Hepatobiliary Associations with Inflammatory Bowel Disease

Expert Rev Gastroenterol Hepatol. 2009;3(6):681-91. © 2009 Expert Reviews Ltd.

Abstract

Hepatobiliary disease is not uncommon in patients with inflammatory bowel disease (IBD). The most common autoimmune hepatic associations are primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). The immunosuppressant medications used in the treatment of IBD also have potential hepatotoxicity. PSC is most commonly associated with IBD, specifically ulcerative colitis. AIH, a more classic autoimmune disease diagnosed commonly in isolation of other conditions in the same individual, is less commonly associated with IBD. Additionally, a subgroup of patients have features of both PSC and AIH, termed overlap syndrome, that is also sometimes seen in IBD patients. This review will discuss the most common liver disease associations seen in patients with IBD: PSC, AIH and overlap syndrome. Additionally, the most common drug-related hepatotoxicities encountered when treating IBD will be reviewed.
Introduction

The association between inflammatory bowel disease (IBD) and hepatobiliary disorders was first described in the late 1800s. Over the past century, knowledge of this association has grown dramatically. IBD has been associated with an increased risk of other autoimmune diseases.[1] Primary sclerosing cholangitis (PSC) is one of the most common extraintestinal manifestations of IBD, particularly in ulcerative colitis (UC) patients.[2] Autoimmune hepatitis (AIH) is also seen, and recently an overlap syndrome has been described in some patients, who have classic features of more than one autoimmune liver disease – either PSC, AIH or primary biliary cirrhosis (PBC).[3,4] There has also been an increase in hepatotoxicity as a sequela of the broadening pharmacologic armamentarium used to treat the underlying IBD.[5]

A true estimation of the prevalence of hepatobiliary disease in IBD patients is difficult to determine. Performance of liver biopsies and cholangiograms on a large number of patients is neither ethical nor feasible. A review of over 500 patients with IBD, however, found abnormal serum aminotransferases in almost a third of individuals, although the level of elevation was generally quite small (less than twice the upper limit of normal [ULN]).[6] Elevation of serum aminotransferases showed no correlation with active versus inactive IBD. The age-adjusted risk of death was 4.8-times higher in those with elevated serum aminotransferases than those with normal values, after excluding for other known liver disease. They also found that the patients with elevated serum aminotransferases were less likely to be on 5-aminosalicylates, but found no difference in other medication use between the two groups. The exact etiology of the abnormalities in the subjects of this study was unclear, owing to the fact that a formal workup was not performed in the majority of patients. Only 6% had identifiable liver disease (5% PSC).

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis is a chronic autoimmune cholestatic liver disease of unclear etiology that is characterized by progressive inflammation and fibrosis of the biliary tree. It may lead to biliary cirrhosis, end-stage liver disease and cholangiocarcinoma (CC). The majority of patients also have IBD.
Epidemiology

In children, the incidence of PSC is 0.23 cases per 100,000 person-years compared with 1.11 cases per 100,000 person-years in adults.[7,8] The prevalence is estimated to be between 8.5 and 13.6 per 100,000 patient years.[9] PSC affects approximately 5% of patients with UC and 3.6% of those with Crohn's disease.[10] The majority of patients with PSC also have IBD. PSC is typically diagnosed after the diagnosis of IBD, but can precede IBD by several years, or the IBD may be picked up incidentally on colonoscopy at the time of PSC diagnosis. In patients with PSC, the IBD course is often mild, rectal-sparing common and more severe right-sided disease, backwash ileitis, and a higher incidence of pouchitis after colectomy, often observed.[11–13] PSC is more common in males, with a 2:1 gender ratio, and typically presents in the fourth to fifth decades of life.[14,15] Smoking has been identified as having a protective effect against the development of PSC, in patients both with and without UC.[16,17] The median time from diagnosis to end-stage liver disease and death or liver transplantation is 12–18 years.[18,19] Neither the presence of IBD, nor the extent of IBD seem to have an impact on the progression of PSC.
Pathophysiology

The precise etiology of PSC remains unclear; however, multiple mechanisms are beleived to play a role, including immunological mechanisms, immunogenetic susceptibility and disorders of the biliary epithelia.[9] The association with other autoimmune disorders, the presence of autoantibodies, specifically high titers of antineutrophil antibodies (pANCA) and low titers of nonspecific antibodies, such as antinuclear antibody (ANA) and antismooth muscle antibody (SMA), support the theory that PSC has an autoimmune component. Additionally, there is an increase in circulating immune complexes and immunoglobulins in the blood. Factors that oppose this autoimmune theory, however, include male predominance and the poor response to immunosuppressive therapy observed.

There is a 100-fold increased risk of PSC in individuals who have a first-degree relative with PSC.[20] Relatives of PSC patients without IBD are also at increased risk for developing UC. It is thought that this genetic susceptibility is based on combinations of alleles of the MHC which encode HLA class I and II molecules, and play a role in the innate immune response. Several high-risk MHC alleles have been linked to the development of PSC (e.g., HLA B8, DR3 and DR6), although there are other non-MHC gene polymorphisms that may also play a role in immune regulation; nevertheless, specific candidate genes have failed to demonstrate reproducible involvement.[17,19,21–24]

Some theorize that PSC is an inflammatory response to bacterial or viral antigens entering the portal circulation through the mucosa in IBD. Flaws of this theory include studies that have failed to show bacteremia in the mesenteric or peripheral blood, small bowel bacterial overgrowth in patients with PSC or pathogens in stool samples. Infectious pathogenic agents that have been suspected by those who support this theory include Helicobacter, Cytomegalovirus, Reovirus and Candida, although initial suggestive studies have not been reproduced.[25–28] A related theory suggests that long-lived lymphocytes generated in the gut persist as memory cells and are translocated to the liver via the enterohepatic circulation. Upon activation, these cells trigger hepatic inflammation.[9] Thus far, there is little evidence to support this theory.
Clinical Presentation

A total of 21–44% of patients are asymptomatic at diagnosis.[9] Of those who are symptomatic, presenting signs and symptoms typically include abdominal pain (33–37%), jaundice (27–30%), pruritus (20–40%), fever (11–35%), diarrhea (8%), hepatomegaly (44–55%), splenomegaly (29–30%), ascites (2–4%), variceal bleeding (2.6–6%) and osteopenic bone disease (50%). Apart from IBD, which is seen in up to 90% of patients with PSC, more than 20% of PSC patients display at least one additional extraintestinal autoimmune feature.[9,29] A total of 10.1% of patients have insulin-dependent diabetes mellitus, 8.4% have thyroid disorders and 4.2% have psoriasis.[9]

Laboratory profiles reveal that PSC patients will have alkaline phosphatase levels over three times the ULN and significant elevation of γ-glutamyl transferase (GGT).[30] Relatively mild elevation of the serum aminotransferases is often seen. Bilirubin levels are typically normal, although rare dominant stricturing in the biliary system and late sequelae such as cirrhosis and intrahepatic disease can result in direct hyperbilirubinemia and pruritis. Early in the disease course, hepatic synthetic function is normal, but later on in the course, hepatic function may be impaired. Multiple autoantibodies can also be positive (e.g., ANA and SMA), although the only one that may have a diagnostic role is pANCA.

Nonspecific portal inflammation, which progresses to periportal fibrosis, is the most common histological finding in PSC. A more specific finding is an 'onion-skin' pattern of periductal fibrosis leading to ductopenia and cholestasis, although this is only seen in approximately 50% of patients (Figures 1 & 2).[31] Fibrous obliterative cholangitis, found in only 5–10% of patients, is pathognomonic for PSC.

Figure 2

Imaging

In conjunction with supportive histological findings, the diagnosis of PSC is made by the presence of characteristic findings of multifocal segmental strictures (i.e., 'beads on a string'), focal dilation of intra- and/or extra-hepatic bile ducts, and mural irregularities on endoscopic retrograde cholangiopancreatography (ERCP) (Figure 3). Although ERCP is considered the gold-standard diagnostic tool, it is invasive and often associated with complications, including pancreatitis, cholangitis, perforation, bleeding and progression of cholestasis in 5–7% of patients.[9,32] Consequently, several groups have studied the sensitivity and specificity of magnetic resonance cholangiopancreatography (MRCP), a less invasive alternative to ERCP, to detect PSC. A recent study of 95 patients (69 PSC patients, 26 controls) undergoing ERCP also underwent MRCP.[32] Using ERCP as the gold standard, MRCP was found to have a sensitivity, specificity and diagnostic accuracy of 86, 77 and 83%, respectively. The authors concluded that although MRCP can be useful to diagnose PSC, the technique is limited early in the disease, with cirrhosis, and in the differentiation of CC. A comparable study in 19 children with PSC who underwent MRCP found a similar sensitivity of 84% and diagnostic accuracy of 84%, with a positive predictive value of 100%.[33] Specificity, however, could not be calculated due to a lack of a true negative.[33] Therefore, MRCP may support the diagnosis, but a negative study would not rule out PSC.[32]

Cholangiocarcinoma

Cholangiocarcinoma is found in 3.3% of adult PSC patients within the first 3 months of diagnosis, and in 5% within the first year.[9] Overall, 5–15% of patients with PSC develop CC with a mean survival of 5–7 months. Smoking and alcohol consumption have been shown to be associated with an increased risk of the development of CC.[34,35]

Cholangiocarcinoma is currently the leading cause of death in patients with PSC, and adult age at diagnosis does not seem to influence prognosis. Bjornsson and Angulo recently described a series of young adults (aged 18–25 years) with concomitant PSC and CC.[36] In general, they had a history of long-standing IBD (mean: 11 years; range: 1–20 years) and the conditions were associated with Crohn's disease more than that of UC. They had a similarly poor outcome to that of older individuals with CC.[36]

The development of CC is unpredictable on the basis of the duration, symptoms and severity of PSC. A liver transplant generally does not improve survival and is therefore not routinely performed in the setting of CC. However, with early detection in patients with perihilar CC confined to the biliary tree, a combination of chemoradiotherapy with liver transplant yielded a 5-year survival of 82%.[37]

Detection of CC can be challenging. Neither computed tomography (CT) nor ultrasound is sensitive enough to reliably detect CC in PSC. However, PET using 2-[18F] fluoro-2-deoxy-D-glucose (FDG) differentiates well between CC and nonmalignant tissue. Prytz et al. performed FDG-PET in 24 patients with PSC within 2 weeks of being listed for liver transplantation, without evidence of malignancy on CT, MRI or ultrasonography.[38] They examined whether the PET findings were valid using a blinded study design comparing pretransplantation FDG-PET results with the histology of explanted livers. They found PET was positive in three patients who had CC, negative in one patient with high-grade hilar duct dysplasia, negative in 20 patients without malignancies and false-positive in one patient with epitheloid granulomas in the liver.[38]

Charatcharoenwitthaya et al. performed a retrospective review of 230 patients with PSC; 23 developed CC, with an annual incidence of 1.2% per year.[37] They compared the sensitivity, specificity, positive and negative predictive value of CA 19–9 with and without various imaging modalities. They also compared a number of cytological techniques (Table 1). No single test was both sensitive enough and specific enough for diagnosis. From this, they concluded that screening using CA 19–9 (with a cut-off value of 20 U/l) in addition to cross-sectional liver imaging is useful for detection of most cases of CC. Confirmation of a diagnosis is best done using cholangiography in addition to cytologic evaluation.[37] Early detection is important, as there may be curative options at the earliest stages. Therefore, yearly screening is recommended in adults. CC has not been reported in children with PSC; therefore, these guidelines do not extend to the pediatric age group.

In addition to an increased risk for CC, patients with PSC also have a higher incidence of colorectal carcinoma (CRC).[39] This is higher than the risk of developing CC, although CC is more likely to lead to death. Patients with PSC–IBD have a 31% chance of developing CRC at 20 years. This is significantly greater than the 8% risk in patients with IBD alone.[39–41] Patients continue to be at an increased risk of CRC even after orthotopic liver transplantation.[40]
Children

Although most patients diagnosed with PSC are adults, the incidence in children is 0.23 cases per 100,000 person-years.[7] Miloh et al. reviewed the charts of 47 pediatric patients with PSC. They found the mean age at diagnosis was 11 ± 4.9 years, and the subjects, as with adults, were predominantly male. A total of 81% of patients were symptomatic at diagnosis. IBD was found in 59%, and AIH (overlap syndrome) in 25% of patients. A total of 65% of patients were found to have bridging fibrosis/cirrhosis at the time of diagnosis. Similar to findings in adult studies, the median survival with a native liver was 12.7 years. The mean serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels at diagnosis (236/233) were higher than those reported in adults (48/83), and highest in patients with overlap syndrome (464/421). This suggests greater hepatocellular injury than is seen in adults.[7]
Older Adults

Some studies have shown two peaks in the age of onset of PSC, with the most common peak at approximately 40 years, and a second peak at 50–60 years. The older patients are much less likely to have IBD. Hirano et al. described a series of 18 patients with PSC whose age of onset was greater than 50 years.[42] They found that older patients have higher IgE, lower IgM, less association with UC and overall better prognosis. They suggest the pathogenesis may be different in this patient population.[42]
Small-duct PSC

There is a subset of patients with PSC who present with the characteristic biochemical and histological features of PSC, without the classic cholangiographic changes. These patients were previously considered to have pericholangitis; however, in 1985, this term was changed to small-duct PSC.[43] The prevalence of small-duct PSC is unknown but it has been reported to comprise 5–16% of PSC cases.[43] The natural history is poorly understood. Early studies required a diagnosis of IBD for diagnosis of small-duct PSC; however, this was abandoned in later studies. Crohn's disease is more often associated with small-duct than large-duct PSC.[8] Bjornsson et al. described a series of 83 patients with small-duct PSC, each well matched with two patients with large-duct PSC.[44] All patients were predominantly male with a mean age at diagnosis of 39 years. A total of 80% had IBD, and the median duration of follow-up was 13 years. A total of 68 of the patients underwent repeat cholangiography, and 19 (22.9%) had unequivocal progression to large-duct PSC. Only one of the patients who progressed to large-duct disease was diagnosed with CC, versus 19 of the 157 (12%) large-duct comparison patients. In the small-duct group, 11 (13.3%) of the patients died, and eight (9.8%) underwent liver transplant versus 45 (28.7%) and 33 (21%) of the large-duct patients, respectively. A total of 47% of the small-duct patients who progressed to large-duct disease went on to liver transplantation or died, versus 15% of those whose disease remained small-duct disease. Treatment with ursodeoxycholic acid (UDCA) did not influence progression to large-duct disease. The authors concluded that patients with small-duct PSC carry a significantly better long-term prognosis than those with large-duct disease; up to a quarter of patients with small-duct PSC may progress to large-duct PSC within an average follow-up of 8 years; CC does not occur in patients with small-duct PSC. Patients with small-duct PSC may progress to end-stage liver disease with the consequent need for liver transplantation without evidence of development of large-duct disease; and small-duct PSC may recur in the allograft.[44]

Figure 3

Treatment

Owing to the fact that the pathogenesis of PSC is unclear, finding appropriate pharmacologic agents that target the disease is difficult. UDCA is the most promising pharmacologic treatment for PSC to date. UDCA is a hydrophilic bile acid that is useful in a variety of cholestatic conditions and has an excellent safety profile. In vitro, there is a direct cytotoxic effect by hydrophobic bile salts on the bile duct epithelium and hepatocytes.[45] As a hydrophilic bile acid, UDCA may be directly cytoprotective by stabilizing cell membranes of the bile duct epithelia and hepatocytes. There may also be an indirect protective effect by displacing hydrophobic bile acids from the bile acid pool, thus decreasing exposure to toxic bile.

Multiple studies have shown improvement in liver laboratory values, as well as in histology in PSC patients, using UDCA. However, these studies have failed to show a difference in clinically relevant outcomes, such as delayed progression to portal hypertension, biliary cirrhosis, liver transplantation, decreased risk of developing CC or patient survival.

Since PSC is thought to be secondary to immune dysregulation, drug trials have also been conducted to test the efficacy of immunomodulators. No significant efficacy has been found with the use of budesonide, prednisone, mycophenolate mofetil, cladibrine, etanercept, pentoxifylline, colchicine, nicotine or penicillamine.[46–54] One study compared UDCA in combination with metronidazole to UDCA alone and found an improved effect on liver chemistries with the addition of metronidazole, although this did not translate to improved histology.[55] Another small study showed improved liver chemistries with the use of tacrolimus, although the study only included ten patients.[56]

There is some debate about the most effective dose of UDCA for the treatment of PSC. Several studies have looked at the effects of both standard-dose (8–15 mg/kg/day) and high-dose (20–30 mg/kg/day) UDCA. All doses result in biochemical improvement and, in the studies that looked at histology, all show improvement in inflammatory infiltrate levels, but no significant improvement in fibrosis. One small pilot study of high-dose UDCA also showed an improved Mayo Risk Score,[57] suggesting a possible improvement of disease progression. However, a larger randomized, placebo-controlled trial failed to show any difference in symptoms, quality of life, or outcomes such as death or progression to CC.[58,56] Recently, Lindor et al. published a double-blind, randomized, controlled trial of high-dose ursodiol versus placebo and found the medication-treated group was at an increased risk of serious adverse effects including the development of cirrhosis, varices, CC, liver transplantation and death, despite an improvement in biochemical responses in this group.[59] The mechanism underlying the adverse effects is unclear, particularly given the lack of these findings in patients treated with lower doses of ursodiol.

A small study by Davies et al. examined the use of oral vancomycin in the treatment of 14 children without IBD whose liver biopsies showed histological evidence of PSC in the absence of features of AIH.[60] All patients received oral vancomycin at a dose of 50 mg/kg/day. Four patients with evidence of cirrhosis on liver biopsy did not have normalization of liver laboratory tests. The remaining ten patients had normalization of the enzymes and received either intermittent short courses or long-term therapy with vancomycin. An increase in liver enzymes and an increase in clinical symptoms were seen when vancomycin was discontinued. Retreatment following relapse once again resulted in normalization of liver enzymes. Post-therapy liver biopsies in two patients showed improvement to normal histology. No patients experienced adverse events.[60]

It is thought that the efficacy of oral vancomycin is due to its antimicrobial effects on as yet unidentified gastrointestinal microorganisms that cause abnormal immunological reactions in the liver. Vancomycin has also been shown to downregulate TNF-α. A larger study in adults is currently underway.
Transplant

Primary sclerosing cholangitis is a slowly progressive disease that eventually leads to biliary cirrhosis and ultimately liver failure. No pharmacologic therapy to date has been successful in halting the progression of the disease. The only life-extending therapy is liver transplantation. PSC is the fourth most common indication for liver transplantation in adults, accounting for 10% of all liver transplants in the USA.[61] Most centers report a 1-year patient and graft survival of approximately 90%.[62] The timing of liver transplantation is difficult, as patients are at risk of acute and chronic rejection, biliary stricturing, hepatic artery thrombosis and a recurrence of PSC. A number of prognostic models have been designed to estimate the survival of individuals with PSC based on clinical, biochemical and histological data. These are designed to be useful models to predict the optimal timing of liver transplantation.

Independent variables that have been associated with poor outcome include advanced age, elevated serum bilirubin and/or AST levels, low hemoglobin and/or serum albumin levels, splenomegaly, hepatomegaly, IBD, a history of variceal bleeding, cholangiographic findings and advanced histological staging. Not all of these variables are included in the individual models, however. For example, the Mayo PSC Risk Score[57] is calculated using age, bilirubin, albumin and AST levels, and variceal bleeding. Studies have compared this tool to the Child–Pugh score, which uses serum bilirubin and albumin levels, the international normalized ratio (INR), ascites and hepatic encephalopathy, and found that the Mayo score is more useful in the early stages of PSC, and the Child–Pugh score is more helpful for patients with advanced disease.[62,63]

Recurrence of PSC post-transplantation occurs in up to 25% of patients. Studies have shown recurrence to be associated with factors such as recipient–donor gender mismatch, use of OKT3, corticosteroid-resistant rejection, recurrent episodes of cellular rejection, clinically significant cytomegalovirus infections and the presence of HLA-DRB1*08.[64–67] A recent study by Alabraba et al. described a large group of patients with PSC undergoing liver transplantation and found that colectomy pre- or peri-transplantation had a significant protective effect against PSC recurrence.[68] There has, however, been inconsistency between studies, as most have not utilized standard histological and radiological criteria, as defined by Graziadei et al..[69]

In a pediatric study, liver transplantation was performed in nine (19%) patients for recurrent cholangitis and/or decompensated cirrhosis, with a mean time from diagnosis to transplant of 7 years, which is similar to that seen in adults.[7] Patients with overlap syndrome were more likely than those without (25 vs 17%) to progress to liver transplantation. Two patients with small-duct disease underwent transplantation without progression to large-duct disease. PSC recurrence in grafts is reported to be up to 27% in children.[70] All patients diagnosed with recurrent PSC were treated with UDCA 20–30 mg/kg/day with resultant significant biochemical improvement.[7]

Autoimmune Hepatitis

Autoimmune hepatitis is another form of chronic liver disease commonly associated with IBD. Unlike PSC, AIH behaves more classically like other autoimmune diseases in that it is more common in females, is almost always associated with positive autoantibodies, and responds to immunosuppressive therapy. AIH may present as acute hepatic failure, acute hepatitis, chronic hepatitis or with complications of cirrhosis. When associated with IBD, it is commonly detected when screening serum aminotransferases are noted to be elevated.
Pathophysiology

The exact pathogenesis of AIH is unclear, although it is thought to arise from a cell-mediated immunologic attack against hepatocytes. A triggering event, such as infection, toxin or drugs, a genetic predisposition that influences autoantigen presentation and T-helper cell recognition, and other determinants of autoantigen display, immunocyte activation and effector cell expansion are known to play a role in AIH pathogenesis. Lankisch et al. recently showed an association between a heterozygous mutation in the AIRE gene, an autoimmune regulator gene responsible for autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy, and children with AIH type I.[71]
Epidemiology

The prevalence of AIH is approximately 17 per 100,000 persons in Northern European populations.[72] AIH accounts for 6% of adult liver transplantations in the USA. It is most commonly seen in Caucasian populations, and 70–80% of patients are female. There is a bimodal age distribution, with onset most commonly between ages 10–30 and 40–50 years. Up to 16% of patients with AIH also have UC.[73]
Diagnosis

Diagnosis is based on a combination of clinical, histological, biochemical and serologic features. The definitive diagnosis requires laboratory findings of characteristic immunoreactivity and consistent hepatic histology and exclusion of other causes of liver disease that can share similar histologic features (especially Wilson's disease, drug-induced hepatitis and viral hepatitis).

Hepatic histology characteristically includes interface hepatitis, defined as inflammatory hepatocyte destruction at the periphery of the lobule with erosion of the limiting plate. Other typical findings include a dense mononuclear and plasmacytic infiltration of the portal area and liver lobule, connective tissue collapse from hepatocyte death, and hepatocellular regeneration with 'rosette' formation (Figure 4).[74]

Figure 4

Autoimmune hepatitis is typically classified into three types based on the pattern of circulating autoantibodies. Type 1 is associated with SMA and ANA, type 2 is associated with antiliver kidney microsomal antibody (LKM), and type 3 is classified as seronegative (i.e., having features of AIH without the presence of the other typical autoantibodies). Mehendiratta et al. recently described a group of 52 patients with AIH and found that 19% of patients were seronegative.[75] There does not seem to be a difference in symptoms, response to medical therapy or long-term prognosis between the groups, and there is a similar rate of associated autoimmune disorders (20%) and family history of autoimmune disease (40%). Differences do include age of onset, HLA associations and frequency of progression to cirrhosis (44–80% of children with AIH type 2 at diagnosis[76]). All three types are associated with IgG elevation, but to various degrees (1 > 3 > 2), and only types 1 and 3 are associated with immunoglobulin A deficiency. Type 1 makes up two-thirds of cases, and is more common in adolescents and adults. Type 2 typically presents in younger children and infants, and has more of a tendency to present with acute liver failure.[74]
Treatment

The overall goals of treatment are to improve symptoms and survival. This is generally achieved by inducing and maintaining remission, defined as normalization of serum aminotransferases and IgG level, negative or low-titer autoantibodies, and histological resolution of inflammation. Conventional treatments utilize immunosuppressive therapy with steroids and azathioprine (AZA) or 6-mercaptopurine (6-MP). Prednisone (2 mg/kg/day, maximum 60 mg/day) should be initiated as soon as the diagnosis has been made, to prevent progression of the disease. The dose should be weaned over 4–8 weeks, driven by improvement in liver function tests. The addition of AZA or 6-MP is common, but the timing of this is variable. AZA/6-MP is not recommended as the initial therapy in patients due to the potential risk of drug-induced hepatotoxicity, but its use is required in up to 85% of patients once initial response to prednisone has been established.[74]

The disease typically responds well to treatment. In the first 2 months of therapy, aminotransferases improve by 80% in the majority of patients. A total of 95% of patients have histological improvement 4 years into their treatment course. Relapse is common, however, with up to 40% of patients requiring a temporary escalation of their steriod dose. The risk of relapse has been found to be higher on an every-other-day steroid regimen than a very low-dose daily schedule. In patients who are refractory to treatment with steroids and AZA/6-MP, or for those who are intolerant to these medications, success has been found with mycophenolate mofetil or calcineurin inhibitors (e.g., tacrolimus and ciclosporin).[77–84] However, these studies are primarily retrospective, and larger randomized, controlled trials are needed.

Cessation of therapy is possible if there is little or no inflammation on liver biopsy after having normal transaminases for at least 1 year, and more than 3 years have passed since diagnosis. Puberty is a time of frequent relapse and therefore discontinuation of therapy during this period is not recommended.

PSC/AIH Overlap Syndrome
Background

Primary sclerosing cholangitis/autoimmune hepatitis overlap syndrome has been used to describe the concomitant occurrence of clinical, biochemical, serological and/or histological features of PSC and AIH, although there is currently no standard definition. The estimation of overlap is quite variable between studies due to difficulties with definition and classification. Studies show between 7.6 and 53.8% of patients with PSC have features of AIH, and 42% of patients with AIH and UC have an abnormal cholangiogram.[73] Overlap syndrome appears to be more common in children and is commonly described as autoimmune sclerosing cholangitis.[85]
Diagnosis

Patients diagnosed with PSC radiographically should be suspected of having overlap syndrome if interface hepatitis is prominent on the histology, IgG levels are elevated, autoantibodies seen in AIH are present (ANA, SMA or LKM), or alkaline phosphatase is lower than expected. Conversely, patients diagnosed with AIH should be suspected of having PSC/AIH overlap syndrome if they have pruritis, elevated alkaline phosphatase or bile duct abnormalities on histology or cholangiography.[73]
Treatment

Patients with overlap syndrome have a moderate response to combination therapy with prednisone, with or without AZA/6-MP and UDCA. Studies have shown long-term survival without transplant to be better in these patients compared with those with PSC alone, although worse than in those with AIH alone. Floreani et al. described a series of seven patients with overlap syndrome, who were all originally diagnosed with AIH.[86] Cholangiography was later performed when resistance to immunosuppressive therapy developed at a mean of 17 months from the original diagnosis. They found more significant elevation of serum aminotransferases and IgG levels and less frequent association with IBD, when compared to a cohort with classical PSC. In follow-up after 5 years of treatment, the overlap syndrome patients treated with a combination of UDCA and immunosuppression showed a significant reduction in AST, a nonsignificant reduction in ALT, and no change in GGT or alkaline phosphatase.[86] The classical PSC patients treated with UDCA alone had no significant improvement in any of the above biochemistries.

Drug-induced Hepatotoxicity
Thiopurines

The thiopurines (6-MP and AZA) have proven useful for the treatment of IBD. There is, however, significant hepatotoxicity associated with their use. In a study of almost 3500 patients, AZA/6-MP-induced hepatotoxicity occurred in 3.4% of patients.[5] Overall, the incidence of hepatotoxicity in IBD patients on 6-MP/AZA is approximately 1% per patient-year, with no difference in the incidence of hepatotoxicity between AZA and 6-MP.[5] Most mild thiopurine-induced liver injury occurs in the first few months of therapy. In a small proportion of patients, transient elevation of hepatic enzymes occurs shortly after the initiation of therapy but resolves spontaneously without the need to adjust the medication dose. If serum transaminases become elevated long after stable doses of 6-MP/AZA, other causes of hepatic dysfunction generally need to be considered.

Serious hepatotoxicity related to thiopurine treatment can be grouped into three categories: hypersensitivity, endothelial cell injury and idiosyncratic cholestatic reaction.[5] Hypersensitivity reactions usually occur within 2–3 weeks of initiation of the drug, with a laboratory profile consistent with cholestatic injury, showing elevations of serum bilirubin and alkaline phosphatase. Endothelial cell injury is dose-dependent and can present any time between 3 months and 3 years after initiation of treatment. It may manifest as peliosis hepatis, nodular regenerative hyperplasia (NRH), veno-occlusive disease, sinusoidal dilatation and/or fibrosis. The idiosyncratic cholestatic reaction can present with severe jaundice. If jaundice occurs after the initiation of AZA or 6-MP, the drug should be discontinued immediately. In this unusual group of patients, resolution of jaundice may not occur after drug withdrawal and may actually continue to progress.[5]

Thiopurine methyltransferase (TPMT) is one of the therapeutically most important enzymes involved in the metabolism of 6-MP to its active and inactive metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP), respectively. Mutations of either one or both alleles encoding the TPMT gene may lead to decreased TPMT activity, resulting in elevated 6-TGN levels and consequent bone marrow suppression. Additionally, individuals with elevated 6-TGN levels, like those receiving treatment with 6-thioguanine, have a higher incidence of NRH. Conversely, elevated 6-MMP levels, seen in patients with high TPMT activity, are also associated with hepatotoxicity, most commonly asymptomatic elevation of the serum aminotransferases.[87,88]

Monitoring of serum aminotransferase levels is essential in all patients on AZA/6-MP, regardless of TPMT activity and metabolite levels. Patients who have an asymptomatic, slight increase in liver tests early in the treatment course should be continued on the drug at the current dose with close monitoring of biochemistries to ensure resolution. In a nonjaundiced patient with moderate-to-severe elevations in serum aminotransferase levels (5 × ULN), the medication dose should be decreased by 50%.[5] If the chemistries normalize, the dose may be escalated back to the original dose; however, if they remain abnormal, the drug should be discontinued. If the serum aminotransferase levels remain abnormal after discontinuation of the drug, a liver biopsy should be considered.
Infliximab

Infliximab, a chimeric monoclonal antibody that binds TNF-α, is used to treat IBD and rheumatoid arthritis. Several case reports have described asymptomatic serum aminotransferase elevation induced by infliximab. Other patients have been reported to develop cholestasis with a positive ANA level, whose symptoms and serum aminotransferases returned to normal after the discontinuation of infliximab and following treatment with prednisone. One patient with rheumatoid arthritis developed cholestatic liver disease 8 months into treatment with infliximab. Liver biopsy showed severe ductal proliferation with collapse and enucleation of the hepatocytes. The patient eventually developed hepatic failure requiring liver transplantation, despite aggressive treatment with steroids.[89,90]

Expert Commentary

Inflammatory bowel disease is frequently associated with liver disease. This review covers the most common causes of hepatobiliary disease in IBD patients, including PSC, AIH, overlap syndrome and drug-induced hepatotoxicity. Studies have found an increased mortality in IBD patients with hepatic dysfunction. Therefore, in patients with IBD, abnormalities in liver enzymes must be worked-up to identify and treat the possible cause.

Five-year View

Although we have come a long way in understanding the possible contributing factors to the etiopathogenesis of PSC and AIH, there remain many outstanding questions. With further knowledge it will be possible to take steps to prevent these diseases and better treat them when they do occur. We predict that in 5 years, we will have advanced our understanding of the underlying cause of PSC, in particular, and will subsequently have improved our ability to pharmacologically target disease progression. Additionally, with improved early detection of CC, treatments may provide better 5-year survival rates in these patients.

David - thanks so much for this info!!!! I'm on 6mp and am dealing with a elevated liver enzyme (ALT) for the first time, and I've been waiting since Monday to hear back from my GI about what to do about this. This article was really helpful to me - under the "Drug-induced Hepatotoxicity: Thiopurines" heading I really appreciated the specifics of this section:

Monitoring of serum aminotransferase levels is essential in all patients on AZA/6-MP, regardless of TPMT activity and metabolite levels. Patients who have an asymptomatic, slight increase in liver tests early in the treatment course should be continued on the drug at the current dose with close monitoring of biochemistries to ensure resolution. In a nonjaundiced patient with moderate-to-severe elevations in serum aminotransferase levels (5 × ULN), the medication dose should be decreased by 50%.[5] If the chemistries normalize, the dose may be escalated back to the original dose; however, if they remain abnormal, the drug should be discontinued. If the serum aminotransferase levels remain abnormal after discontinuation of the drug, a liver biopsy should be considered.

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As my levels are only elevated a bit over 2x the upper limit of the normal range I'm not so worried now. Again, I really, really appreciate these articles you've been posting!!!

InkyStinky said:

David - thanks so much for this info!!!! I'm on 6mp and am dealing with a elevated liver enzyme (ALT) for the first time, and I've been waiting since Monday to hear back from my GI about what to do about this. This article was really helpful to me - under the "Drug-induced Hepatotoxicity: Thiopurines" heading I really appreciated the specifics of this section:



As my levels are only elevated a bit over 2x the upper limit of the normal range I'm not so worried now. Again, I really, really appreciate these articles you've been posting!!!

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I'm glad you find them useful, glad tp be of help. If you'd ever like a PDF of the full article, PM me & I'll email it to you.

David

Bump.

Whoa. Thanks David. I'm going on Humira, and it's nice to know what I should look out for.

any chance we can sticky this one ? It's a wealth of information and rather hard to find in the search when trying to find information on PSC

I don't have a problem with making a sticky T. As you rightly point out, it is a wealth of information and if need be it can always be unstickied!

Dusty.

Yes, I completely missed it, and I just underwent a bunch of tests because of elevated liver enzymes. Finally had an EUS done. Nothing there, thank goodness, but they have no explanation for the elevated LFT's.

I've had psc/aih with crohns since 1999. Im now 31. I was first diagnosed with the liver problems then the crohns. I've had very high levels of alt,alp,ggt and ast since 1999. Recently started remicade, during induction had a sub total colectomy and lfts have increased significantly, not sure if it's remicade or something else. Waiting on results of biopsy and mrcp I had yesterday.

Thanks for the info

Does anyone object to me editing in a summary at the start of the first post? This stuff is pretty heavy and long. I know it sat in one of my browser tabs for three days before I worked up the will to read it

Miss Underestimated said:

Yes, I completely missed it, and I just underwent a bunch of tests because of elevated liver enzymes. Finally had an EUS done. Nothing there, thank goodness, but they have no explanation for the elevated LFT's.

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A quick read for ya just because I recently researched this and it was on my mind. Long shot, I realize, but I know that stuff is interesting to you

Summary is great idea. I know I missed it due to time limitations. No doubt I would have found it later, if the tests had turned up anything significant. Thank goodness they didn't - so far.

You just never know which thread is going to have the juicy information tidbit, huh?

This information is very interesting. I am having bile duct problems and have been diagnosed with Sphincter of Oddi Dysfunction. Have recently had ERCP and sphincterotomy and have a stent in place as the moment which is due to be removed next week. Still having pain under my ribcage. Have high GGT. I have had Crohn's for 36 years and have ileostomy. I had my gallbladder out last year.

PSC and Vancomycin

THE CASE OF THE DISAPPEARING LIVER DISEASE

IT WAS THE TYPE OF CASE THAT MAKES DOCTORS FEEL HELPLESS.

The 15-year-old boy’s lab tests indicated his liver function was badly impaired. He had a double whammy of two serious gastrointestinal diseases, both lacking cures. On top of it all, his colon was infected with an aggressive bacterial strain, Clostridium difficile.
Although pediatric gastroenterologist Kenneth Cox, MD, had little to offer for the teen’s other problems, he could at least treat the infection. He prescribed the antibiotic vancomycin.
And something very strange happened. The liver-disease symptoms vanished.
“At first I thought it was a coincidence,” says Cox, now chief medical officer at Lucile Packard Children’s Hospital, recalling the moment in 1993 when he saw the first hint of improvement. Maybe he had misattributed symptoms of infection to liver disease, he thought. “But then I stopped the antibiotic, and the liver disease came back, even though the infection was gone.”
So Cox, who is also associate chair of pediatrics and senior associate dean for pediatric and obstetric clinical affairs at the Stanford School of Medicine, gave a second round of vancomycin. Once again, the teenager’s appetite returned, his pain disappeared and his liver tests normalized.
Cox tried vancomycin in a handful of other patients who shared the teen’s liver and colon diagnoses but had never had C. difficile. These kids had been told that their liver disease, primary sclerosing cholangitis, was untreatable. Even a liver transplant was not a guaranteed cure — the disease could recur and destroy a new organ. Yet with vancomycin, the PSC disappeared.
The discovery left Cox in an unusual position. A coincidence — a serendipitous colon infection, of all things — left him holding a potential silver bullet for a devastating and poorly understood pathology.
“The problem is that I’m dealing with a very small group of kids with an unusual disease,” he says. “How do I get the science to prove that vancomycin works, so that all of my colleagues would say, ‘This is the therapy’?”

UNEXPLAINED DESTRUCTION

PSC starts in the “biliary tree,” the tree-shaped network of tubes that carry newly manufactured bile from the liver through the bile duct to the intestine, where bile aids digestion and absorption of dietary fat. In PSC, for reasons no one understands, the tubes become blocked by inflammation. So bile backs up, destroying liver cells and eventually causing cirrhosis.
The rare disease, which occurs in about 10 people of every million, leaves patients feeling severely unwell, with abdominal pain, itching, jaundice, poor appetite, deep fatigue and signs of malnourishment. It can hit people of any age. About three-quarters of PSC patients — including the 15-year-old who started Cox’s research odyssey — also have the more-common diagnosis of inflammatory bowel disease, another poorly understood condition, which is characterized by inflammation and ulceration of the intestine, diarrhea, abdominal pain and a host of other problems.
Cox and his Stanford collaborators believe that if they can figure out how vancomycin alleviates PSC, they’ll solve two mysteries at once. Not only will they have the evidence to convince other physicians that vancomycin is a good PSC treatment, but by finding out how the drug works, they may also learn how PSC begins — which may open doors to better therapies.
Although the research task is daunting, beneath Cox’s caution about its challenges is a definite sense of excitement.
“Most discoveries come by careful observation. I feel lucky that I’ve made this observation,” he says. “The remarkable part is, not only do the liver tests get better, but the children also feel so much better. If you take a look at these children before and after therapy, they don’t look like the same child.”

RESCUING A TODDLER’S LIVER

One of the most dramatic vancomycin-induced transformations came in 2005, after Cox’s team suggested the drug to Lyn Woodward and Melissa Hartman. Their little girl had been through the diagnostic wringer.
Things began to go wrong for Ellery Woodward-Hartman at 8 months of age, when her growth started to lag behind that of her twin brother, Robert. Her liver function gradually worsened; no one could figure out why. By the time she turned 2, Ellery’s liver was scarred with cirrhosis and she was badly jaundiced. Before Cox saw her, other physicians had tested Ellery for everything from cystic fibrosis to lymphoma to HIV. None of those diagnoses fit, and her liver was getting worse. Woodward and Hartman were told to anticipate a liver transplant.
“I thought, this can’t be happening,” Hartman says.
In late October 2005, Cox’s pediatric gastroenterology fellow, Anca Safta, MD, read Ellery’s chart. The symptoms lined up with PSC, Safta and Cox agreed. Safta proposed vancomycin treatment to the family.
“She said, ‘I know about Ellery; we have something that can help her,’” Woodward says, recalling her first conversation with Safta.
“There’s a line from Emily Dickinson: ‘Hope is the thing with feathers,’” Hartman says. “I thought of that poem. It was such a relief.”
‘MOST DISCOVERIES COME BY CAREFUL OBSERVATION. I FEEL LUCKY THAT I’VE MADE THIS OBSERVATION.’
Cox wasn’t sure a child as sick as Ellery would benefit from the therapy; his other patients had mostly been at earlier stages of PSC illness. Maybe the antibiotic would at least give her a few months to get stronger before a transplant, he told Woodward and Hartman. Cox wrote the prescription and told the family he would follow up with them soon.

CLUES FROM THE CLINIC

Since 1993, Cox has tried vancomycin on every PSC patient he’s treated, slowly accumulating evidence for the drug’s effects. In 2008, he published clinical observations of the first 14 patients, showing the drug caused improvement in blood markers of liver failure. The index patient, now an adult, is no longer in Cox’s care, but last Cox knew, he continued to do well. To date, 33 of Cox’s patients, plus a handful of others cared for by colleagues around the country, have received the drug. But it’s still largely unknown as a PSC therapy.
Funding has been one obstacle to advancing the research. So far, the work has proceeded without traditional funding sources such as NIH grants. Instead, patients’ families have financed the research via a parent-launched nonprofit, the Children’s PSC Foundation. Cox is now working to secure pharmaceutical company funding for a multicenter study to enable researchers to try the drug in a larger group of adults and children.
Bile normally moves from the liver through the branching network of ducts to the intestine, where it digests dietary fat. In primary sclerosing cholangitis, a rare liver disease, inflammation blocks the ducts. As a result, bile backs up, damaging the liver.

FILLING THE KNOWLEDGE GAPS

In spite of the limited resources, Cox has assembled a multidisciplinary team of Stanford collaborators to figure out how vancomycin works. The scientists are starting from one important clue: They know oral vancomycin, the drug formulation Cox uses for PSC, is not absorbed from the intestine. Yet PSC’s trail of destruction starts with inflammation outside the intestine, in the tubes that drain bile from the liver to the gut. The drug must be acting at a distance — but how?
One hypothesis is that PSC arises when pathogenic bacteria in the gut backflow into the bile duct and start a destructive inflammatory response. Normally, everything moves down the duct in one direction, from liver to intestine.
“Essentially, this would be regurgitation of bacteria into the bile drainage system,” says project collaborator David Relman, MD, a professor of infectious diseases and of microbiology and immunology at Stanford.
Another possibility is that bacteria somehow escape from the gut to the blood, then travel through the blood to the bile duct and trigger inflammation.
Under these hypotheses, which Relman’s laboratory is starting to investigate, vancomycin would resolve PSC with its antibiotic action, killing gut bacteria. To determine if that’s happening, the researchers are first taking a census of the bacterial communities in healthy children’s small intestines.
“Almost everything we know so far about the usual gut microbe community is based on adults,” Relman says.
The researchers plan to compare gut microbes in healthy kids to those in PSC patients before and after vancomycin. Their major obstacle — indeed, the reason we know so little about kids’ gut microbes — is the difficulty of sampling the small intestine’s contents. It would be unethical to perform invasive endoscopy on children who have no medical indication for the procedure, so the control samples in Relman’s new study will come from kids receiving endoscopy to investigate non-PSC complaints such as chronic abdominal pain. It’s also challenging to find “control” children who have not received recent courses of antibiotics. “That we know messes with the normal picture,” Relman says.
Still, he is optimistic about the lab’s prospects for cataloguing the gut microbes of kids with and without PSC. If kids with PSC have “different” bacteria before vancomycin treatment and return to a normal bacterial profile with the drug, it would provide strong circumstantial evidence that bacteria initiate PSC. And it would be a good starting point for studies of how the bacteria incite disease.

AN UNEXPECTED MODUS OPERANDI

Another possibility, however, is that in PSC vancomycin is acting as more than an antibiotic. Though textbooks label it a bacteria-killer, the Stanford team suspects vancomycin is also changing patients’ inflammatory response.
Although the idea might seem strange at first, there’s a well-established precedent for antibiotics quieting inflammation. In the last decade, several groups of researchers have demonstrated that, for example, tetracycline’s anti-inflammatory activity contributes to its effectiveness against rheumatoid arthritis, that macrolide antibiotics reduce inflammation in chronic airway disease, and that amoxicillin lowers bowel inflammation in ulcerative colitis.
If vancomycin is acting as an anti-inflammatory in PSC, says Kari Nadeau, MD, PhD, an assistant professor of pediatric immunology and allergy at Stanford, that suggests PSC is a disease of immune function run amok.
Scott Seki of Nadeau’s group already has some enlightening preliminary data. Regulatory T cells, the immune cells that prevent autoimmune disease by tamping down the inflammatory response, exhibit interesting changes during vancomycin treatment, he has found.
Using blood samples drawn before and after vancomycin therapy, Seki showed that the drug doubles PSC patients’ levels of regulatory T cells. Evidence from other autoimmune diseases suggests this change is big enough to cause therapeutically useful drops in inflammation — in other words, it may explain why vancomycin works. Two other experiments in Nadeau’s lab also pointed to regulatory T cells as key players in the vancomycin response. However, this information is still drawn from observations of a very small group of patients, so the team is now working to expand and strengthen their data.
If the findings about the regulatory T cells do turn out to be the PSC linchpin, Nadeau says, “We might infer that some kind of inflammatory process is turned on early in the life of these children that we should move quickly to try to regulate.”
And if the antibacterial effects of vancomycin are key, Relman says, the best approach would be to design a drug that gets rid of PSC-provoking bacteria but acts more selectively. Right now, vancomycin is probably killing beneficial bacteria that have nothing to do with PSC, he adds. “We’d rather not be using a sledgehammer if something more precise and elegant could be devised.”

SURPRISE ENDING

In mid-November 2005, Ellery Woodward-Hartman’s case was presented to the transplant selection committee at Packard Children’s. Though medical records from her pre-vancomycin days clearly pointed toward transplant, the liver-function tests performed after her first 10 days on vancomycin looked promising. The committee decided to re-evaluate her case in December.
A few weeks later, after about a month on vancomycin, Ellery and her family saw their physicians again. “Dr. Safta and Dr. Cox couldn’t believe how well she looked,” Woodward recalls. Ellery’s jaundice had cleared up. Her belly, previously swollen with fluids that accumulated when her liver function was at its worst, had returned to a healthy shape. She was still tiny in comparison with her twin but she was more energetic.
And by the time the transplant committee reconsidered her case, it was clear that the vancomycin was a success. Ellery didn’t need a liver transplant.
“With the degree of disease she had, I was very surprised,” says Safta, now an assistant professor of pediatric gastroenterology at the University of Maryland. Woodward and Hartman feel extremely grateful for the compassionate care Safta provided when Ellery was at her worst, and they still send periodic updates. “It’s just amazing where Ellery has gotten to,” Safta says. “She’s probably the only one with such severity of cirrhosis that has turned the corner like this.”
Now, after more than five years on vancomycin, Ellery is a thriving 7-year-old. Like other patients taking the drug for PSC, she continues to use it without side effects. Though her liver still bears the scars of cirrhosis, and there’s a possibility she may need a transplant at a future date, her liver-function tests are now normal. Her growth has caught up to her brother’s.
“I can’t even calculate what Dr. Cox has been able to do for Ellery,” Woodward says.
Cox sees Ellery’s case as a gratifying success, and he’s encouraged that emerging Stanford science supports the therapy he discovered by accident. This type of discovery is “one of the rewards of being an academic physician,” he says. His collaborators agree. In a project like this, “the patients talk to you through their data,” says Nadeau. “If they’re getting better, that’s what you take as real. That’s what inspires you to go back to the lab and figure out what is happening.”
But there’s one last hurdle: Cox worries that too many patients like Ellery are never offered vancomycin. More than 6,000 people have received liver transplants because of PSC, he says. Though it sounds like a large number, the disease is rare enough that many gastroenterologists never see a case — and so they aren’t reading the literature about new treatment advances. To try to bridge the gap, Cox has partnered with the Children’s PSC Foundation in hopes of helping physicians and patients’ families learn about the treatment.
At a recent foundation fundraiser, he got to meet a few children who had received the therapy from other doctors.
“Kids came up to say it had changed their lives,” Cox says. “They were so thankful. That makes me think this is the right thing to be doing.”

Source:
http://stanmed.stanford.edu/2011spring/article6.html

The Roundup pesticide can cause gallbladder stasis. See video entitled "Jeffrey Smith and Tom Malterre, MS, CN Discuss GMOs and Gluten"

BTT1023

BTT1023 is a fully human monoclonal antibody targeting VAP-1 (vascular adhesion protein-1). VAP-1 is a completely new therapeutic target. The safety and efficacy of BTT1023 has earlier been investigated in small clinical trials in rheumatoid arthritis and psoriasis patients. In March 2015, BTT1023 transitioned into Phase 2 development in fibrotic conditions and received Orphan Drug Designation in the EU for the treatment of primary sclerosing cholangitis.

PROGRAM STATUS

In March 2015, Biotie announced (Stock Exchange Release) the start of patient enrolment into a Phase 2a clinical study evaluating BTT1023 in primary sclerosing cholangitis (PSC). PSC is a progressive immune mediated biliary disease characterised by bile duct inflammation and fibrosis, and accompanying hepatic fibrosis, that frequently results in the need for liver transplantation. The study is being funded through the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership in the UK. The grant holder and Co-Investigator for the study is Professor David Adams, Director of the NIHR Biomedical Research Unit in Liver Disease and Centre for Liver Research at the University of Birmingham, UK.

The BUTEO study (BTT1023, a human monoclonal antibody targeting vascular adhesion protein (VAP-1), in the treatment of patients with primary sclerosing cholangitis) is being conducted in the UK and is an investigator-sponsored open label, single arm, multi-centre study that will evaluate efficacy, safety and pharmacokinetic properties of BTT1023 in 41 patients with PSC. Patients will receive BTT1023 via intravenous infusion every two weeks over an 11 week treatment period. The primary efficacy endpoint is a reduction of elevated levels of alkaline phosphatase, a blood biomarker of bile duct inflammation; secondary endpoints include various measures of liver injury and fibrosis. The two-stage study design includes a pre-planned futility analysis. Based on current estimates, it is expected that the requisite number of patients will have been treated by the end of 2016 to enable the futility analysis to be completed.

BTT1023 has received Orphan Drug Designation in the EU for the treatment of PSC. Biotie retains full rights to BTT1023.

Excellent info David ...Thanks a lot