Ursodeoxycholic Acid


Article Author:
Ted George Achufusi


Article Editor:
Navid Mahabadi


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


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James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
9/8/2019 11:26:39 PM

Indications

Use of ursodeoxycholic acid (UDCA) in the treatment of liver disease dates back more than a hundred years when it was first employed in traditional Chinese medicine by herbalists and physicians alike. Before discovering its effectiveness in dissolving gallstones, its primary use as a liver tonic.[1][2] Today, there is extensive evidence suggesting that UDCA is beneficial in various types of liver pathology. However, the greatest amount of data still points to its therapeutic effect in treating gallstone disease.

Gallstone disease is a common and exceedingly costly digestive disorder if considering the number of hospital admissions and cholecystectomies performed in the United States annually. It is a complex disorder where both genetic and environmental factors contribute to the susceptibility of the disease. The primary non-invasive treatment for cholesterol gallstones is oral litholysis with bile acids. UDCA has been shown to decrease the biliary cholesterol saturation markedly and has found use as an alternative to cholecystectomy in patients with gallstone disease.[3] Currently, gallstone disease is not an FDA-approved indication for UDCA use.

Biliary sludge is considered to be another therapeutic target of UDCA therapy. It’s an occurrence commonly precipitated by rapid weight loss, pregnancy, and total parenteral nutrition.  A clinical study in which patients with idiopathic acute pancreatitis attributed to microscopic gallstones or biliary sludge, had complete resolution of gallbladder microlithiasis after UDCA treatment, demonstrating its therapeutic effect.[4][1]

UDCA is commonly used to treat patients with primary biliary cholangitis (formerly known as primary biliary cirrhosis), an immune-mediated cholestatic liver disease characterized by destruction of intrahepatic bile ducts. UDCA is the only drug approved by the U.S Food and Drug Administration for treatment of primary biliary cholangitis. Studies suggest that UDCA can significantly delay the progression of liver cirrhosis in patients with early stages of PBC.[5][6].  In one study, the probability of remaining free of extensive fibrosis or cirrhosis after UDCA treatment was 76% and 61%, after being treated for 4 and 8 years, respectively. [7] Similar results have been observed in other case-control studies as well.

UDCA has been shown to have a role in treating patients with primary sclerosing cholangitis. However, its use in PSC has not come without controversy. Primary biliary cirrhosis is a rare, progressive, immuno-mediated hepatobiliary disease. Currently, there is no proven medical therapy for patients with PSC, but UDCA has been established as first-line therapy for those suffering from the condition.  The most significant two clinical trials of UDCA in PSC had somewhat disappointing results.  One trial only showed a minimal trend toward statistically significant benefit with moderate doses of UDCA, and researchers terminated the other trial where high dose UDCA was used due to excessive adverse effects.  Despite the lack of data regarding long term efficacy, many experts still recommend moderate doses of UDCA in PSC. Lack of sufficient data regarding long term efficacy might explain why PSC is not an FDA-approved indication for UDCA treatment.[8] 

Current data also supports UDCA treatment in intrahepatic cholestasis of pregnancy; a unique pregnancy-related disorder which can manifest during the late third trimester of pregnancy.  A recent meta-analysis which looked at 12 RCTs involving 662 patients with ICP, UDCA was associated with resolution of pruritus, reduced serum levels of bile acids, and decrease of serum levels of alanine aminotransferase. The same meta-analysis also demonstrated reduced adverse maternal and fetal outcomes among pregnant women with ICP.[9] Despite the current data, the FDA does not list ICP as an indication for UDCA treatment.

UDCA has also found use in the treatment of cystic fibrosis, graft vs. host disease involving the liver, liver allograft rejection, bile duct-paucity syndromes such as biliary atresia, and non-alcoholic steatohepatitis. However, more studies need to take place to determine the therapeutic potential of UDCA in these disorders, and the FDA has not approved the drug for treating these liver conditions.

Mechanism of Action

Ursodeoxycholic acid acts on the liver through a variety of complex and complementary mechanisms, including alterations in the bile acid pool, serving as a cytoprotectant, immunomodulating substance, and choleretic. Furthermore, UDCA markedly decreases biliary cholesterol saturation by inhibiting the absorption of cholesterol in the intestine and its secretion into bile demonstrated by reduced cholesterol fraction of biliary lipids.[1][3]

The cytoprotective effect of UDCA is attributable to its ability to protect hepatocytes and cholangiocytes from bile acid-induced damage. Bile acids stimulate the formation of reactive oxygen species which induce inflammatory processes and cholecystitis.[10] Evidence suggests that bile acids damage cells by causing mitochondrial dysfunction. UDCA offers cytoprotection in hepatic epithelia by preserving cell structures, including plasma membranes and mitochondria while stimulating anti-apoptotic pathways. Additionally, UDCA can prevent Kupffer cells, the resident macrophages in the liver, from generating reactive oxygen species, thus decreasing the level of oxidate stress in hepatocytes.[3][11]

Therapeutic concentrations of ursodeoxycholic acid can shift the concentration of bile acids from hydrophobicity to hydrophilicity.[12] Hydrophobic bile acids, including deoxycholic acid and chenodeoxycholic acid, have been shown to have a toxic effect on hepatocytes by increasing cell membrane permeability and inducing apoptosis. There are suggestions that UDCA competitively displaces the endogenous bile acids at the level of ileal absorption or the hepatocyte level, thus decreasing the concentration of toxic hydrophobic bile acids while simultaneously increasing the absorption of hydrophilic bile acids.[4] Depending on the dosage, UDCA and its conjugates account for approximately 19 to 64% of total biliary bile acids.[3]

The choleretic effect of UDCA is attributable to its ability to induce secretion of bile acids. This effect is comparable to endogenous bile acids; however, without the potential toxicity, which makes it useful in treating cholestatic disorders. In fact, prior studies have shown that in patients with primary biliary cirrhosis and primary sclerosing cholangitis, UDCA therapy improved the excretion rates and transit time of bile acid analogs.[4][13] UDCA induces vesicular exocytosis in cholestatic hepatocytes by indirectly increasing intracellular calcium levels. In animal models, high levels of intracellular calcium were shown to stimulate transport proteins and vesicular exocytosis.[4][14] Other proposed mechanisms behind UDCA-induced choleresis include modulation of membrane transport proteins such as the chloride-bicarb anion exchanger (AE2) which was found to be diminished in biliary epithelia of PBC patients. UDCA administration was found to upregulate the expression of AE2 transporter when compared to the placebo group.[4][15]

UDCA has also been shown to have an immunomodulating effect on hepatocytes. In rats with extrahepatic obstruction caused by bile duct ligation,  researchers observed an increased hepatic expression of major histocompatibility complex (MHC) class I antigens. Similarly, patients with cholestasis resulting from primary biliary cirrhosis, have the same aberrant expression of MHC class I antigens on hepatocytes and bile duct cells. Expression of these antigens could lead to immune-mediated destruction by activated lymphocytes, causing hepatic injury. UDCA has been shown to reduce the expression of class I antigens in several cholestatic liver disorders.[16]

Administration

Ursodeoxycholic acid is a film-coated tablet available for oral administration. The absorption of the drug is enhanced by other bile acids, therefore it is recommended that the drug is taken during meals with food to facilitate biliary secretion by the gallbladder.[17]

Adverse Effects

Ursodeoxycholic acid is a mostly well-tolerated drug. In most clinical trials, diarrhea was the most frequent adverse event observed during UDCA treatment in patients with gallstone disease, with a reported incidence of 2 to 9%. The mechanism behind this side effect is unclear. However, researchers have proposed that bacterial conversion of UDCA to chenodeoxycholic acid, which serves as a potent secretory substance, could be a significant contributor to this side effect. In patients with primary biliary cirrhosis, right upper quadrant abdominal pain was the most common reported side effect. Reports also exist of skin reactions in those with primary biliary cirrhosis. The most common dermatological manifestation was an exacerbation of pruritus even though in other trials UDCA has demonstrated effectiveness in relieving pruritus in patients with PBC.[18]

Contraindications

Use of ursodeoxycholic acid is contraindicated in patients with obstructive cholestasis, due to a potential risk of biliary integrity disruption. Also, UDCA has not received approval for use in early pregnancy because of insufficient data regarding the risk of UDCA on the fetus during the first trimester of pregnancy.[19]

Monitoring

There is limited data on the therapeutic index of ursodeoxycholic acid. However, most data suggest that UDCA in doses of 5 to 25 mg/kg appears to be safe and well-tolerated. In patients with PBC, a dose of 13 to 15 mg/kg is preferred. The dose of 10 to 15 mg/kg used in most large trials was mostly for gallstone dissolution.[20]

Toxicity

UDCA has been shown to have potentially toxic molecular properties. UDCA breaks down into toxic lithocholic acid. After being absorbed in the small intestine, UDCA undergoes hepatic conjugation.  Beyond conjugation, UDCA does not experience further break down by the liver or intestinal mucosa. It becomes oxidized or reduced, yielding either 7-keto-lithocholic acid or lithocholic acid. Litcholic acid can be toxic to liver cells and even cause liver failure in those with compromised sulfation. It also leads to segmental bile duct injury, hepatocyte failure, and death.[21]

Enhancing Healthcare Team Outcomes

The large number of studies and data published on UDCA demonstrates the therapeutic effect of this drug on various forms of cholestatic liver disease. The efficacy of UDCA in primary biliary cholangitis is evident. Prolonged administration of ursodeoxycholic acid for patients with primary biliary cholangitis (PBC) is associated with survival benefit and delaying of liver transplantation. There is evidence that it might even prevent the progression of the histologic stage of PBC. A comprehensive review of three randomized trials from United Staes, Canada, and France included more than 500 patients with PBC treated with UDCA, with a median length of follow up of 4 years. Patients treated with UDCA had significantly longer transplant-free survival, with a 32% reduced risk of death or transplantation. However, it is essential to note that up to 40% percent of patients with PBC exhibit an inadequate response to UDCA and may continue to experience disease progression. In these cases, second-line agents merit consideration.[22] Recent data also suggest UDCA might have a role in the management of PSC, cystic fibrosis, graft-versus-host-disease, and other hepatobiliary disorders, however, concrete data regarding therapeutic potential and long term effects are currently lacking. Due to its multi-functionality, it is difficult to envision a viable substitute agent for UDCA that combines as many hepatoprotective effects with similar efficacy. The significant progress made in the understanding of the anti-cholestatic mechanisms of UDCA has allowed for successful testing of new therapeutic applications, even beyond liver and gallbladder disease. Several alternative drugs are under investigation in pre-clinical trials, however, unless there's an agent proven to be more effective than the current therapy, UDCA will most likely remain as the go-to agent for treating cholestatic liver disease.

The use of UDCA requires monitoring by the pharmacist in tandem with the prescribing clinician (MD, DO, NP, PA). While the drug is safe, it can exacerbate pruritis and cause abdominal discomfort. The pharmacist should notify the clinician if the side effects become intolerable. Nursing can assess for therapeutic effectiveness and adverse events at follow-up visits, which is particularly important if the drug is used off-label, and report these to the rest of the team. As more data regarding indications and use of UDCA becomes available from ongoing research, all members of the interprofessional healthcare team need to keep current, so they can optimally drive patient outcomes. [Level V]


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Ursodeoxycholic Acid - Questions

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A patient with right upper quadrant pain is found to have gallstones. She wants a medical cure for her disease and is administered ursodeoxycholic acid. What is this agent's mechanism of action?



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An obese female with right upper quadrant pain is found to have gallstones. She is treated with an agent that lowers cholesterol production by the liver. What is this agent?



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A 28-year old obese female with a BMI of 33 is about to undergo a gastric sleeve procedure. She has been screened by the internist and cleared for surgery. However, the clinician has started her on ursodeoxycholic acid. What is the reason for initiating this medication in this particular patient?



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A 43-year-old woman comes to the office after abnormal serum liver chemistry findings were found during her annual physical examination. Overall, the patient appears to be in good health and has no other chronic medical issues. She does not take any medications. She states that she has felt more tired than usual lately. However, she attributes this to menopause. She denies hot flashes, changes in sleep pattern, or weight loss. The patient does not use alcohol, tobacco, or illicit drugs. She works in a medical office. Her father died at age 65 from unknown liver disease. Vital signs are within normal limits, and physical exam is mostly unremarkable except for small bilateral xanthelasmata but no scleral icterus. Her abdomen is soft and nontender with no hepatosplenomegaly. Labs are significant for alkaline phosphatase 620 U/L, aspartate aminotransferase 62 U/L, alanine transaminase 74 U/L. Abdominal ultrasound reveals a normal size liver and no evidence of gallstones. Which of the following may help slow the progression of this patient's disease?



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Ursodeoxycholic Acid - References

References

Guarino MP,Cocca S,Altomare A,Emerenziani S,Cicala M, Ursodeoxycholic acid therapy in gallbladder disease, a story not yet completed. World journal of gastroenterology. 2013 Aug 21;     [PubMed]
Makino I,Tanaka H, From a choleretic to an immunomodulator: historical review of ursodeoxycholic acid as a medicament. Journal of gastroenterology and hepatology. 1998 Jun;     [PubMed]
Roma MG,Toledo FD,Boaglio AC,Basiglio CL,Crocenzi FA,Sánchez Pozzi EJ, Ursodeoxycholic acid in cholestasis: linking action mechanisms to therapeutic applications. Clinical science (London, England : 1979). 2011 Dec;     [PubMed]
Lazaridis KN,Gores GJ,Lindor KD, Ursodeoxycholic acid 'mechanisms of action and clinical use in hepatobiliary disorders'. Journal of hepatology. 2001 Jul;     [PubMed]
Copaci I,Micu L,Iliescu L,Voiculescu M, New therapeutical indications of ursodeoxycholic acid. Romanian journal of gastroenterology. 2005 Sep;     [PubMed]
Tabibian JH,Ali AH,Lindor KD, Primary Sclerosing Cholangitis, Part 1: Epidemiology, Etiopathogenesis, Clinical Features, and Treatment. Gastroenterology     [PubMed]
Kong X,Kong Y,Zhang F,Wang T,Yan J, Evaluating the effectiveness and safety of ursodeoxycholic acid in treatment of intrahepatic cholestasis of pregnancy: A meta-analysis (a prisma-compliant study). Medicine. 2016 Oct;     [PubMed]
Ljubuncic P,Fuhrman B,Oiknine J,Aviram M,Bomzon A, Effect of deoxycholic acid and ursodeoxycholic acid on lipid peroxidation in cultured macrophages. Gut. 1996 Sep;     [PubMed]
Combes B,Carithers RL Jr,Maddrey WC,Munoz S,Garcia-Tsao G,Bonner GF,Boyer JL,Luketic VA,Shiffman ML,Peters MG,White H,Zetterman RK,Risser R,Rossi SS,Hofmann AF, Biliary bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid. Hepatology (Baltimore, Md.). 1999 Jun;     [PubMed]
Jazrawi RP,de Caestecker JS,Goggin PM,Britten AJ,Joseph AE,Maxwell JD,Northfield TC, Kinetics of hepatic bile acid handling in cholestatic liver disease: effect of ursodeoxycholic acid. Gastroenterology. 1994 Jan;     [PubMed]
Heuman DM, Hepatoprotective properties of ursodeoxycholic acid. Gastroenterology. 1993 Jun;     [PubMed]
Medina JF,Martínez-Ansó,Vazquez JJ,Prieto J, Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology (Baltimore, Md.). 1997 Jan;     [PubMed]
Hillaire S,Boucher E,Calmus Y,Gane P,Ballet F,Franco D,Moukthar M,Poupon R, Effects of bile acids and cholestasis on major histocompatibility complex class I in human and rat hepatocytes. Gastroenterology. 1994 Sep;     [PubMed]
Saksena S,Tandon RK, Ursodeoxycholic acid in the treatment of liver diseases. Postgraduate medical journal. 1997 Feb;     [PubMed]
Hempfling W,Dilger K,Beuers U, Systematic review: ursodeoxycholic acid--adverse effects and drug interactions. Alimentary pharmacology     [PubMed]
Bessone F,Roma MG, Is ursodeoxycholic acid detrimental in obstructive cholestasis? A propos of a case of malignant biliary obstruction. Annals of hepatology. 2016 May-Jun;     [PubMed]
Verma A,Jazrawi RP,Ahmed HA,Davis T,Bland JM,Benson M,Orchard RT,Theodossi A,Maxwell JD,Northfield TC, Optimum dose of ursodeoxycholic acid in primary biliary cirrhosis. European journal of gastroenterology     [PubMed]
Kotb MA, Molecular mechanisms of ursodeoxycholic acid toxicity     [PubMed]
Ward JBJ,Lajczak NK,Kelly OB,O'Dwyer AM,Giddam AK,Ní Gabhann J,Franco P,Tambuwala MM,Jefferies CA,Keely S,Roda A,Keely SJ, Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. American journal of physiology. Gastrointestinal and liver physiology. 2017 Jun 1;     [PubMed]
Patel A,Seetharam A, Primary Biliary Cholangitis: Disease Pathogenesis and Implications for Established and Novel Therapeutics. Journal of clinical and experimental hepatology. 2016 Dec;     [PubMed]
Chascsa D,Carey EJ,Lindor KD, Old and new treatments for primary biliary cholangitis. Liver international : official journal of the International Association for the Study of the Liver. 2017 Apr;     [PubMed]
Bahar R,Wong KA,Liu CH,Bowlus CL, Update on New Drugs and Those in Development for the Treatment of Primary Biliary Cholangitis. Gastroenterology     [PubMed]

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