C. Michael Johnson

Splanchnic lipolysis in human obesity.

Elevated FFA concentrations have been shown to reproduce some of the metabolic abnormalities of obesity. It has been hypothesized that visceral adipose tissue lipolysis releases excess FFAs into the portal vein, exposing the liver to higher FFA concentrations. We used isotope dilution/hepatic vein catheterization techniques to examine whether intra-abdominal fat contributes a greater portion of hepatic FFA delivery in visceral obesity. Obese women (n = 24) and men (n = 20) with a range of obesity phenotypes, taken together with healthy, lean women (n = 12) and men (n = 12), were studied. Systemic, splanchnic, and leg FFA kinetics were measured. The results showed that plasma FFA concentrations were approximately 20% greater in obese men and obese women. The contribution of splanchnic lipolysis to hepatic FFA delivery ranged from less than 10% to almost 50% and increased as a function of visceral fat in women (r = 0.49, P = 0.002) and in men (r = 0.52, P = 0.002); the slope of the relationship was greater in women than in men (P < 0.05). Leg and splanchnic tissues contributed a greater portion of systemic FFA release in obese men and women than in lean men and women. We conclude that the contribution of visceral adipose tissue lipolysis to hepatic FFA delivery increases with increasing visceral fat in humans and that this effect is greater in women than in men.

The Management of Patients with Advanced Carcinoid Tumors and Islet Cell Carcinomas

Among the rarest of cancers, the gastrointestinal neuroendocrine tumors (islet cell carcinomas and carcinoid tumors) present difficult and complex challenges for individual patient management. When the tumors metastasize, patients have a variety of clinical presentations including manifestations of tumor bulk and bizarre syndromes resulting from massive hormone production. Table 4. SI Units When physicians analyze therapeutic options for patients with metastatic carcinoid tumors or islet cell carcinomas, they should consider the course of the patients malignant disease, the distribution of metastasis, the severity of clinical manifestations, and the relative contributions of the hormonal syndromes and tumor bulk to symptoms and disability. The oncologist must be conservative, because these diseases frequently run an indolent course, allowing years of comfortable life with no treatment whatsoever. However, aggressive approaches may be justified when the patient develops disabling symptoms because tumor debulking or correction of mechanical problems may sometimes provide the patient with additional years of comfortable life. If the patient has a clinically dominant hormonal syndrome and has no imminent threat from tumor bulk, it is frequently possible to produce substantial palliation with minimal therapeutic risk. In earlier years, only patients with gastrinoma could be helped in this manner by the use of histamine-2 blockers (for example, adequate doses of cimetidine or ranitidine or, more recently, omeprazole [Prilosec, Merck and Company, West Point, Pennsylvania]). The development and clinical application of an analog of somatostatin (octreotide; Sandostatin, Sandoz Pharmaceuticals, East Hanover, New Jersey) has provided a novel and frequently highly effective tool for control of almost all the endocrine syndromes. Striking decreases in hormonal levels and substantial or complete relief from symptoms can be achieved in approximately 80% of patients [1, 2]. Although octreotide usually produces only minimal immediate side effects, gallstones are a frequent long-term complication. However, octreotide therapy is cumbersome to the patient and is costly. Further, most patients become resistant to this therapy; for patients with carcinoid tumor, the median interval is about 1 year and for patients with islet cell carcinomas, only a few months. For these reasons, octreotide therapy for the carcinoid syndrome should be reserved for patients with severe flushing or diarrhea. In those with islet cell carcinomas, it should be used primarily to restore the patient to a better general and nutritional status so that more aggressive and definitive therapy can be undertaken with an acceptable risk. Regression rates after systemic chemotherapy or immunotherapy (using either single drugs or drug combinations) for metastatic carcinoid tumors and islet cell carcinomas have been variable, as is typical for solid tumors [3]. For carcinoid tumors, regression rates (even with our most effective regimens) seldom exceed 20%, and the discouragingly short duration of these responses hardly justifies the risks and side effects of treatment. For this reason, we urge that systemic therapy for carcinoid tumors be carried out in a research setting. For islet cell carcinoma, however, treatment may be of true clinical value. Streptozocin (Zanosar, The Upjohn Company, Kalamazoo, Michigan) seems to have specific cytotoxicity for the islet cell carcinoma and produces credible tumor regressions in about 30% of patients. Because of its minimal hematologic toxicity, it is useful in drug combinations with chemotherapeutic agents that are dose limited by leukopenia and thrombocytopenia. In a randomized trial, fluorouracil plus streptozocin was found to produce a 45% regression rate and seemed to improve survival when compared with streptozocin alone [4]. In a recent randomized trial, the combination of doxorubicin and streptozocin increased the regression rate to 69% and produced a statistically significant increase in survival [5]. However, fewer than one third of patients have a substantive and prolonged response to chemotherapy, and it produces considerable toxicity. A special consideration in managing these patients is the usually dominant involvement of the liver in the metastatic process. For selected patients, the surgeon can make a major and usually long-lasting contribution by resection of large solitary tumor masses or well-localized clusters of metastatic lesions [6]. With modern surgical technology, operative morbidity and mortality have been reduced to acceptable levels. Among 40 such patients reported by McEntee and colleagues [6], only a single postoperative death occurred. Usually, however, the diffuse nature of hepatic metastasis precludes effective surgical debulking. Therefore, hepatic artery infusion of various drugs has been attempted but with little documented evidence of success. Occlusion of hepatic arterial flow is attractive, because metastatic tumor neovascularity and oxygenation derive almost entirely from the hepatic artery. In contrast, hepatocytes are resilient, and viability may be maintained through the portal vein until rearterialization occurs. Although many researchers have shown that hepatic artery occlusion effectively shrinks primary or metastatic cancer in the liver, for the more common and more aggressive malignant diseases, tumor regrowth occurs so quickly that any net gain is difficult to discern. Because carcinoid tumors and islet cell carcinomas usually grow slowly, lasting benefit may be possible using hepatic artery occlusion. This review documents our experience with hepatic arterial occlusion, by either surgical ligation or embolization, in selected patients with neuroendocrine tumors and hepatic-dominant metastatic disease. Although frequent and substantial tumor regressions were produced, the duration of these regressions, even with these indolent neoplasms, was discouragingly short. We therefore developed and tested a regimen of sequential hepatic arterial occlusion and chemotherapy with the hope that regressions could be enhanced and prolonged. For chemotherapy, we elected to give each of the drugs that have been most active for these tumors when used alone (that is, fluorouracil, streptozocin, doxorubicin, and dacarbazine [DTIC]). Methods Patient Selection All patients selected for study had histologically confirmed carcinoid tumor or islet cell carcinoma with metastasis clinically limited to or dominant in the liver. They were ambulatory and maintaining a reasonable state of oral nutrition (at least 1200 calories daily). One or more measurable parameters of malignant disease were required to serve as objective indicators of response to therapy. For liver metastasis, this required clearly demarcated lesions on liver imaging that measured at least 5 cm in greatest diameter using radioisotope scanning or at least 3 cm in diameter using computed tomography or magnetic resonance imaging. Alternatively, if the patient had malignant hepatomegaly with a distinct liver edge extended at least 5 cm below the xiphoid or costal margins on quiet respiration, this was also used as a marker for response to therapy. In the absence of measurable liver involvement, hormonal assays could be used alone as markers for response to therapy, if they were greater than twice the upper limit of normal. Contraindications to study entry were a total serum bilirubin level more than 51.3 mol/L (3 mg/dL), previous radiation therapy to the liver or hepatic arterial chemotherapy, and the standard contraindications for each of the involved cytotoxic drugs. In practice, protocol entry was limited to those patients who, in the judgment of the physician, had clinically significant symptoms related to tumor bulk or to the endocrine syndrome or had extensive metastasis associated with abnormal test results for liver function. Treatment Hepatic artery occlusion was done by surgical ligation in those patients who had other specific indications for abdominal surgery (for example, an obstructing carcinoid tumor of the small bowel) or for those patients in whom catheterization and embolization were not considered to be technically feasible. For all other patients, occlusion was done by catheterization and embolization. Before hepatic artery occlusion by either method, the anatomy of the hepatic vasculature was determined by angiography. If any evidence of portal vein occlusion or compromise of portal vein flow was noted, occlusion was not done. In patients having operative tumor devascularization, the hepatic artery was approached for ligation through the gastrohepatic ligament of the lesser omentum. The primary right and left hepatic arteries were ligated and divided individually distal to the gastroduodenal artery. Dearterialization was completed by division of the entire gastrohepatic omentum from the diaphragm to the bile duct. Any accessory or replaced hepatic arteries were also identified, ligated, and divided; lymphoareolar tissue in the hepatoduodenal ligament was also divided. Cholecystectomy was done to avoid gallbladder ischemia. For occlusion by embolization, the hepatic artery was selectively catheterized with injection of embolic material, usually gel foam or polyvinyl alcohol or both. Because of the technical difficulty encountered in the procedure, the pretreatment impairment of liver function, and the total mass and distribution of hepatic metastasis, eight patients had embolization done at two or three sittings separated by 3 to 4 work-week intervals. After hepatic artery occlusion, the patient was observed in the hospital for a minimum of 5 days to monitor complications. In some instances, prophylactic antibiotics were used. The patient was released from hospital when there was no clinical evidence of complications, definite recovery of abnormal test results for liver function, and reduction of fever. Sequential chemother

Contribution of leg and splanchnic free fatty acid (FFA) kinetics to postabsorptive FFA flux in men and women.

We have previously shown that upper-body adipose tissue is more lipolytically active than lower-body adipose tissue in lean and obese women. The present studies were conducted to determine whether these regional differences are also present in men. Twenty-five lean, healthy men and 24 lean, healthy women underwent measures of body composition, postabsorptive systemic free fatty acid (FFA) flux, and leg and splanchnic FFA uptake and release. Upper-body adipose tissue was more lipolytically active than lower-body adipose tissue in both men (53.4 +/- 32.2 v 26.6 +/- 12.9 micromol x kg fat(-1) x min(-1), P < .001, respectively) and women (41.2 +/- 22.3 v 18.4 +/- 8.2 micromol x kg fat(-1) x min(-1), P < .001, respectively). The correlations between leg FFA release and systemic FFA flux were modest in women and men (r = .38, P = .07 and r = .56, P = .003, respectively) as were the correlations between splanchnic FFA release and systemic FFA flux (r = .41, P = .06 and r = .40, P = .07, respectively). No effect of gender on the relationship between leg or splanchnic FFA release and systemic FFA flux was detected. In summary, upper-body FFA release is greater than lower-body FFA release in both men and women, and the relationship between leg or splanchnic FFA release and systemic FFA release is weak and similar in men and women. These findings suggest that regional differences in postabsorptive FFA kinetics are unlikely to be responsible for differences in regional fat distribution.

Percutaneous Transluminal Angioplasty in the Lower Extremities: A 5-Year Experience

From January 1979 to March 1984, percutaneous transluminal angioplasty (PTA) was used to treat 148 limbs of 135 Mayo Clinic patients with occlusive arterial disease of the lower extremities. The procedure was technically successful in more than 95% of the attempts. The outcome was clinical improvement in 89 limbs and no improvement in 40 limbs; in 19 limbs, PTA was technically successful but the patient was dismissed from the hospital and lost to follow-up before the extent of improvement could be determined. Mean ankle/brachial pressure indices increased after PTA in those with clinical improvement but not in those without improvement. Clinical improvement was less likely to follow PTA in patients with advanced age, diabetes, severe initial symptoms, low ankle/brachial indices, or distal occlusive disease. In patients with improvement after PTA, the mean follow-up period was 33 months; during that time, failure (defined as recurrence of the original symptoms or the need for repeat PTA or operation) occurred at a rate of 6.4% per year. Serious complications occurred after three procedures (2.0%). We conclude that PTA is technically feasible and generally safe for many patients with occlusive arterial disease of the lower limbs.

Splanchnic Spillover of Extracellular Lipase–Generated Fatty Acids in Overweight and Obese Humans

OBJECTIVE—Triglyceride-rich lipoproteins, primarily chylomicrons, can contribute to plasma free fatty acid (FFA) concentrations via spillover of fatty acids during intravascular hydrolysis into the venous effluent of some tissues. The present study was undertaken to determine whether spillover occurs in the splanchnic bed of humans. RESEARCH DESIGN AND METHODS—Arterial and hepatic venous blood was sampled in postabsorptive (n = 6; study A) and postprandial (n = 5; study B) obese humans during infusion of carbon-labeled (14C or 13C) oleate and 3H triolein, the latter incorporated into a lipid emulsion as a surrogate for chylomicrons. Spillover was determined by measuring production of 3H oleate. RESULTS—Splanchnic spillover was higher than nonsplanchnic systemic spillover in both study A (60 ± 7 vs. 24 ± 6%; P < 0.01) and study B (54 ± 3 vs. 16 ± 5%; P < 0.005). Because portal vein sampling is not feasible in humans, assumptions regarding actual spillover in nonhepatic splanchnic tissues were required for the spillover calculation. A mathematical model was developed and demonstrated that nonhepatic splanchnic spillover rates in study A and study B of 69 and 80%, respectively, provided the best fit with the data. There was preferential splanchnic uptake of triglyceride fatty acids compared with FFAs in study B (fractional extraction 61 ± 3 vs. 33 ± 2%; P < 0.005). CONCLUSIONS—These data confirm previous studies indicating that the transport of FFAs and triglyceride fatty acids are partitioned in tissues and indicate that splanchnic spillover from triglyceride-rich lipoproteins may be a significant source of both portal venous and systemic FFAs.

Rheumatoid vasculitis manifesting as intra-abdominal hemorrhage.

Rheumatoid vasculitis, an extra-articular component of rheumatoid arthritis, causes a wide spectrum of manifestations that range from clinically insignificant to life-threatening disease. As a systemic necrotizing arteritis, rheumatoid vasculitis is usually characterized by end-organ ischemia. Herein we describe a patient with abdominal pain and syncope due to intra-abdominal hemorrhage from a ruptured aneurysm of the inferior pancreaticoduodenal artery in the setting of rheumatoid vasculitis. Although the intra-abdominal hemorrhage was the unusual manifestation of rheumatoid vasculitis in this patient, he had a history of prior extra-articular rheumatoid disease, including pulmonary fibrosis and Sjögrens syndrome with associated parotid lymphoproliferative disease. In patients with rheumatoid arthritis who have abdominal pain and an unexplained rapidly decreasing hemoglobin concentration, the diagnosis of intra-abdominal hemorrhage from a ruptured visceral aneurysm due to rheumatoid vasculitis should be considered, even in the absence of other indications of systemic vasculitis.

Safety and Diagnostic Yield of Transjugular Renal Biopsy

PURPOSE To evaluate the safety and tissue acquisition with transjugular renal biopsy (TJRB) by using the Quick-Core method in patients who were at high risk for complications with percutaneous renal biopsy. MATERIALS AND METHODS This was a retrospective study, and indication for the transjugular route, complications, clinical and laboratory data, and adequacy of samples were abstracted from patient records. TJRB was performed when the patient had thrombocytopenia or coagulopathy and was at high risk for bleeding from percutaneous renal biopsy. Follow-up images were available in 25 patients; nine underwent abdominal ultrasonography (US) and 17 underwent computed tomography (CT) (one patient underwent both US and CT). The hemoglobin level, prothrombin time, international normalized ratio (INR), partial thromboplastin time, platelet count, and serum creatinine level were obtained before and after biopsy, and these findings were correlated with clinical outcomes. RESULTS Thirty-nine patients underwent 39 TJRB procedures and comprise the current study population. The procedure was technically successful in 38 of the 39 patients (97%). Twenty-four of 39 patients (63%) had a platelet count of less than or equal to 75 x 10(9)/L, 11 (29%) had an elevated INR of more than 1.4, and seven received therapeutic anticoagulation. Patients with a platelet count of less than or equal to 75 x 10(9)/L or those with an elevated INR of more than 1.4 after transfusion were not at increased risk of hematoma formation (P = not statistically significant). The mean serum creatinine level at biopsy was 283 mumol/L +/- 150. A mean of 1.8 cores +/- 1.1 were obtained, with 5.0 glomeruli +/- 3.8, 2.1 glomeruli +/- 2.8, and 2.4 glomeruli +/- 3 at light, immunofluorescence, and electron microscopy, respectively. The renal tissue was sufficient for diagnosis in 92% of patients. Major complications occurred in one patient (2.6%). Minor complications-primarily renal hematoma-occurred in 52% of the patients. Contrast medium-induced nephropathy occurred in three patients (7.8%), two of whom also had renal hematomas. CONCLUSIONS TJRB is a relatively safe and effective diagnostic tool in high-risk patients with coagulopathy and thrombocytopenia who require renal tissue for accurate diagnosis.

Management of inferior pancreaticoduodenal artery aneurysms: A 4-year, single center experience

Inferior pancreaticoduodenal artery aneurysms are uncommon visceral artery aneurysms usually difficult to resect, and, if untreated, have a propensity to rupture with catastrophic results. We reviewed the clinical and treatment records of four patients encountered in our institution within the last 4 years. Three patients presented as bleeding emergencies from single aneurysms and were successfully treated by transcatheter embolization using coaxial technique and a variety of embolic agents. One nonemergent, asymptomatic patient had surgical resection of two inferior pancreaticoduodenal artery aneurysms due to unfavorable anatomy for embolization. Embolization therapy appears to be the treatment of choice in the emergency setting. Patients with unsuitable anatomy for embolization may still re quire surgical intervention.

Renal Artery Stent Placement for Restoration of Renal Function in Hemodialysis Recipients with Renal Artery Stenosis

PURPOSE Renal artery stent placement to treat renal artery stenosis (RAS) in patients undergoing hemodialysis is not performed commonly. We present our outcomes of discontinuation of hemodialysis after treating patients with RAS by stent placement on acute (< or =30 days of hemodialysis) and chronic hemodialysis (>30 days). MATERIALS AND METHODS A retrospective study was conducted in 16 patients (nine men) with an average age of 74.6 years +/- 10.6 (range, 49-86 y) who underwent treatment of 22 RAS for acute renal failure (n = 8) or uncontrolled hypertension with chronic hemodialysis (n = 8). The average follow-up was 448 days +/- 450 (median, 363.5 d; range, 6-1,583 d). The primary outcome consisted of discontinuation of hemodialysis, death, and transplantation. Secondary endpoints included restenosis, changes in blood pressure (and use of medications), and estimated glomerular filtration rate (eGFR). RESULTS After the stent procedure, eight patients were able to discontinue hemodialysis and remained free from dialysis over a mean period of 564 days +/- 533. The predictors of discontinuation of hemodialysis were 24-hour proteinuria, eGFR before renal artery stent placement, and size of the kidney on ultrasound studies (P < .05 for all three). There was no difference in patients who were undergoing acute versus chronic hemodialysis. There were three minor complications, and one patient died 6 days after the procedure because of multiple cardiovascular problems. CONCLUSIONS Renal artery stent placement for the treatment of RAS in patients receiving hemodialysis can result in discontinuation of hemodialysis in patients with low proteinuria level and adequate kidney size and eGFR.

Percutaneous Placement of the Greenfield Vena Caval Filter

During the period from August 1986 to August 1987, 50 patients underwent percutaneous placement of a Greenfield vena caval filter from the right femoral vein, left femoral vein, or right internal jugular vein at our institution. All 50 patients had a contraindication to anticoagulation therapy or had complications of anticoagulation for deep venous thrombosis or pulmonary emboli. The percutaneous placement was accomplished in the angiographic suite with use of local anesthesia and was well tolerated by all patients. Only three complications related to the percutaneous approach occurred during the short-term follow-up (3 months to 1 year). These complications were deep venous thrombosis of the leg in two patients and misplacement of the filter in one patient. The three patients tolerated these complications well. We conclude that placement of Greenfield vena caval filters can be readily accomplished by means of percutaneous entry. Our experience demonstrated minimal associated morbidity and no mortality.