Carlo Di Padova

Methyl tert-butyl ether fails to dissolve retained radiolucent common bile duct stones.

Methyl tert-butyl ether (MTBE) has been recently proposed as a new therapeutic modality for the dissolution of cholesterol gallstones. To further evaluate efficacy and tolerability of this new litholytic agent, we have administered MTBE to 3 patients with nonobstructive radiolucent common bile duct stones after recent surgery. Methyl tert-butyl ether (8-11 ml/day) was infused after aspiration of bile via a Teflon catheter inserted through the postoperative T tube. Gentle aspiration and reinfusion were performed continuously to generate stirring. The total amount of MTBE retrieved during the entire procedure was equivalent to approximately 30% of the volume infused. In all cases, MTBE failed to dissolve the radiolucent stones, which were then dissolved with continuous infusion of monooctanoin via the biliary catheter. The characteristic odor of MTBE was detected on the breath of the patients, and nausea and somnolence developed during the treatment. Serum hepatic and pancreatic enzymes did not change after MTBE. In the third subject, who received 11 ml/day of MTBE for 2 consecutive days (total of 22 ml), histologic evidence of duodenitis was found around the papilla. In our opinion, the lack of efficacy of MTBE in dissolving retained radiolucent common bile duct stones was mainly related to its leakage from the common bile duct into the duodenum and the ensuing local chemical toxicity and systemic absorption. As MTBE needs a persistent stone-solvent contact to exert its litholytic action and, at the same time, its toxicity prevents the infusion of larger doses, MTBE use should be restricted to stones placed in closed chambers, such as the gallbladder.

Influence of S-adenosyl-L-methionine on irreversible binding of ethynylestradiol to rat liver microsomes, and its implication in bile secretion.

Abstract A three-day administration of ethynylestradiol (EE) (5 mg/kg per day) is shown to decrease the bile flow in the rat by reducing both the bile salt dependent and independent fractions of the bile. Protection against this effect is observed in rats given S -adenosyl- l -methionine (SAMe) in addition to EE. The protection is accompanied by a significant decrease of the binding of EE to liver microsomal proteins suggesting that SAMe administration may favour the estrogen elimination as a methylated derivative.

Excision and primary closure of pilonidal sinus using a drain for antiseptic wound flushing

BACKGROUND In the case of pilonidus sinus treated with primary intention surgery the uneventful healing is still difficult to obtain, as indirectly proven by the number of different procedures that have been suggested, such as cyst excision with or without primary closure, excision followed by marsupialisation, and excision followed by skin flap transposition. The procedure described here involves excision and primary closure, with a drain being used to flush the operative cavity with an antiseptic solution. METHODS Two hundred and forty-three patients (173 men and 70 women) were treated by excising the pilonidal sinus and placing a 12F suction drain at the base of the wound, with its tip being brought out in the left gluteal region at least 5 cm laterally to the lower end of the suture. Suction was stopped on the first postoperative day and the drain was cut just above the skin. On day 2, a 5F catheter was inserted through the drain and the cavity was flushed with an antiseptic solution followed by sterile saline solution; the same treatment was repeated on days 4 and 6. The drain was removed on day 8 or 9, some of the stitches on day 8 or 9 and the rest on day 9 or 10. The surgery was performed on a day hospital basis in 207 cases; the remaining 36 were hospitalized overnight and discharged on the following day. RESULTS Healing was always by first intention, with none of the 243 patients experiencing any complications. The postoperative follow-up now ranges from 5 to 15 years, and there have not been any recurrences. CONCLUSIONS The drainage of blood from the bottom of the wound and the use of antiseptic/saline flushing are essential for primary intention healing and the avoidance of recurrences.

Bile secretion and liver microsomal mixed function oxidase system in mice with griseofulvin-induced hepatic protoporphyria

Administration of 2.5% griseofulvin in the diet to male CD1 mice produced protoporphyria and cholestasis. Protoporphyria became evident as early as after 10 days of treatment, whereas cholestasis, expressed in terms of total bile flow reduction, developed only after 45 days of griseofulvin. Bile flow impairment was due both to the length of treatment and to the severity of liver protoporphyria. Griseofulvin administration was also associated with a significant modification of the relative amounts of hepatic microsomal cytochromes P-450 and b5, a loss in concentration/mg of protein of cytochrome P-450 and a concomitant increase of b5. Despite these changes, the activity of aniline hydroxylase expressed per mg of microsomal protein, assessed in vitro, was not modified.

S-Adenosylmethionine Counteracts Oral Contraceptive Hepatotoxicity in Women

ABSTRACT: Previous experimental and clinical investigations have pointed out a causal relationship between estrogens and the impairment of bile secretory apparatus, resulting in lithogenic bile and cholestasis. Recent studies have also shown that S-adenosylmethionine (SAMe) counteracts both estrogen-induced bile cholesterol supersaturation and intrahepatic cholestasis. The aim of this investigation was to verify whether SAMe could also reverse the abnormalities of some liver function tests that may develop in susceptible women after the intake of estrogen-containing oral contraceptives. Twelve women out of a group of 228 subjects exhibited abnormal blood values of transaminases, antithrombin III or bile acids after two cycles of a contraceptive pill containing 30 meg ethynylestradiol. These subjects volunteered to receive the same contraceptive pill plus oral SAMe (600 mg/day) for another two cycles. Due to the small number of cases who developed abnormal hepatic function tests after oral contraceptive, it was not possible to divide them into a control group who continued on the “pill” plus placebo and a treatment group in whom SAMe was given with the oral contraceptive. In all cases the administration of SAMe induced the normalization of liver function tests. If further clinical trials confirm these findings, it may be possible to propose SAMe administration to women at an increased risk of developing estrogen-related hepatotoxicity.

3-hydroxy-3-methylglutaric acid (HMGA) reduces dietary cholesterol induction of saturated bile in hamster

3-Hydroxy-3-methylglutaric acid (HMGA) is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoAR) and strongly reduces cholesterol biosynthesis both in vitro and in vivo. Since the effects of this compound on biliary lipid composition are hitherto unknown, we have investigated whether it prevents dietary cholesterol induction of saturated bile in the hamster. Female Golden Syrian hamsters have been divided into four groups and treated for 10 weeks as follows: I) Standard diet, containing 0.8 mg cholesterol/g food; II) Standard diet plus HMGA (100 mg/kg b.w./day per os); III) Lithogenic diet containing 2.4 mg cholesterol/g food; IV) Lithogenic diet plus HMGA as above. The results indicate that HMGA is effective in reducing both bile cholesterol supersaturation and hypercholesterolemia. Inhibition of hepatic cholesterogenesis at the level of mevalonate synthesis by HMGCoAR and reduction of intestinal cholesterol absorption may be responsible for these effects.

Effect of Ethanol on Biliary Unconjugated Bilirubin and Its Implication in Pigment Gallstone Pathogenesis in Humans

Though some epidemiological investigations support the association between pigment gallstone formation and chronic alcoholism with cirrhosis, little attention has been paid to the influence of alcohol itself on biliary bilirubin secretion, so that the pathogenesis of pigment cholelithiasis in alcoholics is hitherto unknown. On different days we intravenously administered ethanol (0.7 g/kg body weight), diluted with 500 ml of saline, or saline alone to 6 non-obese patients with an indwelling T tube and reestablished enterohepatic bile circulation. At the time of the investigation bile cultures were negative for aerobic and anaerobic bacteria. Ethanol significantly increased biliary unconjugated bilirubin in respect to control values. The phenomenon reached a maximum 2 h after alcohol infusion when the value of unconjugated bilirubin averaged 2.37 +/- 0.30% of total bilirubin in contrast to 0.65 +/- 0.14% in control conditions (p less than 0.01), and subsided 6 h after the end of ethanol infusion. Since increased amounts of biliary unconjugated bilirubin predispose to pigment stone formation, it can be speculated that alcohol contributes to pigment cholelithiasis pathogenesis by enhancing the biliary concentrations of this form of pigment.

Acute ethanol administration increases biliary concentrations of total and unconjugated bilirubin in rabbits

Epidemiological investigations have revealed that alcoholic cirrhosis is associated with a high frequency of pigment gallstones, but only scantly information is available on the effects of ethanol on biliary secretion of bilirubin. We have injected intravenously 1.0 and 1.5 g/kg body wt of ethanol into six cholecystectomized rabbits with a common bile duct fistula. Experiments were performed ten days after surgery and a stream-splitting apparatus was interposed in the circuit in order to withdraw continuously biliary samples without interruption of enterohepatic bile circulation. Analysis of hourly data showed that both ethanol doses significantly increase the biliary concentration of total bilirubin, without affecting bile flow and lipid composition. Alcohol also promoted the efflux of unconjugated bilirubin into bile. The maximum effect occurred within the first 5 hr following alcohol administration. Thereafter the bile returned to normal. Since excessive concentrations of biliary unconjugated bilirubin favor pigment gallstone development, it can be speculated that alcohol acts as a risk factor for pigment lithiasis by enhancing the biliary levels of this form of pigment.

Effects of ethinyl estradiol on bile secretion and liver microsomal mixed function oxidase system in the mouse

In the search for an animal model suitable for the study of ethinyl estradiol (EE) induced alterations of bile secretion, we have investigated the effects of three different doses (50-500-5000 microg/kg body wt., orally for 10 days) of EE on bile flow and composition and on liver microsomal mixed function oxidase system in female Albino-Swiss mice. No difference of bile flow was found between control and EE-treated mice. The decrease of bile acid secretion was dose-related and significant in animals treated with 500 and 5000 microg/kg of EE. Cholesterol output was similar in control and EE-treated animals. The molar ratio of bile acid to biliary cholesterol was significantly lower in all groups of EE-treated mice as compared with controls. The specific activities of 3,4-benzpyrene hydroxylase, aniline hydroxylase and NADPH cytochrome-c-reductase, as well as the content of cytochromes P-450 and b(5) decreased proportionally, in a dose dependent manner and significantly after 500 and 5000 microg/kg of EE. Our data indicate that mice, following EE, develop a lithogenic bile without obvious cholestasis. Moreover, they demonstrate a decrease of liver microsomal enzyme activities and cytochromes and suggest a relationship between the impairment of liver microsomal mixed function oxidase system and the changes of bile lipid composition.

BILE AND BILIARY LIPID SECRETION IN RATS WITH HEXACHLOROBENZENE-INDUCED PORPHYRIA. EFFECT OF S-ADENOSYL-L-METHIONINE ADMINISTRATION

We investigated liver morphology and biliary function in vivo in rats made porphyric by hexachlorobenzene (HCB). In one group of HCB rats we also evaluated whether S-adenosyl-L-methionine (SAMe), administered during the last 15 days of HCB treatment, attenuated liver injury and the accumulation of porphyrins (HCB + SAMe group). In HCB rats we found: (a) a 100% increase in liver weight; (b) a 500-fold increase in total liver porphyrins (TLP); (c) significantly increased serum bilirubin and cholesterol levels; (d) unchanged total bile flow (TBF) but enhanced levels of the bile acid independent fraction (BAIF); and (e) decreased excretion in bile of bile acids (BA), phospholipids (PL) and cholesterol (CHO) (58, 65 and 47%, respectively, expressed as mmol/min per kg liver). SAMe was found to partially reverse HCB-related effects. TLP levels were about 65% lower in HCB + SAMe treated rats than in HCB rats. However, while SAMe restored bile CHO excretion to control values, it did not influence bile excretion of BA, PL, or BAIF. In conclusion, HCB-induced porphyria was characterized by a complex derangement of liver morphology and biliary function that was unrelated to the extent of porphyrin accumulation in the liver.