Anton E A Joseph

Kinetics of hepatic bile acid handling in cholestatic liver disease: Effect of ursodeoxycholic acid

BACKGROUND/AIMS Ursodeoxycholic acid (UDCA) is clinically beneficial in chronic cholestatic liver disease, but the underlying mechanisms are unclear. It has been suggested that intrahepatic retention of endogenous hydrophobic bile acids contributes to cholestasis and that the hydrophilic bile acid UDCA reduces this retention; the aim of our study was to test these hypotheses. METHODS Twelve patients with primary biliary cirrhosis (PBC) and 5 with primary sclerosing cholangitis (PSC) were studied before and during UDCA (10 mg.kg-1.day-1) and compared with 11 healthy controls. Following intravenous 75Se labeled homocholic acid taurine (75SeHCAT) in the fasting state, abdominal gamma camera imaging was performed for 90 minutes. Initial hepatic uptake, transit time, net, and absolute excretory rates for 75SeHCAT were measured. RESULTS Mean initial hepatic uptake was not different between patients and controls (17.2% and 19.9% dose/minute, not significant). However, net and absolute excretory rates were significantly reduced in patients (1.4% vs. 3.7% dose/minute, P < 0.0001; and 2.35% vs. 3.96% dose/minute, P < 0.02, respectively), and hepatic transit time was prolonged (18.7 minutes vs. 11.6 minutes, P < 0.002). UDCA improved net and absolute hepatic excretory rates and transit time (1.43% to 1.96% dose/minute, P < 0.001; 2.35% to 3.15% dose/minute, P < 0.005 and 18.7 to 14.7 minutes, P < 0.001, respectively). However, UDCA did not alter initial hepatic uptake. CONCLUSIONS In PBC and PSC, there is a defect in hepatic bile acid excretion but not in uptake, implying bile acid retention. This retention is reduced by UDCA.

Gallstone recurrence after medical dissolution: An overestimated threat?

We assessed gallstone recurrence rate in 42 patients diagnosed as having complete gallstone dissolution on bile acid therapy. By contrast with most previous studies, this diagnosis was based on ultrasound as well as on radiology, and only patients having their first gallstone recurrence were included in the study. Patients were followed for periods varying from 6 months to 7 years (median 30 months). Eleven patients had recurrences, giving an overall recurrence rate of 26%. A life analysis table was constructed by an actuarial method to compensate for the different lengths of follow-up in individual patients. Corrected recurrence rates by life table analysis were 15%, 21%, 25%, 36%, 45%, 45% and 45% at 1, 2, 3, 4, 5, 6 and 7 years respectively; for the same time intervals, cumulative recurrence rate overestimated the risk of gallstone recurrence (14%, 22%, 31%, 50%, 61%, 79% and 92%). We conclude that previous figures for recurrence rate have been an overestimate; but recurrence rate remains substantial over the first 5 years, and then levels off.

Gallbladder abnormalities in acute infectious hepatitis. A prospective study.

We have studied the gallbladder and its contents by ultrasonography in 31 patients with acute viral hepatitis and 23 age-matched controls. Liver cell necrosis was assessed by raised transaminase levels within 24–48 hr of ultrasonography in all patients. Gallbladder wall (GBW) measured 5.16±0.4 mm (mean±sem) in patients and 2.0±0.06 mm in controls (P<0.001). GBW was thickened (>3 mm) in 21 patients (68%), with double wall appearance in 5 (16%), and sludge was seen in the gallbladder cavity in 7 (23%). GBW thickness was significantly related to serum albumin (r=−0.45,P<0.01) and bilirubin (r=0.50,P<0.004), but not to the serum transaminase levels. On repeat measurements after recovery in 13 patients, GBW thickness fell from 5.84±0.49 mm during acute hepatitis to 2.46±0.21 mm (P<0.001).We have studied the gallbladder and its contents by ultrasonography in 31 patients with acute viral hepatitis and 23 age-matched controls. Liver cell necrosis was assessed by raised transaminase levels within 24–48 hr of ultrasonography in all patients. Gallbladder wall (GBW) measured 5.16±0.4 mm (mean±sem) in patients and 2.0±0.06 mm in controls (P<0.001). GBW was thickened (>3 mm) in 21 patients (68%), with double wall appearance in 5 (16%), and sludge was seen in the gallbladder cavity in 7 (23%). GBW thickness was significantly related to serum albumin (r=−0.45,P<0.01) and bilirubin (r=0.50,P<0.004), but not to the serum transaminase levels. On repeat measurements after recovery in 13 patients, GBW thickness fell from 5.84±0.49 mm during acute hepatitis to 2.46±0.21 mm (P<0.001).

Direct measurement of first-pass ileal clearance of a bile acid in humans

The purpose of this study was to develop and validate a method of directly measuring ileal bile acid absorption efficiency during a single enterohepatic cycle (first-pass ileal clearance). This has become feasible for the first time because of the availability of the synthetic gamma-labeled bile acid 75Selena-homocholic acid-taurine (75SeHCAT). Together with the corresponding natural bile acid cholic acid-taurine (labeled with 14C), SeHCAT was infused distal to an occluding balloon situated beyond the ampulla of Vater in six healthy subjects. Completion of a single enterohepatic cycle was assessed by obtaining a plateau for 75SeHCAT activity proximal to the occluding balloon, which prevented further cycles. Unabsorbed 75SeHCAT was collected after total gut washout, which was administered distal to the occluding balloon. 75SeHCAT activity in the rectal effluent measured by gamma counter was compared with that of absorbed 75SeHCAT level measured by gamma camera and was used to calculate first-pass ileal clearance. This was very efficient (mean value, 96%) and showed very little variation in the six subjects studied (range, 95%-97%). A parallel time-activity course in hepatic bile for 14C and 75Se during a single enterohepatic cycle, together with a ratio of unity for 14C/75Se in samples obtained at different time intervals, suggests that 75SeHCAT is handled by the ileum like the natural bile acid cholic acid-taurine. Extrapolation of 75SeHCAT first-pass ileal clearance to that of the natural bile acid therefore seems justifiable. In a subsidiary experiment, ileal absorption efficiency per day for 75SeHCAT was also measured by scanning the gallbladder area on 5 successive days after the measurement of first-pass ileal clearance. In contrast with absorption efficiency per cycle, absorption efficiency per day varied widely (49%-86%), implying a possible wide variation in recycling frequency per day.

Hepatic handling of a synthetic γ-labeled bile acid (75SeHCAT)

Abstract 75 Se-homocholic acid-taurine ( 75 SeHCAT) is the first available γ-labeled bile acid, and should therefore be handled more efficiently and specifically by the liver than previous hepatoscintigraphic agents. We have measured serum and hepatic kinetics for 75 SeHCAT, and compared them with those for the conventional hepatobiliary scintigraphic agent 99m Tc-hepatoiminodiacetic acid, and with serum kinetics for the corresponding natural bile acid, [ 14 C]cholic acid-taurine. We used a dynamic scintigraphic technique and serial blood sampling in 8 subjects. Initial hepatic uptake rate was identical to initial serum disappearance rate (14% dose/min) for 75 SeHCAT, but significantly lower for 99m Tchepatoiminodiacetic acid (6% vs. 14% dose/min, p 75 SeHCAT (13 min vs. 22 min, p 75 SeHCAT (14.3% and 1.5% dose/min) than for [ 14 C]cholic acid-taurine (21.3% and 2.8% dose/min, respectively), and plasma clearance was also lower (275 vs. 670 ml/min). In vitro, 75 SeHCAT was bound to serum proteins more completely than [ 14 C]cholic acid-taurine (90.4% vs. 86.5%, p 75 SeHCAT provides a hepatoscintigraphic agent that is handled more efficiently and specifically by the liver than the conventionally used agent 99m Tc-hepatoiminodiacetic acid. It is not cleared from the serum as rapidly as [ 14 C]cholic acid-taurine, probably due to its stronger protein binding. The clinical value of 75 SeHCAT in assessing liver disease should be investigated.

Fecal leukocytosis, indium-111-labelled autologous polymorphonuclear leukocyte abdominal scanning, and quantitative fecal indium-111 excretion in acute gastroenteritis and enteropathogen carriage.

Abdominal scintiscans were performed and three-day fecal indium-111 radioactivity measured, following injection of indium-111-labeled polymorphonuclear leukocytes, in patients with acute gastroenteritis, enteropathogen carriage, exacerbations of chronic inflammatory bowel disease, and patients without gastrointestinal symptoms. The colon was more commonly inflamed than the small intestine in acute gastroenteritis. Fecal indium-111 radioactivity excretion was elevated in gastroenteritis and in chronic inflammatory bowel disease. The magnitude of the intestinal inflammatory response, as measured by fecal indium-111 excretion, is equivalent in acute gastroenteritis caused by a defined enteropathogen and exacerbations of chronic inflammatory bowel disease. All patients with microscopically detected fecal leukocytosis gave positive intestinal scintiscans, whereas negative scans were obtained on patients without fecal leukocytosis. The results of this study suggest that indium-111-labeled polymorphonuclear leukocytes can be used to study pathophysiology of the enteric inflammatory response in acute infectious gastroenteritis.

The General Medical Council and the future of revalidation: Revalidation, discretionary points, clinical excellence awards—steps on the same ladder

EDITOR—With reference to the article by Esmail,1 the purpose of revalidation is to ensure that doctors provide safe, effective health care for patients. The quality of health care that the patient receives could therefore be the basis of revalidation, rather than a measure of the skills and knowledge of the doctor. Clinical governance could be adapted for purposes …

I certified deaths after judicial executions--and I believe capital punishment should be abolished.

Working in forensic medicine in Sri Lanka included gruesome duties for Anton E Joseph

Where “revalidation” came from

People using word processing software will have noticed that “revalidation” is not included in their dictionary. Reviewing the etymology, I discovered that revalidation was included in the Oxford English Dictionary ( OED ) only in its 2004 update. However, long before that the General Medical Council had used it in the context of assessing a doctor’s fitness to practise. So who …

A question for Andrew Lansley.

May I ask the health secretary one question?1 Are you ignorant of the Health Act 1999 and the statement of clinical governance that was formulated so elegantly by Liam Donaldson? “Clinical governance is the framework through which NHS organisations are accountable for continuously …