Methylprednisolone Administration in Primary Biliary Cirrhosis Increases Cholic Acid Turnover, Synthesis, and Deoxycholate Concentration in Bile

As immunosuppressive agents, corticosteroids maybe considered an appropriate treatment for primarybiliary cirrhosis, even if bone loss and other sideeffects may occur. We studied biliary lipid metabolism in 10 nonicteric patients, with histologicallyproven primary biliary cirrhosis (stage I-IV). Weadministered methylprednisolone (24 mg daily) for 30days to ascertain its effects on biliary lipidmetabolism, which are largely still unknown. All patientsunderwent a 30-day drug-washout period before enteringthe trial. The following parameters were studied beforeand after methylprednisolone treatment: serum biochemistry; cholic acid pool size, kineticsand synthesis; biliary lipid secretion; biliary bileacid pattern; biliary lipid molar percentage; andcholesterol saturation index. Methylprednisolone induced a statistically significant (Wilcoxon ranktest) increase in cholic acid turnover (from 0.26± 0.04 to 0.50 ± 0.05 K/day, P = 0.005)and synthesis (from 0.42 ± 0.12 to 0.78 ±0.11 mmol/day, P = 0.04), and in bile deoxycholic acid molarpercentage (from 19.4 ± 2.7 to 30.6 ± 4.4%molar, P = 0.01). On the other hand, a significantdecrease in biliary cholesterol molar percentage (from7.9 ± 0.7 to 6.4 ± 0.5 % molar, P =0.005), cholesterol saturation index (from 1.11 ±0.11 to 0.95 ± 0.07, P = 0.05), and biliarycholesterol secretion (from 64.7 ± 5.4 to 53.0± 4.5 mol/hr, P = 0.005) was observed. These findings show thatshort-term administration of methylprednisolone inpatients with primary biliary cirrhosis does not induceexpansion of the cholic acid pool but increases cholicacid synthesis and turnover, as well as intestinalproduction of deoxycholic acid. If long-term treatmentis considered, the beneficial immunosuppressive effectsof corticosteroids have to be weighed against the hepatotoxic properties of deoxycholicacid.     

Gallstone Dissolution with Oral Bile Acid Therapy Importance of Pretreatment CT Scanning and Reasons for Nonresponse

In patients with cholesterol-rich gallbladderstones and a patent cystic duct, complete stoneclearance rates of 65-90% have been reported with oralbile acids (OBAs) alone or with adjuvant lithotripsy (extracorporeal shock-wave lithotripsy; ESWL).The aims of the present study were to analyzepretreatment gallstone characteristics that predict thespeed and completeness of dissolution with OBAs ±ESWL, and to assess, in patients with incompletedissolution, the reasons for the poor response. Wecompared pretreatment gallstone characteristics in 43patients who became stone-free after a median of 9months OBAs ± ESWL with those in 43 age- andsex-matched patients whose stones failed to dissolveafter two years of treatment. In those with incompletegallstone dissolution, we repeated the oralcholecystogram and computed tomogram (CT) and, in selectedpatients, obtained gallbladder bile by percutaneousfine-needle puncture. In patients who became stone-free,those with stones that were isodense with bile and/or had CT scores of 75 Hounsfield units had thefastest dissolution rates. In the 43 nonresponders, themain causes for treatment failure were impairedgallbladder contractility and acquired stonecalcification. CT-lucent, noncholesterol stones, or failure ofdesaturation of bile with the prescribed bile acids,occurred in a minority. We conclude that thepretreatment CT attenuation score predicts both thespeed and completeness of gallstone dissolution. Inpatients with incomplete stone dissolution, thecombination of oral cholecystography, CT, and analysisof gallbladder bile will determine the underlyingreasons for treatment failure in most, but not all,cases.     

Bile Acid Diarrhea: Prevalence,Pathogenesis, and Therapy

Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn’s disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as ⁷⁵selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD.     

Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment

Background

We encountered 7 Japanese patients with bile acid synthesis disorders (BASD) including 3β-hydroxy-Δ⁵-C₂₇-steroid dehydrogenase/isomerase (3β-HSD) deficiency (n?=?3), Δ⁴-3-oxosteroid 5β-reductase (5β-reductase) deficiency (n?=?3), and oxysterol 7α-hydroxylase deficiency (n?=?1) over 21 years between 1996 and 2017.

Aim

We aimed to clarify long-term outcome in the 7 patients with BASD as well as long-term efficacy of chenodeoxycholic acid (CDCA) treatment in the 5 patients with 3β-HSD deficiency or 5β-reductase deficiency.

Methods

Diagnoses were made from bile acid and genetic analyses. Bile acid analysis in serum and urine was performed using gas chromatography–mass spectrometry. Clinical and laboratory findings and bile acid profiles at diagnosis and most recent visit were retrospectively obtained from medical records. Long-term outcome included follow-up duration, treatments, growth, education/employment, complications of treatment, and other problems.

Results

Medians with ranges of current patient ages and duration of CDCA treatment are 10 years (8 to 43) and 10 years (8 to 21), respectively. All 7 patients, who had homozygous or compound heterozygous mutations in the HSD3B7, SRD5B1, or CYP7B1 gene, are currently in good health without liver dysfunction. In the 5 patients with CDCA treatment, hepatic function gradually improved following initiation. No adverse effects were noted.

Conclusions

We concluded that CDCA treatment is effective in 3β-HSD deficiency and 5β-reductase deficiency, as cholic acid has been in other countries. BASD carry a good prognosis following early diagnosis and initiation of long-term CDCA treatment.

     

Combined Bile Acid Therapy is More Effective on Biliary Lipids and Dissolution Rates than Monotherapy After Gallstone Lithotripsy

Background: Accurate sampling to gallbladder bile for biliary analysis is essential for determining any potential difference between combined bile acid therapy and monotherapy in gallstone patients.
Methods: In 104 gallstone patients undergoing extracorporeal shock wave lithotripsy with following bile acid therapy [either chenodeoxycholic acid (500 mg/day) and ursodeoxycholic acid (500 mg/day), group I (n = 53), or ursodeoxycholic acid alone (1000 mg/day), group II (n = 51)], bile samples, obtained by direct fine needle puncture of the gallbladder, were investigated for biliary lipids, total biliary protein concentration, and nucleation time before and after 12 months of bile acid therapy.
Results: Initially, a negative correlation was found between nucleation time and number of gallstones and between total biliary protein concentration and nucleation lime ( r = -0.52 and r = -0.49 in group I vs r = -0.56 and r = -0.51 in group II, p < 0.01 in each group). The correlation between total biliary protein concentration and nucleation time was also found after 12 months of bile acid treatment ( r = -0.54 in group I vs r = -0.47 in group II, p < 0.01 in each group). In group I, the decrease in cholesterol saturation index, biliary cholesterol, cholic acid, deoxycholic acid, and total protein concentration was more pronounced than in group II ( p < 0.01). The same effect was found concerning the prolongation of nucleation time ( p < 0.01). Furthermore, dissolution rates were higher in group I compared with group II (80.4 vs 69.0%, p < 0.01).
Conclusion: In gallstone patients, combined therapy with urso- and che-nodeoxycholic acid is superior to either ursodeoxycholic acid alone or biliary parameters in bile samples obtained by direct line needle puncture of the gallbladder.     

Long-term Course in Collagenous Colitis and the Impact of Bile Acid Malabsorption and Bile Acid Sequestrants on Histopathology and Clinical Features

Background: Bile acid malabsorption is common in collagenous colitis, although long-term follow-up data on the impact of bile acids are limited. The aim was to study whether bile acid malabsorption is a permanent finding, with an impact on histopathology and clinical features in collagenous colitis. Methods:     

Comparison of Three Bile Acid Provocation Tests: Intravenous Cholecystokinin,a Standard Test Meal,and an Oral Bile Acid Load in Healthy Subjects

Three different bile acid provocation tests—an intravenous stimulation with cholecystokinin (CCK), a test meal, and an oral bile acid load of 500 mg chenodeoxycholic acid (CDAF—were compared in 12 healthy subjects. Blood samples were drawn every 30min for 3 h, and serum bile acids (SBA) were measured by an enzymatic method (Enzabile®). The CCK stimulation gave significant SB A elevations only at 30 min. After the test meal and the CDA loading tests SB A elevations were observed from 30 min and throughout the observation period. Maximal increases were obtained at 120 min after the test meal but already at 30 min after the CDA loading test. We conclude that among these three bile acid provocation tests the oral CDA loading test is to be preferred because it gives marked and rapid elevation of SBA in all subjects and is independent of bile acid pool size and normal function of the gallbladder.     

Tolterodine: A Safe and Effective Treatment for Older Patients with Overactive Bladder

OBJECTIVE: To investigate the clinical safety and efficacy of two dosages of tolterodine in older patients with symptoms attributable to overactive bladder. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group, multinational, phase III study. SETTING: Incontinence, older care, urological, and urogynecological clinics in the United Kingdom, France, and the Republic of Ireland. PARTICIPANTS: One hundred and seventy-seven older patients (age > or =65 years) with symptoms of urinary urgency, increased frequency of micturition (> or =8 micturitions/24 hours), and/or urge incontinence (> or =1 episode/24 hours). INTERVENTION: Tolterodine 1 mg or 2 mg twice daily (bid), or placebo, for 4 weeks. MEASUREMENTS: Safety and tolerability were evaluated through spontaneously reported adverse events, electrocardiogram, and blood pressure measurements. Efficacy was assessed using micturition diary variables: mean change from baseline in frequency of micturition and number of incontinence episodes/24 hours. RESULTS: The mean age of the patient population was 75 years. Overall, > or =87% of patients completed the study. Neither dosage of tolterodine was associated with serious drug-related adverse events during the study. No cardiac arrythmogenic events were noted. Dry mouth (mild to moderate intensity) was the most common adverse event in both the placebo and tolterodine treatment groups. Three percent of patients in the tolterodine 2 mg bid group discontinued treatment because of dry mouth, compared with 2% of placebo-treated patients. Compared with placebo, statistically significant decreases in micturition frequency were apparent in both tolterodine treatment groups. Furthermore, patients treated with tolterodine 2 mg bid had statistically significant decreases in urge incontinence episodes/24 hours and increases in volume voided per micturition compared with placebo. CONCLUSION: Tolterodine (taken for 4 weeks) is safe and shows efficacy, particularly at a dosage of 2 mg bid, in the treatment of older patients with urinary symptoms attributable to overactive bladder.     

Self-Management of Oral Anticoagulant Therapy: A Review

Patient self-management of oral anticoagulant therapy has over the last years gained increasing attention and widespread use. The method implies self-testing using a coagulometer (point-of-care device) and self-dosaging of coumarin. The method entails advantages for selected patients, who do not need to go to the hospital or family doctor for blood specimen and drug dosage adjustment. In contrast to patients on conventional management, patients performing self-managing have a reduced binding to the health care system, and it allows these patients unhindered to travel and manage their job or school. Therefore, the patients have a high degree of compliance because they are highly motivated. This has been the main justification for patient self-management. Furthermore, the conducted trials have also indicated a better quality of treatment compared to conventional management. In this paper the different aspects of this new treatment modality are critically reviewed, with special focus on the published clinical studies and the evaluation of the used coagulometers.     

LDL Apheresis: An Effective and Safe Treatment for Refractory Hypercholesterolemia

Through the efforts of Edward H. Ahrens, LDL apheresis became available for the treatment of patients, often with familial hypercholesterolemia, who have no alternative therapy for severely elevated LDL cholesterol levels. In the U.S., the FDA has approved this treatment for individuals on maximum diet and drugs with an LDL cholesterol greater than 300 mg/dL or greater than 200 mg/dL with coronary artery disease. Unlike plasmapheresis, apolipoprotein B‐containing lipoproteins (LDL, Lp(a), and VLDL) are selectively removed by heparin precipitation or columns containing dextran sulfate cellulose or antibodies to apolipoprotein B. The acute lowering of LDL‐cholesterol by a typical 2 ‐ 3 h treatment is up to 80%, and the time‐averaged lowering in the 1 to 2 week interval between treatments is up to 50%, with very few side effects. The lowering of LDL‐cholesterol and other cardioprotective effects of LDL apheresis have reduced chest pain, prevented new disability and prolonged life. Whole blood compatible columns in development offer the possibility of simpler and less expensive treatments.     

Stimulation of Gallbladder by Intravenous Infusion of Amino Acid: A New Method to Obtain Duodenal Bile for Bile Analyses

Bile analysis is performed on duodenal bile obtained after stimulation of the gallbladder (GB) with cholecystokinin or its analog. Rapid amino acids (AA) infusion contracts the GB. Our objective was to assess qualitatively the adequacy of duodenal bile obtained following AA infusion. We prospectively studied 15 patients each with non ulcer dyspepsia (NUD) and gallstones (GS), and 17 patients with acute idiopathic pancreatitis (AIP). Duodenal bile was obtained after duodenal intubation and stimulation of GB by rapid AA infusion. The GB contractile response to AA infusion was assessed by functional ultrasonography. Bile was analyzed for lipids, nucleation time, cholesterol saturation index (CSI), and biliary crystals. Adequate duodenal bile could be collected in all but one patient with AIP and one with GS. The mean ± sd percent ejection fraction of GB following AA infusion in patients with NUD, GS and AIP was 53.41 ± 16.23, 52.06 ± 16.07, and 43.37 ± 14.16, respectively. Biliary microscopy showed the presence of cholesterol monohydrate crystals (CMC) in 7 of 16 patients with AIP, 12 of 14 patients with GS, and 1 of 15 patients with NUD. Mean CSIs in patients with NUD, GS, CMC-positive AIP, and CMC-negative AIP were 0.78, 1.97, 1.85, and 1.00, respectively. Nucleation time in patients with NUD and gallstones was 21.1 and 8.42 days, respectively. In conclusion, qualitatively adequate bile can be obtained for chemical and microscopic examination following rapid intravenous infusion of AA to stimulate the GB.     

A Cheap Oral Therapy for Paget's Disease of Bone

Summary: A cheap oral therapy for Paget's disease of bone.
Nine patients with painful Paget's disease of bone were treated for 200 days with a drug combination designed to elevate plasma calcium, hence stimulating the production of endogenous calcitonin and suppressing that of parathyroid hormone. This combination was oral calcium, a thiazide diuretic, a low phosphorus diet and aluminium hydroxide.
Eight of the nine patients experienced sustained pain relief after 20–70 days. The mean plasma alkaline phosphatase (expressed as a percentage of the pre-treatment level) commenced to fall after 30 days of treatment and at 120 days was 58% of the pre-treatment level; this fall was sustained at 200 days. There was a mean rise of 0 08 mmol/l in plasma calcium; there was no significant change in plasma inorganic phosphorus or plasma creatinine. In view of the extremely low cost of this drug combination and its lack of side-effects, it is suggested it be considered as a treatment for Paget's disease of bone.     

Reduced Anticoagulation with Antiplatelet Therapy Alone is Safe and Effective after "Bail-Out" Stenting for Failed Angioplasty

The aim of this retrospective study was to compare the safety and efficacy of antiplatelet therapy alone with conventional anticoagulation with warfarin after òbail-outó coronary stenting for failed balloon angioplasty at a tertiary referral centre. Eighty-two consecutive patients undergoing òbail-outó stenting over a 22-month-period were studied. Forty patients received antiplatelet therapy alone with aspirin and ticlopidine and 42 patients received anticoagulation with warfarin for 30 days. The main outcome measures examined were death, myocardial infarction, coronary artery bypass surgery, repeat angioplasty, and significant vascular complications. The angiographic procedural success rate was 100% in both groups. At six weeks there were no deaths and no patient required emergency coronary artery bypass surgery in either group. There were three (7.1%, p = NS) stent thromboses and two (4.8%, p = NS) Q-wave myocardial infarctions in the warfarin group as compared to none in the antiplatelet group. There was a significantly higher incidence of vascular complications in the warfarin group (21.4% vs. 0%, p = 0.004). The length of hospital stay was significantly shorter in the antiplatelet group [3.4 (2.0) vs. 7.8 (2.6) days, p < 0.001]. This study suggests that reduced anticoagulation with antiplatelet therapy alone after òbail-outó stenting is an effective and safe strategy which reduces vascular complications and hospital stay without increasing the rate of stent thrombosis.