We read with interest the recent guidelines for the management of cystic fibrosis-associated liver disease (CFLD), particularly the section addressing indications and dosing of ursodeoxycholic acid (UDCA) . The guidelines recommended the use of UDCA, at an initial dose of 20 mg/kg/day and as soon as the diagnosis of CFLD is made, in order to delay disease progression. However, the use of UDCA in all cholestatic diseases, including CFLD, is controversial and not as clear-cut as the recommendations suggest.
Ursodeoxycholic acid has been observed to reduce abnormalities in liver biochemistry tests (such as GGT, AST and ALT). However, it is well-recognised that liver biochemistry is a poor and unreliable marker of the severity and progression of liver disease, and progression can occur in the presence of normal liver biochemistry markers. In fact, there are no reliable markers or predictors of early liver disease or of disease progression. Furthermore, the diagnosis of CFLD is usually made after severe, clinically significant liver disease with cirrhosis and portal hypertension has already developed.
The consensus guidelines recommend the use of Ursodeoxycholic acid for all individuals with CF who have at least two of the following: hepatomegaly and/or splenomegaly; abnormal liver biochemistry on at least 3 consecutive determinations over 12 months (after excluding other causes of liver disease); and ultrasonographic evidence of hepato-biliary involvement (increased and/or heterogeneous echogenicity, irregular margins, nodularity, and bile duct dilatation) or portal hypertension. Severe CFLD with portal hypertension occurs in only 3–5% of CF patients, suggesting that the majority of CF patients with abnormalities in liver biochemistry tests do not progress to clinically significant CFLD . Furthermore, there is no evidence that persistent abnormalities in liver biochemistry, is a predictor of severe liver disease. Increased and/or heterogeneous echogenicity of the liver is non-specific and may be due to steatosis rather than fibrosis/cirrhosis. In a prospective study of suspected CFLD patients with abnormal clinical, biochemical (raised ALT for 6 months) and ultrasound findings, neither clinical examination, serum ALT levels nor ultrasound findings predicted presence of liver fibrosis or the development of portal hypertension . Thus, if the aforementioned criteria are followed it is likely that the majority of patients that are subjected to UCDA are unlikely to develop clinically significant CFLD. Conversely, patients not fitting with the suggested diagnostic criteria may still be at risk of developing clinically significant liver disease.
Treatment of CFLD with Ursodeoxycholic acid was recommended in the North American consensus guideline published more than a decade ago . Although that guideline recognised that there was no clinically proven short- or long-term benefit using UDCA in CFLD, the recommendation was on the basis of lack of harm and potential benefit in CFLD due to the reported benefits of UDCA in another liver disease of primary biliary cirrhosis. The recently published guidelines also acknowledge that there is no clinically proven benefit from UDCA therapy in CFLD; however, we believe that a more detailed discussion of potential adverse effects and dosage is necessary, given recent experience with UDCA in other cholestatic conditions. UDCA therapy, previously recommended in primary sclerosing cholangitis and primary biliary cirrhosis, has recently been called into question. We believe that attention should be paid to the findings of a well conducted, randomised double-blind placebo-controlled trial of high dose (28–30 mg/kg/day) UDCA in primary sclerosing cholangitis. Although this study showed improvement in liver biochemistry on UDCA therapy, it was terminated early by the National Institutes of Health's Data Monitoring and Safety Board due to increased risk of major adverse events (death and liver transplantation) in the UDCA treatment arm in comparison with the placebo arm. A higher dose of UDCA was used in this PSC study than the recommended initial dose of 20 mg/kg/day stated in the CFLD recommendations. However, the guidelines also recommended the increase in UDCA dose “if necessary” depending on liver biochemistry results. Of note, patients need not have abnormalities in liver biochemistry tests to fulfil the consensus definition of CFLD, and intestinal absorption of UDCA may vary among patients with pancreatic insufficient CF. Lower doses of UDCA have yet to be evaluated for long term safety and efficacy in CFLD.
The role and use of Ursodeoxycholic acid is controversial and the evidence for and against its use requires critical appraisal, especially in best practise guidance/guidelines written by expert hepatologists. Simply put, at present, there are no convincing data to demonstrate that UDCA is efficacious or harmful in CFLD. Future studies addressing the aforementioned issues are urgently needed before firm recommendations for or against the use of UDCA can be made.