Ursodeoxycholic acid is used to dissolve gallstones in patients who do not want surgery or cannot have surgery to remove gallstones.
Actigall (ursodeoxycholic acid) is also used to prevent gallstone formation in overweight patients who are losing weight quickly.
Actigall is a bile acid, a substance produced naturally by the body and stored in the gallbladder. It works by decreasing the production of cholesterol and dissolving the cholesterol in the bile so that it cannot form stones.
This drug is sometimes prescribed for other uses; consult your doctor or pharmacist for more information.
Gallstone disease continues to be a relevant problem for the health system and one of the most common and costly digestive diseases if we consider the number of cholecystectomies performed annually throughout the world and the rate of hospital admission for gallstone disease complicated.
Gallstone disease is a complex disorder in which environmental and genetic factors contribute to susceptibility to the disease. Risk factors include age, gender, race, parity, and dietary factors.
The use of ursodeoxycholic acid in treating liver diseases dates back to traditional Chinese medicine during the Tang Dynasty. For centuries, the Chinese drug “Shorea spp.”, Derived from the bile of adult black bears, has been used to cure various hepatobiliary disorders.
Only at the beginning of the 20th century, Ursodeoxycholic acid was identified from polar bear bile by Hammarsten, a Swedish researcher, who called this uncharacterized bile acid ursocoleinic acid. The bile acid he identified as chenodeoxycholic acid.
It is said anecdotally that the sample ran out during the purification process and ceased to crystallize.
Twenty years later, in 1927, Shoda of Okayama University isolated Ursodeoxycholic acid from imported Chinese bear bile, succeeded in crystallizing it, and then called it by its current name, that is, Urso-deoxycholic (“urso,” in Latin), being the predominant bile acid in bears.
Until Makino et al. demonstrated that ursodeoxycholic acid treatment resulted in the dissolution of cholesterol gallstones, ursodeoxycholic acid was predominantly used in Japan as a liver tonic in doses too small to have a significant therapeutic effect.
Subsequently, its use spread worldwide after further confirmation of its effectiveness and safety.
From the time of commercialization to the present, many researchers worldwide have been involved in biochemists—currently, clinical studies on ursodeoxycholic acid, demonstrating its extreme versatility.
Ursodeoxycholic acid can be used as a therapeutic tool in cholestatic liver diseases and is currently considered the only medical treatment officially approved by the US Food and Drug Administration to treat primary biliary cirrhosis.
It can also be a therapeutic tool for non-cholestatic and non-hepatobiliary diseases.
For example, it appears to exert an antiproliferative effect in preventing colon cancer and adenoma recurrence, an immunomodulatory effect in AIDS patients, and plays a protective role in idiopathic recurrent pancreatitis.
Finally, ursodeoxycholic acid, thanks to its biochemical structure, can penetrate the blood-brain barrier so that in the future, an application of Ursodeoxycholic acid may be found as a stabilizer of the cell membrane in disorders of the central nervous system.
Despite the extensive accumulated evidence regarding the possible use of ursodeoxycholic acid in various diseases, the most significant proof remains the beneficial effect in dissolving cholesterol gallstones.
Ursodeoxycholic acid in gallstone disease
Ursodeoxycholic acid, in pharmacological doses, notably reduces bile cholesterol saturation by 40% -60% by inhibiting the absorption of cholesterol in the intestine and the secretion of cholesterol in the bile, as indicated by a decrease in the fraction of cholesterol from bile lipids.
In addition, it is well known that ursodeoxycholic acid reduces the toxicity of bile acids that can damage cell membranes and cause cholestasis through different means of action:
By inhibiting the absorption of hydrophobic endogenous bile acids from the small intestine, exerting a choleretic function that induces dilution of endogenous bile salts in the bile ducts and protecting hepatocytes against toxic bile acids.
Since Makino et al. first reported the dissolution of gallstones with ursodeoxycholic acid, it has been used primarily to treat cholesterol stones in the gallbladder as an alternative to cholecystectomy.
Although gallstones are composed primarily of cholesterol, only a few patients (<10% of the total) can be treated with systemic dissolution therapy using Ursodeoxycholic acid.
How to take actigall
Candidates for ursodeoxycholic acid therapy must have cholesterol-enriched non-calcified gallstones <20 mm in diameter and a proprietary cystic duct.
The recommended dose of ursodeoxycholic acid for gallbladder stones is 8-10 mg/kg per day; larger quantities offer no additional benefit.
A 30% -60% dissolution rate (approximately 1mm decrease in stone diameter per month) has been reported. However, the initial gallstone diameter is the most critical factor affecting the speed. Dissolution.
Actigall in stone dissolution
A clinical study demonstrated the complete disappearance of small stones (<5 mm) with ursodeoxycholic acid treatment after six months (90% in approximately 90% of cases).
After complete dissolution, ursodeoxycholic acid should be continued for another three months to confirm the breakdown of microscopic stones that may not be detected by ultrasound.
The absence or minimal change in gallstone diameter within 6 to 12 months of ursodeoxycholic acid treatment represents a poor prognostic sign for dissolution.
The possibility of reducing by dissolving the size of large stones (> 20 mm in diameter) or multiple is very low (less than 40% -50% after one year of treatment).
Bile mud has been considered another therapeutic target for ursodeoxycholic acid. Sludge formation in the biliary system can be accelerated, for example, by rapid weight loss, pregnancy, total parenteral nutrition, and solid organ transplantation.
Benefits of using actigall
The beneficial effect of ursodeoxycholic acid in this condition has been demonstrated in a clinical study in which idiopathic acute pancreatitis has been associated with microscopic gallstones or bile sludge.
In one study, administration of ursodeoxycholic acid within 3 to 6 months prevented the recurrence of gallstones and further episodes of pancreatitis during a 44-month follow-up.
Limit of actigall therapy
The most significant limitation of ursodeoxycholic acid therapy for the dissolution of gallstones is the high recurrence rate.
Several studies have reported a recurrence rate of 30% -50% at five years and 50% -70% at 12 years, after successful treatment, especially in patients with multiple gallstones.
For these reasons, the therapeutic effect of ursodeoxycholic acid in patients with symptomatic gallstones has been controversial in recent decades.
But the usefulness of this bile acid as a therapeutic tool has been successively reconsidered for its dissolving capacity and its dissolving capacity. For the anti-inflammatory effect.
A long-term follow-up study on ursodeoxycholic acid treatment showed a significant decrease in the incidence of complications from gallstone disease.
In particular, this study showed that ursodeoxycholic acid treatment in patients with symptomatic gallstones reduced the incidence of biliary pain and acute cholecystitis compared to no therapy over 18 years.
Interestingly, this therapeutic effect was independent of the dissolution of gallstones.
This suggests that ursodeoxycholic acid could achieve these effects by restoring the typical environment of the gallbladder that more recent studies on gallstone disease have clearly shown to be characterized by an inflammatory state.
A more recent 3-month, randomized, placebo-controlled study showed that ursodeoxycholic acid had no beneficial effect on biliary pain or complications.
It should be noted that there are significant differences in the recurrence rates of biliary pain and the need for cholecystectomy between these two studies.
Tomida et al. reported recurrence rates of <10% in those patients who received ursodeoxycholic acid compared to 40% in those who received a placebo after four years.
In contrast, in the most recent clinical trial, the need for cholecystectomy after 100 days on Ursodeoxycholic acid or placebo reached almost 75%.
These differences suggest that ursodeoxycholic acid may not be effective in patients with more advanced chronic inflammatory gallbladder disease.
Previous findings show that ursodeoxycholic acid treatment:
- It restores the muscular functions of the gallbladder and reduces the biochemical markers of oxidative stress and inflammation.
- They may support and partially explain the beneficial effects in patients with symptomatic gallstones of the gallbladder that were independent of gallstone dissolution.
Anti-inflammatory effects of actigall
A series of in vitro studies have investigated the anti-inflammatory effect of ursodeoxycholic acid. Cystic duct ligation in guinea pigs does not cause acute cholecystitis unless the bile is lithogenic with cholesterol and concentrated bile is injected into the gallbladder.
Guinea pigs undergoing common bile duct ligation develop acute cholecystitis within 2-3 days, along with biochemical and pathologic changes similar to those found in human acute cholecystitis, with or without gallstones.
The muscle cells of the gallbladder have:
Increased levels of reactive oxygen species (ROS), lipid peroxidation and prostaglandin E2 (PGE2), your response to cholecystokinin (CCK-8), PGE2, and potassium chloride are affected and associated with a significant reduction in receptor binding of these ligands.
These abnormalities were reproduced by treating normal human muscle cells with H2O2 or hydrophobic bile acids (Tauro-chenodeoxycholic acid).
And they are prevented by pretreatment with PGE2 or free radical scavenger catalase, suggesting that hydrophobic bile acids damage receptors and calcium.
Channels of the gallbladder muscle cells stimulate the generation of reactive oxygen species.
Effects of actigall on the gallbladder muscles
Interestingly, in vitro studies have shown that muscle cells preincubated with ursodeoxycholic acid prevent Tauro-chenodeoxycholic-induced cell damage and the production of reactive oxygen species.
This specific beneficial effect of ursodeoxycholic acid has been confirmed in a 4-week, randomized, double-blind study conducted by one group, comparing the results of ursodeoxycholic acid with those of placebo in patients scheduled to undergo cholecystectomy for symptomatic gallbladder stones.
In particular, the study revealed that ursodeoxycholic acid pretreatment restores normal contraction of gallbladder muscle cells by:
Reduce cholesterol content in plasma membranes and H2O2 levels, lipid oxidation, platelet-activating factor-like lipids, and PGE2 production and catalase activity.
These results are consistent with data reported in a non-randomized study showing better contraction of the gallbladder muscle girdle in patients treated with ursodeoxycholic acid for three weeks compared to patients receiving no treatment.
These data support the hypothesis that lithogenic bile containing excess cholesterol creates a permissive environment in the gallbladders that disrupts the average balance between hydrophobic bile acids and the protective mechanisms of the gallbladder.
Bile acids stimulate the formation of reactive oxygen species, capable of initiating inflammatory processes and cholecystitis.
Thus, by reducing excess cholesterol and “neutralizing” hydrophobic bile acids, ursodeoxycholic acid restores the balance between aggressive bile factors and the protective mechanisms of the gallbladder.
Hydrophobic bile acids, such as chenodeoxycholic acid and deoxycholic acid, have also been shown to have a toxic effect on the liver, mainly through the generation of reactive oxygen species.
In particular, hydrophobic bile acids, after hepatic retention, can affect not only hepatocytes but also resident macrophages (i.e., Küpffer cells) that generate reactive oxygen species and increase the level of oxidative stress.
Therapeutic concentrations of ursodeoxycholic acid enrich the bile acid pool with ursodeoxycholic acid, resulting in a profile change from hydrophobicity to hydrophilicity.
Administration of ursodeoxycholic acid has been shown to prevent and reduce hydrophobic bile acid damage to the liver.
In fact, in addition to the displacement of hydrophobic bile acids, ursodeoxycholic acid appears to exert a beneficial effect by preventing hydrophobic bile acid-induced stimulation of macrophage oxidative processes.
A study by one group suggests that ursodeoxycholic acid appears to exert a preventative action on the effects of hydrophobic bile acids on macrophage oxidative processes in the gallbladder.
The data emerging from this study reveal the appearance, in surgically removed gallbladders of patients with cholesterol gallstones, of an increase in the number of macrophages in the muscle layer compared to the normal gallbladder.
Of interest is this 4-week, randomized, double-blind study comparing the effects of ursodeoxycholic acid with placebo in patients with symptomatic gallbladder stones.
Scheduled to undergo cholecystectomy showed that this hydrophilic bile acid leads to a decrease in the number of activated macrophages in the muscle layer and reduced production of PGE2 in the gallbladder muscle.
PGs are catalytic products of cyclooxygenase-2 (COX2) and are well-known gastrointestinal smooth muscle function modulators.
Many studies on ursodeoxycholic acid in the gallbladder and liver disease published in recent years indicate the beneficial effect of this bile acid, supported by the most recent advances in understanding its impact in terms of anti-inflammatory medication.
In fact, as only a small number of patients can benefit from actigall, in terms of dissolution therapy, its specific beneficial effect is also related to the prevention of complications in carriers of symptomatic gallstones, which is independent of stone dissolution.
This hydrophilic bile acid could be an alternative therapeutic approach in high-risk surgical patients with symptomatic gallbladder stones.