Short-bowel syndrome - surgical treatment with long-term benefit?

Survival and management of patients with irreversible intestinal failure has been made possible by the development of total parenteral nutrition (TPN). Despite the progress of TPN severe and even fatal complications might occur. Different non-surgical and surgical therapies can be employed to either improve intestinal function or restore enteral autonomy to obviate the need for TPN. A comprehensive review of the pertinent literature on different treatment modalities for short-bowel syndrome and our own experience are presented to judge long-term benefit and make recommendations on up-to-date surgical management.

Heterotopic intestinal transplantation aggravates the insult of chronic rejection.

BACKGROUND: Intestinal grafts are placed either heterotopically (out of continuity) or orthotopically (in continuity); the latter is believed to be advantageous, as intraluminal nutrients and intestinal secretions might modulate the intestinal immune status and possibly delay rejection. METHODS: This study was designed to delineate the effects of heterotopic versus orthotopic allograft position on the morphology and function of intestinal smooth muscle in our rat model of chronic rejection. Syngeneic orthotopic grafts were evaluated to control for changes due to the transplantation process. RESULTS: Histochemistry of the graft's muscularis externa showed a significant thickening due to hyperplasia and hypertrophy, which was most pronounced in heterotopic grafts (control = 92+/-2.4 microm, syngeneic grafts = 140+/-6.7 microm, orthotopic allografts = 278+/-26.6 microm, heterotopic allografts = 456+/-50 microm). In terms of function, muscle strips from allografts only generated 23% of the total bethanechol-induced contractile force in vitro compared to unoperated controls and syngeneic grafts. The mean resting membrane potential of control and isograft muscle cells was -69 +/- 0.9 mV with a slow-wave amplitude of 20+/-0.5 mV. Chronic rejection hyperpolarized the resting membrane potential of orthotopic allografts (-66 +/- 0.5 mV) and even more so of heterotopic allografts (-58 +/- 3.4 mV). Slow-wave amplitudes were decreased in orthotopic (14+/-0.9 mV) and nearly abolished in heterotopic allografts (2+/-1.2 mV). CONCLUSIONS: Our data indicate that allografts in heterotopic position are most susceptible to the insult of chronic rejection exemplified by increased proliferative and hypertrophic transformation of intestinal smooth muscle and a marked decrease in mechanical and electrical activity.

Chronic rejection causes early destruction of the intrinsic nervous system in rat intestinal transplants.

Chronic rejection is the major cause of late intestinal allograft dysfunction. We have previously shown that chronic rejection alters the muscularis externa of the graft. This study determined structural and functional changes to the enteric nerves during chronic rejection. Chronic rejection was achieved in orthotopic intestinal transplants (ACI to Lewis) by limited immunosuppression. Syngeneic transplants (ACI to ACI) and unoperated ACI rats served as controls. Animals were clinically healthy and showed no significant alterations in the mucosal architecture on postoperative day 90. Staining for NADPH diaphorase activity (nitric oxide synthase-containing neurons) and with neurofilament antibody RT-97 revealed that chronic rejection decreased the number of jejunal myenteric ganglia by approximately 50%. Inhibitory junction potentials (IJPs) to circular muscle cells were determined by electrical field stimulation (EFS). In controls and syngeneic grafts, EFS caused a stimulus-dependent increase in IJP amplitude, with a maximal amplitude of 9 +/- 0.4 and 10 +/- 0.8 mV, respectively. Chronic rejection in allografts markedly increased the threshold for IJP initiation and decreased the maximal IJP amplitude (5 +/- 0.8 mV). Our data indicate that chronic rejection severely damages the muscularis and the enteric nervous system before mucosal changes become evident.

[Indications for total parenteral nutrition or small intestine transplantation?--Prognostic factors in short bowel syndrome]. / Indikation zur total parenteralen Ernährung (TPE) oder Dünndarmtransplantation?--Prognosefaktoren beim Kurzdarmsyndrom.

After massive intestinal resection resulting in short bowel syndrome it is often unclear if the patient will remain on total parenteral nutrition (TPN) or regain enteral autonomy. Small bowel transplantation or bowel-lengthening procedures could potentially be a therapeutic option for patients confined to life-long parenteral nutrition. Initiated early in the course of the disease this could prevent frequent serious complications of long-term parenteral nutrition. However, it is unclear which factors determine the outcome of these patients. For further information on the long-term prognosis, data of 33 patients with short bowel syndrome operated in our institution from 1982 to 1995 were retrospectively analyzed and the present status of all living patients evaluated. Gender, age or underlying disease had no influence on the adaptation of the small intestine or the duration of TPN in the surviving patients. Return to enteral autonomy mainly depended upon the length of the remaining small and large bowel. Thus the further course of the disease can be predicted and necessary measures can be taken as this information is always available at the time of initial surgery.

Decreased mucosal IgA levels in ileum of patients with chronic ulcerative colitis.

Patients with chronic ulcerative colitis (CUC) are known to have decreased spontaneous IgA secretion by colonic mononuclear cells. The aim of this study was to determine whether a similar alteration exists in the apparently healthy ileum of patients with CUC. The concentration of IgA was measured in the supernatant from homogenized mucosal ileal biopsies using a sandwich-type ELISA. The concentration of IgA was significantly (P = 0.025) decreased in the ileum of patients with CUC (N = 24) in comparison to normal ileum (N = 10). The number of mucosal IgA-containing mononuclear cells (MNC) was also determined using an avidin-biotin-immunoperoxidase technique on paraffin-embedded ileal sections. Although reduced, the number of positive cells and their distribution was not significantly different in the ileum of patients with CUC (N = 20) when compared to normal ileum (N = 10). We suggest that decreased mucosal IgA levels are a panintestinal condition in CUC and that this is a primary alteration rather than a secondary response to the inflammatory process. Considering the role of IgA, we propose that decreased mucosal IgA levels in CUC may predispose to the disease by a reduction of the immune-mediated exclusion mechanism and/or by an impairment of the down-regulation of the inflammatory response.

[Surgical therapy of short bowel syndrome]. / Chirurgische Therapie des Kurzdarmsyndroms.

Advances in medical and surgical technique and the development of home parenteral nutrition have led to an increasing number of patients with short-bowel syndrome. Many patients could benefit from definite surgical therapy as long-term parenteral nutrition besides being expensive frequently causes severe complications. Various techniques to prolongate intestinal transit and increase the absorptive area of the remaining small bowel have been experimentally developed and some have been successfully employed in humans. The recent discovery of new potent immunosuppressive agents has initiated clinical endeavours at intestinal transplantation. The various techniques for the surgical therapy of short-bowel syndrome with their indications and potential risks are reviewed.

Functional impairment of enteric smooth muscle and nerves caused by chronic intestinal allograft rejection regresses after FK506 rescue.

We have previously demonstrated that subclinical chronic rejection (CR) induces structural and functional alterations in enteric smooth muscle and nerves in a rat model of small intestinal transplantation. This study was designed to investigate the effect of prolonged FK506 rescue therapy on these sequelae of CR. Immunohistochemistry of BrdU-labeled muscle cells demonstrated that active proliferation of intestinal smooth muscle caused by CR was successfully aborted by FK506 rescue therapy after a period of 30 days (control = 0.14 +/- 0.09; CR = 30.4 +/- 1.73; rescue = 2.4 +/- 0.63 cells/jejunal cross-section, P < 0.01). However, FK506 did not reverse the already established increase in muscular thickness (control = 92 +/- 2.4; CR = 193 +/- 10.6; rescue = 188 +/- 8.1 microns) due to CR. Bethanechol stimulated circular muscle contractility was improved markedly with rescue therapy (maximal contractile force reached 39.5% of control values in CR grafts and 68.8% after rescue). Rescue therapy did not reverse the loss of NADPH-diaphorase positive myenteric ganglia (control = 37 +/- 1.4; CR = 28 +/- 2.9; rescue = 23 +/- 1.7 ganglia/cross-section). Despite the persistent loss of ganglia, inhibitory junction potentials (IJPs) improved significantly returning to control values with FK506 (control = 10 +/- 0.5; CR = 5 +/- 0.3; CR rescue = 10 +/- 0.7 mV; IJPs recorded at 1 pulse/150V/0.75 ms). Although structural changes in enteric smooth muscle and myenteric neurons induced by CR were not reversed, the progression of subclinical CR can be effectively curbed by FK506 rescue therapy. The improvement in muscular mechanics and inhibitory neural innervation is probably due to the cessation of infiltrating immunocytes and sprouting of remaining myenteric nerves.

[Long-term prognosis of short bowel syndrome: analysis of 30 cases]. / Pronostic éloigné du syndrome du grêle court: analyse de 30 cas.

To determine the influence of the underlining disease on the duration of total parenteral nutrition (TPN) and on the long-term prognosis, data from 30 admitted patients with permanent (n = 23) and temporary (n = 7 short bowel syndrome were retrospectively analyzed and the present status of all living patients evaluated. Patients with "permanent short bowel" after thrombosis of the superior mesenteric artery (group I, n = 13) or malignant tumours (group II, n = 3) had a decreased survival compared to patients with other causes such as ileus, intestinal volvulus-thrombosis of mesenteric veins or benign tumors (group III, n = 7). Within the first six postoperative months, all patients in group I and all patients in group II died of the underlying disease whereas none died in group III. One patient in group I and one patient in group III died as a result of complications related to TPN. The different underlying diseases had no influence on the adaptation of the small intestine or on the duration of TPN in the surviving patients. Return to enteral autonomy seems to mainly depend on the length of the remaining small and large bowel and early enteral feeding. Complications of parenteral nutrition and possible options for the surgical treatment of the short bowel syndrome are discussed.

[Metabolism and function of nitric oxide in the liver]. / Metabolismus und Funktion von Nitric oxide in der Leber.

Nitric oxide (NO) is rapidly gaining importance as an ubiquitous biological mediator. Very different physiologic and pathophysiologic reactions are regulated by the endogenous biosynthesis or the release of NO from drugs. Besides its functions as an endothelium derived relaxing factor and inhibitory neurotransmitter, NO plays a key role in inflammation and immunity. The liver appears to have a central position in this complex scenario as both parenchymal and non-parenchymal cells synthesize NO under immune stimulation. Many aspects of the metabolism and the mode of action of NO, which are still unclear, remain to be further investigated and confirmed in the human system. Recent cloning of an inducible human NO synthase reveals new perspectives. The following article reviews the present scientific knowledge of the metabolism and function of hepatic NO.

Small bowel transplantation and chronic rejection alter rat intestinal smooth muscle structure and function.

BACKGROUND: The purpose of this study was to determine whether morphologic and functional changes in intestinal smooth muscle occur after small bowel transplantation (SBTx) and during chronic rejection. METHODS: Orthotopic SBTx was performed in syngeneic (ACI-ACI, n = 6) and allogeneic (ACI-Lewis, n = 6) rat strain combinations. The latter received temporary immunosuppression (cyclosporine 15 mg/kg/body weight on postoperative days 0 to 6 once a day, postoperative days 7 to 28 every other day), which led to clinically quiescent chronic rejection of the graft by 90 days after SBTx. At that time structure and function of the jejunal muscularis externa were evaluated with histochemistry, mechanical organ bath, and intracellular electrical recording techniques. RESULTS: Histochemistry showed a 1.5-fold thickening of the intestinal muscularis externa of syngeneic grafts, although contractile properties and intracellular electrical activity were not significantly different from controls. Allogeneic, chronically rejecting grafts showed a threefold increase in the thickness of the muscularis externa as a result of both smooth muscle hyperplasia and hypertrophy. Muscle strips from chronically rejecting grafts generated only 23% of the maximal contractile force generated by controls (bethanechol 300 mumol/L). Median effective concentration and threshold values were not significantly different. Intracellular electrical activity of circular smooth muscle cells revealed a significantly more depolarized resting membrane potential and a reduction in slow wave amplitude compared with controls. CONCLUSIONS: Syngeneic SBTx resulted in a significant thickening of the muscularis externa with an apparent adaptation to control in vitro physiologic function. Allogeneic SBTx subject to chronic rejection leads to profound morphologic changes and functional impairments. Changes in muscle structure and function evolve before the clinical signs of graft rejection.