Paneth cells release granules into the lumen of the crypts of Lieberkuhn in the small intestine where their component proteins participate in mucosal immunity. The granules contain a number of proteins associated with roles in host defense, including lysozyme, secretory phospholipase A2, and alpha-defensins, termed cryptdins. Mouse cryptdins 1-6 and recombinant human Paneth cell alpha-defensin HD-5 are potent antimicrobial agents against certain microorganisms. As defensins, they kill microbes by disruption of the target cell membrane. The peptides are coded by individual, two-exon genes that map to homologous regions of chromosome 8 in mice and humans, and the differential expression of certain mouse cryptdin genes provides markers for studies of crypt ontogeny and epithelial cell differentiation and lineage determination. Neutrophil alpha-defensin peptides exhibit numerous biological activities in addition to antimicrobial function including regulation of cell volume, chemotaxis, mitogenicity, and inhibition of natural killer cell activity. When administered apically, mouse cryptdins 2 and 3 can reversibly stimulate human T-84 intestinal epithelial cells to secrete chloride ion, suggesting that alpha-defensins from Paneth cells also may be multifunctional. Thus, cryptdins and varied Paneth cell secretory products seem to contribute both to innate immunity of the crypt lumen and to defining the apical environment of neighboring cells.

Short-bowel syndrome is the malabsorptive state that follows extensive resection of the small intestine. Potential long-term survival without parenteral nutrition heavily depends on stimulation of the process of intestinal adaptation, through which the remaining small intestine gradually increases its absorptive capacity. This process is heavily nutrient dependent, and aggressive use of enteral nutrition is required to stimulate its completion. A combination of osmotic sensitivities, nutrient malabsorption, bowel dilatation and dysmotility, and changes in bacterial flora influence the symptoms and the management of this disorder. Chronic complications include parenteral nutrition-induced liver disease, nutrient deficiency states, and, frequently, small bowel bacterial overgrowth. Intestinal transplantation has been successfully developed in some centers in the United States, and preliminary experience suggest a long-term survival of 50%-75%, better in patients receiving an isolated intestinal transplant than a combined liver/bowel transplant. The ultimate role of intestinal transplantation is still undergoing evaluation.

The benefit of mesalamine for maintenance of remission in Crohn's disease is controversial. The aim of this study was to assess the effectiveness of mesalamine in maintaining remission of quiescent Crohn's disease.

The Whipple procedure has undergone a remarkable gradual evolution in the last 20 years, of which many gastroenterologists are unaware. Improvements in staging, particularly staging laparoscopy with ultrasonography, have reduced the incidence of negative laparotomies. The forbidding mortality of pancreaticoduodenectomy, approximately 20% just a generation ago, has decreased precipitously in high-volume referral centers. Near zero mortality rates are now common. Morbidity and length of stay have also been reduced. Cardiac and pulmonary complications have been markedly reduced, whereas others such as pancreatic fistula still remain a problem. Modifications of the procedure have been introduced to improve long-term outcome of pancreatic cancer and to lessen digestive sequelae. Total pancreatectomy and large regional excisions did not improve results. However, 5-year survival rates of 20% are now reported by several centers for adenocarcinoma of the pancreas, and long-term survival rates for other periampullary tumors are approximately 40%. Pylorus-sparing procedures can be performed and may lessen postoperative sequelae. The clinical consequences of improved results are that large numbers of procedures are being performed at specialty centers, providing the opportunity to perform clinical trials, and that the procedure is used more widely, for instance, in benign diseases such as chronic pancreatitis.

The oligopeptide transporter (Pept-1), which is located in the intestinal brush border membrane, provides a major mechanism for protein absorption in the human intestine. Expression cloning of the gene encoding Pept-1 has predicted a 78,810-kilodalton protein consisting of 708 amino acid residues and possessing 12 putative membrane-spanning domains. The characterization of its function by in vivo and in vitro studies has shown that (1) it transports dipeptides and tripeptides but not free amino acids or peptides with more than three amino acid residues, and (2) its driving force for uphill transport requires proton binding and presence of an inside-negative membrane potential. There has also been cloning of a membrane protein (HPT-1) which appears to be associated with the oligopeptide transporter. However, the nature of association has not yet been determined. A human intestinal cell line (Caco-2), which expresses Pept-1, has been used to investigate the effects of metabolic and pathological factors on dipeptide transport. These studies suggest that the insulin stimulates dipeptide transport by increasing membrane insertion of oligopeptide transporter from a preformed cytoplasmic pool, and cholera toxin decreases dipeptide transport by inhibiting the activity of Pept-1 through an increase in the intracellular concentration of adenosine 3',5'-cyclic monophosphate. Lastly, Pept-1 seems to play important roles in nutritional and pharmacological therapies; for example, it has allowed the use of oligopeptides as a source of nitrogen for enteral feeding and the use of oral route for delivery of peptidomimetic drugs such as beta-lactam antibiotics.

The current chapter deals with the concept, clinical manifestations and diagnostic tools of the hepatopulmonary syndrome (HPS) and highlights its most salient pathophysiological, mechanistic and therapeutic aspects. Defined as a clinical triad, including a chronic liver disorder, pulmonary gas exchange abnormalities and generalized pulmonary vascular dilatations, in the absence of intrinsic cardiopulmonary disease, this entity is currently growing in interest with both clinicians and surgeons. The combination of arterial hypoxaemia, high cardiac output with normal or low pulmonary artery pressure, and finger clubbing in a patient with advanced liver disease should strongly suggest the diagnosis of HPS. Its potential high prevalence together with failure of numerous therapeutic approaches depicts a life-threatening unique clinical condition that may dramatically benefit with an elective indication of liver transplantation (LT). A better orchestration of the concepts of the pathophysiology of this lung-liver interplay may foster our knowledge and improve the clinical management and indications of LT.

In the past few years, there have been important advances in the field of pathogenesis and management of ascites and hepatorenal syndrome in cirrhosis. A new pathogenic theory of ascites and renal dysfunction in cirrhosis has been presented and previously ill-defined conditions, such as refractory ascites and hepatorenal syndrome, have been defined precisely. The link between the diseased liver and the disturbances in renal function and vasoactive systems is not completely known, but a large body of evidence indicates that it consists of a circulatory dysfunction that affects mainly the arterial circulation and is characterized by an inability to maintain an effective arterial blood volume within normal limits. The research on the mechanisms of this circulatory dysfunction will give valuable information in the design of more pathophysiologically oriented therapeutic approaches to the management of ascites.

The role of surgery in portal hypertension remains a topic of debate. For the past 100 years, various surgical procedures have been used to treat variceal bleeding, refractory ascites, and end-stage liver disease. The past decade has seen significant advances in pharmacotherapy, endoscopy, interventional radiology, and surgery for the management of patients with portal hypertension. Liver transplantation has come of age in the 1990s and is now an accepted therapy for patients with end-stage liver disease. The wide array of management options can complicate the decision making process and defines the need to evaluate these patients fully. Factors such as the aetiology and extent of liver disease, response to prior medical, endoscopic, and other interventional treatments, and possibility of future liver transplantation must be considered. This manuscript will review the history of surgical treatments of portal hypertension, describe the surgical procedures with their advantages and disadvantages, and evaluate their role in the elective and emergent settings.

Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure recently introduced for the management of complications of portal hypertension. TIPS can be placed in the liver with relative ease by a skilled radiologist with a low risk of mortality. The major complications following the procedure are infection, especially in patients undergoing emergency TIPS, intra-abdominal haemorrhage from capsular punctures, and long-term problems related to encephalopathy and stenosis of the shunt. Encephalopathy is more of a problem in older patients with wide diameter shunts. Stenosis of the shunt is related to pseudo-intimal hyperplasia, probably related to transection of bile ductules during placement of the shunt. In view of the high rate of encephalopathy and stenosis following the shunt, a careful follow-up of all patients, including ultrasonographic and angiographic examination of the shunt, is mandatory. TIPS is used predominantly for the control of acute variceal haemorrhage, prevention of recurrent variceal bleeding, and refractory ascites when conventional treatment has failed. However, the role of TIPS in the management of complications of portal hypertension still awaits the outcome of clinical trials.

Recent advances in the pharmacology of portal hypertension are reviewed, against the background of existing knowledge and current clinical research. The most recent trials are analysed, and conclusions made about the use of drugs in acute variceal haemorrhage, as well as directions for further clinical trials and research.

Endoscopic treatments for bleeding gastro-oesophageal varices include injection sclerotherapy, variceal obturation with tissue adhesives and variceal rubber band ligation. Today, endoscopic treatments are not recommended for the primary prophylaxis of variceal bleeding. Acute injection sclerotherapy remains a quick and simple technique for the control of active bleeding from oesophageal varices. Its efficacy may be improved by the early administration of vasoactive drugs. Banding ligation is the optimal endoscopic treatment for the prevention of rebleeding from oesophageal varices. The use of tissue adhesives and thrombin as injectates to treat bleeding fundal gastric varices and oesophageal varices not responding to vasoactive drugs or sclerotherapy is promising but needs further assessment by means of randomized controlled trials.

The introduction of pharmacological therapy has been one of the major advances in the treatment of the complications of portal hypertension. Many drugs have been shown to reduce portal hypertension in patients with cirrhosis. However, the most widely used drugs and the only ones for which there is sufficient evidence, are the beta-blockers. These drugs have been, up to now, the only accepted prophylactic therapy for oesophageal variceal bleeding and are also an alternative treatment to sclerotherapy or surgery to prevent variceal rebleeding. A reduction in portal pressure gradient by beta-blockers below 12 mmHg or by more than 20% of baseline values is associated with almost a total protection from oesophageal bleeding. Such a marked response in portal pressure is only achieved in some patients receiving propranolol. New pharmacological approaches with a greater portal pressure reducing effect may improve the beneficial effect of drugs in preventing variceal bleeding. The more promising approach is the combined administration of beta-blockers and isosorbide-5-mononitrate, which has been shown to potentiate the reduction in portal pressure and to be highly effective in initial randomized clinical trials.

The term portal hypertensive gastropathy (PHG) defines a wide spectrum of diffuse macroscopic lesions that appear in the gastric mucosa of patients with portal hypertension. Histologically, these lesions correspond to dilated vessels in the mucosa and submucosa in the absence of erosions or inflammation. Endoscopically, the lesions are classified as mild when mosaic pattern or superficial reddening are present, and severe when gastric mucosa appear with diffuse cherry red spots. Mild lesions are highly prevalent (65-90%), whereas severe lesions are present in only 10-25% of cirrhotic patients. The pathogenesis of PHG is not well known, but both venous congestion related with raised portal pressure and increased gastric blood flow seem to be crucial factors for its development. Variceal sclerosis may contribute to the development or aggravation of the lesions. Bleeding is the unique clinical manifestation of PHG, and occurs only in those patients with severe lesions. During a 5-year follow-up, the risk of overt bleeding or chronic bleeding, which induces anaemia, is 60 % and 90%, respectively, for patients with severe PHG. Propranolol is the only pharmacological treatment that has been proven useful in preventing bleeding from PHG. Porto-systemic shunts and liver transplantation are also effective.