Oral Chenodeoxycholic Acid Research Articles

Congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variation in 2 cases and literature review

Objective: To summarize the clinical features and genetic characteristics of Congenital bile acid synthetic disorder type 3 (BASD3) disorder caused by CYP7B1 gene variation. Methods: This was a case series study. Clinical data and genetic results of 2 cases of congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variations in the Department of Infectious Diseases, Children's Hospital of Fudan University at Xiamen and Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University from January 2021 to December 2023 were retrospectively collected and analyzed. Literature up to December 2023 was searched from electronic databases of China National Knowledge Infrastructure (CNKI), Wanfang Data and PubMed with the combined keywords of " Congenital bile acid synthetic disorder type 3""Oxysterol 7-alpha-hydroxylase""Oxysterol 7α-Hydroxylase Deficiency""BASD3" and "CYP7B1 liver" both in Chinese and English. The main clinical features and genetic characteristics of BASD3 disorder caused by CYP7B1 gene variations were summarized. Results: Two BASD3 patients, 1 male and 1 female, were admitted at the ages of 3 months and 18 days, and 2 months and 7 days, respectively. Both patients presented with neonatal cholestasis and hepatomegaly. Biochemical evidence indicated direct hyper-bilirubinemia with elevated aminotransferase levels, while gamma-glutamyltransferase (GGT) and total bile acid levels were normal or nearly normal. Patient 1 was a compound heterozygotes of the CYP7B1 gene variants c.525-526insCAAGTTGG(p.Asp176GInfs*15) and c.334C>T(p.Arg112Ter). Patient 1 jaundice resolved and liver function tests normalized after oral administration of chenodeoxycholic acid (CDCA). Patient 2 was homozygous for variant c.334C>T(p.Arg112Ter) in CYP7B1 gene. Patient 2 was in liver failure status already and not reactive to oral CDCA administration. Patient 2 received living-related liver transplantation for enhanced abdominal CT revealed a liver tumor likely vascular origin. Literature review revealed no cases of BASD3 reported in Chinese literature, including 2 patients in this study, while 12 patients (9 males and 3 females) were reported in 9 English literatures. All of the 12 manifested jaundice and hepatosplenomegaly in infancy, with cirrhosis, liver failure, kidney enlargement, hypoglycemia, and spontaneous bleeding in some cases, polycystic kidney disease was demonstrated in 5 cases of them. The c.334C>T (p.Arg112Ter) of the CYP7B1 gene was homozygous in 4 cases and compound heterozygous in 2 cases. Among the 12 children, 6 cases received CDCA treatment, while 6 cases not. Four survived with their native liver in the 6 cases who received CDCA therapy, while none in the 6 cases not received CDCA therapy. Conclusions: BASD3 is a rare hereditary cholestatic disorder. Markedly elevated levels of conjugated bilirubin and aminotransferases, with normal or nearly normal GGT and total bile acid levels can serve as diagnostic clue. c.334C>T is the most common pathogenic variant of the CYP7B1 gene. Timely administration of CDCA may save the liver.

Features of the metabolic syndrome and subclinical atherosclerosis in patients with cerebrotendinous xanthomatosis: An augmented risk for premature cardiovascular disease.

Background: Cerebrotendinous xanthomatosis (CTX) is a rare lipid storage disease, caused by deficiency of sterol-27-hydroxylase. Xanthomatous lesions in numerous tissues, and an elevation of cholestanol levels, characterize the disease. Its natural course is progressive neurologic deterioration, leading to premature death. Chronic treatment with oral chenodeoxycholic acid (CDCA) reduces cholestanol levels. Occurrence of premature atherosclerosis has been described in CTX in an unknown mechanism. Aim: The aim of the current work was to evaluate the potential metabolic abnormalities and preclinical vascular changes in Israeli CTX patients. Methods: Ten subjects with CTX were studied. Features of the metabolic syndrome were evaluated, and carotid intima media thickness (cIMT) was measured in the common carotid arteries. Results: All patients were diagnosed with CTX, and all received treatment with CDCA, which resulted in normalization of their plasma cholestanol levels. At the conclusion of the follow up, risk factors for CVD and features of MS were present in all the patients and in three patients, cIMT was higher compared to control subjects. Conclusion: Cardiovascular risk factors and premature vascular changes exist in young CTX patients and proper assessment should be implemented with preventive measures to reduce the risk of atherosclerotic cardiovascular disease in CTX patients.

Duodenal-jejunal bypass reduces serum ceramides via inhibiting intestinal bile acid-farnesoid X receptor pathway.

BACKGROUNDBile acids play an important role in the amelioration of type 2 diabetes following duodenal-jejunal bypass (DJB). Serum bile acids are elevated postoperatively. However, the clinical relevance is not known. Bile acids in the peripheral circulation reflect the amount of bile acids in the gut. Therefore, a further investigation of luminal bile acids following DJB is of great significance.AIMTo investigate changes of luminal bile acids following DJB.METHODSSalicylhydroxamic acid (SHAM), DJB, and DJB with oral chenodeoxycholic acid (CDCA) supplementation were performed in a high-fat-diet/streptozotocin-induced diabetic rat model. Body weight, energy intake, oral glucose tolerance test, luminal bile acids, serum ceramides and intestinal ceramide synthesis were analyzed at week 12 postoperatively.RESULTSCompared to SHAM, DJB achieved rapid and durable improvement in glucose tolerance and led to increased total luminal bile acid concentrations with preferentially increased proportion of farnesoid X receptor (FXR) - inhibitory bile acids within the common limb. Intestinal ceramide synthesis was repressed with decreased serum ceramides, and this phenomenon could be partially antagonized by luminal supplementation of FXR activating bile acid CDCA.CONCLUSIONDJB significantly changes luminal bile acid composition with increased proportion FXR-inhibitory bile acids and reduces serum ceramide levels. There observations suggest a novel mechanism of bile acids in metabolic regulation after DJB.

Genetic spectrum and clinical characteristics of 3\u03b2-hydroxy-\u03945-C27-steroid oxidoreductase (HSD3B7) deficiency in China

BackgroundBiallelic variants in HSD3B7 cause 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency, a life-threatening but treatable liver disease. The goal of this study was to obtain detailed information on the correlation between the genotype and phenotype of HSD3B7 deficiency and to report on responses to primary bile acid therapy.MethodsThe medical records of a cohort of 39 unrelated patients with genetically and biochemically confirmed HSD3B7 deficiency were examined to determine whether there exist genotype-phenotype relationships in this bile acid synthesis disorder.ResultsIn all, 34 of the 44 variants identified in HSD3B7 were novel. A total of 32 patients presented early with neonatal cholestasis, and 7 presented after 1-year of age with liver failure (n = 1), liver cirrhosis (n = 3), cholestasis (n = 1), renal cysts and abnormal liver biochemistries (n = 1), and coagulopathy from vitamin K1 deficiency and abnormal liver biochemistries (n = 1). Renal lesions, including renal cysts, renal stones, calcium deposition and renal enlargement were observed in 10 of 35 patients. Thirty-three patients were treated with oral chenodeoxycholic acid (CDCA) resulting in normalization of liver biochemistries in 24, while 2 showed a significant clinical improvement, and 7 underwent liver transplantation or died. Remarkably, renal lesions in 6 patients resolved after CDCA treatment, or liver transplantation. There were no significant correlations between genotype and clinical outcomes.ConclusionsIn what is the largest cohort of patients with HSD3B7 deficiency thus far studied, renal lesions were a notable clinical feature of HSD3B7 deficiency and these were resolved with suppression of atypical bile acids by oral CDCA administration.

Gene supplementation of CYP27A1 in the liver restores bile acid metabolism in a mouse model of cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene, encoding the sterol 27-hydroxylase. Disruption of the bile acid biosynthesis pathway and accumulation of toxic precursors such as cholestanol cause chronic diarrhea, bilateral juvenile cataracts, tissue deposition of cholestanol and cholesterol (xanthomas), and progressive motor/neuropsychiatric alterations. We have evaluated the therapeutic potential of adeno-associated virus (AAV) vectors expressing CYP27A1 in a CTX mouse model. We found that a vector equipped with a strong liver-specific promoter (albumin enhancer fused with the α1 anti-trypsin promoter) is well tolerated and shows therapeutic effect at relatively low doses (1.5 × 1012 viral genomes [vg]/kg), when less than 20% of hepatocytes overexpress the transgene. This vector restored bile acid metabolism and normalized the concentration of most bile acids in plasma. By contrast, standard treatment (oral chenodeoxycholic acid [CDCA]), while reducing cholestanol, did not normalize bile acid composition in plasma and resulted in supra-physiological levels of CDCA and its derivatives. At the transcriptional level, only the vector was able to avoid the induction of xenobiotic-induced pathways in mouse liver. In conclusion, the overexpression of CYP27A1 in a fraction of hepatocytes using AAV vectors is well tolerated and provides full metabolic restoration in Cyp27a1−/− mice. These features make gene therapy a feasible option for the etiological treatment of CTX patients.

Successful treatment of infantile oxysterol 7\u03b1-hydroxylase deficiency with oral chenodeoxycholic acid

BackgroundDeficiency of oxysterol 7α-hydroxylase, encoded by CYP7B1, is associated with fatal infantile progressive intrahepatic cholestasis and hereditary spastic paraplegia type 5. Most reported patients with CYP7B1 mutations presenting with liver disease in infancy have died of liver failure. However, it was recently reported that two patients treated with chenodeoxycholic acid survived. Correlations between the phenotype and genotype of CYP7B1 deficiency have not been clearly established.Case presentationA 5-month-7-day-old Chinese baby from non-consanguineous parents was referred for progressive cholestasis and prolonged prothrombin time from one month of age. Genetic testing revealed compound heterozygous mutations c.187C > T(p.R63X)/c.334C > T(p.R112X) in CYP7B1, and fast atom bombardment mass spectrometry analysis of the urinary bile acid confirmed the presence of atypical hepatotoxic 3β-hydroxy-Δ5-bile acids. While awaiting liver transplantation she was orally administered chenodeoxycholic acid. Her liver function rapidly improved, urine atypical bile acids normalized, and she thrived well until the last follow-up at 23 months of age. Her 15-year-old brother, with no history of infantile cholestasis but harboring the same mutations in CYP7B1, had gait abnormality from 13 years of age. Neurological examination revealed hyper-reflexia and spasticity of the lower limbs. Brain MRI revealed enlarged perivascular space in the bilateral basal ganglia and white matter of frontal parietal.ConclusionsIn summary, these findings highlight that the phenotype of CYP7B1 deficiency varies widely, even in siblings and that early administration of chenodeoxycholic acid may improve prognosis.

Differential effects of bile acids on the postprandial secretion of gut hormones: a randomized crossover study.

Bile acids (BA) regulate postprandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The postprandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effects of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on postprandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon, and ghrelin. Twelve healthy volunteers underwent a mixed meal test 60 min after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg), or no BA in a randomized crossover study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin, and fibroblast growth factor 19 were measured prior to BA administration at -60 and 0 min (just prior to mixed meal) and 15, 30, 60, 120, 180, and 240 min after the meal. UDCA and CDCA provoked differential gut hormone responses; UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced postprandial secretion of GIP, with an associated reduction in postprandial insulin secretion. Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmed in obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.NEW & NOTEWORTHY Oral CDCA and UDCA have different effects on gut and pancreatic hormone secretion. A single dose of CDCA increased fasting secretion of the hormones GLP-1 and OXM with an accompanying increase in insulin secretion. CDCA also reduced postprandial GIP secretion, which was associated with reduced insulin. In contrast, UDCA did not change gut hormone secretion fasting or postprandially. Oral CDCA could be beneficial to patients with obesity and diabetes.

Oral chenodeoxycholic acid increases post-prandial anorectic gut hormone levels and increases indices of insulin sensitivity

Oral chenodeoxycholic acid increases post-prandial anorectic gut hormone levels and increases indices of insulin sensitivity

Experimental Evidence of Liver Injury by BSEP-Inhibiting Drugs With a Bile Salt Supplementation in Rats.

The bile salt export pump (BSEP, ABCB11) mediates bile acid efflux from hepatocytes into bile. Although the inhibition of BSEP has been implicated as an important mechanism of drug-induced liver injury (DILI), liver injury caused by BSEP-inhibiting drugs is rarely reproduced in experimental animals, probably due to species differences in bile acid composition between humans and rodents. In this study, we tested whether supplementation with chenodeoxycholic acid (CDCA) sodium, a hydrophobic bile salt, could sensitize rats to liver injury caused by a BSEP-inhibiting drug. A potent BSEP inhibitor, ketoconazole (KTZ), which is associated with clinical DILI, was intragastrically administered simultaneously with CDCA at a nontoxic dose once a day for 3 days. Plasma transaminase levels significantly increased in rats receiving CDCA+KTZ, whereas neither treatment with CDCA alone, KTZ alone nor a combination of CDCA and miconazole, a safe analog to KTZ, induced liver injury. In CDCA+KTZ-treated rats, most bile acid species in the liver significantly increased compared with treatment with vehicle or CDCA alone, suggesting that KTZ administration inhibited bile acid excretion. Furthermore, hepatic mRNA expression levels of a bile acid synthesis enzyme, Cyp7a1, and a basolateral bile salt influx transporter, Ntcp, decreased, whereas a canalicular phosphatidylcholine flippase, Mdr2, increased in the CDCA+KTZ group to compensate for hepatic bile acid accumulation. In conclusion, we found that oral CDCA supplementation predisposed rats to KTZ-induced liver injury due to the hepatic accumulation of bile acids. This method may be useful for assessing the potential of BSEP-inhibiting drugs inducing liver injury in vivo.

A preventable ataxia: Cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis is an autosomal recessive inborn error of metabolism that is an often missed but treatable cause of hereditary ataxia. We report a case of cerebrotendinous xanthomatosis (CTX) that was diagnosed only after the development of cognitive decline and adult onset ataxia in a 35-year-old man. He had poor scholastic performance in childhood followed by gradually progressive cognitive decline. He presented to us with severe cerebellar ataxia and oculomotor apraxia. The key features that led to the diagnosis of CTX were the history of cataracts in childhood and Achilles tendon xanthoma. His brain magnetic resonance imaging showed characteristic features of CTX, and the diagnosis was confirmed by demonstrating the mutation in exon 2 of the CYP27A1 gene. The recognition of CTX earlier could have prevented his significant disabilities. The definitive treatment is oral chenodeoxycholic acid, which will prevent the accumulation of the cholestanol, which is thought to be responsible for the neurotoxicity.

Prolonged fibroblast growth factor 19 response in patients with primary sclerosing cholangitis after an oral chenodeoxycholic acid challenge

BackgroundBile salts likely contribute to liver injury in patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Fibroblast growth factor 19 (FGF19) is a bile salt-induced enterokine with hepatoprotective potential as it suppresses de novo bile salt synthesis. Here, we evaluated the bile salt receptor FXR/FGF19 gut–liver axis in PSC and PBC patients.MethodsFasted patients with PSC (n = 12) and PBC (n = 10), and healthy controls (HC; n = 10) were orally challenged with the natural FXR agonist chenodeoxycholic acid (CDCA 15 mg/kg). Blood was sampled hourly until 8 h afterwards. Serum FGF19 and bile salt excursions were determined. Serum levels of 7α-hydroxy-4-cholesten-3-one (C4), reflecting bile salt synthesis, were measured as a biomarker of FGF19 response.ResultsBaseline serum FGF19 levels were comparable between groups, while fasted bile salt levels in PSC patients were elevated. Upon CDCA challenge, HC and PBC patients showed a serum FGF19 peak after 4 h followed by a decline. PSC patients showed a prolonged and elevated serum FGF19 response up to 8 h, combined with a sustained serum elevation of CDCA and other bile salts. In general, C4 levels declined following FGF19 elevation. In PSC patients with less favorable prognosis, baseline C4 levels were drastically suppressed and did not further decline.ConclusionFollowing an oral CDCA challenge, PSC patients showed an impaired clearance of CDCA and a prolonged serum FGF19 response. FXR agonist therapy in PSC could cause prolonged exposure to elevated levels of FGF19, and we propose careful monitoring for detrimental side effects in patient studies.

Evaluation of cholesterol metabolism in cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a treatable bile acid disorder caused by mutations of CYP27A1. The pathogenesis of neurological damage has not been completely explained. Oral chenodeoxycholic acid (CDCA) can lead to clinical stabilization, but in a subgroup of patients the disease progresses despite treatment. In the present study, we aimed at clarifying cholesterol metabolism abnormalities and their response to CDCA treatment, in order to identify reliable diagnostic and prognostic markers and understand if differences exist between stable patients and those with neurological progression. We enrolled 19 untreated CTX patients and assessed serum profile of bile acids intermediates, oxysterols, cholesterol, lathosterol, and plant sterols. Then we performed a long-term follow up during CDCA therapy, and compared biochemical data with neurological outcome. We observed increase of cholestanol, 7α-hydroxy-4-cholesten-3-one (7αC4), lathosterol, and plant sterols, whereas 27-hydroxycholesterol (27-OHC) was extremely low or absent. CDCA treatment at a daily dose of 750mg normalized all biochemical parameters except for 7αC4 which persisted slightly higher than normal in most patients, and 27-OHC which was not modified by therapy. Biochemical evaluation did not reveal significant differences between stable and worsening patients. Cholestanol and 7αC4 represent important markers for CTX diagnosis and monitoring of therapy. Treatment with CDCA should aim at normalizing serum 7αC4 as well as cholestanol, since 7αC4 better mirrors 7α-hydroxylation rate and is thought to be correlated with cholestanol accumulation in the brain. Assessment of serum 27-OHC is a very good tool for biochemical diagnosis at any stage of disease. Lathosterol and plant sterols should be considered as additional markers for diagnosis and monitoring of therapy. Further studies including long-term assessment of bile acid intermediates in cerebrospinal fluid are needed in patients who show clinical progression despite treatment.

Juvenile Cataract Morphology in 3 Siblings Not Yet Diagnosed with Cerebrotendinous Xanthomatosis

Cerebrotendinous xanthomatosis is a progressive neurodegenerative storage disease caused by recessive CYP27A1 mutations and is characterized by abnormal deposition of cholestanol and cholesterol in multiple tissues, including the lens and brain. Oral chenodeoxycholic acid is preventive and can be therapeutic, but is not used optimally because the condition typically is diagnosed late or not at all. When affected children demonstrate lens opacities, ophthalmologists have the unique potential to facilitate earlier diagnosis and treatment by recognizing the juvenile cataract phenotype. This study highlights the morphology of lens opacities in a family with genetically confirmed disease. Prospective case series. Four siblings and their 2 parents, who are first cousins. Ophthalmic examination, general physical examination, and exome sequencing guided by homozygosity analysis. Ophthalmic findings, general clinical findings, and results of CYP27A1 candidate gene testing. Two sisters, each visually symptomatic before 10 years of age, had a unique pattern of bilateral fleck deposits throughout the lens with significant posterior capsular cataract. When initially examined at 8 years of age, their then-asymptomatic younger brother had the same bilateral fleck deposits with minimal posterior capsular opacity; 1 year later, he demonstrated anterior capsular opacity and became symptomatic. Both asymptomatic parents had few but distinct similar flecks localized at or near the anterior Y-suture, whereas an asymptomatic sister did not. Genetic analysis revealed homozygosity for a known CYP27A1 mutation (c.1263+1G → A) in the 3 symptomatic siblings, heterozygosity for the mutation in the 2 parents, and no mutation in the asymptomatic sister. When specifically questioned, the 3 affected children had experienced recurrent bouts of diarrhea in early childhood, which is a common feature of the disease. An unusual pattern of fleck lenticular deposits was seen in affected children. With time, capsular opacities (posterior only or posterior and anterior) developed and caused visual symptoms. Such juvenile lenticular findings should raise suspicion for this treatable metabolic disorder, especially when in the context of recurrent diarrhea during early childhood. Asymptomatic fleck-like opacities at or near the anterior Y-suture may be a carrier sign. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Two neonatal cholestasis patients with mutations in the SRD5B1 (AKR1D1) gene: diagnosis and bile acid profiles during chenodeoxycholic acid treatment

In two Japanese infants with neonatal cholestasis, 3-oxo-Δ(4)-steroid 5β-reductase deficiency was diagnosed based on mutations of the SRD5B1 gene. Unusual bile acids such as elevated 3-oxo-Δ(4) bile acids were detected in their serum and urine by gas chromatography-mass spectrometry. We studied effects of oral chenodeoxycholic acid treatment. SRD5B1 gene analysis used peripheral lymphocyte genomic DNA. Diagnosis and treatment of these two patients were investigated retrospectively and prospectively investigated. With respect to SRD5B1, one patient was heterozygous (R266Q, a novel mutation) while the other was a compound heterozygote (G223E/R261C). Chenodeoxycholic acid treatment was effective in improving liver function and decreasing unusual bile acids such as 7α-hydroxy- and 7α,12α-dihydroxy-3-oxo-4-cholen-24-oic acids in serum and urine. Primary bile acid treatment using chenodeoxycholic acid was effective for these patients treated in early infancy before the late stage of chronic cholestatic liver dysfunction.

Tu1883 Activation of the Nuclear Receptor FXR by Oral Chenodeoxycholic Acid in Patients With Crohn's Colitis: Potential Therapeutic Consequences for Inflammatory Bowel Disease

Tu1883 Activation of the Nuclear Receptor FXR by Oral Chenodeoxycholic Acid in Patients With Crohn's Colitis: Potential Therapeutic Consequences for Inflammatory Bowel Disease

Cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid-storage disease caused by mutations in the sterol 27-hydroxylase gene. The accumulation of cholestanol in various tissues characterizes this disease. Diagnosis is based on determination of urinary bile alcohols. Therapy with chenodeoxycholic acid may arrest the progression of the disease. A 55-year-old woman presented with a slowly progressive paraparesia and two firm subcutaneous tumors over the knees. Her medical history revealed difficulty in standing and walking since infancy, bilateral juvenile cataracts, and mental retardation. Histopathologic examination of one subcutaneous tumor was consistent with tendinous xanthoma. Substantial elevation of urinary bile alcohols confirmed the diagnosis. Treatment with oral chenodeoxycholic acid was started, with only mild improvement of spasticity. Recognition of tendon xanthomas in a young patient with neurologic symptoms or cataracts (or both) is crucial to start early treatment and to avoid irreversible neurologic sequelae. (J Am Acad Dermatol 2001;45:292-5.)

Determination of individual serum bile acids in chronic liver diseases: fasting levels and results of oral chenodeoxycholic acid tolerance test.

Fifteen bile acids in serum of 5 normal subjects and 21 patients with chronic liver diseases were fractionated by high performance liquid chromatography. Fasting total bile acids (TBA), glycocholic acid, taurocholic acid, glycochenodeoxycholic acid (GCDCA), and taurochenodeoxycholic acid (TCDCA) were significantly increased in patients with liver cirrhosis as compared with normal subjects. The cholic acid (CA) level and the ratio of the sum of free and conjugated CA to the sum of free and conjugated chenodeoxycholic acid (CDCA) were significantly elevated in patients with compensated as compared with decompensated liver cirrhosis, and were useful for differentiation of the two conditions. Serum bile acid levels were determined after oral administration of 500 mg of CDCA in the 5 normal subjects and 11 patients with liver disease. The TBA level reached a peak 90 min after CDCA administration in patients with chronic hepatitis and after 120 min in those with liver cirrhosis. The increase in the TBA level was significantly greater in patients with liver disease than in normal subjects. CDCA, GCDCA, and TCDCA showed changes similar to those in TBA. In patients with decompensated liver cirrhosis, the reduction in the TBA and CDCA levels after the peaks was slow, and GCDCA and TCDCA levels continued to increase until 180 min after the administration of CDCA. The TBA and CDCA levels 180 min after CDCA administration were significantly different among normal subjects, patients with chronic hepatitis, those with compensated liver cirrhosis, and those with decompensated liver cirrhosis, suggesting the usefulness of CDCA administration in differentiation of these conditions.

7 - Gallstone Dissolution — A Progress Report

Cholesterol gallstone formation occurs in three stages. First, the bile must be saturated with cholesterol, thereby allowing cholesterol crystals to form. Then, nucleation and growth of the gallstone can occur, although little is known about these latter two stages. Therapy for dissolution of gallstones is directed at desaturating the bile. Chenodeoxycholic acid (CDCA), the most extensively tested agent, is successful in dissolving 60 per cent of radiolucent gallstones; however, long-term safety remains to be demonstrated. Ursodeoxycholic acid (UDCA), the 7 beta epimer of CDCA, is a promising agent for cholesterol gallstone dissolution, but it, other potential agents, and dietary manipulations require more extensive study. An important problem, the prevention of recurrence of gallstones after dissolution, also needs resolution. Medical dissolution probably will be applicable as an alternative to cholecystectomy for most patients with radiolucent gallstones, but the specific relative indications remain to be determined. A variety of modalities, both medical and surgical, are being used for the treatment of retained or reformed bile duct stones. These include T-tube infusions, oral CDCA, and extraction either through the T-tube tract or after endoscopic papillotomy. Further studies, including controlled trials, are necessary to determine the relative indications for these methods.

THE NON-OPERATIVE MANAGEMENT OF GALLSTONES

During the last decade the non-surgical management of gallbladder stones has become possible. Oral chenodeoxycholic acid (CDCA) and more recently, ursodeoxycholic acid (UDCA), have proved to be safe and effective. For the treatment of bile duct stones, various methods including flushing, chemical dissolution and mechanical procedures are now available. A combination of these techniques can be used in a logical sequence and should enable the successful treatment of most patients with bile ducts stones.

The effect of oral chenodeoxycholic acid on cholesterol solubility in hepatic bile.

By oral administration of chenodeoxycholic acid (CDCA) varying in dose for 7 consecutive days to patients who underwent cholecystectomy with biliary drainage for cholesterol gallstone, the biliary cholesterol dissolubility was studied in pursuit of the optimum dose in CDCA therapy for cholesterol gallstone. The rate of dissolution of biliary cholesterol by CDCA administration was highest in cases of 250 mg/day in dose, followed by those of 750 mg/day. When the dose was observed from per kg of body weight, the dissolubility of cholesterol was highest in the case of 6.3 mg/kg, followed by one of 12 mg/kg. Thus, it is presumed that in CDCA therapy for cholesterol gallstone a dose of 250 mg/day is too small and 750 mg/day too large in amount from the viewpoint of its effectiveness. The optimum dose probably lies between 5 mg/kg and 12 mg/kg. A transient elevation in levels of SGOT and SGPT was observed only in one case treated with 750 mg/kg.