal stoma and protal hypertension: an uncommon site of variceal bleeding. Arch Surg 1977;112:501–504.
137. Wiesner RH, LaRusso NF, Dozois RR et al
. Peristomal varices after proctocolectomy in patients with primary sclerosing cholangitis. Gastroenterology 1986;90:316–322.
138. Naidu SG, Castle EP, Kriegshauser JS et al
. Direct percutaneous embolization of bleeding stomal varices. Cardiovasc Intervent Radiol 2010;33:201–204.
139. Teo TK, Sabri SS, Turba UC et al
. Obliteration of bleeding peristomal varices with balloon-occluded retrograde transvenous obliteration using sodium tetradecyl sulfate foam. J Vasc Interv Radiol 2011;22:1049–1051.
140. Lindor KD, Gershwin ME, Poupon R et al
. Primary biliary cirrhosis. Hepatology 2009;50:291–308.
141. Gasser RW. Cholestasis and metabolic bone disease - a clinical review. Wien Med Wochenschr 2008;158:553–557.
142. Angulo P, Therneau TM, Jorgensen A et al
. Bone disease in patients with primary sclerosing cholangitis: prevalence, severity and prediction of progression. J Hepatol 1998;29:729–735.
143. Guichelaar MM, Schmoll J, Malinchoc M et al
. Fractures and avascular necrosis before and after orthotopic liver transplantation: long-term follow-up and predictive factors. Hepatology 2007;4:1198–1207.
144. Guanabens N, Pares A, Marinoso L et al
. Factors influencing the development of metabolic bone disease in primary biliary cirrhosis. Am J Gastroenterol 1990;85:1356–1362.
145. Herlong HF, Recker RR, Maddrey WC. Bone disease in primary biliary cirrhosis: Histologic features and response to 25-hydroxyvitamin D. Gastroenterology 1982;83:103–108.
146. Janes CH, Dickson ER, Okazaki R et al
. Role of hyperbilirubinemia in the impairment of osteoblast proliferation associated with cholestatic jaundice. J Clin Invest 1995;95:2581–2586.
147. Lindor KD, Janes CH, Crippin JS et al
. Bone disease in primary biliary cirrhosis: does ursodeoxycholic acid make a difference? Hepatology 1995;21:389–392.
148. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. report of a WHO study group. World Health Organ Tech Rep Ser 1994;843:1–129.
149. Zein CO, Jorgensen RA, Clarke B et al
. Alendronate improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled trial. Hepatology 2005;42:762–771.