Andrea A. Gossard

Complications of Endoscopic Retrograde Cholangiopancreatography in Primary Sclerosing Cholangitis

OBJECTIVES:Endoscopic retrograde cholangiopancreatography (ERCP) is commonly performed in patients with primary sclerosing cholangitis (PSC). The risk of complications associated with this procedure is not well established in these patients. The aim of this retrospective study was to compare the risk of ERCP complications in PSC vs. non-PSC patients.METHODS:We identified all Mayo Clinic patients who underwent ERCP in 2005. Procedural and clinical data were collected. Complications were defined as hospitalizations for pancreatitis, cholangitis, perforation, and bleeding.RESULTS:A total of 168 patients with PSC and 981 patients without PSC had at least one ERCP examination in the calendar year 2005. PSC patients were younger (48 years±15 vs. 60 years±19, P<0.000) and had a higher prevalence of portal hypertension (31.5% vs. 4%, P<0.0001). PSC patients had more biopsies (39% vs. 15%, P<0.0001), brushings (37% vs. 8%, P<0.001), balloon dilatations (48% vs. 15%, P<0.0001), duct cytology (20% vs. 3%, P<0.0001) and intraductal ultrasounds (11% vs. 5%, P=0.007) than non-PSC patients. The duration of the procedure was longer in the PSC group (51 min±29 vs. 40 min±28, P<0.0001). The overall rate of complications in patients with PSC when compared to non-PSC patients was not significantly different (18/168 (11%) vs. 76/981(8%), P=0.2). The incidence of cholangitis was higher in the PSC group (4% vs. 0.2%, P<0.0002) despite routine use of antibiotics before the procedure in PSC patients. The duration of the procedure was longer in PSC patients who developed cholangitis (86 min±28 vs. 51 min±29, P=0.02). The risks of complications such as pancreatitis, perforation, and bleeding were not significantly different between the two groups despite their demographic and procedural variations. The duration of hospitalization due to complications was also not significantly different between the two groups.CONCLUSIONS:Complications requiring hospitalizations occur in over 10% of PSC patients undergoing ERCP. Cholangitis occurs more often in PSC patients and correlates with the length of the procedure. Further studies to confirm the role of aggressive prophylactic antibiotics in patients with PSC who undergo prolonged procedures are warranted.

Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis

BACKGROUND Primary sclerosing cholangitis results in elevated but fluctuating serum alkaline phosphatase levels that occasionally return to normal. AIMS To investigate the frequency of normalization of alkaline phosphatase in newly diagnosed primary sclerosing cholangitis patients and the subsequent clinical outcomes. METHODS Records of newly diagnosed primary sclerosing cholangitis patients were examined retrospectively for laboratory values and clinical end points (cholangiocarcinoma, liver transplantation and death) within 10 years of diagnosis. Data from a recent prospective ursodeoxycholic acid treatment trial were also studied. RESULTS Eighty-seven patients met the inclusion criteria. Normalization of alkaline phosphatase was seen in 35 (40%) patients. Five (14%) patients with normalization reached an end point whereas 17 (33%) of the patients with persistent elevation reached an end point (P = 0.02). Ursodeoxycholic acid was used similarly by both groups. When the investigative criteria were applied to a prospective trial, there was again a significant relationship between normalization of alkaline phosphatase and survival in patients receiving ursodeoxycholic acid (P < 0.01) and the placebo group (P = 0.02). CONCLUSIONS Serum alkaline phosphatase was found to normalize in a high proportion of newly diagnosed primary sclerosing cholangitis patients. This was significantly associated with a better prognosis in a retrospective cohort and when data from a prospective treatment trial was evaluated.

Primary sclerosing cholangitis associated with elevated immunoglobulinG4: Clinical characteristics and response to therapy

Steroid responsive biliary strictures in patients fulfilling criteria for primary sclerosing cholangitis (PSC) have been reported. The clinical course and response to therapy in patients with PSC with elevated immunoglobulin G4 (IgG4) levels has not been investigated previously. Patients with PSC were screened for IgG4-related biliary disease during 2006 to 2008 and data were collected prospectively. A total of 33 out of 285 (12%) patients with PSC (18 males) had elevated IgG4 (>140mg/dL) with a median age of 46 years (interquartile range 29-60); 24 could be evaluated. All patients had both intrahepatic and extrahepatic biliary strictures. Pancreatic disorders were found in 4 (17%), and 11 of 24 (46%) presented with jaundice; 8 of 24 (33%) received biliary stenting for a median time of 4 months (0-6). Liver cirrhosis was diagnosed in 12 of the 24 (50%). Overall, 18 patients were treated with corticosteroids and 6 patients managed conservatively. Nine of 10 patients with elevated bilirubin had improvement. Alkaline phosphatase decreased significantly at 2 months and at last follow-up. IgG4 levels at baseline were 242 (216-357) mg/dL and decreased to 109 (80-236) at 2 months (P < 0.05) and 174 (115-269) at last follow-up (P < 0.05). A total of 39% had adverse effects of steroids, mostly hyperglycemia. Relapses occurred in 7 of the 14 (50%), but biliary stents could be removed in all. Elevated IgG4 levels were observed in 12% of typical patients with PSC. Prevalence of cirrhosis was high, suggesting a severe liver disease course. Most patients had a good biochemical response to steroids, but adverse effects were common. Future work should be directed at finding therapy that is more effective, better tolerated, and of more lasting benefit.

Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study.

OBJECTIVES: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of young adults that is associated with significant morbidity and mortality. No effective medical therapy is available. Minocycline has been found to exert biological effects independent of its antimicrobial properties, including anti‐inflammatory activities such as inhibition of inducible nitric oxide synthase, upregulation of interleukin 10, and direct suppressive effect on B‐ and T‐cell function. Minocycline may also inhibit cell death pathways by reducing both proapoptotic and proinflammatory enzyme activation. We sought to investigate the safety and efficacy of minocycline among patients with PSC. METHODS: We evaluated the efficacy of minocycline in patients with PSC in a pilot study. Sixteen patients with PSC were enrolled. Minocycline, 100 mg orally twice daily, was given for 1 year. RESULTS: A statistically significant improvement in serum alkaline phosphatase activity (330 U/I vs. 265 U/I, P=0.04) and Mayo risk score (0.55 vs. 0.02, P=0.05) occurred with treatment. Serum bilirubin and albumin remained essentially unchanged while on treatment. CONCLUSIONS: The results of this pilot study indicate that minocycline is reasonably well tolerated and potentially effective in patients with PSC. These findings might be explained by the anti‐inflammatory and antiapoptotic properties of minocycline. Though the data presented are too preliminary to support the clinical use of minocycline in the treatment of PSC at this time, its use should be further investigated.

Secondary Sclerosing Cholangitis: A Comparison to Primary Sclerosing Cholangitis

OBJECTIVES:The natural history of secondary sclerosing cholangitis (SSC) is ill-defined. In order to better determine the natural history of this condition, we retrospectively reviewed data from the Mayo Clinic in Rochester, Minnesota. We also compared the natural history of patients diagnosed with SSC to a cohort with a diagnosis of primary sclerosing cholangitis (PSC).METHODS:We used a computer-assisted search to identify patients with a diagnosis of SSC seen from 1992 to 2002. The diagnosis was confirmed by chart review and information about age, gender, etiology, therapy, and clinical course was sought. We excluded those presumed SSC patients who had a history of inflammatory bowel disease, those with malignancy at the time of diagnosis, and those who had undergone liver transplantation prior to the diagnosis of SSC. Patients with PSC matched for age, gender, and serum bilirubin level served as disease controls.RESULTS:We identified 31 patients, average age 57, (range 28–79). The causes of SSC included surgical trauma from cholecystectomy (13 patients), intraductal stones (12 patients), recurrent pancreatitis (4 patients), and abdominal injury (2 patients). Nine patients with SSC ultimately required liver transplantation and 4 patients have died. When compared to matched patients with PSC, the survival free of transplant was significantly shortened (p < 0.03).CONCLUSIONS:When the long-term outcome of SSC patients was compared to matched PSC controls, the SSC patients had a poorer outcome. The natural history of SSC is characterized by a shortened life expectancy.

High dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis

Aliment Pharmacol Ther 2011; 34: 1185–1192

Tacrolimus for the treatment of primary sclerosing cholangitis

Background: Results from a pilot investigation with tacrolimus for primary sclerosing cholangitis (PSC) demonstrated biochemical improvement without excessive drug toxicity. To date, no confirmatory study has been performed.

Development of autoimmune hepatitis in primary biliary cirrhosis

Aim/Background: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown aetiology. Up to 10% of patients with typical features of PBC will have additional features of autoimmune hepatitis (AIH). A subset, however, have no such features but go on to develop a ‘sequential’ AIH overlap syndrome.

Fluoxetine for the treatment of fatigue in primary biliary cirrhosis: a randomized, double-blind controlled trial.

Fatigue is a common symptom in primary biliary cirrhosis (PBC). In animal models of cholestasis, abnormalities in serotonin neurotransmission are observed with fatigue. The role of selective serotonin reuptake inhibitors in fatigue-related PBC, however, is unknown. A double-blind, placebo-controlled study design was conducted to determine the safety and efficacy of fluoxetine for the treatment of fatigue in PBC. Patients were randomized to fluoxetine, 20 mg daily, or matched placebo for 8 weeks’ duration. Fatigue was assessed by the Fisk Fatigue Impact Scale (FFIS). The primary study endpoint was a ≥50% reduction in overall FFIS score at the end of treatment. Health-related quality of life (HRQL) was assessed as a secondary endpoint. Among 220 consecutively screened patients, only 18 (9%) eligible individuals were randomized to fluoxetine (n=10) or placebo (n=8) for 8 weeks. Baseline variables including median FFIS scores (52 vs 42; P=0.21) were similar between treatment arms (P > 0.05). After 8 weeks of therapy, no statistically significant change in median FFIS score was observed in the fluoxetine group. Median FFIS score in the placebo group was reduced (42 to 28), but not statistically significant. No difference in HRQL was observed between treatment arms after 8 weeks. Fourteen (78%) patients completed therapy, while four (22%) individuals withdrew from the trial. Three of the four patients had drug-related adverse events with fluoxetine. In this study, fluoxetine did not improve fatigue in PBC and was associated with adverse events.

Autoimmune hepatitis: a review

Autoimmune hepatitis (AIH) is an inflammatory liver disease that predominantly affects females. The disease is characterized histologically by interface hepatitis, biochemically by increased aspartate and alanine aminotransferase levels, and serologically by the presence of autoantibodies and elevated levels of immunoglobulin G. AIH affects both adults and children, and is particularly aggressive in the latter group. It is a relatively rare but devastating disease, which progresses rapidly unless immunosuppressive treatment is started promptly. Treatment is often successful at inducing remission of disease, and this can lead to a normal life expectancy. However, progression to cirrhosis can and does occur in some. For those with advanced-stage disease and complications, consideration of liver transplantation is appropriate.