Ursodeoxycholic acid

Introduction

Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, which is physiologically the by-product of intestinal bacteria acting on primary bile acids secreted by the liver into the biliary system and the gut.

Pharmacologically, UDCA is chemically synthesized and is licensed in the treatment of cholesterol-rich gallstones, primary biliary cirrhosis, and the prophylaxis of gallstone formation in patients undergoing rapid weight loss.

UDCA is also used to treat cholestasis of pregnancy, primary sclerosing cholangitis and other cholestatic diseases, such as the liver disease of cystic fibrosis and progressive familial intrahepatic cholestasis. It is also used as a general “ hepatoprotective,” as it can improve abnormal liver function tests nonspecifically, as in chronic hepatitis C.

Commercial preparations of UDCA are shown in Table 11.1.

Table 11.1 Commercial names for UCDA

Pharmacology

UCDA suppresses hepatic synthesis and secretion of cholesterol and inhibits intestinal absorption of cholesterol. It is rapidly absorbed from the GI tract and is 90% bioavailable. It is 96–98% protein-bound in plasma, and undergoes entero-hepatic recycling. In the liver, it is partly conjugated before excretion into the bile. In the gut, a small amount of both free and conjugated UDCA is metabolized by bacteria (7α dehydroxylation) to lithocholic acid. The latter is mainly excreted in feces but 20% is absorbed and sulphated by the liver. Excretion of UDCA conjugates is almost 100% fecal.

With continued administration, UDCA concentrations in bile reach a steady state in approximately 3 weeks. UDCA solubilizes the normally insoluble cholesterol in normal bile, and also leads to dispersion of cholesterol as liquid crystals. Thus, even though administration of high doses (e.g., 15–18 mg/kg/day) does not result in concentrating UDCA to more than 60% of the total bile acid pool, UDCA-rich bile effectively solubilizes cholesterol and increases the concentration level at which saturation of cholesterol occurs.

Thus, the bile of patients with gallstones treated with UCDA changes from cholesterol-precipitating to cholesterol-solubilizing, which facilitates cholesterol stone dissolution. UDCA competes with endogenous bile acids for absorption in the terminal ileum, interrupting their enterohepatic circulation and thereby increasing their elimination in feces.

When UDCA is discontinued, its concentration in bile falls rapidly to about 5–10% of its steady-state level after about 1 week.

In cholestatic liver disease or injury, the therapeutic action of UDCA is based on experimental evidence. There are 3 major mechanisms of action: (1) protection against the cytotoxicity of hydrophobic bile acids by changing the composition of mixed phospholipid-rich micelles in bile, thus reducing bile acid cytotoxic effects on the cholangiocytes; (2) stimulation of hepatobiliary secretion by activating and/or inserting transporter molecules (such as MRP2) into the canalicular membrane of the hepatocyte; and (3) protection of hepatocytes against bile acid-induced apoptosis.

Drug interactions

The effectiveness of UDCA is reduced with co-administration of cholestyramine, charcoal and aluminium-based antacids. Oestrogens and clofibrate increase cholesterol elimination in bile and may also decrease the effectiveness of UCDA. Administration of UCDA reduces the effectiveness of dapsone and may increase concentrations in blood of cyclosporine, and nitrendipine.

Licensed therapeutic indications

Gallstone dissolution

This indication is for cholesterol-rich gallstones (ie radiolucent stones without calcium deposits), in patients with a functioning gall bladder. UCDA is given as 6–12 mg/Kg/day orally as a single dose or 2–3 divided doses. It is continued for 3–4 months after ultrasound evidence of dissolution of stones. With 10 mg/kg/day dosing, complete stone dissolution occurs in about 30% of patients with uncalcified gallstones less than 20 mm in maximal diameter, treated for up to 2 years. Larger diameter stones are unlikely to dissolve while smaller stones have increased chances of dissolution. If there are floating or floatable stones (indicating a high cholesterol content), gallstone dissolution is increased up to 50%.

However, stone recurrence after dissolution occurs in 30–50% within 5 years of stopping UDCA, and continued ultrasound monitoring is necessary after therapy.

Gallstone prevention

Prophylaxis of gallstone formation is indicated in obese patients undergoing rapid weight loss. The dose of UDCA for this indication is 300mg twice a day, as larger doses do not have a greater preventative effect. Studies demonstrate that between 6% and 9% of UDCA-treated patients developed gall stones compared to 23% in placebo groups despite similar loss in weight in both groups.

Primary biliary cirrhosis (PBC)

In 2 meta-analyses, which included a wide spectrum of severity of PBC from mild to moderate/severe, the use of UDCA (13–15 mg/Kg/day) did not decrease mortality, or the rate of liver transplantation. However, in early PBC there is nonrandomized evidence that sustained biochemical amelioration of abnormal liver function tests after one year of UDCA (13–15 mg/kg) administration (i.e., a reduction of alkaline phosphatase <3x the upper limit of the normal range, with a total serum bilirubin of 1 mg/dl or less, together with a serum aspartate transaminase 2 times the upper limit of normal) significantly improved 10-year transplantation free survival.This evidence is the basis for the licence in PBC. If the biochemical parameters do not reach the “response” criteria thresholds it is likely that further UDCA may not be effective, but stopping rules have not been formally evaluated for biochemical nonresponders.

Special circumstances

Pregnancy

UCDA has a category B rating from the US FDA. However, UDCA is used to treat cholestasis of pregnancy, which develops in the late 2nd and 3rd trimesters, avoiding the potentially higher-risk period for teratogenicity. There are no attributable reports of teratogenicity with UDCA.

A meta analysis of 9 randomized studies showed that UCDA (dose range from 600 mg to 1000 mg/day) was significantly associated with total resolution of pruritus, normalization of alanine aminotransferase levels, fewer premature births, and a decreased need for neonatal intensive care. The authors recommended UDCA as first-line therapy for cholestasis of pregnancy up to the time of delivery. A recent randomized study confirmed a reduction in pruritus but less than that perceived a priori to be clinically important by both patients and clinicians; planned early delivery did not increase Caesarean section rates.The safety of UDCA during lactation has not been established, so UDCA should be discontinued after delivery.

Primary sclerosing cholangitis (PSC)

As UDCA ameliorates abnormalities of liver function tests, it is used to treat PSC, but there has been no evidence of clinical effectiveness with standard dosing as for PBC. Its therapeutic effectiveness has been further debated since a randomized trial of higher dose (28–30 mg/Kg/day) in PSC demonstrated, despite significant improvement of liver function tests as in PBC, an adjusted increased risk (hazard ratio 2.1) of death, liver transplantation, and worsening MELD score There were also more adverse events in UCDA-treated patients. This trial has changed the perception of clinicians that UCDA is completely safe in patients with chronic liver disease. Thus, patients with PSC should not be given more than 15 mg/Kg/day of UDCA outside of clinical trials.

Use in children

The safety and effectiveness of UCDA in children has not been established; the recommended dose is 10–15 mg/Kg/day in 2–3 divided doses.

Adverse reactions

UDCA can cause diarrhea, pruritus, nausea, vomiting, and gallstone calcification. In randomized trials for treatment or prevention of gallstones there were no significant differences in side effects compared to placebo, whereas in treatment of cholestatic liver diseases, UDCA resulted in more side effects than placebo or no treatment. There have been no reported fatalities attributable to use of UCDA. Neither accidental nor intentional overdosing with UCDA has been reported: doses in the range of 16–20 mg/kg/day have been tolerated for 6–37 months without symptoms in patients treated for gallstones.

Contraindications for the use of UDCA are shown in Table 11.2.

Table 11.2 Contraindications for use of UCDA

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