Richard J. Stenger

Methadone disposition in patients with chronic liver disease

Chronic liver disease is common in methadone‐maintained patients. We studied the disposition of this drug in 14 patients with biopsy‐proved chronic liver disease and five otherwise healthy subjects receiving methadone maintenance treatment. The patients were divided into three groups based on the severity of liver disease, with group I having the most severe disease. The apparent terminal half‐life of methadone was longer in group I than in groups II and III (moderate and mild chronic liver disease, P < 0.01) and the contrast group (P < 0.05). All other kinetic indices determined for group I and all kinetic indices in groups II and III were essentially the same as those in the contrast subjects or in the other patient groups. Seven patients, including all five in group I, had flattened plasma methadone concentration‐time curves. The data suggest that the maintenance dosage of methadone need not be changed in stable chronic liver disease.

Histopathology of testis in acquired immune deficiency syndrome

Histologic sections from the testes of 32 autopsied patients with acquired immune deficiency syndrome (AIDS) were examined. Almost invariably the testes displayed decreased spermatogenesis, and 20 of the 32 cases showed marked hypospermatogenesis with Sertoli cells predominantly lining the tubules. Although the seminiferous tubules were generally of normal size, the tunica propria at the periphery of the tubules was mildly to moderately thickened in 19 cases and markedly thickened in 10. The interstitial cells of Leydig were unaltered in most patients, with only 4 testes showing Leydig cell hyperplasia. The testicular blood vessels were slightly thickened in many patients, but 5 exhibited moderate to marked intimal proliferation with narrowing of the lumen. Mononuclear inflammatory infiltration of the testicular interstitium was slight in 11 cases, moderate in 6. Only 7 of the 28 AIDS patients with opportunistic infections had evidence of direct involvement of the testes by the infectious organisms. We concluded that the extragonadal endocrine balance of AIDS patients may be deranged due to the infectious process and so deserves clinical evaluation.

An animal model of pigment cholelithiasis

Pigment stones of high calcium content were induced in male hamsters of the Harlan Sprague-Dawley strain fed a nutritionally adequate semipurified diet for a period of 14 weeks. The diet contained moderate amounts of cholesterol (0.30 percent) and ethinyl estradiol (15 micrograms/day per animal). At sacrifice, the incidence of pigment stones was 50 percent. When stones were present, they were in the form of numerous black amorphous rods about 0.1 to 0.4 mm in length. Infrared analysis of the dried stones indicated the following composition: calcium phosphate 26.7 percent, calcium bilirubinate 12.8 percent, cholesterol 15.1 percent, and protein 45.4 percent. Pigment stones were associated with an elevated biliary total calcium level (probably induced by the dietary cholesterol) and a paradoxic decrease in the biliary total bilirubin level. The lithogenic diet produced marked elevations in liver and plasma cholesterol levels and cholesterol saturation of bile, but no cholesterol crystals or stones were observed. The accumulation of elevated levels of cholesterol in the livers of the experimental animals produced mild to moderate hepatotoxicity. The precise mechanism of the dietary induction of pigment stones in this hamster model remains to be elucidated.

Hyodeoxycholic acid: A new approach to gallstone prevention***

Hyodeoxycholic acid and its isomer, 6 beta-hyodeoxycholic acid, when added to a lithogenic diet prevented the formation of cholesterol gallstones and crystals in prairie dogs. This beneficial effect occurred in the presence of bile supersaturated with cholesterol. Hyodeoxycholic acid abolished the feedback inhibition of hepatic hydroxymethylglutaryl coenzyme A reductase activity, the rate-limiting enzyme of cholesterol synthesis, and prevented elevations in serum and liver cholesterol observed in animals fed a 0.4 percent cholesterol diet. The gallbladder bile of the animals fed hyodeoxycholic acid and 6 beta-hyodeoxycholic acid contained abundant liquid crystals. This suggests that these bile acids prevented the transition of cholesterol from its liquid crystalline phase to solid crystals and stones.

A Case of Chronic Liver Disease Due to Tolazamide

Although chlorpropamide and tolbutamide are well recognized as causes of hepatotoxicity, there are only 3 reported cases of hepatic injury caused by a third oral hypoglycemic agent, tolazamide. In 2 of these cases, the liver-function tests returned to normal when the drug was discontinued. In the third case, the patient had cholestasis from chlorpropamide before administration of tolazamide and developed chronic liver disease. We are reporting the second instance of chronic liver disease induced by tolazamide. Our patient had been taking chlorpropamide, but she had no evidence of liver disease before administration of tolazamide. Tolazamide should be considered as a drug capable of producing hepatotoxicity that on occasion may be chronic.

Tumors of the ampulla of Vater: early diagnosis by intraampullary biopsy during endoscopic cannulation. Two case presentations and a review of the literature.

In 2 cases of ampullary tumor, the diagnosis was made by intraampullary biopsy after an abnormality was discovered via the fluoroscope during endoscopic retrograde cholangiopancreatography. One case was a villotubular adenoma with dysplasia and carcinoma in situ, and the other, a polypoid adenocarcinoma of the ampulla of Vater. These tumors were not visualized on upper gastrointestinal barium studies and conventional duodenoscopy nor by direct vision during endoscopic retrograde cholangiopancreatography. In the past the diagnosis of ampullary neoplasm has been most often made of surgery and on autopsy. Only in 11 of 538 patients reviewed was the diagnosis made by biopsy of a tumor visible at endoscopy. As demonstrated by the two cases we report, intraampullary biopsy of lesions visualized on fluoroscopy during endoscopic retrograde cholangiopancreatography may facilitate early diagnosis.

Age, sex and source of hamster affect experimental cholesterol cholelithiasis

In the present study, we examined the effect of the following factors on a hamster model of cholesterol cholelithiasis: (i) the source of the golden Syrian hamsters (Sasco, Omaha, NE or Charles River, Wilmington, MA), (ii) the sex of the experimental animals and (iii) their age (4 wkvs. 8 wk of age). All hamsters were fed a semipurified diet which contained cholesterol (0.3%) and palmitic acid (1.2%). No cholesterol gallstones formed in any of the female hamsters regardless of age or source. The 4-week-old male hamsters from Sasco had the greatest incidence of gallstones (93%). The 8-week-old male hamsters tended to have a lower incidence of cholesterol gallstones than the younger ones, regardless of the commercial supplier (67vs. 93% for Sasco and 27vs. 40% for Charles River). Female hamsters has higher liver and serum cholesterol levels than the male hamsters; Charles River hamsters had lower serum cholesterol concentrations than the Sasco animals. Total biliary lipid concentrations were highest in Sasco male hamsters, but biliary cholesterol (mol%) was lower in the males than in the females (4.2–4.5%vs. 6.1–7.1%) regardless of age. The cholesterol saturation indices were higher in the Sasco females than the corresponding males; these values were lower in the Sasco hamsters than the Charles River animals, regardless of age or sex. The male Sasco hamsters had a higher total biliary bile acid concentration (98.9 mg/mL) than the Sasco females (58.9 mg/mL) and the Charles River animals (24.6% mg/mL for males and 38.2 mg/mL for females). The percentage of chenodeoxycholic acid in bile was significantly lower, and the percentage of cholic acid was higher in all females as compared to males. We conclude that there is a sex, age and “strain” difference in cholesterol cholelithiasis in hamsters; it is important to consider these factors when working with the hamster model of gallstone disease. All female hamsters were markedly resistant to the induction of cholesterol gallstone disease.

7-Methyl bile acids: Effects of chenodeoxycholic acid, cholic acid, and their 7β-methyl analogues on the formation of cholesterol gallstones in the prairie dog

The purpose of this study was to compare the effects of the naturally occurring bile acids (chenodeoxycholic acid and cholic acid) with their 7-methyl analogues (3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid) on gallstone formation and prevention and cholesterol metabolism in the prairie dog. Sixty animals were fed a semipurified diet, containing 0.4% cholesterol, with one of the following acids (0.1%): chenodeoxycholic, cholic, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic, or 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid. This concentration of dietary bile acids amounts to a dose of 27-30 mg/kg.day. After 8 wk, 89% of control animals had gallstones and 94% had cholesterol crystals. Chenodeoxycholic and 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acids decreased the incidence of gallstones to 50%. Cholic acid and 3 alpha,7 alpha,12 alpha-tri-hydroxy-7 beta-methyl-5 beta-cholanoic acid did not prevent gallstone formation. The liver cholesterol level was decreased by chenodeoxycholic acid, whereas cholic and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acids increased serum and liver cholesterol. Each administered bile acid became the predominant biliary bile acid and 7-methyl analogues did not increase secondary bile acids. Fecal analysis of radioactive metabolites using 14C-labeled 7-methyl analogues showed that these compounds are resistant to bacterial 7-dehydroxylation. It was concluded that 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid inhibited gallstone formation as effectively as chenodeoxycholic acid, whereas both cholic and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acids were not effective. The effects of 7-methyl analogues on the parameters of cholesterol metabolism that we studied were similar to those of their parent compounds, chenodeoxycholic and cholic acids. Thus, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid but not 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid offers promise in cholelitholytic therapy for the prevention and possibly dissolution of cholesterol gallstones.

Effects of chlordane pretreatment on the hepatotoxicity of carbon tetrachloride

Abstract Male albine rats weighing approximately 200 g received intraperitoneal injections of chlordane (25 mg/kg) in olive oil on each of three successive days. Controls included animals given only olive oil and untreated rats. Twenty-four hours after the last dose, augmented hepatic drug-metabolizing enzyme activity in chlordane-treated rats was reflected in vivo by a reduction in zoxazolamine-paralysis time and in vitro by an increased hepatic microsomal cytochrome P -450 level. The insecticide-treated animals did not, however, display any increase of hepatic microsomal NADPH-cytochrome c reductase activity. In chlordane-treated rats, electron microscopy revealed overt proliferation of smooth endoplasmic reticulum in the hepatocytes, particularly in those located in the central one-third to one-half of the liver lobules. Olive oil-treated controls showed no alterations in paralysis time, microsomal enzyme activity, or hepatocellular ultrastructure, when compared to the untreated animals. Identically prepared chlordane-treated and control rats then were challenged with an intraperitoneal injection of carbon tetrachloride (0.5 ml of a 25% solution of CCl 4 in olive oil). Some animals from each group were killed at 4 hr after the toxic challenge; and it was determined that, in each category, there was a sharp drop in hepatic microsomal cytochrome P -450 but no change in NADPH-cytochrome c reductase, as compared to prechallenge levels. The reduction in cytochrome P -450 was most striking in the insecticide-stimulated rats. The remaining animals from each CCl 4 -injected group were sacrificed at 48 hr after the toxic challenge. Histologic slides prepared from their livers revealed more extensive hepatocellular necrosis in the chlordane-pretreated rats than was found in either the olive oil-pretreated rats or the animals with no treatment prior to CCl 4 administration. It was concluded that chlordane can induce smooth-membrane proliferation and can enhance drug-metabolizing enzyme systems in rat liver and that these changes are associated with an enhanced hepatotoxic response to CCl 4 administration. It was suggested that a sharp fall in hepatic microsomal cytochrome P -450 might serve as a relatively early indicator of toxic injury in an induced liver.

Cholelithiasis in hamsters: Effects of cholic acid and calcium on gallstone formation

Dietary cholic acid (0.1%) and/or calcium (2.6% as calcium carbonate) were added to a semipurified diet containing cholesterol and ethynyl estradiol to determine whether the incidence of pigment and/or cholesterol gallstones would be changed. Male golden Syrian hamsters were fed the experimental diets for 96 days (Group 1, control; Group 3, cholic acid plus calcium) or only an average of 60 days (Group 2, 0.1% cholic acid). Animals in Group 2 became ill (weight loss, low food intake, diarrhea) possibly due to cholic acid (or deoxycholic acid) toxicity. Cholesterol gallstones and crystals were absent in all experimental groups. The incidence of pigment gallstones was: control, Group 1, 12/16; 0.1% cholic acid, Group 2, 3/13; and 0.1% cholic acid plus calcium, Group 3, 11/22. Cholic acid with or without calcium produced an elevation of both liver and plasma cholesterol: Group 2, 80.1 mg/g and 501 mg/dl; Group 3, 103.7 mg/g and 475 mg/dl vs Group 1, 65 mg/g and 209 mg/dl, respectively. The lithogenic indices of the bile were lower in Groups 2 and 3 compared to Group 1, controls, 0.45 and 0.58 vs 1.16, respectively. The extent of the portal tract pathology could not be correlated with the presence or absence of pigment gallstones or with the levels of lithocholic acid in the hamster bile. In summary, when semipurified diets were supplemented with ethynyl estradiol and cholic acid, with and without calcium supplementation, no cholesterol gallstones formed and the incidence of pigment gallstones was not altered.