Pigment vs cholesterol cholelithiasis: Clinical and epidemiological aspects

This prospective study demonstrated that among 92 consecutive patients who underwent cholecystectomy for gallstones at an urban university hospital, 27% had pigment stones and 73% had cholesterol stones. Age, sex, and weight, but not race, were significant determinants of stone type. The mean hemoglobin, direct and total serum bilirubin, and fasting glucose concentrations were similar for each group. The presence of alcoholism, diabetes, thyroid disease, or heterozygous hemoglobinopathy did not influence stone type. The average patient with pigment stones is a lean man or woman 63 years old; in contrast, the composite patient with cholesterol stones is a modestly overweight woman 43 years old.     

Pigment vs cholesterol cholelithiasis: Comparison of stone and bile composition

This report presents a comparative study of gallstone and gallbladder bile composition from 100 unselected American patients, 23 with pigment and 77 with cholesterol cholelithiasis. Cholesterol stones were predominantly composed of cholesterol, whereas pigment stones were mainly composed of an unidentified residue, bilirubin, and bile salts. The residue in pigment stones was not calcium bilirubinate, which sharply contrasts with the composition of bile pigment calcium stones found in Japanese subjects. Bile composition of the two groups differed in that the cholesterol content of biles surrounding pigment stones was significantly less than that of biles surrounding cholesterol stones. Bilirubin in biles was conjugated, but the pigment extracted from stones was unconjugated bilirubin. This study indicates that (1) pigment stones account for an appreciable percentage of gallstone specimens found at cholecystectomy, and (2) pigment stone formation involves the precipitation of bilirubin, bile salts, and unidentified material which is not calcium bilirubinate.Presented at the meetings of the American Federation of Clinical Research, April 29, 1973, Atlantic City, New Jersey. Supported in part by NIH grant AM 14543. Dr. Trotman is a former NIH trainee under NIH grant AM 05462 and currently a recipient of a Macy Foundation Faculty Fellowship.     

Normal antipyrine metabolism in patients with cholesterol cholelithiasis

Plasma antipyrine half-lives and metabolic clearances were measured after a single oral dose of antipyrine in 10 control subjects, 12 patients with gallstones, and 9 patients having undergone cholecystectomy for cholesterol cholelithiasis, to determine whether impairment of hepatic antipyrine metabolism occurs in patients with cholesterol cholelithiasis. The plasma antipyrine half-life and metabolic clearances in the control subjects were 11.7±1.0 hours and 42.5±3.3 ml/min, respectively; in patients with gallstones, 12.3±1.3 hours and 36.0±3.2 ml/min, respectively; and in patients having undergone cholecystectomy, 13.2±1.8 hours and 33.8±4.2 ml/min, respectively. Values for antipyrine half-life and metabolic clearance were not statistically different in these three groups. This study suggests the presence of normal hepatic antipyrine metabolism in patients with cholesterol cholelithiasis.     

Kinetics of cholesterol and bile acids in patients with cholesterol cholelithiasis.

The kinetics of cholesterol and bile acid was determined from a 10-week analysis of the biliary lipids after a single injection of labeled cholesterol in parallel with a conventional 1-week study of primary bile acid kinetics. Six healthy controls and 6 patients with cholesterol cholelithiasis were studied. Two of the 6 cholesterol cholelithiasis subjects had kinetic values that were very similar to the controls and the other 4 were significantly different. These 4 patients had significantly smaller primary bile acid pools and significantly lower fractional conversions of cholesterol to both primary bile acids, with concomitantly lower bile acid flux. No significant differences were obtained for the size of the rapidly miscible cholesterol pool, the fractional rate of loss and flux of biliary neutral sterol, and the fractional turnover of the primary bile acid pools. These kinetic data support the hypothesis that in some patients with cholesterol cholelithiasis there is defective conversion of cholesterol to bile acids.     

Pigment vs. cholesterol microlithiasis: comparison of clinical features, bacteriology, stone and gallbladder composition

We compared 16 cases of pigment microlithiasis with 12 cases of cholesterol microlithiasis. In each case we made a spectrophotometric and diffractometric analysis of the composition of the stones, also analysing bile bacteriology, bile lipid composition and cholesterol saturation indices. The two groups were comparable as regards sex, age, symptoms and clinical features. Pigment microcalculi were often asymptomatic (41.7%), but more often associated with bile bacteria (43.7%) or acute pancreatitis (25%). The results were such as to permit us to view cholesterol microlithiasis and pigment microlithiasis as having different pathogenetic and clinical aspects, and thus as being different diseases.     

Biliary proteins and the nucleation defect in cholesterol cholelithiasis

A study was performed to determine whether differences in gallbladder proteins might be present in patients with rapidly nucleating bile. Gallbladder and hepatic bile protein concentrations were measured using a fluorometric assay. The method was validated by an independent technique, i.e., hydrolysis and amino acid analysis. Persons with cholesterol gallstones had significantly higher gallbladder bile protein concentrations than patients without gallbladder disease or patients with pigment stones. The protein concentration correlated with the in vitro nucleation time in the cholesterol stone group. Gallbladder bile proteins were also purified by chromatography and gradient ultracentrifugation. Proteins from patients with cholesterol gallstones accelerated the nucleation time of control bile, whereas protein from controls had little effect. Hepatic bile protein concentrations were similar in persons with and without cholesterol gallstones. The gallbladder-to-hepatic bile ratios of a variety of solutes were examined. The ratio for protein in the cholesterol gallstone group can be explained straightforwardly by water reabsorption in the gallbladder, whereas the very low ratio in patients without cholesterol gallstones suggests that their gallbladders reduce protein mass by a process such as protein absorption or degradation during water absorption in the gallbladder.     

Biliary aminopeptidase-N and the cholesterol crystallisation defect in cholelithiasis.

This study compared the response to adenine arabinoside 5'-monophosphate (ARA AMP) in 60 patients with chronic hepatitis B according to the pretreatment serum hepatitis B virus DNA concentration. The level of hepatitis B virus replication was defined as low (30 patients) or high (30 patients) when serum hepatitis B virus DNA concentration was below or above 100 pg/ml, respectively. Patients received a 28 day course of ARA AMP and a second course of ARA AMP was given six months later to patients with persistent hepatitis B virus replication. At the end of the first course of ARA AMP, 11 of the patients (37%) with low replication and one of the patients (3%) with high replication became negative for hepatitis B virus DNA (p = 0.0012); five of the patients (17%) with low replication and none of the patients with high replication had HBe seroconversion (p = 0.06). Two of these five patients lost HBsAg. Kinetics of serum hepatitis B virus DNA during treatment showed a considerable but transient antiviral effect of ARA AMP. Three of 32 retreated patients became negative for hepatitis B virus DNA and one patient had HBe seroconversion. In conclusion, ARA AMP exerts a considerable but transient antiviral effect on hepatitis B virus. Complete and sustained inhibition of hepatitis B virus replication was only obtained in the patients with low hepatitis B virus replication.     

Aspirin does not inhibit cholesterol cholelithiasis in two established animal models.

The effect of aspirin on cholesterol cholelithiasis was examined in the hamster and the prairie dog. In the prairie dog, diets were composed of semipurified components of chow, plus cholesterol (1.2%), with and without aspirin. Animals were studied for either 2 weeks or 4 weeks. Cholesterol gallstones were present in all groups at the end of each period; aspirin did not alter the incidence of cholelithiasis. All animals studied had cholesterol crystals in the bile when they were killed. Liver cholesterol levels in prairie dogs with and without aspirin tended to be lower in animals fed chow than in animals fed semipurified diets. There were no significant differences in cholesterol levels in the plasma or bile. The cholesterol saturation index of all biles approached unity when animals were fed chow with aspirin; animals fed the semipurified diets had cholesterol saturation indices of less than 1.0. The prairie dogs fed aspirin plus cholesterol in the semipurified diet showed increased levels of biliary chenodeoxycholic acid amidates and concomitant decreased levels of cholic acid amidates compared with animals fed the same diet without aspirin. Hamsters fed aspirin plus cholesterol in a semipurified diet tended to have a greater incidence of gallstones than animals given no aspirin (80% vs. 55%). Liver and bile cholesterol levels were similar with and without aspirin; plasma cholesterol levels increased significantly with aspirin [14.20 vs. 7.80 mmol/L (549 vs. 301 mg/dL)]. Lithogenic indices in all hamsters were above unity; biliary lipids, total lipid concentration, and biliary bile acid composition were similar. These results show that the addition of aspirin to a lithogenic diet does not reduce the incidence of cholelithiasis.     

Mechanism for the transit-induced increase in colonic deoxycholic acid formation in cholesterol cholelithiasis

BACKGROUND & AIMS: Many patients with cholesterol gallbladder stones (GBS) have a high percentage of deoxycholic acid (DCA) in gallbladder bile (all of which are in the conjugated form), probably as a result of prolonged large bowel transit times (LBTT). However, whether the prolonged LBTT increases DCA formation, solubilization, or absorption (or all 3) is not known. METHODS: In 40 subjects (20 with GBS; age range, 24-74 years), we measured LBTT using radiopaque markers, and intestinal luminal pH by radiotelemetry. We also measured quantitative anaerobic bacteriology and the activities of 2 bile acid-metabolizing enzymes in fresh cecal aspirates obtained during clinically indicated unprepared colonoscopy, and related these results to the percentage of DCA in fasting serum measured by gas chromatography-mass spectrometry. RESULTS: Compared with controls, GBS patients had longer LBTT (mean 23.1 +/- SEM 2.8 h vs. 36.5 +/- 3.3 h; P < 0.01); more total (2.7 +/- 0.6 x 10(9) vs. 5.9 +/- 1.5 x 10(9) cfu/mL) and Gram-positive (9.5 +/- 3.1 x 10(8) vs. 18.0 +/- 4.1 x 10(8) cfu/mL; P < 0.05) anaerobes; and greater 7alpha-dehydroxylating (7alpha-DH) activity (3.39 +/- 0.59 vs. 10.37 +/- 1.15 x 10(-4) U/mg protein) in the cecal aspirates. They also had higher intracolonic pH values (P < 0.02) and increased percentages of DCA in fasting serum (13.4% +/- 1.52% vs. 21.8% +/- 2. 19%; P < 0.005). Results of univariate and multivariate analyses confirmed that LBTT was critical in determining the percentage of DCA in serum and showed that 7alpha-DH activity and apparent distal colonic pH were also significant independent variables. CONCLUSIONS: Slow colonic transit (more time), increased Gram-positive anaerobes (more bacteria), and greater 7alpha-DH activity (more enzyme) favor enhanced DCA formation; transit-induced increases in distal colonic luminal pH favor enhanced DCA solubilization/bioavailability; and increases in LBTT (more time) again favor DCA absorption.     

MDR3 mutations associated with intrahepatic and gallbladder cholesterol cholelithiasis: an update

Background: The recurrent microlithiasis represents one of the most frequent clinical forms of lithiasis of the bile ducts. This affection is characterized by the presence of cholesterolic microgallstones on hepatic canaliculars, and belongs to a heterogeneous group of autosomal recessive liver disorders. Radiological diagnosis can be confirmed by analysis of MDR3 gene, coding a protein involved in physiologic translocation of phospholipids in bile. Discovery of MDR3 mutations is of particular interest, since normally associated with good effectiveness of medication by ursodesoxycholic acid. AIM: To review MDR3 mutations in humans associated with recurrent cholesterol microlithiasis and to suggest a practical approach for MDR3 gene analysis. Results: 48 mutations of MDR3 gene have been reported in humans to date, from which 43 (89.5%) in the coding region, and 5 splice site mutations have been associated to cholesterol cholelithiasis. 21 (43.8%) of the 43 precited mutations are located in only 8 exons on 28, near transmembrane or nucleotide binding domains of the protein. From the 22 remaining described mutations, 9 (18.8%) are restricted to exon 14. We suggest therefore to start analysis of MDR3 gene by screening exons 6, 7, 9, 10, 12, 14, 17, 23 and 24 with an appropriate protocol in this diagnosis associated with effective treatment. In conclusion such therapeutic orientation is valuable, since recurrent cholesterolic microlithiasis occurs relatively early in life, and by the fact that recurrence of symptoms may occur despite cholecystectomy, or shock-wave therapy.     

Molecular genetics of cholesterol cholelithiasis: identification of human and murine gallstone genes

Cholesterol cholelithiasis is one of the most common gastroenterological diseases in Western countries. It is a polygenic disease resulting from disturbed biliary cholesterol homeostasis. Association studies identified six human gallstone candidate genes. Polymorphisms in the genes encoding the apolipoproteins B and E, phospholipid flippase ( ABCB4), cholesterol ester transfer protein ( CETP), cholesterol-7alpha-hydroxylase ( CYP7A1) and ileal bile acid transporter ( SLC10A2) are correlated with gallstone prevalence. Quantitative Trait Locus (QTL) analysis localises additional unknown gallstone genes in inbred mice. Based on the natural variation of cholesterol gallstone susceptibility among different inbred strains, 5 lithogenic ( Lith) loci have been identified. Hepatobiliary transporters (e. g. bile salt export pump Abcb11) and key proteins of the lipoprotein metabolism (e. g. hepatic lipase Lipc) could be established as creedal candidate genes for Lith loci. The rapid progress of mouse and human genome projects provides the basis for the analysis of orthologous human LITH genes in gallstone patients, which might offer new prospects for individual risk assessment and molecular targets for stone prevention.     

Effect of dietary cholesterol and indomethacin on cholelithiasis and gallbladder motility in guinea pig

This study examines the effects of dietary cholesterol and subcutaneous indomethacin on gallstone formation, gallbladder motility, and bile composition in guinea pigs. Guinea pigs on cholesterol diets developed gallstones which were not primarily composed of cholesterol and were not prevented by indomethacin. Animals receiving cholesterol diets showed significant gallbladder enlargement which was inhibited by indomethacin. Cholesterol did not alter gallbladder pressure-volume relationships or the response to CCK, while indomethacin diminished gallbladder tone. Although cholesterol feeding did not appear to alter smooth muscle contractility in the guinea pig gallbladder, it caused significant gallbladder enlargement by a mechanism which may be dependent on prostaglandins.This study was supported by National Institutes of Health grant AM 15304.     

Immunoallergic interstitial nephritis vs. cholesterol atheroembolism. Differentiating characteristics

The commonest clinical presentation of both immunoalergic interstitial nephritis (IIN) and atheroembolic renal disease (ATD) is an acute renal failure accompanied by skin lesions and eosinophilia. As a consequence, differential diagnosis between both entities is often very difficult. We have performed a comparative retrospective study of those patients diagnosed as having IIN or ATD in our Hospital in the period 1980-2000. A total of 42 patients have been diagnosed of IIN and 16 of ATD. Demographic data, as well as clinical and laboratory parameters and outcomes of every studied patient were analysed. We found a significantly higher prevalence of male sex (100% vs 57%, p < 0.01), previous history of hypertension (100% vs 55%, p < 0.01), chronic renal insufficiency (56% vs 17%, p < 0.01), ischemic heart disease (56% vs 14%, p < 0.001), peripheral ischemic disease, endovascular procedures (87% vs 7%, p < 0.001) and anticoagulant treatments (25% vs 5%, p < 0.001) among patients with ATD as compared with IIN, respectively. On the contrary, previous infections (45% vs 12%, p < 0.01) and exposure to new drugs (100% vs 40%, p < 0.001) were significantly more frequent among IIN patients in compare with ATD. ATD patients showed skin lesions consisting of livedo reticularis and digital infarcts (63% vs 31%, p < 0.05) accompanied by blood pressure increase (100% vs 24%, p < 0.001), whereas IIN patients showed fever (41% vs 19%, p < 0.05) and cutaneous rash as significant clinical manifestations, respectively. The number of ATD patients with proteinuria > 1 g/24 h was significantly higher, but no differences between both groups in the prevalence of urinary sediment abnormalities were observed. The prevalence of absolute eosinophilia was high in both groups (88% among ATD patients, 64% among IIN patients; pNS). Prognosis of both entities was clearly different: Almost all patients with ATD died (69%) or evolved to end-stage renal failure, whereas most patients with IIN showed a recovery of renal function after withdrawal of responsible drugs and steroid treatment. In summary, the analysis of clinical and laboratory data allows an initial differential diagnosis in patients suspected as having IIN or ATD.