R. Hermon Dowling

Chenodeoxycholic acid treatment of gallstones. A follow-up report and analysis of factors influencing response to therapy.

We treated 70 patients with gallstones with chenodeoxycholic acid over 3 1/2 years and analyzed the factors influencing the outcome of therapy. This treatment was unsuccessful in 11 patients with radiopaque gallstones and in seven with nonfunctioning gallbladders, but 64 per cent with radiolucent gallstones treated for six months or more showed partial or complete gallstone dissolution, and of those whose bile became unsaturated with cholesterol, 100 per cent had evidence of dissolution. In patients with partial or complete gallstone dissolution, the mean post-treatment biliary cholesterol saturation index--0.78 +/- 0.04 (S.E.M.)--was significantly less (P less than 0.001), and the dose of chenodeoxycholic acid (14.4 +/- 1.0 mg per kilogram of body weight per day) significantly more (P less than 0.025) than in those whose gallstones did not change (1.15 +/- 0.04 and 10.6 +/- 1.2 respectively). In patients with radiolucent gallstones, the dose of chenodeoxycholic acid should be based on body weight; 14 to 15 mg per kilogram of body weight per day effectively lowers the saturation index and dissolves gallstones.

Enhanced growth of small bowel in transgenic mice overexpressing bovine growth hormone

BACKGROUND Transgenic mice with a bovine growth hormone gene linked to a mouse metallothionein I promoter (growth hormone transgenics) are a model of chronic growth hormone excess. METHODS Growth of small bowel mucosa in ad libitum-fed growth hormone transgenics and wild type littermates and in growth hormone transgenics pair fed with wild-type littermates were compared. RESULTS In both groups, body weight and small bowel weight were greater in growth hormone transgenics. Similarly, mucosal mass was 50%-100% greater in growth hormone transgenics, and the effect was greatest in proximal bowel. Villus height, measured in jejunum, was also greater in growth hormone transgenics. Measurements of mucosal proliferation did not differ between the growth hormone transgenics and wild type. Abundance of insulin-like growth factor-I messenger RNA in bowel was greater in growth hormone transgenics. CONCLUSIONS Chronic growth hormone excess results in increased growth of small bowel mucosa. This effect appears to be specific because it occurred in ad libitum-fed and diet-restricted growth hormone transgenics, influenced villus height, and was more pronounced in upper than lower small bowel. The effect of chronic growth hormone excess does not appear to be secondary to an increase in the rate of mucosal proliferation, suggesting an effect on lifespan of mucosal cells.

Cholecystokinin and Secretin Prevent the Intestinal Mucosal Hypoplasia of Total Parenteral Nutrition in the Dog

Because the pancreas undergoes involutional changes during total parenteral nutrition (TPN) and because pancreatico-biliary secretions are trophic to the intestine, we studied jejunal and ileal structure and function and exocrine pancreatic function before and after 6 weeks of TPN in two groups of beagle dogs, one of which had TPN alone, the other having TPN plus daily stimulation of pancreatico-biliary secretions with intravenous infusions of cholecystokinin (CCK) and secretin. The injections of 1 U each per kg of body weight per day of CCK and secretin completely prevented the proximal and distal small bowel mucosal hypoplasia which developed in the TPN alone group. They also resulted in significant increases in in vivo galactose absorption (64 mM) per unit length of jejunum and ileum. However, there was no significant change in mucosal alpha-glucosidase and catalase activity or in in vitro mucosal uptake of 1 mM [14C]leucine when expressed per unit weight of intestinal mucosa. The capacity of the pancreas to respond to CCK and secretin was unaffected by excluding food from the intestine with 6 weeks of TPN in terms of pH, volume, and peak secretion rates of bicarbonate and protein, but maximum amylase output (units per 15 min per kg of body weight) fell significantly (P less than 0.05) from a mean of 1022 +/- 155 to 874 +/- 426 in TPN alone group and to 472 +/- 79 in the TPN dogs given CCK and secretin. These results show that daily CCK and secretin is trophic to the intestine of dogs nourished by TPN but do not indicate whether this trophic effect is attributable to CCK alone, secretin alone, the combination of the two hormones, or to the resultant stimulation of pancreatico-biliary secretions.

IS RECURRENCE INEVITABLE AFTER GALLSTONE DISSOLUTION BY BILE-ACID TREATMENT?

Gallstone dissolution was observed on 60 occasions in 54 patients; in 6, recurrent stones were dissolved by a second course of medical treatment. When complete gallstone dissolution was confirmed (by two consecutive cholecystograms, 3 months apart) bile-acid treatment was stopped, and the patients were followed for up to 71/2 years with oral cholecystograms taken annually (or sooner if symptoms suggested early recurrence). Recurrence was detected 30 times after the 60 episode of gallstone dissolution (50%), in 25 of the 54 patients (46%), and in 25 of 46 patients who had had at least one post-dissolution X-ray before recurrence (54%). In 21 of these 25 patients (84%) the recurrence was observed within 2 years of treatment being stopped. There were no significant differences in clinical details and pre-treatment gallstone characteristics between the 25 gallstone-recurrent (at any time) and the 29 gallstone-free (at the time of study) patients, nor between a subgroup of patients in whom recurrent stones developed rapidly (less than or equal to 1 year) and a subgroup who remained gallstone-free for 3 years. It is concluded that long-term follow-up is advisable and that post-dissolution treatment will be necessary to prevent gallstone recurrence.

PREVENTION OF GALLSTONE RECURRENCE BY NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

In laboratory animals, non-steroidal anti-inflammatory drugs (NSAIDs) are reported to inhibit diet-induced gallstone formation. To see if these drugs had a similar effect in man, 82 patients who had taken part in a comparison of ursodeoxycholic acid, placebo, and diet for prevention of gallstone recurrence were sent questionnaires about their use of NSAIDs during the period of the trial. 75 replied. After a mean follow-up of 33 (SEM 4) months none of the 12 regular users of NSAIDs had had gallstone recurrences, compared with 20 of the 63 who never or rarely used these drugs (p less than 0.02).

PIEZO-CERAMIC LITHOTRIPSY OF GALLBLADDER STONES: INITIAL EXPERIENCE IN 38 PATIENTS

The efficacy, safety, and side-effects of a piezo-ceramic system for extracorporeal shock-wave lithotripsy of gallbladder stones were assessed in the first 38 patients treated. Gallstone fragmentation was achieved in 34 patients; 25 required more than 1 treatment session (range 1-5). Extracorporeal shock-wave lithotripsy, conducted without sedation, analgesia, or anaesthesia, was well tolerated by all patients; no patient reported pain or discomfort either during or after the procedure. Side-effects were negligible: transient microscopic haematuria in 2 patients, transiently abnormal liver function tests in 1, and short-lived cutaneous petechiae in 4. Initial experience shows that lithotripsy with this system is effective, safe, and well tolerated.

Response of plasma and tissue levels of enteroglucagon immunoreactivity to intestinal resection, lactation and hyperphagia.

Abstract Elevation of plasma enteroglucagon has been described in the presence of intestinal hyperplasia in both animals and man. In order to investigate whether enteroglucagon plays a role in the stimulation of small intestinal growth, fasting plasma and small intestinal tissue levels of enteroglucagon immunoreactivity were measured in control rats and in 3 different rat models of intestinal adaptation: 5 weeks after proximal and distal small bowel resection, on the 12th day of lactation and following 5 weeks of cold acclimation induced hyperphagia. Plasma enteroglucagon levels increased significantly from the control value of 89±(SEM) 13.1 fmol/ml to 147±13.6 after proximal resection (p

Hepatic HMGCoA reductase in human cholelithiasis: effects of chenodeoxycholic and ursodeoxycholic acids*

Abstract. To study further the role of hepatic cholesterol synthesis in patients with gallstones, the activity of the rate‐limiting step in cholesterbgenesis, hydroxy‐methyl glutaryl co‐enzyme A reductase (HMGCoAR), was measured in operative wedge liver biopsies from ten patients with untreated cholesterol gallstones, six with pigment stones and ten controls. Hepatic HMGCoAR was also measured in six patients with cholesterol‐rich gallstones treated for 1–24 months with 14‐6‐18‐6 mg chenodeoxycholic acid (CDCA) kg‐1 day‐1, in two patients with radiolucent pigment stones treated with 17‐3 and 17‐7 mg CDCA kg‐1 day‐1 and in ten other patients with cholesterol‐rich stones given 4–5‐7‐2 mg ursodeoxycholic acid kg‐1 day‐1 for 1–6 months. HMGCoAR activity was also related to the free and esterified cholesterol content of both hepatic homogenates and the microsomal fractions.

Calcium and carbonate ion concentrations in gallbladder and hepatic bile

Calcium carbonate is a major component of gallstones, but there are few data on calcium and carbonate (CO3(2-)) concentrations in human bile. Therefore, in patients undergoing cholecystectomy for gallstones, total [CaTOT] and free ionized [Ca2+] calcium concentrations, pH, PCO2, and total [CO2] were measured and [CO3(2-)] was derived in gallbladder and hepatic bile (aspirated anaerobically at surgery or from T tubes). Gallbladder bile had lower pH (6.96 vs. 7.30) and total [CO2] (14.1 vs. 21.6 mmol/L), higher PCO2 (53.8 vs. 40.2 mm Hg), lower [CO3(2-)] (2.52 vs. 6.11 x 10(5) mol/L) and lower [Ca2+] x [CO3(2-)] ion product (1.88 vs. 4.74 x 10(-8) mol/L) than did hepatic bile. Gallbladder bile pH correlated positively with total [CO2], [CO3(2-)], and [Ca2+] x [CO3(2-)] but negatively with PCO2. Patients with surface gallstone calcification had similar gallbladder bile [CaTOT] and [Ca2+] but higher gallbladder bile pH (7.30 vs. 6.90), lower PCO2 (42.9 vs. 57.2 mm Hg), higher [CO3(2-)] (7.29 vs. 1.84 x 10(-5) mol/L), and higher [Ca2+] x [CO3(2-)] ion product [4.73 vs. 1.45 x 10(-8) (mol/L)2] than those with radiolucent gallstones. There were no differences in these parameters between patients with cholesterol stones and those with pigment stones. These data suggest that the human gallbladder acidifies bile by secreting hydrogen ion and that impairment of this secretion is one cause of calcified gallstone formation in humans.

Pituitary hormones and the small bowel: effect of hypophysectomy on intestinal adaptation to small bowel resection in the rat†

Abstract. The influence of pituitary hormones on intestinal adaptation to small bowel resection was studied by examining jejunal and ileal structure and function in control and in sham‐operated rats, and in animals with 50% proximal or distal resection which were divided into three main groups: normally‐fed, hypophysectomized, and pair‐fed. The pituitary was removed 2 weeks before intestinal surgery and gut structure and function were studied 4 weeks later. The effectiveness of hypophysectomy was confirmed by histological examination of the aspirated pituitary, and by showing a significant subsequent reduction in weight of the testes and adrenals. Food intake and body weight fell significantly after removing the pituitary; intestinal surgery caused a transient further decrease in food intake.