The Medical Management of Primary Sclerosing Cholangitis

Abstract

Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic liver disease of uncertain etiology characterized by the destruction of the intrahepatic and/or extrahepatic ducts through inflammation and fibrosis. This ultimately leads to biliary complications including cirrhosis, cholangiocarcinoma, and eventually death. Given the uncertainty surrounding the pathogenesis of the disease, a number of different medical therapies have been studied in the treatment of PSC. However, there currently are no effective medical therapies known to halt the progression of disease. The only definitive therapy for PSC is liver transplantation. This review will primarily focus on the medical approaches that have been studied for the treatment of PSC as well as on the management of symptoms commonly associated with the disease.

Introduction

PSC is a rare, chronic cholestatic liver disease of uncertain etiology with a prevalence of 8.5 to 13 cases per 100,000 persons.[1] It is characterized by the destruction of the intrahepatic and/or extrahepatic ducts through chronic inflammation and fibrosis, leading to biliary complications including bile stasis, cirrhosis, and ultimately liver transplantation or death by 7 to 12 years after diagnosis. PSC can affect both large and small bile ducts.[2] PSC is also associated with a 10% to 20% lifetime risk for the development of cholangiocarcinoma, and 70% of patients with PSC will have concomitant ulcerative colitis.[1–3]

PSC typically presents in the fourth or fifth decade of life, more commonly in whites and Northern European men than women.[4] Patients often have abnormal liver biochemistries or symptoms typical of PSC such as fatigue, pruritus, or jaundice. The diagnosis is then confirmed by imaging studies that show diffuse beading of the bile ducts in large-duct PSC, or by histology and biochemical studies that reveal typical features of PSC with a normal cholangiogram in small-duct PSC. Causes of secondary sclerosing cholangitis (a form of sclerosing cholangitis also characterized by biliary stricturing and dilatation, when a clear cause for the biliary damage can be identified such as an infectious or ischemic cause) must also be excluded.[4,5]

As mentioned previously, the cause of PSC is unknown, and even though it is thought that the disease may have an autoimmune origin, PSC often responds unfavorably to immunosuppressive therapy.[2] This continued uncertainty surrounding the pathogenesis of the disease has hindered the development of effective medical management. Thus, attempts at managing this progressive disease have been aimed at preventing the progression and complications associated with PSC as well as at controlling the associated symptoms. One medical therapy that continues to be extensively studied in the treatment of PSC is ursodeoxycholic acid (UDCA).

Ursodeoxycholic Acid

UDCA is a hydrophilic dihydroxy bile acid that has been used for the treatment of other cholestatic diseases including primary biliary cirrhosis (PBC), drug and parenteral nutrition-induced cholestasis, pregnancy-induced intrahepatic cholestasis, cystic fibrosis, progressive familial intrahepatic cholestasis, and chronic graft-versus-host disease.[6] In humans under normal physiologic conditions, the nontoxic, hydrophilic UDCA represents 3% of the normal bile acid pool. The mechanism of action of UDCA is complex and has been thoroughly reviewed elsewhere.[7] Even though no drug has been shown to alter the natural progression and history of PSC, UDCA has been extensively studied for the management of cholestatic liver diseases.[5]

UDCA has been studied in cholestatic liver diseases since the 1980s. Early studies on the effects of UDCA on PBC showed an improvement in standard liver function tests.[8,9] These results led to the study of UDCA in other cholestatic liver diseases, including PSC, particularly because side effects from UDCA are rare (most common being diarrhea) and because it has proven to be a safe drug.[10] An improvement in liver enzyme levels (alkaline phosphatase, bilirubin, alanine aminotransferase, and gamma-glutamyl transpeptidase [GGT]), was also demonstrated in patients with PSC who were treated with UDCA.[11–14] Symptoms of fatigue and pruritus were also improved by UDCA.[12,14]

Initial studies of UDCA conducted in patients with PSC were very small and used daily doses that ranged from 8 to 15 mg/kg. Results were encouraging as to effects on serum liver biochemistries and even histology.[15–17] However, results of larger studies were not as promising. In 1996, De Maria and colleagues[18] evaluated the efficacy of UDCA 300 mg twice daily vs colchicine 0.6 mg twice daily and also a control group of untreated patients with PSC. This was a randomized, controlled study involving 59 patients with PSC over a 2-year period. No difference was found between groups with respect to liver function, liver injury, or findings on endoscopic retrograde cholangiopancreatography (ERCP).

Lindor [19] reported similar findings in 1997 in one of the largest trials conducted to date to evaluate the efficacy of UDCA in PSC. This randomized, double-blind study compared UDCA (13-15 mg/kg/day) with placebo in 105 patients with PSC, with a median follow up of 2.2 years. The primary outcome was time to treatment failure, which was defined as death; liver transplantation; histologic progression to cirrhosis or by 2 stages (of 4); development of varices, ascites, or encephalopathy; marked worsening of fatigue or pruritus; sustained quadrupling of the serum bilirubin concentration; inability to tolerate the drug; or voluntary withdrawal from the study. There was no difference in this primary outcome measure between groups. Even though 51% of study patients had stage 3 or 4 disease at baseline, no significant difference in time to treatment failure was found even when comparing only those patients with early (stage) histologic disease. Overall, UDCA did not significantly improve symptoms or histologic findings in this group of patients with well-documented PSC. In 1998, van Hoogstraten and colleagues[20] confirmed some of Lindor's observations. They studied the effects of UDCA (10 mg/kg/day) given as single vs multiple daily doses in a 2-year randomized, controlled trial that included 48 patients with PSC. Liver biochemistries (alkaline phosphatase, GGT, and aspartate aminotransferase) significantly improved in both groups, although there was no advantage for the multiple-dose UDCA regimen over the single-dose regimen. These findings were followed by a later study done by Okolicsanyi and colleagues,[21] who in 2003 showed that patients with PSC treated with 8 to 13 mg/kg/day of UDCA had a significant improvement in liver biochemistries and symptoms.

High-Dose UDCA

Although UDCA was reported to improve liver enzyme levels in patients with PSC, the clinical benefits with respect to its effect on liver histology, symptoms, and radiologic appearance were not as clear. Therefore, it was hypothesized that higher doses of UDCA might be needed to see a beneficial effect on disease progression and survival. In this context, Harnois and colleagues[22] assessed the tolerability and effectiveness of high-dose UDCA (25–30 mg/kg/day) in a pilot study that enrolled 30 patients with PSC who were treated for 1 year. Changes in the Mayo risk score at 1 year of treatment and projected survival at 4 years of treatment were then compared with the results from the randomized, placebo-controlled trial conducted by Lindor[19] that examined the efficacy of 13 to 15 mg/kg/day of UDCA vs placebo. The higher-dose UDCA was well tolerated, was associated with improvement in liver biochemistries, and of particular interest, resulted in a significant improvement in the Mayo risk score after 1 year of treatment, which translated into a significant improvement in 4-year survival.[21] Compared with the findings from Lindor's study, the study by Harnois and coworkers found that the projected mortality rate was significantly higher among patients treated with placebo compared with patients who received high-dose UDCA (25–30 mg/kg/day), but no significant difference was found in the mortality rate between placebo and UDCA 13 to 15 mg/kg/day.[22] Despite the finding that UDCA dosed at 25 to 30 mg/kg/day had a positive effect in this study, Rost and colleagues[23] subsequently showed that biliary enrichment of UDCA actually reaches a plateau at 22 to 25 mg/kg/day, suggesting that such a high dose of UDCA (ie, 25–30 mg/kg/day) may not be needed regardless of whether it is well tolerated.

These encouraging results with high-dose UDCA were also seen in a 2-year double-blind, placebo-controlled study conducted by Mitchell and colleagues[24] in which 26 patients with PSC were randomized to 20 mg/kg/day of UDCA or placebo. Similar to what was done in van Hoogstraten's study, cholangiography and liver biopsy were performed at study entry and after 2 years. Mitchell and coworkers found that while symptoms did not significantly improve with high-dose (20 mg/kg/day) UDCA, there was significant improvement in liver function tests (alkaline phosphatase, GGT) compared with placebo, and high-dose UDCA was well tolerated. However, of particular note, there was a significant reduction in liver fibrosis as assessed by staging, and in progression of cholangiographic appearance, in the high-dose UDCA group compared with placebo.

In 2005, Olsson and colleagues[25] conducted a randomized, placebo-controlled study involving 219 patients with PSC to assess the efficacy of higher-dose UDCA (17-23 mg/kg/day) vs placebo. The primary study endpoints were death (mainly from liver failure or cholangiocarcinoma) or liver transplantation. They found that the use of higher-dose UDCA significantly improved liver biochemistries – however, there was no difference between the 2 groups in terms of quality of life or symptoms. Additionally, although the combined endpoint of death or liver transplantation improved in the UDCA group compared with placebo, it did not reach statistical significance. The study authors did see a trend toward improved survival without liver transplantation in the UDCA-treated patients, but they determined that the study was underpowered to truly exclude a significant effect on survival. Overall, the higher-dose UDCA was well tolerated, but results revealed no significant beneficial effects on survival or prevention of cholangiocarcinoma in PSC. A large randomized, controlled trial of high-dose UDCA in patients with PSC currently in progress at the Mayo Clinic will hopefully help to address this issue more definitively.

Some studies have also shown a beneficial effect associated with the use of UDCA on the incidence of colonic neoplasia and cholangiocarcinoma in patients with PSC. PSC is associated with a 10% to 20% lifetime risk for the development of cholangiocarcinoma, and patients with ulcerative colitis and PSC are at a higher risk for colonic dysplasia and colon cancer (0.5% to 1% per year of disease).[1,2,26,27] Studies have demonstrated that UDCA use is associated with a lower prevalence of colonic neoplasia in patients with PSC and concomitant ulcerative colitis.[26–28] Indeed, an experimental study in rats found that treatment with UDCA reduced hepatocarcinogenesis.[29] In a recent study, Rudolph and colleagues[30] sought to examine the influence of UDCA on the incidence of cholangiocarcinoma in patients with PSC. From 1987 to 2005, 150 patients with PSC but without cholangiocarcinoma at entry were included in the study. Subjects were treated with UDCA that was gradually increased in dosage throughout the study (to 18-21 mg/kg/day), as higher doses seemed to show beneficial effects. Liver biochemistries significantly improved during treatment. The annual incidence of cholangiocarcinoma was 0.49%, which decreased with time of treatment to a point such that after 8.3 years of treatment with UDCA, no other patients developed cholangiocarcinoma.

Overall, data supporting the use of UDCA in patients with PSC are encouraging. Low-dose (8-15 mg/kg/day) and high-dose UDCA have demonstrated clinical benefits in patients with PSC. However, a consensus has not been reached regarding whether treatment with UDCA can halt disease progression in PSC. Table 1, Table 2 and Table 3 summarize the results of studies assessing the clinical effects of UDCA in PSC.

Table 1.

Uncontrolled Trials of UDCA for Treatment of PSC

Author/Year	No. of Patients	Dose of UDCA/Duration	Biochemical Response	Symptom Improvement	Histologic Response
Podda et al[11] 1989	6	250-750 mg/day 6 months	Yes	NA	NA
Chazouilleres et al[12] 1990	15	750-1250 mg/day 6 months	Yes	NA	NA
O'Brien et al[14] 1991	12	10 mg/kg 30 months with 24 months of treatment	Yes	NA	NA
van Milligan de Wit et al[16] 1999	17	12-15 mg/kg/day 1 year	Yes	NA	NO

UDCA = ursodeoxycholic acid; PSC = primary sclerosing cholangitis; NA = not available

Table 2.

Controlled Trials of UDCA for Treatment of PSC

Author/Year	No. of Patients	Dose of UDCA/Duration	Biochemical Response	Symptom Improvement	Histologic Response
Beuers et al[15] 1992	14	13-15 mg/kg/day 1 year	Yes	No	Yes
Stiehl et al[17] 1994	20	750 mg/day 3 months controlled	Yes	No	Yes
De Maria et al[18] 1996	59	600 mg/day 2 years	No	NA	No
Lindor[19] 1997	105	13-15 mg/kg/day 2.2 years median follow-up	Yes	No	No
van Hoogstraten et al[20] 1998	48	10 mg/kg/day 2 years	Yes	No	No
Okolicsanyi et al[21] 2003	86	8-13 mg/kg/day Retrospective	Yes	Yes	NA

UDCA = ursodeoxycholic acid; PSC = primary sclerosing cholangitis; NA = not available

Table 3.

High-Dose UDCA for PSC Treatment

Author/Year/Design	No. of Patients	Dose of UDCA/Duration	Biochemical Response	Symptom Improvement	Significant Histologic Response
Harnois et al[22] 2001 Open label, historical controls	30	25-30 mg/kg/day 1 year	Yes	NA, but improved survival	NA
Mitchell et al[24] 2001 Randomized, placebo-controlled	26	20 mg/kg/day 2 years	Yes	No	Yes
Olsson et al[25] 2005 Randomized, placebo-controlled	219	17-23 mg/kg/day 5 years	Yes	No, but a trend toward improved survival	NA

UDCA = ursodeoxycholic acid; PSC = primary sclerosing cholangitis; A = not available

UDCA Combined With Other Therapies

Given some of the promising results reported for UDCA in the treatment of patients with PSC, a number of studies have set out to assess the utility of UDCA given in combination with other drugs in these patients as well (Table 4).

Table 4.

UDCA in Combination Therapy for PSC

Author/Year/Type of Trial	No. of Patients	Dose of UDCA/Duration	Biochemical Response	Symptom Improvement	Histologic Response
Lindor et al[31] 1996 Uncontrolled	19	13-15 mg/kg/day of UDCA + MTX 0.25 mg/kg/week 2 years	Yes, but not different than the UDCA alone group	No	No
Stiehl et al[36] 1997 Uncontrolled	65	750 mg/day of UDCA + endoscopic intervention Mean 45 months	Yes	NA, but showed improved survival	NA
Schramm et al[32] 1999 Uncontrolled	15	UDCA 500-750 mg/day + azathiopurine 1-1.5 mg/kg/day + prednisolone 1 mg/kg/day initially, then tapering to 5-10 mg/day Median of 41 months	Yes	Yes	Yes
Van Hoogstraten et al[33] 2000 Randomized, Double-blind Non Placebo-controlled		12 mg/kg/day UDCA + budesonide (3 mg/day or 9 mg/day) or prednisone 10 mg/day 8 weeks	Yes in the prednisone group, but no change in the budesonide group	Yes in the prednisone group, but no change in the budesonide group	NA
Sterling et al[34] 2004 Randomized Controlled Pilot Study	25	13-15 mg/kg/day UDCA ± MMF 2000 mg/day 2 years	Yes, but not different than the UDCA alone group	NA	No
Farkkila et al[35] 2004 Randomized, Placebo-controlled	80	UDCA 15 mg/kg/day ± MTZ 600-800 mg/day 36 months	Yes in both groups, but AP decreased more in the combination group	NA, but improved Mayo risk score occurred in the combination therapy group	No

UDCA = ursodeoxycholic acid; PSC = primary sclerosing cholangitis; NA = not available; MTX = methotrexate; MMF = mycophenolate mofetil; MTZ = metronidazole; AP = alkaline phosphatase

UDCA + Methotrexate

Lindor and colleagues[31] conducted a pilot study to investigate the safety and efficacy of combination treatment with UDCA (13-15 mg/kg/day) and oral methotrexate (0.25 mg/kg/wk) over a 2-year period in 19 patients with PSC. The results were then compared with those from a group of 10 concurrently studied nonrandomized patients with PSC who were receiving UDCA alone. The study authors found that the use of UDCA in combination with methotrexate was not associated with any significant improvement in liver biochemistries (alkaline phophatase, aspartate aminotransferase, bilirubin, albumin), symptoms, or liver histology compared with UDCA alone. Moreover, the combination therapy regimen was associated with increased toxicity.

UDCA + Steroids

Schramm and colleagues[32] studied the utility of combined therapy with UDCA (500-750 mg/day), prednisolone (1 mg/kg per day initially, then tapering to 5-10 mg/day), and azathioprine (1-1.5 mg/kg/day) in a pilot study of 15 patients with PSC treated for a median of 41 months. Liver enzyme levels significantly declined in all patients, including 7 patients who had previously been treated with UDCA (500-750 mg/day) alone. Ten patients underwent follow-up liver biopsy and ERCP; 60% had histologic improvement compared with baseline biopsy. Only 10% of patients showed deterioration on ERCP findings at follow-up. Overall, this combination regimen was well tolerated in 87% of patients.

An 8-week double-blind, randomized pilot study by van Hoogstraten and colleagues[33] examined the utility of additional treatment with budesonide (3 mg or 9 mg) or prednisone (10 mg) in 18 patients with PSC who had been treated with UDCA (12 mg/kg/day) for 5 months without achieving remission. Only pruritus and alkaline phosphatase levels decreased in the prednisone group, whereas no clinical or laboratory changes were observed in the budesonide groups. Although pruritus significantly decreased in the prednisone groups, this study was not placebo-controlled and was only short-term. Given the serious systemic side effects associated with corticosteroids, their use has generally been discouraged in the long-term treatment of patients with cholestatic liver disease.

UDCA + Mycophenolate Mofetil

Sterling and colleagues[34] reported results from a 2-year randomized pilot study involving 25 patients with PSC treated with UDCA (13-15 mg/kg/day) alone or in combination with the immunosuppressant, mycophenolate mofetil given at a dose of 1000 mg twice daily. Liver biopsy and cholangiography were performed at study entry and after 2 years of treatment. There were no significant differences found with respect to liver enzyme levels, histologic stage, or cholangiograms between the 2 groups. Thus, although well tolerated, mycophenolate mofetil + UDCA does not appear to provide any additional benefit over UDCA alone in the treatment of PSC.

UDCA + Metronidazole

Investigators recruited 80 patients with PSC into a randomized, placebo-controlled study to explore the effect of UDCA + metronidazole vs UDCA + placebo on disease progression in PSC.[35] Subjects were randomized to either UDCA (15 mg/kg/day) + placebo or UDCA (15 mg/kg/day) + metronidazole (600-800 mg/day) for 36 months. Serum liver biochemistries improved in both study groups, but serum alkaline phosphatase improved more significantly in the UDCA + metronidazole group. However, no statistically significant benefit was seen between the 2 treatment groups with respect to disease progression (assessed by histology or ERCP).

UDCA + Endoscopic Therapy

Stiehl and colleagues[36] studied survival in 65 patients with PSC who were treated with UDCA (750 mg/day) and endoscopic therapy (consisting of repeated balloon dilatations) when necessary. The mean follow-up period was 45 months. Eighteen percent of patients had major duct stenosis at study entry and major duct stenosis requiring endoscopic intervention developed in another 11 patients during UDCA treatment, and thus the authors concluded that UDCA did not prevent major duct stenosis. During follow-up, only 1 patient died of cholangiocarcinoma, and 1 patient needed liver transplantation. Both of these patients had a major duct stenosis. The actuarial survival without liver transplantation after treatment with UDCA + endoscopic therapy was significantly improved compared with the predicted survival.

Although the use of UDCA has shown some promising effects on liver biochemistries in patients with PSC, its overall impact on disease progression (assessed by ERCP or liver histology), symptoms, and prognosis has been inconclusive. Additional larger, randomized, placebo-controlled trials are needed to better assess the utility of UDCA in this setting.

Other Therapies

In addition to UDCA, a number of other therapies have also been evaluated for their utility in the treatment of PSC; some of these key data are discussed below. These medications either have been associated with a decreased risk for PSC (ie, nicotine), have shown encouraging results in the treatment of other diseases with a presumed immunologiic basis (ie, budesonide, bezafibrate, methotrexate, tacrolimus and mycophenolate mofetil), or have shown a promising effect in the treatment of PSC in small pilot studies (ie, methotrexate, colchicine, tacrolimus). However, there is still no evidence supporting a specific medical therapy capable of halting disease progression in PSC, and none of the drugs discussed below has been approved for the treatment of PSC.

Budesonide

Angulo and colleagues[37] evaluated the safety and efficacy of budesonide in PSC. This study involved 21 patients with PSC who were treated with oral budesonide (9 mg/day) for a period of 1 year. Although serum levels of alkaline phosphatase and aspartate aminotransferase as well as the degree of portal inflammation significantly improved at the end of treatment, there were no significant changes in Mayo risk score or stage of disease. In addition, there was a marked loss of bone mass of the femoral neck and lumbar spine at the end of treatment.

Nicotine

Smoking has been associated with a decreased risk of ulcerative colitis and PSC.[38–42] Although oral nicotine and transdermal nicotine patches have been studied for their utility in the treatment of patients with PSC, these studies have not demonstrated any improvement in liver biochemistries or symptoms commonly associated with PSC. In addition, side effects were seen in the patients taking nicotine, including nausea, vomiting, dizziness, and insomnia. Therefore, neither oral nor transdermal nicotine appear to have any role in PSC treatment.[38,39]

Bezafibrate

Bezafibrate, a fibric acid derivative, is used for the treatment of hyperlipidemia and has been shown to improve liver enzyme levels in patients with PBC . In addition to its effects on lipid metabolism, bezafibrate may also reduce biliary inflammation.[43–45] Bezafibrate has been shown to significantly improve liver biochemistries in patients with PSC in a very small study and in case reports from Japan.[43,44,46] Bezafibrate was also well tolerated without significant side effects.[43] Thus, additional studies are warranted to assess the utility of bezafibrate in PSC.

Oral Methotrexate

The efficacy of 0.2 mg/kg/wk oral methotrexate was assessed in a pilot study involving 10 patients with PSC without signs of portal hypertension who were treated for at least 1 year.[47] Liver biochemistries improved in all patients. After 1 year of treatment, 9 patients had liver biopsy; 66% showed histologic improvement with a reduction in inflammation whereas 33% had stable histologic findings. Six patients underwent repeat cholangiogram after treatment and 2 showed improvement. Overall, no toxicity was seen in these 10 patients.

In follow-up to these findings, the same group conducted a prospective placebo-controlled, double-blind trial to evaluate the effectiveness of methotrexate vs placebo in 24 PSC patients over 2 years.[48] Whereas serum levels of alkaline phosphatase improved in the methotrexate-treated group, no significant changes were seen in other liver enzyme levels. More important, no significant changes were seen in histology or ERCP findings between the 2 groups (methotrexate vs placebo). Overall, there was no significant toxicity from methotrexate. On the basis of these findings, methotrexate does not appear to have a role in the treatment of patients with PSC and advanced liver disease.[49]

Colchicine

Colchicine is considered to have antifibrotic properties and has been studied in patients with cholestatic liver disease, including PSC.[10,50] Lindor and colleagues[51] evaluated the efficacy of colchicine (0.6 mg twice daily) given in combination with prednisone (10 mg/day) in 12 patients with PSC over a 2-year period compared with untreated historical controls. At 6 and 12 months, the treatment group had a significant improvement in liver biochemistries over baseline compared with untreated controls, but after 2 years there was no significant difference in liver biochemistries or histology between the 2 groups. After 2 years, 2 patients in the control group died whereas none died in the treatment group, suggesting a possible trend toward improved survival in the treatment group.

A randomized, double-blind, placebo-controlled trial from Sweden evaluated 84 patients with PSC who received either 1 mg/day of colchicine or placebo for 3 years.[50] Liver enzyme levels were checked at 6-month intervals and liver biopsies were performed pre- and post-study. The investigators found no beneficial effect of colchicine on liver biochemistries, histology, symptoms, or survival. On the basis of these findings, colchicine does not appear to have a role in the treatment of PSC.

Tacrolimus

Tacrolimus is an immunosuppressive macrolide antibiotic commonly used in transplant patients. In a small pilot study by Van Thiel and colleagues,[52] 10 patients with PSC were treated with tacrolimus for a period of almost 1 year and showed improvement in liver biochemistries without significant adverse events on serum blood urea nitrogen and creatinine levels and only a transient fall in the platelet count.

These encouraging results led to an open-label, phase 2 study assessing the efficacy of tacrolimus (0.05 mg/kg twice daily) in 16 patients with PSC over a 1-year period.[53] Only 50% of patients completed the 1 year of treatment, while 31% stopped therapy secondary to drug-related adverse events such as diarrhea, nausea, vomiting, tremor, headache, parasthesia, abdominal pain, fatigue, joint pain, heartburn, ataxia, and pruritus. However, patients who completed therapy had a significant improvement in alkaline phosphatase and aspartate aminotransferase levels. Larger trials are needed to further evaluate the potential utility of tacrolimus in the treatment of PSC.

Mycophenolate Mofetil

Talwalkar and colleagues[54] studied the safety and efficacy of mycophenolate mofetil (1-3 g/day) in 30 patients with PSC over a 1-year period. Of the 30 patients, 47% had stage 3-4 liver disease at study entry. Twenty-three patients completed therapy and a significant improvement was seen in serum alkaline phosphatase levels at the end of treatment. However, no other significant changes in liver biochemistries or Mayo risk score were appreciated. It has been suggested that immunosuppressive therapy should be started before the development of irreversible fibrosis and stricturing,[55] which may explain why mycophenolate mofetil did not have a positive effect in this study population, as 47% had advanced fibrosis.

Other Medical Therapies

Additional medical therapies that have been evaluated for their potential utility in the treatment of PSC include pencillamine, etanercept, pentoxifylline, azathioprine, cladibrine, and pirfenidone, but none of these agents has been shown to have a definitive beneficial effect in the treatment of patients with PSC.[56–61] The efficacy of combination therapy with cyclosporine + steroids as well of sulfasalazine have also been studied in the treatment of patients with PSC. Although data were encouraging, larger randomized trials are needed to better evaluate these approaches.[62,63]

Symptomatic Management of PSC

The 2 most common symptoms associated with PSC and other cholestatic liver diseases are fatigue and pruritus. Fatigue can be a major problem in patients with cholestatic liver disease, and unfortunately, it can be difficult to treat as well. UDCA has been shown in a few studies to improve fatigue.[12,13,16] It has been suggested that fatigue may just be a symptom of depression, which is a common comorbid medical problem in patients with chronic diseases.[64] A more recent study by van Os and colleagues,[65] however, failed to demonstrate an increased frequency of depression in patients with PSC. One study assessed the efficacy of the antidepressant fluvoxamine in the treatment of fatigue in patients with cholestatic liver diseases but found no statistically significant beneficial effect on quality of life or fatigue.[66] Pruritus was also not improved after 6 weeks of treatment.[66] The authors did comment that the trial may have failed to detect a true therapeutic effect of fluvoxamine because the number of patients enrolled in the study was lower than expected and the number of patients discontinuing treatment was higher than expected. Therefore, a beneficial treatment effect may have been missed. [66] Despite these negative results, it is important to look for and to treat conditions that can cause or worsen fatigue, including depression, anemia, adrenal insufficiency, sleep disorders, and hypothyroidism.

Pruritus is a debilitating symptom associated with cholestatic liver diseases. A recent randomized, double-blind, placebo-controlled study conducted by Mayo and colleagues[67] evaluated the efficacy of the selective serotonin reuptake inhibitor sertraline for cholestatic pruritis. They found that sertraline seemed to be an effective treatment for pruritis caused by chronic liver disease. Sertraline was also shown to improve skin manifestations associated with cholestatic pruritus. Overall, sertraline was well tolerated, but some of the reported side effects in the study included an increase in bowel frequency and fatigue, visual hallucinations, and dizziness. Other side effects associated with sertraline have included insomnia, headaches, and nausea.[66] Whereas these positive results for sertraline support its potential use as a first-line therapy for the treatment of pruritus in cholestatic liver disease, other studies have suggested that cholestyramine, a bile acid binding resin, may have a preferred role as a first-line therapy in this setting because of its lack of significant side effects.[6] Opioid antagonists such as naloxone have also been shown to be effective in the treatment of pruritus. Although an opioid withdrawal reaction can occur, it usually resolves in a few days after starting treatment.[6] Other agents/approaches that have been used in the management of cholestatic pruritus with variable success include rifampicin, antihistamines, ondansetron, phenobarbital, propofol, S-adenosyl methioine, gabapentin, plasmapheresis, albumin dialysis, and phototherapy.[66] Agents that have specifically been shown to improve pruritus in patients with PSC include UDCA, prednisone, and etanercept.[12,14,17,33,57] However, despite all of these potential therapies, management of pruritus can be quite challenging.

In addition to fatigue and pruritus, patients with PSC are at risk for fat-soluble vitamin deficiency and osteoporosis.[68,69] Jorgensen and colleagues[68] evaluated fat-soluble vitamin levels in patients with PSC enrolled in a clinical trial. Vitamin A deficiency was seen in 40% of patients, vitamin D deficiency in 14%, and vitamin E deficiency was seen in 2% of patients. This study also looked at a group of patients with PSC being evaluated for liver transplantation and found that 82% were deficient in vitamin A, 57% were deficient in vitamin D, and 43% were deficient in vitamin E. The investigators concluded that fat-soluble vitamin deficiencies are common in patients with PSC, particularly as their disease advances, and supplementation should be given as needed.

Vitamin D deficiency is just one of the risk factors for bone loss and osteoporosis in patients with PSC. Although osteoporosis does not seem to be as prevalent in PSC as in PBC, it still poses additional management issues, especially in patients with concomitant inflammatory bowel disease.[69] There are no evidence-based reports outlining osteoporosis management in patients with PSC, but in general, therapy includes lifestyle modifications such as weight-bearing exercises, smoking cessation, and limiting alcohol intake as well as supplementation with vitamin D and calcium. Bisphosphonate therapy may also be considered in this setting.[6]

Conclusion

PSC is a rare cholestatic liver disease of unclear etiology. Many different therapies have been evaluated as potential options for these patients. Although a few studies have indeed shown promising results for high-dose UDCA as well as for some other medical therapies, as discussed in this review, there is still no evidence supporting a specific medical therapy capable of halting disease progression in PSC. Therefore, the definitive therapy for patients with PSC who have advanced disease is still liver transplantation. At present, management of PSC remains focused on treating the symptoms and complications that are associated with disease progression and entails close surveillance of patients with advanced liver disease.