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Laparoscopic cholecystotomy (LCT) with subsequent extraction of gallstones and primary closure of the gallbladder has been introduced as an alternative therapy for patients with cholecystolithiasis and preserved gallbladder function. However, stone recurrence has to be considered as a major drawback that might be related to lithogenic factors of gallbladder bile or the composition of gallbladder stones. Therefore, these were studied in relation to stone recurrence within an observation period of 1 to 5 years (median, 3.6 years) in 50 patients after LCT. The concentrations of total and individual bile acids, phospholipids, cholesterol, total lipids, mucin, protein, and the cholesterol saturation indices in gallbladder bile were not significantly different between 10 patients with and 40 patients without stone recurrence. However, the crystal observation time was significantly (P < .02) shorter (range, 1-2 days; median, 1.5) in the bile of patients with stone recurrence compared to those without (range, 1-21 days, median 3.5). Moreover, all 10 stone recurrences were observed in the 28 patients with a crystal observation time in the bile of less than or equal to 2 days (approximate annual risk: 12%-15%), and no recurrences were observed in the 22 patients with a crystal observation time greater than 2 days (P < .0001) or in patients with pigment stones. The rapid formation of cholesterol monohydrate crystals in bile seems to be the major risk factor for recurrent stones after LCT. These are most likely cholesterol stones and, therefore, are amenable to oral bile-acid prevention or treatment.

In elderly patients with gallstone disease, a gallstone ileus must be considered for unexplained abdominal pain. This is demonstrated in the following case report.A 75-year-old female patient presented with a 72-hour history of abdominal pain, nausea and vomiting. The patient's abdomen was mildly distended, although soft and nontender with bowel sounds present. Plain radiographs and ultrasound investigation of the abdomen were compatible with small bowel obstruction. To clarify the etiology, an abdominal computed tomography scan was obtained. These examinations disclosed air in the biliary tree, dilated small bowel and an impacted intraluminal abnormality in the terminal ileum compatible with a gallstone. Operative intervention confirmed the presence of a 3 cm obstructing calculus in the terminal ileum that was removed by an enterolithotomy. A two-step cholecystectomy and closure of the cholecystoduodenal fistula were performed 8 weeks later. The patient's recovery was uneventful.Although rare in a general population, gallstone ileus accounts for 25% of nonstrangulated small bowel obstructions in patients over the age of 65. The radiographic picture and ultrasound of small bowel obstruction and the presence of air in the biliary tree are suggestive for the diagnosis of a gallstone ileus. In our patient, the computed tomography and ultrasound findings confirmed the diagnosis and led to a prompt and directed surgical intervention. In patients with comorbid factors a two-step approach with enterolithotomy in a first and cholecystectomy in a second operation should be the therapeutic strategy of choice.

Associations between the polymorphism of apolipoprotein E, which plays an important role in cholesterol metabolism and cholesterol gallstone formation, have been reported recently. Patients with the apo E4 isoform showed increased numbers and cholesterol contents of their stones, a higher frequency of cholesterol crystals in bile, increased susceptibility to gallstone fragmentation by extracorporeal shock-wave lithotripsy and an increase in recurrence rate after dissolution. A recent study, however, showed that fast cholesterol crystallization in bile is associated with multiple stones but not with apo E4. Therefore the mechanism for an increased risk of gallstone formation in patients with the apo E4 isoform still remains under debate.To clarify this issue we investigated 37 patients with gallstones (10 with the apo E4 allele and 27 without the allele). Gallbladder biles were examined for total cholesterol and other lipids, cholesterol saturation index, crystal observation time, crystal mass, total protein and mucin. Moreover, number of gallstones and cholesterol in gallstones was compared in both groups.The crystal observation time (2.5 vs. 2.0 days, median) and the cholesterol saturation index (1.34 +/- 0.45 vs. 1.43 +/- 0.74) did not differ significantly between the apo E4 and the non apo E4 group. Total biliary lipids (11.6 +/- 3.8 vs. 9.3 +/- 3.9 g 100 mL-1, P = 0.126) and total biliary cholesterol (21.8 +/- 9.7 vs. 15.7 +/- 7 mmol L-1, P = 0.067) tended to be elevated in the apo E4 group. Crystal mass (3.60 +/- 4.10 vs. 2.38 +/- 2.70 mmol L-1), biliary total protein (8.6 +/- 3.5 vs. 8.3 +/- 6.6 mg mL-1) and mucin (0.55 +/- 0.38 vs. 0.66 +/- 0.67 mg mL-1), number (solitary/multiple) of gallstones and cholesterol in gallstones were not different in both groups of patients.In comparison to the non apo E4 patients the apo E4 group showed a trend to elevated biliary cholesterol whereas crystal observation time, cholesterol saturation index, crystal mass, number of gallstones, cholesterol content of gallstones and total protein and mucin were not different. These findings do not suggest an association of the apo E isoform and the formation of cholesterol gallstones

Phospholipase A2 (PLA2) and its enzymatic products free fatty acids (FFAs) and 2-lysolecithin are physiological constituents of bile. Their role in the crystallization of cholesterol in gallbladder bile of patients with cholesterol gallstones is still controversial.To clarify this issue we evaluated the activity of PLA2 and the concentration and pattern of FFAs in the gallbladder bile of cholesterol stone patients. We furthermore added PLA2, FFAs and 2-lysolecithin to isotropic gallbladder bile, determined the crystal observation time (COT) and counted the cholesterol crystals in a crystal growth assay for up to 21 days.A PLA2 activity of 1.8 +/- 1.2 U L(-1) and total FFA concentrations of 1.32 +/- 0.71 mmol L(-1) were determined. After incubation of bile for 24 h at 37 degrees C total FFAs increased to 2.72 +/- 1.29 mmol L(-1) (P0.005). Biliary saturated and unsaturated FFAs were found in equal proportions before and after incubation, pointing to an additional presence of lipases other than PLA2. A COTof 1 day was observed in all gallbladder biles and increased to 1.7 +/- 0.5 days after addition of 5 U L(-1) of PLA2 (P0.01). An even higher COT of 2.5 +/- 0.8 days was seen after addition of 5 mmol L(-1) of a 'biliary' mixture of FFAs (P0.005) but the COT remained unchanged after addition of 5 mmol L(-1) of 2-lysolecithin. However, in the crystal growth assay in gallbladder bile addition of 5 U L(-1) of PLA2, of 5 mmol L(-1) of 'biliary' FFAs and of 5 mmol L(-1) of 2-lysolecithin decreased significantly the number of cholesterol crystals formed during follow-up.An elevated activity of PLA2 in gallbladder bile may counteract the formation of cholesterol crystals through increased formation of FFAs and 2-lysolecithin. However, regarding the comparatively low activity of PLA2 in gallbladder bile PLA2 seems to be of only minor pathophysiological importance in the formation of cholesterol gallstones.

The role of carbohydrate-deficient transferrin (CDT) as a reliable marker for the detection of chronic alcohol abuse has been discussed controversially.Therefore, we investigated CDT in the sera from 405 subjects with different alcohol intake. Besides healthy control subjects (n = 42), inpatients and outpatients in a department of gastroenterology (n = 325) and patients admitted to a department of otorhinolaryngology (n = 38) were studied. A total of 213 patients suffered from various forms of liver diseases, and 89 patients had liver transplantation. CDT values were determined by a double-antibody radioimmunoassay.In the 241 alcohol-abstinent subjects, CDT levels ranged from 3 to 90 units L-1 (median = 12); the 92 moderate drinkers (20-60 g of alcohol per day) showed values from 3 to 40 units L-1 (median = 12), and the 72 subjects with chronic alcohol abuse (60 g per day) revealed CDT levels from 3 to 100 units L-1 (median = 16). The diagnostic specificity for alcohol abuse was 86.8% for men (sensitivity 36.9%) and 95% for women (sensitivity 0%).Our data indicate that measurement of CDT does not reach clinical use in the detection of chronic alcohol abuse in an unselected population because of its insufficient specificity and sensitivity.

Serum CA 19-9 is increased in patients with different gastrointestinal malignancies. Unfortunately, CA 19-9 is also detected in high concentrations in normal bile causing unspecific serum elevations during inflammatory disease of the biliary tract and cholestasis. In order to identify the source of CA 19-9 in bile, the capacity of cultured human gallbladder epithelial cells (HGBEC) to secrete CA 19-9 was investigated. Cells were harvested from gallbladders removed by cholecystectomy and cultured for up to 14 days in collagen I coated 24-well culture dishes. CA 19-9 was measured in the culture medium by a solid-phase CA 19-9 EIA (Boehringer). In addition, culture medium was separated by Sepharose 4B-Cl, Concanavalin-A (Con-A) and CA 19-9 affinity chromatography. Significant CA 19-9 activity was measured in the culture medium after a 24 hour incubation period. Following separation of the culture medium by Sepharose 4B-Cl and Con-A affinity chromatography, 90% of the CA 19-9 activity was recovered in the exclusion volume (2000 kDa) from which 90% were identified as Con-A negative. A close correlation was found between CA 19-9 and concentrations of mucin purified from human gallbladder bile. Furthermore, CA 19-9 affinity chromatography selectively extracted mucins from the culture medium of HGBEC. Finally, addition of the mucin secretagogue bethanechol (6 mM) to the culture medium increased CA 19-9 activity in the medium. In conclusion, normal HGBEC secrete mucins carrying the epitope of CA 19-9. During inflammatory biliary disease unspecific elevation of CA 19-9 in serum may reflect both inflammatory hypersecretion and leakage of biliary mucins into serum.

Cholesterin wird in der Blasengalle in Form von niedermolekularen gemischten Mizellen aus Gallensauren und Phospholipiden und hochmolekularen Phospholipidvesikeln transportiert. Cholesterinmonohydratkristalle bilden sich bevorzugt aus den instabilen Cholesterinphospholipidvesikeln und sind Voraussetzung fur die Entstehung von Cholesterinsteinen. Mit Hilfe der Gelchromatographie mit Elution von Galleproben vor und nach Dialyse konnte gezeigt werden, das die biliaren Proteine uberwiegend mit den gemischten Mizellen assoziiert sind. Diese Interaktion kann durch KBr-Gradientenzentrifugation nicht gelost werden und wirkt der Bildung von instabilen Phospholipidcholesterinvesikeln entgegen. Trotz hoherer Proteinkonzentration in der Blasengalle von Patienten mit Cholesterinsteinen ist dort diese protektive Wirkung der Proteine z. T. aufgehoben.

Torasemide is a new loop diuretic with a longer half-life and longer action than furosemide in healthy subjects. In order to evaluate the pharmacodynamic effects, single oral doses of furosemide (80 mg) and torasemide (20 mg), which were equipotent in healthy subjects, were given to 14 patients with cirrhosis and ascites. Before the study patients underwent an equilibration period of 4 days without diuretics. The drugs were alternated following a randomized double-blind cross-over design after a wash-out period of at least 2 days. Urine was collected at defined intervals for 24 h after drug administration and blood samples were taken before, 6 h and 24 h after medication. Torasemide induced greater cumulative 24 h diuresis (2863 +/- 343 vs. 2111 +/- 184 ml, p0.01) than furosemide. Torasemide did not differ from furosemide for cumulative 0-6 h sodium excretion (96 +/- 17 vs. 92 +/- 23 mmol sodium) but caused a more pronounced cumulative 6-24 h natriuresis (38 +/- 11 vs. 17 +/- 4 mmol, p0.05). Five patients exhibited a weak response to furosemide (0-36 mmol sodium/24 h, median 24 mmol; 690-1460 ml urinary volume/24 h, median 1325 ml). These patients showed significantly higher natriuresis and diuresis following torasemide (26-136 mmol sodium/24 h, median 78 mmol, p0.05; 1670-3610 ml urinary volume/24 h, median 2200 ml, p0.05). Twenty-four hours after administration of both drugs there were no significant changes in hemodynamic, renal or hormonal parameters. No adverse effects were noted with either treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The existence of marked elevations of ascitic fluid cholesterol has been observed in patients with peritoneal carcinomatosis compared to patients with cirrhosis and has been found useful in differential diagnosis. This finding could be caused by an enhanced movement of plasma lipoproteins into the peritoneal cavity. To test this hypothesis we determined the fasting concentrations of total, high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol, apolipoprotein-A1 (apo-A1) and apolipoprotein-B (apo-B) in serum and ascites of 17 patients with cirrhosis and 16 patients with peritoneal carcinomatosis. The movement of proteins from plasma to ascites was calculated from the ascites/serum concentration ratios of six different sized proteins with a molecular mass ranging from 54 kDa to 971 kDa. Mean values (mg/dl) for total cholesterol (92.6 vs. 21.0), HDL-cholesterol (15.6 vs. 1.8), LDL-cholesterol (63.4 vs. 16.1), apo-A1 (50.2 vs. 13.6) and apo-B (41.2 vs. 12.9) in ascites were significantly higher in peritoneal carcinomatosis than in cirrhosis. These differences could only partially be explained by the higher serum concentrations of these parameters in peritoneal carcinomatosis, but were mainly due to a lower selectivity for the movement of plasma proteins and lipoproteins into ascites (mean ascites/serum (A/S) ratio: 0.30-0.77) in peritoneal carcinomatosis as compared to cirrhosis (mean ascites/serum ratio: 0.11-0.21). In both groups about 85% of the total cholesterol in serum and ascites consisted of HDL- and LDL-cholesterol. These findings support the hypothesis that elevations in ascitic cholesterol in peritoneal carcinomatosis compared to cirrhosis are mainly caused by the increased movement of plasma HDL and LDL into the peritoneal cavity.

Eine erhohte Ausscheidung von Cholesterin im Urin bei malignen Erkrankungen wurde erstmals von Bloch und Sobotka (1938) nachgewiesen und in neuerer Zeit von anderen Autoren bestatigt [1, 8]. Auf Grund der Untersuchungen von Acevedo et al. schien die Cholesterinbestimmung im Urin insbesondere zur Diagnostik von Karzinomen des Urogenitaltrakts geeignet [1–5]. Einflusse nicht maligner Erkrankungen wurden jedoch weniger berucksichtigt, daneben blieb die wichtige Frage unbeantwortet, ob auch Karzinome in Fruhstadien mit dieser Methode erfast werden konnen.

Die in vitro-Diagnostik der Schilddrusenfunktion hat durch die Einfuhrung des i.v. TRH-Kurztestes eine wesentliche Bereicherung erfahren. Die diagnostische Wertigkeit dieses Verfahrens wird jedoch dadurch belastet, das in etwa 12–20% klinisch euthyreoter Patienten die erwartete Mehrsekretion von TSH auf i.v. TRH-Gabe ausbleibt, obwohl die Schilddrusenhormone im Plasma im normalen Mesbereich liegen [1–4]. Fur diese Konstellation von Befunden wurden die Begriffe „sub- oder praklinische“ Hyperthyreose gepragt. Der weite Normalbereich der Schilddrusenhormonkonzentration schien zu erklaren, warum individuelle Werte fur einen gegebenen Patienten zwar zu hoch, absolut gesehen aber noch normal sein konnen [81. Die klinische Bedeutung dieser sogenannten subklinischen Hyperthyreosen ist z. Z. noch unklar, zumal bei einem Teil dieser Patienten durch protrahierte TSH-Stimulation mit oralem TRH eine offenbar euthyreote Stoffwechsellage bewiesen werden konnte [5–7, 11].

The effect of a new potent choleretic drug (Febuprol) on lipid composition and cholesterol nucleation time in gallbladder bile was studied in 8 patients with cholesterol gallstones. Nine untreated patients with cholesterol cholecystolithiasis and functioning gallbladder served as controls. Under Febuprol treatment (3 X 100 mg for 6-10 days) mean concentrations of total bile acids (125.4 vs. 59.5 mmol/l), phospholipids (46.1 vs. 25.6 mmol/l) and total lipids (10.4 vs. 5.9 g/dl) were significantly higher (p less than 0.01) than in controls. No significant difference between both groups was calculated for the mean values of cholesterol (17.8 vs. 13.3 mmol/l), cholesterol saturation index (1.5 vs. 2.1) and cholesterol nucleation time (2.1 vs. 2.6 days). Our findings are compatible with a choleretic effect of Febuprol but no alteration of the rapid cholesterol crystallisation in gallbladder bile of patients with cholesterol gallstones was found.

In 35 patients with Graves' ophthalmopathy (GO) thyroid function was tested by T3-RIA, T4-RIA, TBI, TRH-test, thyroid scanning, and determination of thyroid autoantibodies. Additional ultrasonography (A-scan), computed tomography (CT) of the orbit, and the determination of an exophthalmogenic serum activity in fish bioassay was performed. Typical alterations for GO were observed in 26 cases with ultrasonography. CT showed an enlargement of medial and/or lateral rectus muscles in 24 of 33 patients, and in 17 cases a region of high density in the apex of the muscle cone. The density of retrobulbar fat after i.v. injection of contrast medium did not differ significantly from that observed in normal men. Characteristic signs of GO were not detected in only 2 cases using both methods together. Exophthalmogenic serum activity was found in the IgG fraction of serum protein. The incidence rate was high (69%), but for diagnostic purpose the fish bioassay cannot be recommended.

High concentrations of lipids in ascites fluid caused by peritoneal carcinomatosis have been described recently. Since their nature has not yet been clarified, we isolated ascitic lipids from 25 patients with various neoplasms for further characterization. After chromatography on Sephadex G-100 gels, the ascitic lipids were fractionated on a Biogel A-5m column in three peaks. The second and third peaks were identified as low and high density lipoproteins, which were most likely of plasmatic origin, and represented the major amounts of ascitic lipids. The first peak was eluted in the void volume, indicating a molecular weight over 5 million. It consisted, on the average, of 65.3% protein, 16.2% triglycerides, 7.4% phospholipids, and 7.0% cholesterol. In a CsCl gradient, this protein-lipid complex floated in the density range from 1.128 to 1.181 g/ml. Sodium dodecyl sulfate: polyacrylamide gel electrophoresis separated up to 11 protein subunits (Mr 29,000 to 97,000), and electron microscopy revealed globular particles of 36 to 64 nm in diameter. The macromolecular complex showed no immunological reaction against anti-alpha- and anti-beta-lipoproteins, but a single precipitation line against anti-liver-specific lipoprotein was seen. The biochemical characteristics of this protein-lipid complex proved to have a close relationship to liver-specific lipoprotein. It is most likely derived from cell membranes of the peritoneum detached by carcinomatosis.

Determination of urinary cholesterol has been suggested to be of possible value in the diagnosis of urogenital carcinomas especially of prostate, kidney and bladder. However, it has not been proven whether this method could be used as a screening test in large numbers of patients. 430 males and 545 females with an age above 50 years were selected for the study. Total urinary cholesterol values exceeding 5.1 mg/24 hours (regarded as positive results) were present in 13 males (3%) and 9 females (1.6%). In addition to benign diseases of the kidney and the urogenital tract, 2 carcinomas of the bladder and 1 carcinoma of the kidney were detected in the male group with elevated urinary cholesterol excretion. In view of the low prevalence of urological carcinomas and the cost of urinary cholesterol determination by GLC, this method cannot be recommended as a primary screening test, but could be of practical value in populations with microscopic haematuria and increased prevalence of urological carcinomas.

Fruhere Untersuchungen zeigten, das Cholesterin bereits unter physiologischen Bedingungen in geringer Menge, etwa 0,5–4,0 mg/d, im Urin ausgeschieden wird (Grunke 1922; Butenandt u. Dannenbaum 1937). Eine gesteigerte Exkretion wurde bei Erkrankungen der Niere, hier insbesondere beim nephrotischen Syndrom, beschrieben, daruber hinaus aber insbesondere auch bei malignen Erkrankungen des Urogenitaltrakts (Frick u. Spiteller 1968; Acevedo et al. 1974, 1975, 1976; Chu et al. 1975; Belis u. Cenedella 1979; Jungst et al. 1979 a, 1979 b, 1980, 1981 a–c).

Bei einem 41jahrigen homosexuellen Mann wurde wahrend eines stationaren Aufenthaltes wegen einer Pneu-mocystis-carinii Pneumonie die Diagnose eines erworbenen Immundefizit-Syndroms (AIDS) gestellt. Ein Jahr spater traten erstmals Sehstorungen auf. In der folgenden Arbeit werden die ophthalmologischen Befunde im Verlauf dargestellt und uber den Erfolg einer experimentellen Therapie berichtet.