Primary biliary cirrhosis
Primary biliary cirrhosis (PBC) is a chronic cholestatic disorder, primarily affecting middle-aged women, and characterized by immune-mediated destruction of small intrahepatic bile ducts. This ongoing destruction of bile ducts results in a failure of bile secretion, with subsequent retention of toxic hydrophobic bile acids causing hepatocyte damage. Thus, treatment of PBC has focused on suppression of this abnormal immune response and reduction of the toxic effects of retained hydrophobic bile acids.
In initial uncontrolled trials, UDCA improved both symptoms (mainly decreased pruritus) and biochemical parameters of cholestasis (bilirubin, gamma-glutamyl transpeptidase, alkaline phosphatase) and inflammation (aminotransferases).12, 124, 125 A controlled multicentre trial in France also demonstrated a significant clinical benefit with respect to the onset of hyperbilirubinemia, ascites or bleeding in the UDCA group compared to placebo.83 Several subsequent controlled studies consistently showed an improvement in biochemical parameters,13, 32, 83, 98, 99, 126 while beneficial effects on symptoms were reported only in a subset of patients in one study (severe fatigue and pruritus were less pronounced)32 (Table 1).
Table 1. . Features of six major randomized, double-blind, controlled trials of ursodeoxycholic acid vs. placebo in the treatment of patients with primary biliary cirrhosis
Data on histological improvement are controversial. While some studies have failed to show histological improvement,99, 127, 128 others have reported improvement of piecemeal necrosis, portal and lobular inflammation, cholestasis, and bile duct paucity.32, 83, 98 However, fibrosis and histological stage, according to the Ludwig criteria,129 do not appear to be favourably influenced by UDCA therapy.
Most importantly, UDCA slows down the progression of PBC and reduces the need for orthotopic liver transplantation (OLT).130–132 Poupon et al. demonstrated that the probability of OLT or death was substantially lower in the group assigned to UDCA for 4 years (13–15 mg/kg/day) compared to those receiving placebo for 2 years and later switched to UDCA for 2 additional years.130 A study from the Mayo Clinic also reported a three-fold higher mortality or need for OLT in patients randomized to placebo compared to UDCA-treated patients.131 Analysis of combined data from three large controlled trials with a total of 548 patients showed a significant prolongation of transplant-free survival after 4 years of UDCA treatment (13–15 mg/kg/day).132 In addition, sub-group analysis demonstrated significantly improved survival, free of OLT, in medium- and high-risk groups (serum bilirubin level above 1.4 and 3.5 mg/dL, respectively) and in the histological stage IV (cirrhosis) sub-group treated by UDCA.132 Bounand et al. showed that serum bilirubin levels remain a valid prognostic factor in PBC under UDCA treatment, because normalization of serum bilirubin level under UDCA therapy was associated with improved clinical outcome.133 In addition, UDCA treatment may have a positive effect on the development of portal hypertension. Two controlled studies reported a lower incidence of newly developed oesophageal varices in patients treated with UDCA,134, 135 although this was not noted in two previous large controlled trials.32, 99 Moreover, UDCA is a highly cost-effective therapy that actually reduces the cost of medical care in PBC patients.136
The response of AMA-negative and AMA-positive PBC patients to UDCA treatment is similar.85 In contrast, patients with PBC and autoimmune hepatitis (overlap syndrome) require combination therapy with UDCA and corticosteroids to obtain complete biochemical response, indicating that overlap syndrome may represent a yet unrecognized cause of resistance to UDCA monotherapy in about 7% of patients with PBC.137
Given the modest effect of UDCA on the natural course of PBC, a number of groups have combined UDCA with other medications, such as prednisone, azathioprine, methotrexate and colchicine, in an attempt to augment the positive effects of UDCA. A controlled trial comparing a colchicine/UDCA combination to UDCA alone revealed a slight advantage of colchicine/UDCA over UDCA monotherapy with regard to progression of portal hypertension, symptoms and laboratory findings, while histology was not improved.138 Similarly, a combination of UDCA (10 mg/kg/day) and prednisone (10 mg/day) for 9 months improved liver enzymes and reduced hepatic inflammation more effectively than UDCA alone, whereas the degree of fibrosis and bile duct damage did not differ between the two groups.139 Controlled studies on combination of UDCA with newer steroids (e.g. budesonide) are currently under way. Lindor et al. reported no added benefit in 32 PBC patients treated with UDCA–methotrexate compared to patients who received UDCA monotherapy.140 This negative finding was confirmed by a study including 25 patients in whom a combination therapy with UDCA–methotrexate was not associated with any additional improvement in biochemical markers, symptoms and histological features.141 In a controlled study including 50 patients, triple therapy with UDCA, prednisone and azathioprine over 1 year revealed an additional beneficial effect with regard to symptoms, biochemical and histological parameters in patients who had previously not achieved complete biochemical response under UDCA monotherapy.142 Unfortunately, no information was given on the prevalence of PBC-autoimmune hepatitis overlaps, although these patients might benefit most from triple therapy.
In summary, UDCA monotherapy at a dose of 13–15 mg/kg/day is recommended for the treatment of PBC patients. Lower doses have failed to show any benefit except a mild improvement in serum liver enzymes.128 Combination of UDCA with other (immunosuppressive) drugs may have additional benefit, but (with the possible exception of PBC-autoimmune hepatitis overlap syndromes) currently should be limited to controlled clinical studies until risks and benefits are better defined.
Primary sclerosing cholangitis
Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease, occurring mostly in young male patients and frequently associated with inflammatory bowel disease, usually chronic ulcerative colitis. It is characterized by intra- and extrahepatic biliary strictures and bile duct fibrosis associated with inflammatory changes involving the portal and periportal regions of the liver. Given the similarities between PSC and PBC, particularly with regard to the profound cholestasis and the deleterious effects of retained toxic bile acids, several trials were initiated to determine the effectiveness of UDCA in the treatment of PSC.
Biochemical improvement in serum liver tests was observed in UDCA-treated PSC patients in early small and mostly uncontrolled studies.97, 143–145 UDCA did not significantly improve symptoms of PSC after 1–2 years of treatment97, 145 but improved histological features in some patients.97 However, after these initial optimistic reports, more recent studies failed to show a positive effect on clinical symptoms and, more importantly, on OLT-free survival and/or overall survival.100, 146, 147 The largest series (105 patients) conducted so far demonstrated that patients treated with UDCA at a dose of 13–15 mg/kg/day experienced some improvement in cholestatic parameters, but that UDCA had no beneficial effect on PSC-related symptoms over a mean follow-up of 2.2 years.100 Furthermore, UDCA neither seems to halt the histological progression of the disease nor to prolong OLT-free survival regardless of the histological stage. However, UDCA in combination with endoscopic treatment of dominant strictures may substantially improve patient survival, as shown by Stiehl et al. for 65 patients with a mean follow-up of 45 months.146
In summary, administration of UDCA in PSC patients at doses of 13–15 mg/kg/day may be justified because a biochemical benefit can be achieved and no alternative treatment is currently available. Prolongation of survival, however, has not yet been demonstrated. In contrast to trials in PBC, the number of PSC patients studied and the median follow-up period have been limited. Moreover, the optimal dose of UDCA remains to be determined. In addition, endoscopic treatment of dominant strictures appears to be an essential adjunct to UDCA therapy.
Intrahepatic cholestasis of pregnancy
Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder of late pregnancy (third trimester) characterized by pruritus of the mother coinciding with an increase in serum bile acids, aminotransferases and bilirubin. The main consequences are disturbed maternal well-being due to severe pruritus and an increased risk of premature delivery and stillbirth. An initial open-label study showed that UDCA improved maternal pruritus and biochemical abnormalities in patients with ICP.148 Several subsequent small series and case reports confirmed these encouraging results.149–152
A controlled study of 24 patients demonstrated improvement of pruritus, jaundice and serum liver tests in mothers during UDCA treatment. Most importantly, relevant aspects of fetal outcome were also significantly improved. All babies of mothers in the UDCA group were delivered at or near term, whereas five of seven babies in the placebo group were born before week 36 and one of them was a stillbirth.153 No adverse effects were observed in mothers or babies. In addition, UDCA decreased elevated endogenous bile acid levels in serum, urine and colostrum of mothers with ICP.101–103, 154
Based on these results, UDCA treatment of ICP may be considered safe for relieving pruritus and improving both biochemical parameters and fetal outcome. However, further larger controlled studies are needed before UDCA treatment of patients with ICP can be generally recommended.
Total parenteral nutrition-associated liver disease
Long-term total parenteral nutrition (TPN) can be associated with a wide spectrum of hepatobiliary disorders, ranging from mild liver function abnormalities to end-stage liver disease requiring OLT. Cholestasis develops most commonly in premature infants and in adults with inflammatory bowel disease, particularly in patients with previous extensive intestinal resection. The pathogenesis of TPN-induced cholestasis is unclear and several factors may play a role, including increased formation of toxic bile acids, translocation of bacterial endotoxin from the intestinal flora, as well as the amount of calories and composition of the TPN.158
UDCA led to a prompt and sustained improvement in hyperbilirubinemia in a single patient who developed severe jaundice while receiving long-term TPN.159 In a subsequent uncontrolled study including seven children with TPN-related liver disease, UDCA treatment (30 mg/kg/day) was associated with normalization of biochemical parameters of cholestasis and disappearance of signs of chronic liver disease (i.e. jaundice and hepatosplenomegaly on ultrasound) within 4–8 weeks.160
These findings suggest that UDCA appears to be an effective and safe treatment in patients with TPN-associated cholestasis. However, larger controlled series are awaited.
Cystic fibrosis (CF) is a genetic disorder characterized by abnormal electrolyte (chloride) transport resulting in thickening of secretions in the bronchial tree, pancreas, intestine and biliary tree; this leads to chronic obstructive pulmonary disease, pancreatic insufficiency, intestinal obstruction and biliary cirrhosis. Abnormal biliary secretions and inspissation of bile with the subsequent development of plugs within small bile ducts cause biliary obstruction (cholestasis) and ultimately result in (focal to multilobular) biliary cirrhosis. Hepatobiliary complications increase with patient age and up to 7% of children and young adults with CF may present with liver cirrhosis.165
UDCA has been used successfully to treat hepatobiliary complications associated with CF. Early uncontrolled studies showed that UDCA significantly improved laboratory tests and nutritional status in CF patients.94, 166, 167 In a controlled trial UDCA distinctly improved nutritional status, pulmonary involvement and patients’ general condition after 1 year of treatment.168 Moreover, histological features improved during UDCA treatment.169 Two studies suggest that higher doses of UDCA (20 mg/kg/day) may be more efficacious than lower doses (5–15 mg/kg/day).94, 170 Thus, UDCA may be considered a safe and efficacious treatment option in patients with CF-related liver disease. Further studies are needed to establish a positive effect of UDCA on the course of the disease and survival.
Other paediatric cholestatic disorders
Several uncontrolled studies have shown beneficial effects of UDCA on biochemical markers of cholestasis and/or cholestasis-related clinical symptoms at doses of at least 15 mg/kg/day in patients with biliary atresia,171, 172 syndromatic paucity of the intrahepatic bile ducts (Alagille syndrome),173 Caroli’s disease,174 progressive familial intrahepatic cholestasis,60, 173 and benign recurrent intrahepatic cholestasis.175