Ursodeoxycholic Acid: Current Clinical Applications in Chronic Hepatobiliary Diseases

Chronic Diseases Continue to Burden Public Health

Chronic diseases remain one of the leading causes of illness worldwide, affecting millions of people and placing a substantial burden on healthcare systems. Data collected in Lithuania in 2016 showed that respiratory diseases were among the most common health conditions, with approximately 302.7 cases per 1,000 inhabitants each year. Cardiovascular diseases followed at 246.3 cases per 1,000 people, while digestive system disorders accounted for 201.2 cases per 1,000 inhabitants annually.

Although conditions such as primary biliary cirrhosis (now more commonly referred to as primary biliary cholangitis), cystic fibrosis, and gallstone disease each affect fewer than 1% of the population, they are chronic disorders that can significantly reduce quality of life. Their long-term nature often requires ongoing monitoring and treatment aimed at slowing disease progression while relieving symptoms.

Primary Biliary Cirrhosis (Primary Biliary Cholangitis)

Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease in which the body's immune system gradually damages the small bile ducts located inside the liver. Over time, this persistent injury interferes with the normal flow of bile and can eventually lead to liver fibrosis and cirrhosis, a process that may take 10 to 20 years to develop.

Although the precise cause of PBC remains unknown, research suggests that the disease develops through a combination of genetic susceptibility and environmental influences. It occurs more frequently in individuals with other autoimmune disorders, including Sjögren's syndrome, systemic sclerosis (scleroderma), Raynaud's syndrome, and CREST syndrome. Smoking, chronic inflammatory conditions, and exposure to certain environmental chemicals have also been identified as possible contributing factors.

The condition affects women far more often than men, with approximately ten women diagnosed for every affected man. Most patients are diagnosed during middle or older age.

One of the challenges of PBC is that more than half of patients have no obvious symptoms when the disease is first detected. Instead, abnormalities are often discovered during routine blood tests, particularly elevated alkaline phosphatase or cholesterol levels.

Diagnosis is typically based on three key features. The first is persistent cholestasis, reflected by elevated serum alkaline phosphatase and gamma-glutamyltransferase (GGT) levels. The second is the presence of antimitochondrial antibodies (AMA), which are considered the hallmark of the disease. The third consists of characteristic microscopic findings showing chronic non-suppurative cholangitis together with destruction of the small interlobular bile ducts.

In the earliest stages, autoimmune activity dominates the disease process. Antimitochondrial antibodies target the mitochondria of bile duct epithelial cells, triggering chronic inflammation. This inflammatory response stimulates the release of chemokines, attracting additional immune cells to the affected tissue. As injury to the bile ducts continues, fibroblasts become activated, leading to progressive fibrosis and scarring.

As bile flow becomes increasingly impaired, patients may begin to experience a range of symptoms associated with chronic cholestasis. Fatigue is reported in approximately 20% to 85% of cases, while itching affects between 20% and 75% of patients. Jaundice develops in 10% to 60% of individuals, xanthomas occur in roughly 15% to 50%, and osteoporosis affects around 35% of patients during the course of the disease.

At present, ursodeoxycholic acid (UDCA) remains the standard first-line treatment for primary biliary cirrhosis. Early initiation of therapy has been shown to improve bile flow, slow disease progression, and reduce the risk of long-term liver complications.

Cystic Fibrosis and Liver Involvement

Cystic fibrosis (CF), also known as mucoviscidosis, is an inherited autosomal recessive disorder caused by mutations in the CFTR gene. This gene produces the cystic fibrosis transmembrane conductance regulator protein, which is expressed in the epithelial cells of the lungs, pancreas, intestines, liver, and sweat glands.

Mutations in CFTR disrupt the normal transport of chloride ions across cell membranes. As chloride secretion decreases, sodium and water absorption increase, leaving body secretions unusually thick and dehydrated. The resulting mucus becomes difficult to clear and tends to accumulate within ducts and airways, causing damage in multiple organs.

The lungs are affected most frequently. Thick mucus obstructs the small airways, making breathing progressively more difficult and contributing to chronic obstructive lung disease, recurrent respiratory infections, and declining lung function.

However, cystic fibrosis is not limited to the respiratory system. Approximately one-third of patients also develop hepatobiliary complications.

In the liver and bile ducts, impaired electrolyte and water transport causes bile to become increasingly concentrated and viscous. This promotes the formation of biliary concretions, enlargement of the bile ducts, thickening of the duct walls, and the gradual development of chronic inflammation and fibrosis.

As liver disease progresses, blood levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) may become elevated. Because liver damage can develop gradually without obvious symptoms, annual liver ultrasound examinations are recommended to monitor structural changes and assess disease progression.

Historically, cystic fibrosis was considered a childhood disease because most patients did not survive into adulthood. Advances in diagnosis, multidisciplinary care, nutritional support, antibiotics, and CFTR-modulating therapies have dramatically improved life expectancy. Today, many individuals with cystic fibrosis can live beyond the age of 50, shifting treatment goals toward preserving long-term organ function and maintaining quality of life.

For patients who develop liver involvement, oral ursodeoxycholic acid therapy is commonly recommended. Clinical evidence indicates that UDCA can improve both the structural and functional condition of the liver and biliary system, making it an important component of long-term management for cystic fibrosis-associated liver disease.

Gallstone Disease

Gallstone disease is one of the most common disorders affecting the hepatobiliary system and is estimated to affect approximately 10% to 15% of adults in Europe.

In many individuals, gallstones are discovered incidentally during abdominal ultrasound examinations performed for unrelated medical reasons. These patients often have no symptoms. On ultrasound, gallstones typically appear as hyperechoic structures that cast an acoustic shadow and move when the patient changes body position.

Gallstones vary considerably in composition. Around 80% are mixed stones containing up to 50% cholesterol, while approximately 10% are composed predominantly of cholesterol, containing more than 50% cholesterol. The remaining pigment stones develop because of disturbances in bilirubin metabolism and are classified as either brown stones, accounting for roughly 5% to 10% of cases, or black stones, which represent up to 5%.

Several factors increase the likelihood of developing cholesterol-rich gallstones. Advancing age, female sex, obesity, physical inactivity, and diets that are high in calories but low in dietary fiber all contribute to higher risk. Hormonal influences, including pregnancy, hormonal contraceptives, and hormone replacement therapy, have also been associated with increased gallstone formation.

The development of cholesterol stones involves several interconnected biological mechanisms. The composition of bile gradually changes, with cholesterol concentrations increasing while bile acid levels decrease. At the same time, bile becomes more concentrated and the gallbladder's ability to empty efficiently declines.

In older adults, cholesterol secretion into bile naturally increases because of enhanced cholesterol synthesis or reduced conversion into bile acids. When gallbladder emptying is impaired, cholesterol-saturated bile begins forming microscopic crystals that gradually enlarge into gallstones.

For patients with symptomatic gallstone disease accompanied by impaired gallbladder function, laparoscopic cholecystectomy remains the treatment of choice.

However, surgery is not appropriate for every patient. Individuals with functioning gallbladders and cholesterol gallstones may instead be treated with oral ursodeoxycholic acid. The greatest success is generally achieved when stones measure no more than 15 mm in diameter on ultrasound or are radiolucent on plain X-ray imaging.

When multiple mobile gallstones are present, additional imaging—such as excretory cholangiography or computed tomography—is recommended to determine stone density. Ideally, stone density should not exceed 60 Hounsfield units (HU), as lower-density cholesterol stones are more likely to respond to dissolution therapy. Ursodeoxycholic acid may also be prescribed before lithotripsy to reduce stone size and relieve symptoms, thereby improving treatment outcomes.

Bile Acid Metabolism and the Role of Ursodeoxycholic Acid

Ursodeoxycholic acid (UDCA) is a naturally occurring bile acid that is present in small quantities in human bile. Although it represents only a minor proportion of the body's total bile acid pool, it plays an important role in maintaining normal bile composition and protecting the liver and biliary system.

Bile acid metabolism is one of the body's most efficient recycling processes. Bile is produced by hepatocytes in the liver before being secreted into the gallbladder, where it is stored between meals. After food enters the small intestine, bile is released to aid in the digestion and absorption of dietary fats. Approximately 95% of bile acids are then reabsorbed through the intestine, transported back to the liver through the bloodstream, and reused in a process known as enterohepatic circulation.

The primary bile acids—cholic acid (CA) and chenodeoxycholic acid (CDCA)—account for roughly 70% of the body's total bile acid pool. Both are synthesized from cholesterol within hepatocytes before being conjugated with either glycine or taurine. These conjugated bile acids are secreted into bile, stored in the gallbladder, and later released into the small intestine during digestion.

Within the intestine, gut microorganisms further modify some bile acids. For example, glycocholic acid, which is formed when cholic acid combines with glycine, can be converted by intestinal bacteria into ursodeoxycholic acid. Under normal physiological conditions, UDCA represents only about 3% of total bile acids.

When administered orally, approximately 80% of UDCA is absorbed from the gastrointestinal tract. Absorption occurs primarily through passive diffusion in the jejunum and upper ileum, while active transport contributes to absorption in the lower ileum. Following absorption, nearly all UDCA is transported to the liver, where it undergoes conjugation before being secreted back into bile and re-entering the enterohepatic circulation.

Only very small amounts of UDCA circulate freely in the bloodstream, with a minor proportion eliminated by the kidneys. Intestinal bacteria also metabolize a small fraction—up to approximately 5%—which is ultimately excreted in the feces.

Therapeutic Effects of Ursodeoxycholic Acid

The understanding of bile acids changed significantly during the late twentieth century following the discovery of nuclear receptors that regulate their biological activity. These discoveries demonstrated that bile acids act not only as digestive compounds but also as important signaling molecules involved in metabolism, inflammation, and liver function. As a result, ursodeoxycholic acid has become an established treatment for several hepatobiliary disorders.

Choleretic Effect

One of the primary therapeutic actions of UDCA is its choleretic effect, meaning that it promotes the production and flow of bile.

Cholestasis develops when bile production or secretion becomes impaired within the liver or bile ducts. UDCA helps restore normal bile flow by influencing gene transcription and increasing the expression of transport proteins responsible for moving bile components through liver cells and bile ducts.

Improved bile production facilitates the removal of potentially toxic bile acids from the liver while promoting their elimination through the intestine. By restoring normal bile circulation, UDCA helps reduce the harmful effects of prolonged bile retention within liver tissue.

Cytoprotective Effect

UDCA also provides direct protection to liver and biliary cells.

Through interactions with mitochondria, the endoplasmic reticulum, and the cell nucleus, UDCA stabilizes the membranes of hepatocytes, cholangiocytes, and other epithelial cells. This stabilization increases resistance to injury caused by toxic bile acids and oxidative stress.

The drug also inhibits cellular apoptosis, or programmed cell death, helping preserve healthy liver tissue during chronic inflammatory diseases. By reducing ongoing cellular injury, UDCA contributes to maintaining normal liver architecture and function.

Immunomodulatory and Anti-Inflammatory Effects

Another important property of UDCA is its ability to regulate immune and inflammatory responses.

In patients with primary biliary cirrhosis (primary biliary cholangitis), treatment with UDCA has been associated not only with clinical improvement but also with reductions in serum concentrations of immunoglobulin M (IgM), immunoglobulin G (IgG), and antimitochondrial antibodies (AMA).

UDCA interacts with several components of the immune system, including T lymphocytes, B lymphocytes, and natural killer cells. These effects help suppress chronic inflammation within the liver and reduce the autoimmune attack directed against hepatocytes and cholangiocytes.

By limiting persistent inflammation, UDCA slows the formation of fibrous connective tissue and may delay the progression of liver fibrosis in chronic cholestatic liver diseases.

Cholesterol-Lowering Effect

UDCA also influences cholesterol metabolism through several complementary mechanisms.

Treatment reduces endogenous cholesterol synthesis within the liver, decreases intestinal cholesterol absorption, and limits cholesterol secretion into bile. These combined effects lower cholesterol concentrations and reduce the amount of cholesterol available for gallstone formation.

Litholytic Effect

One of the best-established clinical applications of UDCA is its ability to dissolve cholesterol-rich gallstones.

The medication restores a healthier balance between hydrophilic and hydrophobic bile acids, reducing the lithogenicity—or stone-forming potential—of bile. As bile becomes less saturated with cholesterol, the formation of new cholesterol crystals is inhibited, while existing cholesterol stones may gradually dissolve in patients whose gallbladder continues to function normally.

This effect makes UDCA a valuable non-surgical treatment option for carefully selected patients with small cholesterol gallstones.

Summary

Although ursodeoxycholic acid naturally represents only a small proportion of human bile acids, it exerts a wide range of beneficial biological effects. By improving bile flow, protecting liver cells, regulating immune responses, lowering cholesterol concentrations, and reducing the formation of cholesterol gallstones, UDCA has become an important therapeutic option in several chronic hepatobiliary disorders.

Current clinical indications include first-line treatment of primary biliary cirrhosis (primary biliary cholangitis), dissolution of selected cholesterol gallstones—typically those measuring up to 2 cm in diameter—and management of liver and biliary complications associated with cystic fibrosis in adolescents aged 6 to 18 years. Ongoing research continues to expand understanding of bile acid biology and may further broaden the therapeutic applications of UDCA in hepatology.

 "Gastroenterology",  JOURNAL "INTERNIST" SUPPLEMENT 2017, No. 1 (16)