Pathogenesis of calcium-containing gallstones. Canine ductular bile, but not gallbladder bile, is supersaturated with calcium carbonate.

Calcium precipitation in bile is a requisite event in the initiation and growth of all pigment gallstones. Calcium solubility in bile is thus of great importance. This is the first attempt to define the ion-product of CaCO3 in bile in any species. If the ion-product: [Ca++] X [CO = 3] exceeds solubility product (K'sp), the sample is supersaturated and CaCO3 precipitation is thermodynamically possible. We have recently determined K'sp of calcite to be 3.76 X 10(-8) mol/liter at 37 degrees C and total ionic strength = 0.16 M. Gallbladder (GB) bile was obtained from 15 anesthetized dogs after 12-24-h fasts. Duct bile was obtained from three dogs (n = 12) during variable taurocholate infusion. Samples were assayed for pH, partial pressure of carbon dioxide (PCO2), total bile salt concentration ([TBS]), total calcium concentration ([Ca]), and free calcium ion concentration ([Ca++]). With increasing [TBS] in both GB and duct bile, there was a linear decline in pH, a curvilinear decline in [HCO-3] and [CO = 3], and linear increase in [Ca++] and [Ca]. All ductular samples were supersaturated with CaCO3, with saturation indices (SI) as high as 17.5 and a mean of 8.36 +/- 1.43 (SE). In sharp contrast, none of the GB samples were supersaturated, due to the marked decline in [CO = 3] upon concentration and acidification of bile. In GB bile, the SI ranged from 0.006 to 0.126, with a mean of 0.039 +/- 0.011. The gallbladder thus produced a change in the SI from a value as high as 17.5 to a value as low as 0.006 in concentrated GB bile, which is a nearly 3,000-fold change. The average change in the SI was approximately 215-fold. Since all duct samples were supersaturated, and since the dog does not normally form gallstones, the data support our previous hypotheses that: (a) in canine bile, as in canine pancreatic juice, a nucleating factor is necessary for CaCO3 precipitation; (b) bile salts are important buffers for Ca++ in bile; and (c) normal GB mucosal function (concentration and acidification of bile) plays an important role in reducing CaCO3 lithogenicity in GB bile.

Isolation of an acidic protein from cholesterol gallstones, which inhibits the precipitation of calcium carbonate in vitro.

In seeking to identify nucleating/antinucleating proteins involved in the pathogenesis of cholesterol gallstones, a major acidic protein was isolated from each of 13 samples of cholesterol gallstones. After the stones were extracted with methyl t-butyl ether to remove cholesterol, and methanol to remove bile salts and other lipids, they were demineralized with EDTA. The extracts were desalted with Sephadex-G25, and the proteins separated by PAGE. A protein was isolated, of molecular weight below 10 kD, which included firmly-bound diazo-positive yellow pigments and contained 24% acidic, but only 7% basic amino acid residues. The presence of N-acetyl glucosamine suggested that this was a glycoprotein. This protein at concentrations as low as 2 micrograms/ml, but neither human serum albumin nor its complex with bilirubin, inhibited calcium carbonate precipitation from a supersaturated solution in vitro. This protein could be precipitated from 0.15 M NaCl solution by the addition of 0.5 M calcium chloride. Considering that cholesterol gallstones contain calcium and pigment at their centers, and that small acidic proteins are important regulators in other biomineralization systems, this protein seems likely to play a role in the pathogenesis of cholesterol gallstones.

Laparoscopic live donor nephrectomy--is it safe?

BACKGROUND: Laparoscopic live donor nephrectomy (LDN) is a less invasive alternative to open nephrectomy (ODN) for living kidney donation. Concerns have been raised regarding the safety of LDN, the short and long term function of kidneys removed by LDN, and a potential higher incidence of urologic complications in LDN transplant recipients. METHODS: Between October 1997 and May 1999, 80 LDNs were performed at our center. All patients were followed longitudinally with office visits and telephone interviews. These LDNs were compared with 50 ODN performed from January 1996 to October 1997. RESULTS: LDN procedures took significantly longer than ODN (4.6 vs. 3.1 hr). However, LDN was associated with significant reduction in i.v. narcotic use, a rapid return to diet, and shorter hospital stay. Of the 80 LDN procedures, a total of 75 (94%) were completed laparoscopically. Five patients were converted to laparotomy: three for hemorrhage and two for complex vascular anatomy. ODN conversion was associated with large donor body habitus and/or obesity. Seven LDN patients had minor complications and 4 had major complications. All major complications consisted of vascular injuries (2 lumbar vein injuries, 1 renal artery, and 1 aortic injury). All patients made complete recoveries. All LDN kidneys functioned immediately posttransplant. We have observed 100% patient and 97% 1-year actuarial graft survival in LDN transplant recipients. There have been no short-or long-term urologic complications in this series. CONCLUSION: With increasing experience and standardization of technique, LDN is a safe and effective procedure. Patients undergoing LDN demonstrate clinically significant, more rapid postoperative recoveries and shorter hospital stays than ODN patients. Excellent initial graft function and long-term graft survival have been observed with LDN kidneys. Urologic complications can be avoided. LDN has become the preferred surgical approach for living kidney donation at our center.

The inflammatory effects of crystalline cholesterol monohydrate in the guinea pig gallbladder in vivo.

BACKGROUND: The etiologic role of crystalline material in inflammatory arthritis is well established. The role of crystals in cholecystitis is unclear. We hypothesized that crystalline cholesterol monohydrate stimulates guinea pig gallbladder inflammation in vivo. METHODS: Crystalline cholesterol monohydrate, lipopolysaccharide (LPS), lysolecithin, polystyrene latex spheres (noninflammatory particles), and saline were instilled into guinea pig gallbladders for 24 to 72 hours after cystic duct ligation. Water transport across gallbladder mucosa was measured. Gallbladder tissue was analyzed for mucus layer thickness, myeloperoxidase, prostaglandin E2 (PGE2) prostaglandin F-1 alpha (PGF-1 alpha), and interleukin-1. Luminal fluid was also examined for PGE2 and PGF-1 alpha. Values for each test were compared with saline controls by using Student's test (p < 0.05). RESULTS: Crystalline cholesterol, LPS, and lysolecithin caused significant reduction in mucus layer thickness, reversed water absorption to secretion across the gallbladder mucosa, caused significant increases in myeloperoxidase and interleukin-1 in gallbladder tissue, and caused significant increases in PGE2 and PGF-1 alpha in luminal fluid. These effects were generally dose- but not time-dependent. Polystyrene latex particles caused no difference in outcomes compared with saline controls. CONCLUSIONS: Crystalline cholesterol monohydrate has dose-dependent inflammatory effects in the guinea pig gallbladder in vivo that are not simply-due to mechanical irritation of the gallbladder wall by crystalline particles. Crystals in the gallbladder may have an etiologic role in cholecystitis.

Increased total and free ionized calcium in a canine model of pigment gallstones.

It has been postulated that precipitation of calcium from bile is important in the formation and growth of pigment gallstones, since they contain large amounts of calcium. Therefore we studied biliary total calcium [( Ca]) and free ionized calcium [( Ca++]) concentrations in 12 dogs before and after 6 weeks of a methionine-deficient, high-cholesterol diet. In all dogs pigment gallstones and sludge formed while the animals were on the diet. Although gallbladder function--as assessed by biliary pH, total bile salt, and bile electrolyte concentrations--was minimally altered by the diet, both [Ca] and [Ca++] increased significantly, from 10.16 +/- 0.19 to 13.16 +/- 0.57 mmol/L and 3.02 +/- 0.07 to 3.76 +/- 0.17 mmol/L, respectively. The observed increases in calcium concentrations, and specifically in [Ca++], early during stone formation in this model would increase the likelihood that bile would become saturated with at least one calcium salt and support the hypothesis that calcium is important in pigment gallstone formation.

Evaluating surgical competency with the American Board of Surgery In-Training Examination, skill testing, and intraoperative assessment.

BACKGROUND: Evaluation of surgical competency should include assessment of knowledge, technical skill, and judgment. The purpose of this study was to determine the relationship between the American Board of Surgery In-Training Examination (ABSITE), skill testing, and intraoperative assessment. METHODS: Postgraduate year 2 (PGY-2) and postgraduate year 3 (PGY-3) surgery residents (n = 33) were tested by means of (1) the ABSITE, (2) skill testing on a laparoscopic video-trainer, and (3) intra-operative global assessments during laparoscopic cholecystectomy. The Pearson correlation was used to determine the correlation between the ABSITE, skill testing, and intraoperative assessments. For the comparison of PGY-2 and PGY-3 resident performance, Wilcoxon rank sum tests were used. RESULTS: The ABSITE scores did not correlate with skill testing or intraoperative assessments (not significant). Skill testing correlated with the intraoperative composite score and with 4 of 8 operative performance criteria (P<.05). The ABSITE scores and skill testing were not different for PGY-2 and PGY-3 residents (not significant). Intraoperative assessments were better in 5 of 8 criteria and the composite score for PGY-3 versus PGY-2 residents (P<.05), which demonstrated construct validity. CONCLUSIONS: The ABSITE measures knowledge but does not correlate with technical skill or operative performance. Residency programs should use multiple assessment instruments to evaluate competency. There may be a role for both skill testing and intraoperative assessment in the evaluation of surgical competency.

Gangrenous cholecystitis: analysis of risk factors and experience with laparoscopic cholecystectomy.

BACKGROUND: Gangrenous cholecystitis occurs in up to 30% of patients admitted with acute cholecystitis. Factors predicting gangrenous disease in patients with acute cholecystitis remain poorly defined, making preoperative diagnosis difficult. Identification of these factors and early diagnosis of gangrenous cholecystitis will indicate more aggressive treatment, earlier operation, and a lower threshold for conversion of laparoscopic to open cholecystectomy. METHODS: We reviewed our experience with acute cholecystitis during the 2-year period of 1995 to 1996. Admitting history, physical examination, operative report, laboratory and radiology data, and pathology report were analyzed for each patient. Acute cholecystitis and its gangrenous complication were diagnosed by both gross and microscopic examination. RESULTS: One hundred fifty-four patients were admitted to the hospital with acute cholecystitis and underwent cholecystectomy; gallbladder gangrene was found in 27 (18%) of these patients. Four patients with gallbladder gangrene underwent open cholecystectomy and 23 patients underwent laparoscopic cholecystectomy, of which 15 (65%) were completed laparoscopically and 8 (35%) had open conversion as a result of severe inflammation. Risk factors for gallbladder gangrene included male gender, age older than 50 years, history of cardiovascular disease, and leukocytosis greater than 17,000 white blood cells/mL. CONCLUSIONS: Older male patients (age older than 50 years) with history of cardiovascular disease, leukocytosis greater than 17,000 white blood cells/mL, and acute cholecystitis have increased risk of gallbladder gangrene and conversion of laparoscopic cholecystectomy to open cholecystectomy. Urgent laparoscopic cholecystectomy with low threshold for conversion to open cholecystectomy should be considered in these patients at high risk for gallbladder gangrene.

Calcium and calcium binding in human gallstone disease.

Precipitation of calcium salts from bile is important in pigment gallstone formation and may serve as a nidus for cholesterol precipitation. We compared gallbladder bile from patients with symptomatic gallstone disease (40 with cholesterol gallstones and 12 with pigment gallstones) with bile from 10 patients undergoing surgery for non-biliary tract disease. Bile from patients with gallstone disease was less concentrated, with decreased sodium, bile salt, and phospholipid concentrations, but elevated biliary calcium concentrations were not observed. The relationship between free ionized calcium and total calcium was similar in all groups, indicating no difference in calcium binding by gallstone-containing bile. We cannot exclude elevated biliary calcium level as a factor in gallstone pathogenesis, as it could be a transient event. The importance of calcium precipitation was supported by our finding that more than half of the samples were saturated or supersaturated with at least one calcium salt, calcium carbonate.

Percutaneous cholecystostomy in the diagnosis and treatment of acute cholecystitis in the high-risk patient.

We performed percutaneous cholecystostomy in 22 critically ill patients with suspected acute cholecystitis. This procedure accurately diagnosed acute cholecystitis in 17 of these 22 patients and excluded the diagnosis in the other 5 patients. Moreover, percutaneous cholecystostomy stabilized the conditions of 16 of the 17 patients with acute cholecystitis, allowing elective surgery in 8 patients and effectively treating 8 patients who never became surgical candidates. Percutaneous cholecystostomy and bile cultures are useful in the diagnosis and treatment of acute cholecystitis and should be performed in critically ill patients with clinical, laboratory, and radiologic evidence of acute cholecystitis and an excessive risk for cholecystectomy.

External duodenal fistula. Causes, complications, and treatment.

We reviewed records of 18 patients with external duodenal fistula. Fourteen patients developed duodenal fistulas following an operation, two following abdominal trauma, and two as a complication of other diseases. Copious drainage of intestinal juice from the abdomen was the most common presenting sign. Contrast fistulography, upper gastrointestinal tract roentgenography, and T-tube cholangiography were useful diagnostic studies. Nine patients were treated nonoperatively; nine patients required at least one operation. Complications occurred frequently; of special interest were three patients who developed postoperative acute cholecystitis. Six patients died (33% mortality). Factors associated with mortality were advanced age (greater than 65 years), uncontrolled infection and multiple organ failure, high-output fistula, malnutrition, delay in diagnosis (more than three days), and multiple reoperations to treat the fistula or complications. External duodenal fistula continues to be a life-threatening problem whether it is postoperative, posttraumatic, or secondary to a disease process.

Treatment of anastomotic leakage following low anterior colon resection.

Four hundred five consecutive cases of low anterior colon resection were studied to determine the best treatment of anastomotic leak. The triad of fever, leukocytosis, and pelvic pain was present in 15 of the 16 cases with leaks. Four (25%) of the 16 patients died. Eleven were managed by proximal decompression and drainage; four died (36%). Three patients underwent takedown of the anastomosis, end colostomy, and distal closure or exteriorization; none died. Neither of the two patients who had drainage alone died. Anastomotic leakage accounted for two thirds of the deaths in this series. Recognition of the clinical triad of fever, leukocytosis, and pelvic pain could lead to earlier diagnosis and improved outcome. Our data suggest that a procedure that includes takedown of the anastomosis, end colostomy, and closure of the rectum is the most efficacious treatment of anastomotic leakage after low anterior colon resection.

Reversal of pigment gallstone disease in a canine model.

Unlike dietary-induced cholesterol gallstones, which may disappear spontaneously when the lithogenic diet is withdrawn, little is known about the natural history of pigment gallstones. We examined whether pigment gallstone disease, which can be uniformly induced in the dog by six weeks of a methionine-deficient diet, can be reversed by return to normal diet. As previously reported, all dogs develop pigment gallstones as well as significant increases in biliary total calcium, free ionized calcium, and cholesterol concentrations after six weeks of a lithogenic diet. These changes are accompanied by a significant increase in the concentration of unconjugated bile salts in bile. In addition, histologic changes in the gallbladder wall occur that are consistent with a moderate degree of chronic cholecystitis. This study clearly demonstrates that return to a normal diet for six weeks allows bile composition to normalize, gallstones to disappear in 50% of dogs, and gallbladder histologic changes to return toward normal. Thus, it would appear that pigment gallstone disease in this model may be reversible, at least early during its course. Although the relevance of these findings to pigment gallstones in humans must be established, the potential for nonoperative treatment of pigment gallstones should not be discounted.

Laparoscopic inguinal hernia repair. A preliminary experience.

OBJECTIVE: To evaluate the safety and efficacy of laparoscopic inguinal hernia repair. DESIGN: Nonrandomized trial. SETTING: Veterans Affairs hospital and a large university hospital. PATIENTS: The study included 38 patients (36 male and two female) who had an acceptable risk for general anesthesia, presented electively, and gave informed consent; patients were excluded for whom general anesthesia had a high risk or who had incarcerated or strangulated hernias. INTERVENTION: Laparoscopic inguinal hernia repair was performed with general anesthesia through bilateral, lower-abdominal, 12-mm lateral rectus sheath ports with an umbilical 30 degrees viewing laparoscope. After the peritoneum was incised and flaps were raised, an onlay patch of polypropylene mesh, secured with staples, covered both indirect and direct hernia regions in each patient. Small hernia sacs were usually reduced or excised. RESULTS: From December 1991 through October 1992, 40 inguinal hernias were repaired; two patients had bilateral hernias. There were 22 indirect and 17 direct inguinal hernias and one femoral hernia. Nine of the hernias repaired were recurrent, and five were sliding hernias. Complications occurred in nine patients, but there were no recurrences during a median follow-up of 26 weeks. All but one patient resumed preoperative activities by 7 days after the operation. CONCLUSIONS: Laparoscopic inguinal hernia repair is an effective operation with low morbidity. Long-term follow-up is needed to determine the durability of the repair.

A foregut carcinoid tumor causing Zollinger-Ellison syndrome.

A patient had severe peptic ulcer disease complicated by gastric outlet obstruction and choledochoduodenal fistula. Serum gastrin levels were elevated preoperatively to 340 ng/L. A 1.5-cm histologically benign carcinoid tumor of the antrum of the stomach was found at surgery, and surgical resection of the tumor resulted in normalization of serum gastrin levels and amelioration of the peptic acid diathesis. The patient remains asymptomatic at one year. Immunohistochemical staining demonstrated that the carcinoid indeed contained gastrin along with chromogranin, cholecystokinin, and neuron-specific enolase. This is a case of Zollinger-Ellison syndrome caused by a benign foregut carcinoid (gastric carcinoid-gastrinoma).

Bilateral adrenal cortical adenomas in primary hyperaldosteronism.

Bilateral adrenal cortical adenomas in the presence of primary hyperaldosteronism is an extremely rare condition. We present a case of primary hyperaldosteronism in which a unilateral hypersecreting aldosterone-producing adenoma coexisted with a large, contralateral adrenal mass ultimately found to be consistent with cortical adenoma. Management consisted of total adrenalectomy and enucleation of adenoma from the opposite adrenal. The patient is normotensive 3 years after surgery. Enucleation as a successful approach to hyperfunctioning cortical adenomas is proposed.

Laparoscopic training on bench models: better and more cost effective than operating room experience?

BACKGROUND: Developing technical skill is essential to surgical training, but using the operating room for basic skill acquisition may be inefficient and expensive, especially for laparoscopic operations. This study determines if laparoscopic skills training using simulated tasks on a video-trainer improves the operative performance of surgery residents. STUDY DESIGN: Second- and third-year residents (n= 27) were prospectively randomized to receive formal laparoscopic skills training or to a control group. At baseline, residents had a validated global assessment of their ability to perform a laparoscopic cholecystectomy based on direct observation by three evaluators who were blinded to the residents' randomization status. Residents were also tested on five standardized video-trainer tasks. The training group practiced the video-trainer tasks as a group for 30 minutes daily for 10 days. The control group received no formal training. All residents repeated the video-trainer test and underwent a second global assessment by the same three blinded evaluators at the end of the 1-month rotation. Within-person improvement was determined; improvement was adjusted for differences in baseline performance. RESULTS: Five residents were unable to participate because of scheduling problems; 9 residents in the training group and 13 residents in the control group completed the study. Baseline laparoscopic experience, video-trainer scores, and global assessments were not significantly different between the two groups. The training group on average practiced the video-trainer tasks 138 times (range 94 to 171 times); the control group did not practice any task. The trained group achieved significantly greater adjusted improvement in video-trainer scores (five of five tasks) and global assessments (four of eight criteria) over the course of the four-week curriculum, compared with controls. CONCLUSIONS: Intense training improves video-eye-hand skills and translates into improved operative performance for junior surgery residents. Surgical curricula should contain laparoscopic skills training.

Inflammatory cytokines alter human gallbladder epithelial cell absorption/secretion.

Gallbladder inflammation is an early feature of gallstone formation in animal models. The inflammatory response is associated with increases in myeloperoxidase and interleukin (IL)-1 activities in the gallbladder wall. The present studies were designed to determine whether inflammatory cytokines directly affect gallbladder epithelial cell absorptive function. Studies were performed using cultured human gallbladder epithelial cells derived from a well-differentiated gallbladder carcinoma. Confluent monolayers were exposed to interleukin-1 (IL-1alpha), IL-1alpha plus its specific receptor inhibitor IL-1ra, tumor necrosis factor (TNF-alpha), lipopolysaccharide, or prostaglandin E2. Unidirectional sodium and chloride fluxes were measured and used to calculate net ion fluxes. Compared to control monolayers, lipopolysaccharide, prostaglandin E2, IL-1alpha, and TNF-alpha decreased mucosal-to-serosal and net sodium and chloride fluxes and increased serosal-to-mucosal movement of sodium and unmeasured ions. The effects of IL-1alpha were completely inhibited by its specific receptor antagonist IL-1ra. Similar to the proinflammatory agents lipopolysaccharide and prostaglandin E2, the inflammatory cytokines IL-1alpha and TNF-alpha directly affected gallbladder epithelial cell absorptive function. Because normal gallbladder absorptive function is protective against gallstone formation, alterations in absorptive function due to inflammation in the gallbladder wall may play a role in gallstone pathogenesis.

Development of an in vivo tumor-mimic model for learning radiofrequency ablation.

Radiofrequency ablation requires accurate probe placement using ultrasound guidance. The purpose of this study was to develop an in vivo tumor-mimic model for learning open and laparoscopic radiofrequency ablation. Tumor-mimics were created in ex vivo porcine livers by injecting a mixture of 3% agarose, 3% cellulose, 7% glycerol, and 0.05% methylene blue, which formed 1 cm hyperechoic, discrete lesions on ultrasound. Open and laparoscopic (using a box-trainer) ablation techniques were practiced. In vivo experiments were then conducted in 10 pigs. Three tumor-mimics were created in each animal using a laparoscopic approach. Lesions were characterized sonographically, ablated using an open (n = 5) or laparoscopic (n = 5) approach, and examined pathologically. An ablation in normal liver tissue was performed as a control. Tissue impedance was recorded. Target creation took 81 minutes per animal and 96% of injections were successful. Tissue impedance (48.8 +/- 5.8 vs. 49.6 +/- 5.4) and ablation size (25.1 +/- 3.4 vs. 24.3 +/- 5.1) were not significantly different for controls (n = 8) and tumor-mimics (n = 26), respectively. One animal died of a pulmonary embolism following injection of agarose into a hepatic vein. The agarose-based tissue-mimic creates realistic sonographic targets for learning ultrasound-guided open and laparoscopic radiofrequency ablation in an in vivo model.

Inflammatory properties of bile from dogs with pigment gallstones.

BACKGROUND: Gallbladder inflammation and mucus hypersecretion are prominent features of cholesterol and pigment gallstones in humans and animals. The factors leading to inflammation and mucus hypersecretion are poorly understood. These studies examine the inflammatory potential of bile from dogs with pigment gallstones. METHODS: Dogs fed a methionine-deficient diet that produces pigment gallstones by 6 weeks were compared to normal dogs. Mucus layer thickness, myeloperoxidase activity, and interleukin-1-like activities were measured in canine gallbladder. The inflammatory potential of canine bile was determined by measuring mucus layer thickness, sodium absorption, myeloperoxidase activity and interleukin-1-like activity in guinea pig gallbladders exposed to normal and lithogenic canine bile for 4 hours. RESULTS: Mean mucus layer thickness, myeloperoxidase, and interleukin-1 activity were significantly greater in canine gallbladders containing pigment gallstones. Bile from dogs with pigment gallstones markedly increased mucus layer thickness, myeloperoxidase activity, and interleukin-1 activity and decreased sodium absorption in normal guinea pig gallbladder. These effects were not eliminated by centrifuging bile to remove crystals and gallstones. CONCLUSIONS: Canine bile from dogs with pigment gallstones contains soluble factors capable of causing inflammation in the gallbladder wall.

Selection of patients for gallstone lithotripsy.

Although alternatives to cholecystectomy are now available to treat patients with gallstones, the primary treatment of gallstone disease remains surgical. It is therefore important to distinguish those patients who would benefit most from nonoperative therapy of gallstones from those who require cholecystectomy while ensuring patient safety. Current criteria for selection of patients for extracorporeal shock-wave lithotripsy (ESWL) are presented herein. In addition, preliminary results from recent in vitro experiments with human gallstones obtained at cholecystectomy are outlined. The current criteria for selection of patients for treatment with ESWL are similar to those used in the initial German experience. They appear to ensure patient safety, but the actual conditions that predict successful treatment of gallstones by ESWL are not yet known, since the clinical and in vitro studies which will define the patient and stone characteristics that predict a successful treatment outcome are still in progress. Thus, current criteria should be considered guidelines for treatment which will most certainly be modified as experience is gained with ESWL.