Regulation of cholesterol metabolism in the dog. I. Effects of complete bile diversion and of cholesterol feeding on absorption, synthesis, accumulation, and excretion rates measured during life.

Six adult pedigreed dogs were studied as long as 3 yr in order to determine the effects of cholesterol feeding and of bile diversion on absorption, synthesis, and storage of cholesterol. These measurements were based on cholesterol balance and isotope kinetic studies. In the six dogs fed a "cholesterol-free" diet with their enterohepatic circulations undisturbed, the rate of cholesterol synthesis ranged from 225 to 508 mg/day (mean 325 mg/day or 12.4 mg/kg/day). In two dogs studied subsequently on cholesterol-containing diets, absorption of cholesterol averaged 81% (range 71-94%) on a dietary intake of 0.5 g/day; on high cholesterol intakes (2.7-3.0 g/day) the rate of absorption dropped to 43-51% of daily intake, but the absolute amounts absorbed were increased. Feeding of cholesterol resulted in acceleration of bile acid formation and excretion, as well as nearly total inhibition of cholesterol synthesis. These two compensatory mechanisms were sufficient to maintain zero balance of cholesterol in the face of a high cholesterol intake. Plasma cholesterol concentrations in the two dogs increased by 37 and 44%. In two other dogs bile was completely diverted into the urinary system for nearly 2 yr. When these dogs were studied on a cholesterol-free diet, the sum of acidic steroids excreted daily in urine plus neutral steroids excreted in feces was seven times as high as before the operation. Since these massive excretory losses could not have been sustained by mobilization from tissue cholesterol pools, and since the rate of disappearance of [4-(14)C]cholesterol from the plasma after single intravenous injection was greatly increased after complete biliary diversion, total daily synthesis of cholesterol must have been greatly accelerated, for synthesis was totally unsuppressed. The increased output of fecal neutral steroids could be the result of transfer of plasma cholesterol across the gut wall or due to increased synthesis in the gut. Plasma cholesterol levels were reduced in these two dogs by 20 and 27%, and triglycerides decreased by 36 and 43%. Accumulation of cholesterol in body pools in the cholesterol-fed dogs appeared to have been prevented, according to antemortem measurements: increased absorption of dietary cholesterol was exactly balanced by suppression of cholesterol synthesis and enhanced bile acid excretion. In the bile-shunted animals, depletion of tissue stores of cholesterol could not be predicted by antemortem measurements.

Regulation of cholesterol metabolism in the dog. II. Effects of complete bile diversion and of cholesterol feeding on pool sizes of tissue cholesterol measured at autopsy.

In six adult pedigreed dogs the effects of high-cholesterol diets or bile diversion on the sizes of body cholesterol pools were studied at autopsy. Total body cholesterol was determined by measuring the cholesterol content of discrete organs and of the eviscerated carcass: neither cholesterol feeding nor bile diversion had altered total body cholesterol or the cholesterol content of individual organs and tissues. These results validated the conclusion based on sterol balance data obtained during life, that high-cholesterol feeding did not lead to substantial expansion of tissue cholesterol pools. THE TOTAL AMOUNT OF EXCHANGEABLE CHOLESTEROL IN THE ANIMALS WITH AN INTACT ENTEROHEPATIC CIRCULATION, WHEN ESTIMATED FROM ISOTOPIC DATA, WAS ESSENTIALLY THE SAME AS THAT MEASURED CHEMICALLY: this indicated that there was little or no nonexchangeable cholesterol in these dogs, except in skin and nervous tissue, regardless of the cholesterol content of the diet. This correspondence of estimates was not obtained in the bile-diverted dogs: we propose that the defect in the isotopic estimates was due to the accelerated rate of cholesterol synthesis in these animals. Gross and microscopic morphology of all organs and tissues was examined. Abnormal findings were limited to the biliary tract and the urinary collecting system of the two bile-diverted dogs: multiple bilirubinate gallstones were found, and mild pyelitis and ureteritis were present on the side of the bilio-renal shunt, but the urinary bladder was normal. Histologic evidence of moderate degree of cholangitis was found in one of the two bile-shunted dogs, but in neither dog was there evidence of impedance of bile flow.

Recurrent Cushing's syndrome due to recurrent adrenocortical tumor--fragmentation or tumor in ectopic adrenal tissue?

A 33-yr-old woman was found to have Cushing's syndrome due to a left adrenal cortical tumor. The tumor and the surrounding adrenal gland were removed intact and in toto. Four years later, she noticed recurrent symptoms of Cushing's syndrome, and 6 yr postoperatively, an adrenal tumor was demonstrable on computed tomography. Fourteen years after the initial procedure, a left adrenal tumor, presumably arising in ectopic adrenal tissue, was removed with relief of her symptoms of Cushing's syndrome. The site and functional capacity of ectopic adrenal tissues are reviewed.

Heart transplantation for end-stage cardiomyopathy caused by an occult pheochromocytoma.

Dilated cardiomyopathy has been found in patients with pheochromocytoma. The cardiomyopathy and resultant congestive heart failure can be progressive and fatal, or reversible, if the source of the excess catecholamines is removed. Histologic and autopsy studies revealed a characteristic focal myocarditis and contraction band necrosis, indicating that the circulating catecholamine excess secreted by the pheochromocytoma is the cause of the cardiomyopathy.

Pheochromocytoma: inherited associations, bilaterality, and cortex preservation.

BACKGROUND: Hereditary pheochromocytoma (HP) is characterized by early onset, bilateral adrenal involvement, low malignancy rate, and genetic linkage with certain familial syndromes. This retrospective review is intended to show the high yield of surveillance, predictable bilaterality, and the challenge of cortex-sparing adrenalectomy. METHODS: From 1964 to 1999, 32 patients with HP were treated at a single institution and followed for a mean of 7 years. There were 15 cases of multiple endocrine neoplasia type 2A (MEN 2A), 12 cases of von Hippel-Lindau (VHL) disease, 3 cases of von Recklinghausen's disease (VRD), and 2 cases of familial pheochromocytoma. Twenty-four of 32 patients underwent bilateral adrenalectomy (9 metachronous). Subtotal resection with orthotopic cortex preservation was performed in 5 patients, and heterotopic autografting was performed in 14 patients. RESULTS: Pheochromocytoma was the first manifestation in 50% of patients with VHL disease and in 27% of patients with MEN 2A. Surveillance uncovered medullary thyroid cancer in 5 of 15 patients with MEN 2A and hemangioblastomas, renal cell carcinoma, and islet cell tumors in 7 of 15 patients with VHL disease and VRD. HP was bilateral in 24 of 32 patients (14/15 in patients with MEN 2A, 7/12 in patients with VHL disease, 2/3 in patients with VRD, and 1/2 in patients with familial pheochromocytoma). In 9 cases of metachronous adrenalectomy, the mean interval was 67 months (range, 9-156 months). Three of 5 patients who underwent orthotopic preservation of the adrenal cortex experienced recurrence compared with 0 of 14 patients with heterotopic autotransplantation of cortical tissue. CONCLUSIONS: Pheochromocytoma frequently heralds coexisting silent VHL disease or MEN-2, mandating surveillance for inherited associations. The long interval of metachronous pheochromocytoma argues against prophylactic removal of the contralateral "normal" adrenal gland. Total adrenalectomy and heterotopic autotransplantation of medulla-free cortex may diminish the need for lifelong steroid substitution and eliminates recurrence.

Diagnostic and interventional laparoscopy and intraoperative ultrasonography in the management of pancreatic disease.

The laparoscopic management of pancreatic disorders has evolved dramatically from its inception in 1911 and its rediscovery in the 1970s. Although investigators once proclaimed that "it seems unlikely that laparoscopy will have any more than an extremely limited use in the investigation of pancreatic disorders," laparoscopy and LUS now have a well-recognized role in the staging of pancreatic cancer and an increasing part in the management of benign pancreatic disease at many institutions. Although the appropriate role of LS and LUS is debatable, the development and refinement of laparoscopic techniques and instrumentation and the improvement of noninvasive diagnostic modalities will provide new data, increase the rate of resection at laparotomy, and allow surgeons to treat a broader range of pancreatic disease by minimally invasive methods. The value of LS and LUS for benign and malignant pancreatic disorders has been clearly demonstrated, but the inevitable issues of hospital resource, operative expertise, and surgical philosophy will ultimately determine the role of laparoscopy and LUS in clinical practice.

Functioning pancreatic acinar cell carcinoma: immunohistochemical and ultrastructural analyses.

Acinar cell carcinoma (ACC) of the pancreas is a rare malignancy accounting for < 1% of pancreatic neoplasms. We report the clinical and biological characteristics of this carcinoma from two cases that were of interest because of their similar presentation: extensive subcutaneous fat necroses from excessive lipase production by these tumors. Immunohistochemical and ultrastructural analyses of both tumors were consistent with an acinar cell line origin. Recognition of the association between subcutaneous panniculitis and pancreatic neoplasm may prevent long delays in the diagnosis and treatment of this malignancy.

S100 protein-positive sustentacular cells in malignant and locally aggressive adrenal pheochromocytomas.

The absence or presence of S100-positive sustentacular cells has been previously shown to be correlated with benign and malignant pheochromocytomas and paragangliomas. We evaluated a total of 17 malignant and recurrent or locally aggressive adrenal pheochromocytomas for their quantity of sustentacular cells. An absence of sustentacular cells was demonstrated in the majority of malignant cases, while the locally aggressive or recurrent group usually contained an abundance of these cells. However, in one malignant case a constant moderate number of sustentacular cells in the primary site and in two sequential metastases was found. We conclude that the absence of sustentacular cells in pheochromocytomas may indicate a lesion with a greater potential for metastasis and that sustentacular cells, when they are present in a malignant pheochromocytoma, are an integral part of the tumor.

Morphometric analysis of benign and malignant adrenal pheochromocytomas.

At present, there are no reliable histologic features that can predict malignancy in adrenal pheochromocytomas other than the documentation of metastases. With the use of computerized interactive morphometry, our aim was to assess nuclei from tissue sections of confirmed cases of benign and malignant pheochromocytomas to determine whether consistent quantitative differences existed between the two. Eight benign cases with at least a 5-year follow-up and nine malignant cases with documented metastases were evaluated. Size distribution plots of the maximum nuclear cord length and of the nuclear area showed a narrow peak for the malignant cases, whereas benign cases showed a right-shifted curve with a wider peak. We concluded that nuclear morphometric analysis of benign and malignant pheochromocytomas yields two distinctive patterns and may be of utility in the assessment of future cases.

Lipid degeneration in a pheochromocytoma histologically mimicking an adrenal cortical tumor.

A recurrent adrenal pheochromocytoma is reported in an 18-year-old woman with a family history of multiple endocrine neoplasia type IIA. The tumor was noteworthy for the presence of numerous fine intracytoplasmic lipid droplets confirmed by fat stain. Immunohistochemical studies revealed cytoplasmic positivity for chromogranin and neuron-specific enolase typical of pheochromocytoma. Electron microscopy demonstrated dense-core neurosecretory granules, in addition to the cytoplasmic lipid vacuoles. The presence of lipid within an adrenal pheochromocytoma is rare and, to our knowledge, has been documented in only one previous case report in the literature.

Transient false-positive hepatobiliary scan associated with ceftriaxone therapy.

Drug related false-positive hepatobiliary imaging is uncommon. The authors present a case of a 54-year-old woman who was treated with intravenous ceftriaxone for bacterial meningitis. Symptoms of acute cholecystitis subsequently developed and a sonogram revealed a gallstone. A Tc-99m DISIDA hepatobiliary study was positive for cystic duct obstruction. After discontinuation of ceftriaxone, the patient's clinical condition improved and, 2 weeks later, a repeat hepatobiliary scan was normal. High doses of ceftriaxone and prolonged administration may lead to formation of pseudocholelithiasis and signs of acute cholecystitis. Although this condition is usually benign and reversible, discontinuation of the drug is warranted when symptoms of acute cholecystitis are accompanied by a positive hepatobiliary scan.

Monooctanoin dissolution of retained biliary stones in high risk patients.

Monooctanoin, a cholesterol solvent, was infused into the biliary tracts of six high risk patients, in an attempt to dissolve retained stones. The infusion rate was constant, 5-10 ml/h. The mean age of the patients was 76 years. Associated medical conditions were primarily cardiac in nature. Duration of infusion averaged 6 days. In two patients, the stones were completely dissolved. One patient was reoperated despite the stones appearing smaller after 6 days of infusion. At surgery, no stones were found. Two patients in whom dissolution was unsuccessful underwent reoperation. In both, retrieved stones were composed of less than 5% cholesterol. Five of the six patients experienced at least one episode of mild abdominal pain and vomiting. None developed cholangitis, pancreatitis, or significant biochemical abnormalities. Two of the three who underwent reoperation tolerated it without difficulty. While mechanical extraction, when feasible, is still the treatment of choice for retained biliary stones, chemical dissolution should be attempted before undertaking reoperation.

Composition of biliary lipids and kinetics of bile acids after cholecystectomy in man.

Postcholecystectomy biliary lipid composition and bile acid kinetics were studied in 24 women and 4 men. Hepatic bile was collected periodically for as long as 4 months without interrupting the enterohepatic circulation and without infecting the biliary system. In 23 patients with cholesterol gallstones, fasting biliary cholesterol made up 10.2% of total lipids in the steady state; in 5 patients with bilirubinate stones, saturation of fasting hepatic bile with cholesterol was lower (8.7% of total lipids). The percentage of deoxycholic acid after cholecystectomy was not higher than that of seven healthy, noncholecystectomized controls. Postcholecystectomy studies of diurnal variation of biliary lipids (7 patients) showed that postprandial hepatic bile had a significantly lower cholesterol saturation than fasting bile. Pool sizes of cholic and chenodeoxycholic acids were low (average 0.4 g/70 kg, each); total synthesis for both bile acids was normal (average 460 mg/day/70 kg), but fractional turnover rates of the two primary bile acids increased after cholecystectomy, probably due to more frequent recycling of the small bile acid pool.

Effects of clofibrate and of an estrogen-progestin combination on fasting biliary lipids and cholic acid kinetics in man.

PIP: The effects of clofibrate and of the combined administration of estrogen plus progestin on the concentration of fasting hepatic bile lipids and on pool sizes and turnover rates of cholic acid were studied. 8 women with normal serum lipids, 1 male with beta-lipoproteinemia, and 1 female with pre-beta-lipoproteinemia were studied after recovery from cholecystecomy. Hepatic bile was collected periodically as long as 4 1/2 months through a closed indwelling cystic duct catheter. Clofibrate lowered serum cholesterol by 15-25% in 3 of the normolipidemic patients. In a patient with hypertriglyceridemia, serum cholesterol fell from 306 to 171 and triglycerides from 520 to 179. Estrogen plus progestin produced a 7% rise in serum cholesterol in 1 patient. Biliary cholesterol increased during clofibrate (7 patients) and hormone (3 patients) administration while bile acid levels were decreased. Cholic acid kinetics in 3 patients showed decreased synthesis rates and pool sizes with both drugs. It is suggested that increased cholesterol saturation of bile during administration of a natural estrogen with progestin to cholecystectomized patients relects an increased propensity to cholesterol formation.^ieng

Tritiated bile acids: problems and recommendations.

Kinetic studies of cholic and chenodeoxycholic acids were carried out in three patients by simultaneous intravenous administration of appropriate pairs of (3)H- and (14)C-labeled compounds. The results obtained indicated two sources of error: chemical impurity and loss of tritium by biological exchange. Precautions are listed for use of tritiated bile acids in studies of pool sizes and turnover rates.

The fate of the dropped gallstones during laparoscopic cholecystectomy.

Stones can be spilled from the gallbladder during laparoscopic cholecystectomy. These stones can be left in the peritoneal cavity or trapped at the trocar site. The potential late sequel and associated morbidity are not well documented. We reviewed the records of four patients who underwent laparoscopic cholecystectomy at Mount Sinai Medical Center in New York City who suffered from late complications attributed to gallstones left in the peritoneal cavity or abdominal wall. Four patients presented 1-14 months after laparoscopic cholecystectomy with intraabdominal and abdominal wall abscesses. The spillage of gallstones was noticed during the initial operation only in one of the patients. Three patients required laparotomy and open drainage of intraabdominal abscesses with drainage of pus and gallstones after failed attempts at percutaneous drainage. Two patients underwent local exploration of an abdominal wall abscess containing stones. Stones left in the abdominal cavity or trapped in trocar sites after laparoscopic cholecystectomy can cause serious late complications requiring repeated surgical interventions. Every effort should be made in order to avoid spillage of stones during dissection of the gallbladder and cystic duct and during retrieval of the gallbladder through the abdominal wall.

Fecal steroid excretion and degradation and breast cancer stage.

Evaluation of excretion and degradation of fecal steroids in 74 women with breast cancer in relation to stage, tumor size, and histopathologic nodal status revealed significant differences in relation to stage of disease and tumor size. The level of total fecal steroids (mean +/- SD in mg/g dry wt) in patients with Stage I disease was 40 + 20, Stage II = 56 +/- 32, and Stage III = 75 +/- 57 (P = 0.006). Secondary fecal steroids in women with Stage I disease were 26 +/- 16, Stage II = 40 +/- 27, and Stage III = 57 +/- 34 (P = 0.003). Fecal steroid excretion and degradation was significantly higher in women with larger tumors, whereas nodal status did not contribute to observed differences indicating that dissemination of disease did not influence the results. These differences were noted to be independent of obesity since similar patterns of fecal steroid excretion were noted within the subgroups of both lean and obese women. Increased levels of total fecal steroids and secondary compounds apparently contribute to tumor promotion and may reflect a potential for excess estrogen synthesis since intestinal bacteria have the ability to synthesize estradiol, estrone, and 3,17-methoxyestradiol from secondary steroids present in the colon.

Prevention of induced atherosclerosis by diversion of bile or blockade of intestinal lymphatics in dogs.

The prevention of induced hypercholesterolemia and atherosclerosis was studied by means of intestinal lymphatic blockade and of bile diversion in the dog. Hypercholesterolemia and atherosclerosis were produced by high cholesterol feeding after induction of hypothyroidism with radio-iodine plus thiouracil. Complete diversion of bile, by shunting all bile into the urinary bladder, effectively prevented hypercholesterolemia and atherosclerosis; in contrast, blockade of the intestinal lymphatics failed to prevent the consequences of the atherogenic regimen, because of the development of collateral lymphatic channels.