Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients.

Dehydrocholic Acid Ameliorates Sodium Taurocholate-Induced Acute Biliary Pancreatitis in Mice.

Acute biliary pancreatitis (ABP) with a high mortality rate is an incurable digestive system disease induced by abnormal bile acid regurgitation due to the biliary obstruction. Dehydrocholic acid (DA) alleviates the severity of cholestatic hepatitis related to biliary inflammation, suggesting DA is potential to develop for the incurable ABP management. Here we identified DA potency and explored the underlying mechanism in ABP. Our data showed that DA administration not only reduced typically clinicopathological parameters including serum levels of amylase and lipase but also suppressed pancreatic tissue edema, necrosis and trypsin activation in ABP mice. We also found that DA significantly reduced the necrosis of pancreatic acinar cells induced by sodium taurocholate (NaT). Further experimental data showed the significant inhibitions of DA on mitochondrial membrane potential depolarization, ATP exhaustion, calcium overload and reactive oxygen species (ROS) erupted in acinar cells induced by NaT, indicating DA could avert acinar cell death through protecting the mitochondrial function, scavenging excessive oxidative stress and balancing calcium. The comprehensive study found DA elevated the expression of transcription factor EB (TFEB) in vitro thus to increase the functional lysosome content. Indeed, DA decreased the Microtubule-associated protein light chain 3 (LC3) II/I ratio as well as ubiquitin-binding protein p62 and Parkin expressions in vivo and in vitro, revealing autophagy restoration maybe through the improvement of TFEB-mediated lysosome biogenesis. These data indicate that DA improves ABP through the mitochondrial protection, antioxidant ability enhancement and autophagy recovery. In conclusion, our study proposes a potential therapy strategy for the incurable ABP.

Surgical outcome in relation to duct size at the porta hepatis and the use of cholagogues in patients with biliary atresia.

BACKGROUND: Small ductules communicating with the bile ducts have been described at the porta hepatis in extrahepatic biliary atresia (EHBA) and these form the basis for hepatic portoenterostomy. The use of cholagogues like dehydrocholic acid (DHC) and ursodeoxycholic acid (UDCA) to enhance bile flow postoperatively has been reported. AIMS: This communication describes our experience with the use of cholagogues following surgery in EHBA and attempts to correlate the outcomes with the diameter of the ductules. MATERIAL AND METHODS: Fifty five EHBA patients treated by the Kasai procedure form the basis of this study; 35 patients treated during 1979-1986 and administered DHC (3-5 mg/kg) postoperatively and 20 patients treated during 1999-2002 and administered UDCA (15 mg/kg) postoperatively. The diameter of ductules was measured using an optical micrometer on 5 microm serial sections; the ducts were classified as type I (no demonstrable ducts, n = 14), type II (< 50 microm, n=22) and type III (> 50 microm, n = 19). The clinical outcome was categorized as 1 (jaundice free survival at 5 years follow-up, n = 7), 2 (initial good response but deteriorated after one year, n = 27) and 3 (expired within one year following surgery, n = 21). The response to surgery was monitored using biochemical liver function tests (LFT), hepatobiliary scintigraphy (HIDA scan) and occurrence of cholangitis. RESULTS: Age did not affect the size of ducts in both DHC and UDCA groups but patients in the DHC group were older than those treated with UDCA (mean age DHC: 105.22 +/- 33.53 days, UDCA: 74.68 +/- 23.73 days; p = 0.009). There was no statistically significant difference between duct size and postoperative LFT in both groups (DHC p = 0.1, UDCA p = 0.5). Bile excretion on HIDA scan was significantly better with larger ducts (DHC p = 0.003, UDCA p = 0.025); overall UDCA showed significantly better bile excretion (p = 0.003) but this was not reflected in the surgical outcome. There was no significant difference in the surgical outcome of those treated with DHC or UDCA but a significantly higher incidence of cholangitis was seen with smaller ducts in the UDCA group (p = 0.02). CONCLUSIONS: There was no correlation between duct diameter and postoperative LFT but type III ducts were associated with better bile flow on HIDA scan. Cholangitis was seen more often with type I and II ducts in both DHC and UDCA groups. UDCA administration seemed to be beneficial in patients with type III ducts in increasing bile flow and reducing cholangitis.

Spasmocanulase in irritable bowel syndrome.

OBJECTIVES: Irritable bowel syndrome is a functional gastro intestinal disorder, with various symptomatology and difficult to treat using several medications. Spasmocanulase, which has an anti-spasmodic and anti-flatulence effect and contains several ingredients, was tried in patients with irritable bowel syndrome, who had been on other medications previously without improvement. METHODS: At the gastroenterology out-patient clinic, Armed Forces Hospital, Riyadh, Kingdom of Saudi Arabia, 21 patients who were diagnosed with irritable bowel syndrome for more than 2 years on treatment and did not benefit from these medications, received spasmocanulase one tablet 3 times a day and followed in the gastroenterology out-patient clinic, every 6 weeks for 6 months. Their previous medications were discontinued which, had been used for different durations and in different combinations included Mebeverine, Colpermin, Normacol, Importal, Librax. The main symptoms were different types of abdominal pain, bloating, flatulence, diarrhea, constipation or both. RESULTS: There was improvement or disappearance of the symptoms in more than 50% of the patients who were not improved on previous medication used for more than 2 years. The overall improvement in symptoms ranged between 43-75% in these patients, when followed up in the clinic at 6 weeks and 3 months. Spasmocanulase caused improvement in abdominal pain, flatulence and bloating compared to their previous medications. Only 43% of patients with diarrhea, showed improvement on spasmocanulase. CONCLUSION: Although the number of patients, we studied is small, this study has shown that spasmocanulase is beneficial in improving symptoms of irritable bowel syndrome.

Choledocholithiasis in an infant of extremely low birthweight.

A five-month-old infant of extremely low birthweight with choledocholithiasis is reported. A baby girl was delivered at 26 weeks gestation as a second twin, weighing 834 g. At 30 days of age, gallbladder stones were found by routine ultrasonography. She had vomiting at 157 days of age. Ultrasonography revealed calculi in the gallbladder and a dilated common bile duct. She was conservatively treated with scopolamine, antibiotics and dehydrocholic and ursodeoxycholic acids, and the calculi had disappeared by 189 days of age. Although conservative treatment succeeded in this patient, further cases should be analysed to establish how to manage choledocholithiasis in such small infants.

Plant natural products active against snake bite--the molecular approach.

The article surveys the substances identified in plants reputed to neutralize the effects of snake venoms. Protective activity of many of them against the lethal action of the venom of the jararaca (Bothrops jararaca) snake was confirmed by biological assays. It was shown that all belong to chemical classes capable of interacting with macromolecular targets--receptors and enzymes. In a few cases it has been shown that exogenous natural micromolecules can mimic the biological activity of endogenous macromolecules. From the evidence presented, it can be inferred that micromolecules which neutralize the action of snake venoms mechanistically replace endogenous antitoxic serum proteins with venom neutralizing capacity such as produced by some animals.

[Role of bile acids and endotoxins in the pathogenesis and therapy of psoriasis]. / Epesavak és endotoxinok szerepe a pikkelysömör kórfejlódésében és kezelésében.

The authors demonstrated significant curative effect of bile acids (Suprachol; Acidum dehydrocholicum) in 551 psoriatic patients. The clinical efficiancy was evaluated by means of PASI-score (Psoriasis Area Severity Index). During this treatment (1-8 weeks) 434 patients (78.8 per cent) became asymptomatic. However, the traditional therapy resulted in 62 patients (24.9 per cent) of 249 sick persons a recovery (p < 0.05). In acute form of psoriasis (184 patients) this curative effect of bile acids was elevated (95.1 per cent). Two years later 319 patients (57.9 per cent) of bile treated 551 people were asymptomatic in contrast with 15 people (6.0 per cent) of 249 traditional treated patients (p < 0.05). In same time among the patients which were treated in acute form of psoriasis 10 (7.2 per cent) of 139 controls and 147 (79.9 per cent) of 184 bile-treated individuals were asymptomatic (p < 0.01). On the basis of their clinical observations (digestive disorders, ultrasonical confirmed gallbladder complaints, etc.) authors supposed that the deficiency of bile acids and the consecutive endotoxin translocation might play a role in the pathogenesis of psoriasis. In normal conditions the bile acids as detergent (physico-chemical defense) can protect the body against enteral endotoxins while split them to atoxic fragments and so preventing consecutive cytokin liberation.

A controlled trial of choleretic and hepatoprotective actions of Livzon and dehydrocholic acid in a model of obstructive jaundice in albino rats.

The authors have tried to examine the hepatoprotective and cholerectic action of a new indigenised drug, Livzon (Hind Chemicals Ltd., Kanpur, India) and compared its action to Decholin (casella-Riedel Pharma GmbH, Frankfurt, Germany), a known hepatoprotective and choleretic agent. Albino rats were chosen as the experimental animals. Obstructive jaundice was created by ligating the common bile ducts after taking liver biopsies. The animals were divided into three groups: (i) Control group-no drug was given, (ii) Livzon trial group, (iii) Decholin group. The animals were reoperated, liver biopsies were taken and histologically examined. The study confirmed the hepatoprotective and choleretic actions of Livzon and Decholin. However, Decholin was more of a choleretic, the Livzon was more hepatoprotective.

Avaliaçäo da atuaçäo do ácido dehidrocólico na funçäo da vesícula bibliar / Therapeutic evolution of dehydrocolic acid (B-Vesil) at gallbladder discinesy

Foi feito um acompanhamento de 10 pacientes com uso do ácido dehidrocólico (B-Vesil), que apresentavam problemas de discinesia biliar. Estes pacientes foram acompanhados com exames complementares os quais demonstraram uma boa resposta ao estímulo de esvaziamento da vesícula biliar

[Effects of dehydrocholic acid (Biliton) on metabolism and liver function in cows]. / Dehydrocholsäure (Biliton)-Wirkungen auf Stoffwechsel und Leberfunktion bei Kühen.

Dehydrocholic acid (Biliton) was given to 9 cows with a predisposition for the fat mobilization syndrome in daily doses of 5.5 g each. This was done two weeks after parturition and the results were compared with those from 9 untreated cows. Five other cows suffering from ketosis or indigestion symptoms were treated too. Decreased concentrations of liver lipids, free fatty acids (FFA), bilirubin, beta-OH-butyrate and urea as well as increased glucose in blood plasma indicated a favourable action of Dehydrocholic acid on metabolism and liver function. We did not observe a significant influence on milk and reproduction parameters. The use of Dehydrocholic acid is recommended for use in liver disturbances.

[Does Hepavis have value in the therapy of fatty liver caused by alcohol poisoning?]. / Hat Hepavis einen Stellenwert in der Therapie der äthyltoxischen Fettleber?

During the therapy of fatty liver (resp. fatty liver hepatitis) the additional application of Hepavis besides the prohibition of alcohol does not have any advantages in comparison to an additional application of a placebo. So the significant decrease of the fat content of the liver under those circumstances seems to be only the consequence of lacking alcohol consume, but not a specific effect of Hepavis. Consequently the treatment of alcoholtoxic fatty liver can be no other than to avoid alcohol, one of the most important causes of illness nowadays.

Hepatobiliary scintigraphy for cholestasis in congenital hepatic fibrosis. Diagnosis and treatment.

A 9-year-old child with congenital hepatic fibrosis had dilated intrahepatic bile ducts and recurrent cholangitis. Choleretic agents were administered to prevent recurrent cholangitis. Response to treatment was monitored with serum bile acid concentrations and computer-assisted technetium Tc 99m iprofenin (Pipida) scintigraphy. Dehydrocholic acid with meals improved hepatobiliary excretion of the radioactive isotope and lowered serum bile acid levels but did not prevent cholangitic attacks when used alone. Sulfamethoxazole and trimethoprim used alone prevented infection, but a steady rise in serum bile acid concentrations suggested increasing cholestasis. During combined drug treatment, the patient remained free of cholangitis for at least two years. Optimal therapy of congenital hepatic fibrosis with cholestasis but without mechanical biliary obstruction may involve the combined use of a choleretic such as dehydrocholic acid plus a suppressive antibiotic.

[Treatment of alcoholic toxic fatty liver. A placebo-controlled trial with hepavis (author's transl)]. / Therapie der alkohol-toxischen Fettleber. Plazebo-kontrollierte Doppelblindstudie mit Hepavis.

A placebo-controlled double-blind study of 30 patients with advanced chronic fatty liver was intended to show how far treatment with a liver preparation, in this case Hepavis, is superior to alcohol abstinence alone. Examination of the laboratory parameters, especially of gamma GT shows that treatment with Hepavis with simultaneous withdrawal of alcohol produces a rapid normalization or improvement of the laboratory findings and consequently an accelerated improvement in the course of the disease. This leads to the conclusion that the pathological activity of the liver cell is reduced more quickly by the constituents of Hepavis than without suitable therapy, and that a more favorable prognosis for the fatty liver as a potential precurser of cirrhosis is to be attained. Not only is elimination of the lipogenic factor, alcohol, essential in the treatment of fatty liver, but also treatment with hepatotropic substances.