Kevin E. Behrns

Hepatic steatosis as a potential risk factor for major hepatic resection

Hepatic steatosis is a recognized risk factor for primary nonfunction of hepatic allografts, but the effect of steatosis on postoperative recovery after major liver resection is unknown. Our aim was to determine if hepatic steatosis is associated with increased perioperative morbidity and mortality in patients undergoing major resection. A retrospective review of medical records of 13 5 patients who had undergone major hepatic resection from 1990 to 1993 was performed. Histopathology of the hepatic parenchyma at the resection margin was reviewed for the presence of macroor microvesicular steatosis. The extent of steatosis was graded as none (group l), mild with less than 30% hepatocytes involved (group 2), or moderate-to-severe with 30% or more hepatocytes involved (group 3). Outcome of patients was correlated with extent of steatosis. Patients with moderate-to-severe steatosis were obese (body mass index = 25.8 +-2 0.5 vs. 26.5 t 1.0+-. 33.4 +2.9; P <0.05 groups 1,2, and 3, respectively) and had an increased serum bilirubin concentration preoperatively. Hepatectomy required a longer operative time for group 3 (290 +-2 9 minutes vs. 287 +13 minutes vs. 35.5 +24 minutes; P <0.05 groups 1,2, and 3, respectively). Likelihood of blood transfusion was 5 1% in group l,S2 % in group 2, and 7 1% in group 3. Mortality was 14% in group 3 vs. 3% in group 1, and 7% in group 2; and liver failure occurred in 14% of patients in group 3 compared to 4% and 9% in groups 1 and 2, respectively. Patients in group 3 also had increased post-operative bilirubin levels compared to preoperative values. Moderate-to-severe hepatic steatosis may be associated with increased perioperative morbidity and mortality, and preoperative identification of steatosis warrants caution prior to major resection.

A Randomized Prospective Multicenter Trial of Pancreaticoduodenectomy With and Without Routine Intraperitoneal Drainage

Objective:To test by randomized prospective multicenter trial the hypothesis that pancreaticoduodenectomy (PD) without the use of intraperitoneal drainage does not increase the frequency or severity of complications. Background:Some surgeons have abandoned the use of drains placed during pancreas resection. Methods:We randomized 137 patients to PD with (n = 68, drain group) and without (n = 69, no-drain group) the use of intraperitoneal drainage and compared the safety of this approach and spectrum of complications between the 2 groups. Results:There were no differences between drain and no-drain cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, baseline quality of life, or operative technique. PD without intraperitoneal drainage was associated with an increase in the number of complications per patient [1 (0-2) vs 2 (1-4), P = 0.029]; an increase in the number of patients who had at least 1 ≥grade 2 complication [35 (52%) vs 47 (68%), P = 0.047]; and a higher average complication severity [2 (0-2) vs 2 (1-3), P = 0.027]. PD without intraperitoneal drainage was associated with a higher incidence of gastroparesis, intra-abdominal fluid collection, intra-abdominal abscess (10% vs 25%, P = 0.027), severe (≥grade 2) diarrhea, need for a postoperative percutaneous drain, and a prolonged length of stay. The Data Safety Monitoring Board stopped the study early because of an increase in mortality from 3% to 12% in the patients undergoing PD without intraperitoneal drainage. Conclusions:This study provides level 1 data, suggesting that elimination of intraperitoneal drainage in all cases of PD increases the frequency and severity of complications.

Gastric acid secretion and vitamin B12 absorption after vertical Roux-en-Y gastric bypass for morbid obesity.

OBJECTIVE This study sought to determine the basal and peak-stimulated acid secretion from the proximal gastric pouch and its relationship to absorption of free and food-bound vitamin B12 after gastric bypass for morbid obesity. SUMMARY BACKGROUND DATA Gastric bypass can be performed safely and provides acceptable weight loss, but concerns remain about possible long-term complications such as vitamin B12 malabsorption. The authors hypothesized that by constructing a small pouch of gastric cardia, acid secretion into the pouch would be low, leading to maldigestion of food-bound vitamin B12 with subsequent malabsorption. METHODS Basal and pentagastrin-stimulated peak acid outputs from the proximal gastric pouch were measured in ten patients after vertical Roux-en-Y gastric bypass using a perfused orogastric tube technique. Absorption of free and food-bound 57Co-vitamin B12 was evaluated separately using 24-hour urinary excretion. RESULTS Basal (mEq/hr, mean +/- standard error of the mean [SEM]) and peak-stimulated (mEq/30 min) acid secretions from the proximal gastric pouch were markedly decreased compared to those for age- and sex-matched hospital control subjects (0.01 +/- 0.01 vs. 4.97 +/- 0.66 and 0.08 +/- 0.04 vs. 12.11 +/- 1.34, respectively; p < 0.001 for each). While absorption of free vitamin B12 was not statistically different from that of control subjects (11 +/- 2 vs. 15 +/- 2%; p > 0.05), absorption of food-bound vitamin B12 was decreased (0.8 +/- 0.2 vs. 3.7 +/- 0.5%; p < 0.01). CONCLUSIONS After vertical Roux-en-Y gastric bypass for morbid obesity, acid secretion is virtually absent and food-bound vitamin B12 is maldigested and subsequently malabsorbed. The results of this study suggest that postoperative vitamin B12 supplementation is important and can be achieved with either monthly parenteral vitamin B12 or daily oral crystalline preparations.

Impaired Autophagy: A Mechanism of Mitochondrial Dysfunction in Anoxic Rat Hepatocytes

Autophagy selectively removes abnormal or damaged organelles such as dysfunctional mitochondria. The mitochondrial permeability transition (MPT) is a marker of impaired mitochondrial function that is evident in hepatic ischemia/reperfusion (I/R) injury. However, the relationship between mitochondrial dysfunction and autophagy in I/R injury is unknown. Cultured rat hepatocytes and mouse livers were exposed to anoxia/reoxygenation (A/R) and I/R, respectively. Expression of autophagy‐related protein 7 (Atg7), Beclin‐1, and Atg12, autophagy regulatory proteins, was analyzed by western blots. Some hepatocytes were incubated with calpain 2 inhibitors or infected with adenoviruses encoding green fluorescent protein (control), Atg7, and Beclin‐1 to augment autophagy. To induce nutrient depletion, a condition stimulating autophagy, hepatocytes were incubated in an amino acid–free and serum‐free medium for 3 hours prior to onset of anoxia. For confocal imaging, hepatocytes were coloaded with calcein and tetramethylrhodamine methyl ester to visualize onset of the MPT and mitochondrial depolarization, respectively. To further examine autophagy, hepatocytes were infected with an adenovirus expressing green fluorescent protein–microtubule‐associated protein light chain 3 (GFP‐LC3) and subjected to A/R. Calpain activity was fluorometrically determined with succinyl‐Leu‐Leu‐Val‐Tyr‐7‐amino‐4‐methylcoumarin. A/R markedly decreased Atg7 and Beclin‐1 concomitantly with a progressive increase in calpain activity. I/R of livers also decreased both proteins. However, inhibition of calpain isoform 2, adenoviral overexpression, and nutrient depletion all substantially suppressed A/R‐induced loss of autophagy proteins, prevented onset of the MPT, and decreased cell death after reoxygenation. Confocal imaging of GFP‐LC3 confirmed A/R‐induced depletion of autophagosomes, which was reversed by nutrient depletion and adenoviral overexpression. Conclusion: Calpain 2–mediated degradation of Atg7 and Beclin‐1 impairs mitochondrial autophagy, and this subsequently leads to MPT‐dependent hepatocyte death after A/R. (HEPATOLOGY 2008.)

Reoperative bariatric surgery : lessons learned to improve patient selection and results

OBJECTIVE The purpose of this study was to determine the spectrum of presentation, safety, and efficacy of operative bariatric surgery. SUMMARY BACKGROUND DATA The only lasting therapy for medically complicated clinically severe obesity is bariatric surgery. Several operative approaches have resulted in disappointing long-term weight loss or an unacceptable incidence of complications that require revisionary surgery. METHODS Sixty-one consecutive patients who underwent reoperative bariatric surgery from 1985 to 1990 were observed prospectively. One, two, or three previous bariatric procedures had been performed in 77%, 18%, and 5% of patients, respectively. Reoperation was required for unsatisfactory weight loss after gastroplasty or gastric bypass (61%), metabolic complications of jejunoileal bypass (23%), or other complications (16%), including stomal obstruction, alkaline- or acid-reflux esophagitis, and anastomotic ulcer. Revisionary procedures included conversion to vertical banded gastroplasty (33% of operations) and vertical Roux-en-Y gastric bypass (52% of operations); partial pancreato-biliary bypass was used selectively in four patients with severe, medically complicated obesity. RESULTS A single patient died postoperatively of a pulmonary embolus; serious morbidity occurred in 11%. Weight loss (mean +/- SEM) after reoperation for unsuccessful weight loss was greater with gastric bypass than with vertical banded gastroplasty (54 +/- 6% versus 24 +/- 6% of excess body weight). Metabolic complications of jejunoileal bypass were corrected, but 67% of the patients were dissatisfied with their postoperative lifestyle because of changes in eating habits or weight gain (64% of patients). Stomal complications and esophageal reflux symptoms were reversed in all patients. CONCLUSIONS Reoperative bariatric surgery in selected patients is safe and effective for unsatisfactory weight loss or for complications of previous bariatric procedures. Conversion to gastric bypass provides more effective weight loss than vertical banded gastroplasty.

Percutaneous Drainage of Pancreatic Pseudocysts Is Associated With a Higher Failure Rate Than Surgical Treatment in Unselected Patients

OBJECTIVE The primary aim was to compare directly the effectiveness of percutaneous drainage versus surgical treatment of pancreatic pseudocysts in unselected patients. The authors also wished to identify factors that may predict a successful outcome with percutaneous drainage. SUMMARY BACKGROUND DATA Pancreatic pseudocysts are a common complication of pancreatitis, and recent data suggest that many pseudocysts may be observed or treated successfully by percutaneous drainage. Failures with percutaneous drainage have been recognized increasingly, and a direct comparison of percutaneous and surgical treatment was initiated to identify factors that may affect outcome with these approaches. METHODS A computerized index search of the medical records of patients with a diagnosis of pancreatic pseudocyst was performed from 1984 to 1995. One hundred seventy-three patients were identified retrospectively and assigned to treatment groups: observation (n = 41), percutaneous drainage (n = 66), or surgical treatment (n = 66). Data on demographics, clinical presentation, pseudocyst etiology and characteristics, diagnostic evaluation, management, and outcome were obtained. Treatment failure was defined as persistence of a symptomatic pseudocyst or the need for additional intervention other than the original treatment. RESULTS The etiology of pancreatitis, clinical presentation, and diagnostic evaluation did not differ between groups. Twenty-seven percent had documented chronic pancreatitis, and the etiology of pancreatitis was alcohol in 61% of patients. Mean pseudocyst size was 4.2 +/- 1 cm, 8.2 +/- 1.1 cm, and 7.4 +/- 1.3 cm in the observed, percutaneously treated, and surgically treated groups, respectively. Expectant treatment was successful in 93% of patients. Percutaneous drainage was successful in 42% of patients, whereas surgical treatment resulted in a success rate of 88%. Patients treated by percutaneous drainage had a higher mortality rate (16% vs. 0%), a higher incidence of complications (64% vs. 27%), and a longer hospital stay (45 +/- 5 days vs. 18 +/- 2 days) than patients treated by surgery. Eighty-seven percent of patients in whom percutaneous drainage failed required surgical salvage therapy. Multiple logistic regression analysis failed to reveal any factors significantly associated with a successful outcome after percutaneous drainage. CONCLUSIONS Percutaneous drainage results in higher mortality and morbidity rates and a longer hospital stay than surgical treatment of pancreatic pseudocysts. The clinical benefit of percutaneous drainage of pancreatic pseudocysts in unselected patients has not been realized, and the role of this treatment should be established in a clinical trial.

Prospective evaluation of gastric acid secretion and cobalamin absorption following gastric bypass for clinically severe obesity

The pathophysiologic mechanism(s) responsible for cobalamin deficiency after Roux-en-Y gastric bypass for clinically severe obesity remains unexplained. Inadequate secretion of intrinsic factor has been postulated, but decreased gastric acid secretion resulting in maldigestion and inadequate liberation of free cobalamin from its native protein-bound form is also possible. The aim of this study was to determine prospectively secretion of gastric acid and absorption of crystalline (free) and protein-bound cobalamin before and after gastric bypass. Eight patients (two men, six women) underwent orogastric intubation of the intact stomach preoperatively and the proximal gastric pouch postoperatively. Gastric acid secretion in the basal and stimulated (pentagastrin, 6 µg/kg) states was determined by a perfused, nonabsorbable marker technique to quantitate recovery of gastric secretion. Absorption of radiolabeled (57Co) crystalline and protein-bound cobalamin was assessed on separate days by 24-hr urinary excretion. After gastric bypass, acid secretion (juvysem) was markedly reduced in basal (9.1±3.6 vs 0.005±0.003 meq/hr;P=0.04) and stimulated (12.8±1.8 vs 0.008±0.003 meq/30 min;P=0.002) states. Absorption of crystalline cobalamin was decreased (15.8±2.5 vs 9.4±1.4%;P=0.08) to a lesser extent than was protein-bound cobalamin (5.9±1.0 vs 1.1±0.3%;P=0.004). In summary, gastric acid secretion from the gastric pouch is negligible after gastric bypass, and food-bound cobalamin is maldigested and subsequently malabsorbed presumably due to pouch achlorhydria. Decreased absorption of free cobalamin suggests decreased cobalamin-intrinsic factor complex formation. This study suggests that cobalamin deficiency after Roux-en-Y gastric bypass results both from inadequate digestion of food-bound cobalamin and from insufficient secretion of intrinsic factor.

Murine Cirrhosis Induces Hepatocyte Epithelial Mesenchymal Transition and Alterations in Survival Signaling Pathways

Hepatocytes that reside in a chronically‐injured liver have altered growth responses compared to hepatocytes in normal liver. Transforming growth factor beta (TGFβ) is upregulated in the cirrhotic liver, and cirrhotic hepatocytes, unlike normal hepatocytes exposed to this cytokine, exhibit decreased apoptosis. In fetal hepatocytes, TGFβ also induces epithelial‐mesenchymal transition (EMT) and signaling changes in cell survival pathways. Here, chronic murine liver injury was induced by twice‐weekly carbon tetrachloride administration for 8 weeks. Normal liver‐derived hepatocytes (NLDH) and cirrhotic liver‐derived hepatocytes (CLDH) were examined for EMT and the small mothers against decapentaplegic homolog (Smad), phosphatidylinositol‐3‐kinase (PI3K/Akt), and mitogen activated protein kinase (MAPK) pathways were investigated. Immunofluorescence imaging of cirrhotic livers demonstrated increased vimentin expression, which was confirmed by immunoblot analysis. In vitro, CLDH exhibited increased vimentin and type 1 collagen expression within cellular extensions consistent with EMT. Treatment with TGFβ augmented the EMT response in CLDH. In contrast, untreated NLDH did not display features of EMT but responded to TGFβ with increased vimentin expression and EMT characteristics. In response to PI3K/Akt inhibition, CLDH had decreased basal and insulin‐stimulated p‐Akt expression and decreased apoptosis compared to NLDH. In both NLDH and CLDH, vimentin expression was dependent on PI3K/Akt activity. CLDH demonstrated increased basal p‐extracellular signal‐regulated kinase expression that was independent of Smad and PI3K/Akt signaling. Inhibition of the MAPK pathway produced a marked increase in CLDH apoptosis. Conclusion: CLDH have increased vimentin and type 1 collagen expression and morphologic features consistent with EMT. In addition, compared to NLDH, the cellular signaling phenotype of CLDH changes from a MAPK‐independent pathway to a MAPK‐dependent cell survival pathway. These findings may have clinical implications for chemoprevention of hepatocellular carcinoma in the cirrhotic liver. (HEPATOLOGY 2008.)

The Natural History of Pancreatitis-Induced Splenic Vein Thrombosis

Objective:To determine the natural history of pancreatitis-induced splenic vein thrombosis with particular attention to the risk of gastric variceal hemorrhage. Summary Background Data:Previous studies have suggested that splenic vein thrombosis results in a high likelihood of gastric variceal bleeding and that splenectomy should be performed to prevent hemorrhage. Recent improvements in cross-sectional imaging have led to the identification of splenic vein thrombosis in patients with minimal symptoms. Our clinical experience suggested that gastric variceal bleeding in these patients was uncommon. Methods:A computerized index search from 1993 to 2002 for the medical records of patients with a diagnosis of pancreatitis was performed. Fifty-three patients with a diagnosis of pancreatitis and splenic vein thrombosis were identified. The medical records of these patients were reviewed, and follow-up was completed, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ). Results:Gastrosplenic varices were identified in 41 patients (77%) with varices evident on computed tomography (CT) in 40 of 53 patients, on esophagogastroduodenoscopy (EGD) in 11 of 36 patients, and on both CT and EGD in 10 of 36 patients. This risk of variceal bleeding was 5% for patients with CT-identified varices and 18% for EGD-identified varices. Overall, only 2 patients (4%) had gastric variceal bleeding and required splenectomy. Functional quality of life was better than historical controls surgically treated for chronic pancreatitis. Conclusion:Gastric variceal bleeding from pancreatitis-induced splenic vein thrombosis occurs in only 4% of patients; therefore, routine splenectomy is not recommended.

Pancreatic lymphoma : is it a surgical disease ?

Primary pancreatic lymphoma is a rare neoplasm that reportedly regresses promptly with aggressive chemotherapy. Recently, the role of surgical management has been relegated to biopsy alone. The aim of this study was to review our experience with primary pancreatic lymphoma and to determine the outcome of patients managed by radiation therapy andlor chemotherapy. From 1952 to 1991, 107 patients with non-Hodgkins lymphoma involving the pancreas were identified. Twelve patients (11%) had primary pancreatic lymphoma. The presenting symptoms and signs were nonspecific: abdominal pain (83%), weight loss (50%), and a palpable mass (58%). Six of the 12 patients (50%) undergoing celiotomy had a pre-operative diagnosis of pancreatic carcinoma. These lym-phomas were large (x = 8 ± 2 cm) and deemed unresect-able because of size, alleged mesenteric vessel encroachment, regional lymph node metastasis, or because of an intraoperative diagnosis of lymphoma. Biopsy alone was performed in 50% of patients and biliary bypass and/or gastroenterostomy was performed in 25% of patients. A single resection (pancreatoduodenectomy) was performed 1 year after a full course of chemotherapy had failed. Ten patients, all of whom died of progressive lymphoma, received primary postoperative radiation therapy andlor chemotherapy, and no patient was disease-free at follow-up. Mean survival was 13 months for patients who received chemotherapy alone (n = 2), 22 months for those treated with radiation therapy only (n = 5), and 26 months for those receiving combined radiation therapy and chemotherapy (n = 3). In view of the poor survival with radiation therapy and chemotherapy and the decreased morbidity and mortality of pancreatectomy in recent years, a more aggressive surgical approach including pancreatic resection or tumor debulking should be adopted.