Serotonin immunoreactivity in pancreatic endocrine neoplasms (carcinoid tumors).

Primary serotonin secreting pancreatic endocrine neoplasms (carcinoid tumors) are extremely rare and may be associated with manifestations of the carcinoid syndrome. Two cases of primary carcinoid tumor of the pancreas with liver metastases showed clinical and biochemical features of the carcinoid syndrome. Both cases demonstrated strong positive immunoreactivity for serotonin within the tumor cells. In an attempt to determine the relationship between pancreatic carcinoid tumors and other pancreatic endocrine neoplasms, immunostains for serotonin were performed on 11 additional islet cell tumors and on non-neoplastic pancreatic tissues. These cases showed serotonin immunoreactivity within islet cell tumors (36%). In addition, focal staining for serotonin was present in non-neoplastic ducts and ductules (88%), acini (22%), and islets of Langerhans (33%). Based on these observations, specific criteria are suggested for the diagnosis of primary pancreatic carcinoid tumor.

Selective splenocaval shunt. Report of 26 cases and review of the literature.

Splenocaval shunting was performed in 26 patients for the treatment of variceal bleeding. The indications for this alternative selective shunt were congenital anomalies of the left renal vein, inadequate outflow from the left renal vein on preoperative venography, or an anatomic relationship of the splenic vein favoring direct splenocaval rather than splenorenal anastomosis. Technical considerations in which splenocaval shunts differ from distal splenorenal shunting relate to exposure of the vena cava. Operative mortality was 7.7% (2/26). Immediate shunt patency was documented in 23 of 24 patients studied, and all 14 shunts studied at 13 to 57 months were patent. Portal perfusion was maintained in 95% (20/21) of the patients when studied at 7 to 10 days after shunting and in 57% (8/14) at late follow-up. This experience with distal splenocaval shunting has reaffirmed its place as an alternative technique to selective distal splenorenal shunts, particularly when the left renal vein is abnormal.

The surgical pathologist's role in liver transplantation.

Liver transplantation has become an option in treating a wide variety of diseases. The surgical pathologist, as a member of the transplantation team, is increasingly involved in the evaluation of allograft dysfunction. Interpretation of the liver allograft biopsy specimen requires integration of clinical history, biochemical data, and histologic patterns of a wide variety of lesions, including harvesting injury, vascular thrombosis, rejection, infection, and recurrent disease. This article reviews the varied histologic appearances of the more common forms of liver allograft injury, the contexts in which they arise, and their distinction from one another.

Muromonab CD-3: a review of its pharmacology, pharmacokinetics, and clinical use in transplantation.

Muromonab CD-3 (OKT-3) is a monoclonal antibody that is highly effective in the treatment of acute rejection in solid organ transplants. Due to its monoclonal nature, each molecule is identical because it is derived from a single antibody-producing clone. OKT-3 is administered only by intravenous injection and has a harmonic half-life of approximately 18 hours. It binds specifically to the CD-3 complex, which is involved in antigen recognition and cell stimulation, on the surface of T lymphocytes. Immediately after administration CD-3-positive T lymphocytes are abruptly removed from the circulation. The route of metabolism for OKT-3 is not clear; it may be removed by opsonization by the reticuloendothelial system when bound to T lymphocytes, or by human antimurine antibody production. The agent has been effective in reversing corticosteroid-resistant acute rejection in renal, liver, and cardiac transplant recipients. Its use in pancreatic and bone marrow recipients is inconclusive. OKT-3 has a considerable number of initial side effects, and some life-threatening reactions may occur. This drug should not be administered to any patient who is greater than 3% usual body weight because of the potential for the development of severe pulmonary edema. OKT-3 may also be associated with a high rate of infection, especially of the viral type. The usual dose is 5 mg administered as an intravenous bolus over 2-4 minutes daily for 10-14 days. Approximately 85% of patients treated with OKT-3 develop reactive human antimurine antibodies that, over time, may lead to tachyphylaxis and neutralization of the murine antibody OKT-3. OKT-3 is potent immunosuppressive agent and is an important prototype of future monoclonal antibodies.

Surgical rescue for failures of cirrhotic sclerotherapy.

Bleeding from gastroesophageal varices remains the most devastating complication of the portal hypertensive syndrome. Endoscopic sclerotherapy has emerged as the best initial treatment for bleeding varices because surgery is obviated and survival may be improved. However, sclerotherapy will fail and surgical rescue will be required in at least a third of patients. There are two viable surgical rescue procedures: shunt surgery and liver transplantation. This paper summarizes the available data and concludes that there is a role for both procedures.

The Emory perspective of the distal splenorenal shunt in 1990.

The distal splenorenal shunt (DSRS) has been extensively studied at Emory University over the past 18 years to define its role in the management of variceal bleeding. DSRS has been applied broadly in many different patient groups and has been evaluated in prospective randomized trials; thus, a considerable amount of data has accrued on the metabolic and hemodynamic consequences of selective variceal decompression. Its current role is defined as primary therapy for variceal bleeding in patients with portal vein thrombosis and good-risk patients with nonalcoholic cirrhosis. As a therapy for patients whose bleeding is not controlled by sclerotherapy, it should be used as the shunt procedure of choice, but patient evaluation must focus on the choice between DSRS and liver transplantation.

Angioplasty for long-term treatment of patients with Budd-Chiari syndrome.

The goal of radiologic intervention in patients with Budd-Chiari syndrome is to control portal hypertension and prevent further hepatocellular damage until collateral hepatic venous outflow channels can develop. Percutaneous balloon angioplasty was used to treat six patients with this syndrome who were followed up for an average of 43 months (range, 12-92 months). Standard interventional radiologic techniques were used to dilate the hepatic veins (two patients), inferior vena cava (three patients), and proximal anastomosis of a mesoatrial shunt (one patient). Angioplasty was the only invasive treatment in three patients, whereas the remaining three patients had previous portosystemic shunts. Clinical and hemodynamic improvement occurred after each angioplasty. Multiple dilatations were required in all patients (average, 3.2; range, 2-5) because of restenosis at the angioplasty site and ongoing hepatocyte necrosis shown by biopsy. Long-term benefit occurred in five patients despite ultimate caval occlusion in two patients and restenosis in one patient. One patient who was almost free of symptoms for 36 months developed gastrointestinal bleeding caused by portal hypertension. This experience suggests that balloon angioplasty is a safe and effective treatment for patients with Budd-Chiari syndrome. The therapy is not definitive, but serves to moderate the severity of the disease until collateral venous pathways develop. Multiple angioplasties are required for the long-term care of these patients.

Surgical options, hematologic evaluation, and pathologic changes in Budd-Chiari syndrome.

This article presents a scheme of management for Budd-Chiari syndrome based on experience with 33 patients. Therapy in acute Budd-Chiari syndrome is dictated by the liver biopsy, with hepatocyte necrosis indicating the need for placement of a decompressive shunt. The type of shunt was determined by intrahepatic vena cava obstruction; a higher morbidity rate was associated with the mesoatrial shunt in 11 patients than with a portacaval shunt in 10 patients. Successful shunt placement allowed stabilization of the liver biopsy and maintenance of good hepatocyte function [galactose elimination capacity (preoperative: 349 +/- 40 mg/minute; 20 months: 344 +/- 60 mg/minute)]. Severe fibrosis and reduced galactose elimination capacity (264 +/- 43 mg/minute) indicated advanced disease--chronic Budd-Chiari syndrome--and were indications for liver transplant. Hematologic evaluation documented a myeloproliferative disorder in 8 of the last 13 patients evaluated; perioperative and late anticoagulation and/or chemotherapy reduced recurrent thrombosis. We conclude that the Budd-Chiari syndrome requires different therapies depending on the stage of disease. If no hepatocyte injury is present on biopsy, therapy may not be needed. Acute, reversible injury can be managed by placement of a decompressive shunt. Irreversible damage requires transplantation. Selection of the right therapy requires a complete evaluation.

The relative role of sclerotherapy vs. surgical procedures in portal hypertension.

This review is a discussion of the evolution of different modes of therapy to treat variceal bleeding. At the present time, endoscopic sclerosis represents the mainstay of therapy for most patients with chronic cirrhosis. In patients who fail sclerotherapy, selective shunt surgery is indicated in patients with good hepatic reserve, and liver transplantation for those who have chronic liver failure.

An in vivo examination of rat brain during sepsis with 31P-NMR spectroscopy.

Neurological symptoms including lethargy, obtundation, and confusion are early and common findings in patients with sepsis. The etiology of the mental status changes that occur during severe infection is not known. We investigated the effects of sepsis on the levels of high-energy phosphates to determine whether decreased energy metabolism was a factor in the depressed neurological state. The time course of changes in brain pH and brain high-energy phosphate metabolites during an Escherichia coli infusion was determined from sequential phosphorus-31 nuclear magnetic resonance (31P-NMR) spectra of ketamine-xylazine-anesthetized rats. A second group of rats received 0.9% saline infusion and served as a control group. Despite severe obtundation and near loss of righting reflex, the rats in the septic group had no significant differences in the brain pH, the ratio of phosphocreatine (PCr) to beta-adenosine 5'-triphosphate (beta-ATP), or in the ratio of PCr to Pi. The only significant decrease in brain high-energy phosphates or pH occurred terminally in the septic rat group and corresponded with a rapidly falling arterial blood pressure. We conclude that the severe neurological depression that is characteristic of sepsis is not due to decreased levels of brain high-energy phosphates or brain acidosis.

Two-stage surgical management of Budd-Chiari syndrome with obstruction of the inferior vena cava.

A two-stage approach to the surgical management of acute Budd-Chiari syndrome complicated by inferior vena caval obstruction was advocated by our group in 1984. This entailed initial hepatic decompression by suprahepatic, mesoatrial shunt, with subsequent takedown of the mesoatrial shunt combined with conversion to a short infrahepatic, portacaval shunt. We report herein the late follow-up results for two patients managed in this manner. While both patients are alive and doing well, both of the courses have been complicated by stenosis of the inferior vena cava. The cause is unclear but probably relates to fibrosis at the hepatic venous orifices. Management was by percutaneous balloon dilation, which relieved the recurrent hepatic congestion. This cautions others considering this approach to provide careful longitudinal follow-up study for such patients.

Proximal abdominal graft for arterialization during hepatic transplantation.

A new method of arterial grafting during orthotopic hepatic transplantations is described herein. The advantages compared with other techniques include better exposure, less extensive dissection, reduced blood loss and, with correct anatomic orientation, a reduced risk of kinking the graft in a blind tunnel.

Distal splenorenal shunt with splenopancreatic disconnection. A 4-year assessment.

The aims of distal splenorenal shunt with splenopancreatic disconnection (DSRS-SPD) were to improve maintenance of portal flow and prevent siphoning of hepatotrophic factors from the pancreas, as occurs after standard DSRS. The main patient population targeted for improvement were alcoholic cirrhotics, who have poorer survival than nonalcoholic cirrhotics and greater loss of portal flow (60%) after standard DSRS. Seventy-eight patients had DSRS-SPD during the study period 1983 to 1987: thirty-two patients were Child's A, 25 were Child's B, and 21 were Child's C. The 35 patients with alcoholic cirrhosis were a significantly poorer risk group by Child's class and galactose elimination capacity (GEC) than the 39 patients with nonalcoholic cirrhosis. Four patients had portal vein thrombosis. At 4-year follow-up, portal perfusion is maintained in 84% alcoholic and 90% nonalcoholic patients, with hepatic and systemic hemodynamics showing identical patterns for both groups. Hepatic function measured by GEC was maintained in alcoholic patients (290 +/- 68 mg/min to 303 +/- 74 mg/min) and nonalcoholics patients (342 +/- 92 to 320 +/- 118 mg/min). Gastric variceal rebleeding occurred in 10 patients--4 early (less than 2 months) and 6 late (18 to 54 months), leading to operation in 4 and transhepatic embolization in 4 patients: 2 of these patients died from this complication. Survival data show an operative mortality rate of 6.4% and overall mortality rate of 30%, with no significant difference between alcoholic and nonalcoholic cirrhotics. DSRS-SPD has significantly improved maintenance of portal perfusion and survival in patients with alcoholic cirrhosis requiring selective shunt for variceal bleeding when compared to standard DSRS. In this population DSRS-SPD is the operation of choice. In patients with nonalcoholic cirrhosis, the current data have not shown DSRS-SPD to have advantage over standard DSRS.

Change in hepatic function, hemodynamics, and morphology after liver transplant. Physiological effect of therapy.

Orthotopic liver transplantation (OLT) has become standard therapy for patients with acute hepatic necrosis and end-stage liver disease. This study measured change in hepatic function (galactose elimination capacity [GEC]), liver blood flow (low dose galactose clearance: flow), hepatic volume (CT scan; volume) and morphology after OLT. The aim was to measure the physiologic response after OLT and compare this response with that after selective shunt (SS) and sclerotherapy (ES) to determine which patients should receive specific therapy. Between January 1987 and November 1988, 37 patients underwent OLT. Operative mortality was 18%, which was similar to that of SS in Child's C cirrhotics. GEC and volume were less in transplant patients than in cirrhotics treated with SS or ES. GEC, flow, and volume normalized after OLT; GEC was preserved after ES and SS, but volume decreased. Three preoperative patterns were observed that can aid in selection of OLT candidates. Patients with chronic cirrhosis (chronic active hepatitis; cryptogenic) need OLT when GEC is less than or equal to 225 mg/min and volume is less than or equal to 50% normal. Patients with Budd-Chiari Syndrome require OLT if cirrhosis has evolved. Patients with sclerosing cholangitis and primary biliary cirrhosis qualify for transplants when complications of the portal hypertensive syndrome develop. The studies can also direct therapy for ES failures. Selective shunt is indicated in those patients with stable disease whose GEC is greater than or equal to 300 mg/min and liver volume is greater than 75% normal; OLT is indicated for cirrhotics with GEC that is less than 225 mg/min and liver volume that is less than 50% predicted normal.

Management of variceal bleeding in patients with noncirrhotic portal vein thrombosis.

Since 1971, 70 patients have been seen at Emory University Hospital with gastroesophageal varices secondary to extrahepatic portal vein thrombosis (PVT). Thirty-seven of these patients had had prior major operative therapy. In only three patients (8%) was shunt surgery successful, and there was a high incidence of rebleeding, other morbidity, and mortality. Of especial note are the serious consequences of simple splenectomy; splenomegaly and thrombycytopenia should rarely, if ever, be used as indication for splenectomy in portal hypertension. In 1977, the use of selective distal splenorenal shunt (DSRS) was begun at Emory in this population and a selective shunt has been possible in 24 of 29 patients (83%) who had had no prior operative therapy. Results have been excellent with a greater than 90% patency rate, long-term portal perfusion in all, no encephalopathy, and late rebleeding in one patient. Quantitative studies at 3-6 years show stability of liver function, significant decrease in spleen size, and rise in platelet count. However, long-term follow-up (greater than 15 years) is required in PVT patients before definitive assessment can be obtained. A specific problem of the PVT patient is late shunt stenosis which requires close observation; dilatation of the shunt was performed in six of the 24 patients with a patent shunt. Poor results with non-shunt operative procedures in PVT were again documented. The proper role of endoscopic variceal sclerotherapy is not yet clear, but appears to be an excellent addition to the therapeutic options. In conclusion, for patients with a patent splenic vein, initial therapy should be a selective shunt; for patients without a patent splenic venous system, endoscopic sclerotherapy is the procedure of choice.

Evaluation and treatment of early hemorrhage of the alimentary tract after selective shunt procedures.

The cause and treatment of early variceal bleeding in 15 patients who had undergone distal splenorenal shunt were reviewed. Eight of these patients were taken from a group of 91 who underwent selective shunts from July 1983 through June 1985 and had extensive preoperative and postoperative evaluation of shunt patency and pressure gradient. Seven patients operated upon before July 1983 were reviewed because they illustrate the cause, diagnosis, successful and unsuccessful management of bleeding after selective shunt. Urgent selective arteriography combined with shunt catheterization is the key diagnostic and therapeutic maneuver. Thrombosis of the shunt can be successfully managed by revising the anastomosis. Stenosis of the shunt can be successfully treated with balloon dilation or operative revision of the anastomosis. When renal vein hypertension (RVH) occurs, there might be inadequate decompression of the varices. A gradient of 10 millimeters of mercury or greater from left renal vein to vena cava is diagnostic. Measurements of 30 patients who had no bleeding and one patient with documented RVH show the gradient decreases over time. Treatment should be supportive until this adaptation occurs. Hemorrhage can also occur in patients with a patient shunt but without a significant pressure gradient. Inadequate decompression of the varices through the short gastric veins leading to the spleen has been proposed as one cause. Termed short gastric hypertension, this syndrome could be expected to parallel RVH because the venous collaterals will enlarge and eventually decompress the varices. Treatment should be aimed toward supporting the patient until this adaptation occurs. A small number of patients continue to bleed despite these therapeutic interventions but can sometimes be salvaged with a total shunt.

Splenopancreatic disconnection. Improved selectivity of distal splenorenal shunt.

UNLABELLED: Distal splenorenal shunt (DSRS) improves survival from variceal bleeding in nonalcoholic cirrhotics but not in alcoholic subjects. The metabolic response after DSRS is also different in alcoholic and nonalcoholic cirrhotics. Portal perfusion, quality of blood perfusing the liver, cardiac output, and liver blood flow do not change in nonalcoholics. In alcoholics, portal perfusion is frequently lost (60%), quality of blood perfusing the liver decreases, and cardiac output and liver blood flow increase. It is proposed that portal flow is lost in alcoholics via pancreatic and colonic collaterals after surgery. Elimination of this sump by adding complete dissection of the splenic vein and division of the splenocolic ligament to DSRS (splenopancreatic disconnection, SPD) could preserve portal perfusion, decrease shunt loss of hepatotrophic factor, and improve survival in alcoholic cirrhotics. This report compares data 1 year after surgery in two groups of cirrhotics: group I (8 nonalcoholic; 16 alcoholic) had DSRS without SPD; group II (17 nonalcoholic; 11 alcoholic) received DSRS + SPD. METHODS: Portal perfusion grade, cardiac output (CO), liver blood flow (f), hepatic function (GEC), and hepatic volume (vol) were measured before and 1 year after surgery. Shunt loss of hepatotrophic factor was estimated by insulin response (change in plasma concentration over 10 minutes: AUC) after arginine stimulation. RESULTS: Groups I and II were similar before surgery. Metabolically, nonalcoholics remained stable after both DSRS and DSRS + SPD. After standard DSRS, alcoholics lost portal perfusion (75%, p less than 0.05), CO, and f increased (p less than 0.05), and quality of blood perfusing the liver was decreased (GEC/f: p less than 0.05). DSRS + SPD preserved portal perfusion better (p less than 0.05) in alcoholic cirrhotics than did DSRS alone. After DSRS + SPD, the metabolic response in alcoholics resembled that of nonalcoholics. CO, f, and GEC/f remained stable. These data show: DSRS + SPD preserves postoperative portal perfusion in alcoholic cirrhotics better than DSRS alone. Metabolic response to DSRS + SPD is similar in alcoholic and nonalcoholic cirrhotics. Because portal perfusion and metabolic integrity are preserved after DSRS + SPD, its use in alcoholic cirrhotics should improve survival.

Distal splenorenal shunt versus endoscopic sclerotherapy for long-term management of variceal bleeding. Preliminary report of a prospective, randomized trial.

This paper reports the preliminary results of a prospective randomized trial comparing endoscopic variceal sclerosis and distal splenorenal shunt (DSRS) in the management of patients with cirrhosis and variceal bleeding. Seventy-one patients have been entered; 36 have received sclerosis and 35 DSRS. Randomization of the study population was stratified on Child's A/B (56%) and Child's C (44%). Sixty-one per cent had alcoholic and 39% non-alcoholic cirrhosis. No patients have been lost to follow-up, which currently stands at a median of 26 months. Rebleeding occurred significantly (p less than 0.05) more frequently in patients in the sclerosis group (19 of 36: 53%) compared to DSRS (1 of 35: 3%), but only 11 of 36 (31%) were not controlled by further sclerosis and failed that therapy. Patients in whom sclerosis failed underwent surgery. Survival was significantly (p less than 0.01) improved in the sclerosis group (+ surgery in 31%), with an 84% 2-year survival compared to a 59% 2-year survival in the DSRS group. Portal perfusion was significantly (p less than 0.05) better maintained in the sclerosis (95%) compared to the DSRS (53%) group. Galactose elimination capacity improved significantly (p less than 0.05) in 21 patients successfully managed by sclerosis at 1 year and was significantly (p less than 0.01) better maintained in the sclerosis compared to DSRS group. The authors conclude that endoscopic sclerosis: has a higher rebleeding rate than DSRS, with one third of patients failing therapy from rebleeding; allows significant improvement in liver function when successful; and gives significantly improved survival in the management of variceal bleeding when backed up by surgical therapy for patients with uncontrolled rebleeding.

Denervated splenopancreatic flap for chronic pancreatitis.

Various surgical procedures have addressed the disabling pain of chronic pancreatitis. Pain control must be weighed against the surgical morbidity and metabolic consequences of operation. Although ductal drainage works well for patients with dilated ducts, a new procedure was devised to avoid the diabetic morbidity of near-total pancreatectomy or pancreaticoduodenectomy in patients with small duct pancreatitis. Five patients have undergone the splenopancreatic flap procedure. The head of the pancreas is resected in a manner similar to near-total pancreatectomy, while the body and tail are denervated by dissection from their bed, with retrograde perfusion from the splenic hilus. All patients are alive a mean of 9 months after operation, and none is diabetic. Only one patient requires narcotic analgesics. Although none is asymptomatic, all have shown significant weight gain, and four of five are vocationally rehabilitated. Flap viability and the absence of transgastric varices have been documented by angiography and CT scanning. Although the durability of pain relief and islet cell function is unknown, these results suggest that this procedure may offer an alternative to major resection in chronic pancreatitis.