Variceal bleeding has a high mortality, as the majority of patients have cirrhosis, with hepatic coma, renal failure, ascites and clotting deficiencies as complicating factors. Bleeding varices must therefore be treated as an emergency. Resuscitation, endoscopic diagnosis and haemostasis are the cornerstones of treatment. Once bleeding varices have been identified, attempts to stop the bleeding must be made at once as this will lessen the chances of hepatic failure developing. Endoscopic sclerotherapy at the time of diagnosis is the best available treatment at present, although profusely bleeding varices can be difficult to see and inject. In these circumstances the passage of a Sengstaken tube should stop the bleeding, allowing later sclerotherapy to be successful. If rebleeding recurs and cannot be controlled, oesophageal transection with a stapling gun may be life-saving, although the varices may later recur and long-term endoscopic follow-up will be necessary. Portacaval shunting and the distal splenorenal shunt involve arduous surgery and are followed by a significant incidence of hepatic encephalopathy; they should be reserved for those few cases when simpler measures have failed, although shunts do lead to permanent decompression of the portal system. The acute variceal bleed may also be dealt with pharmacologically. Vasopressin, used in combination with nitroglycerin to lessen the harmful side-effects, is cheaper and as effective as terlipressin or somatostatin and its synthetic analogue octreotide. Several courses of injection sclerotherapy will be required to eliminate oesophageal varices. Thereafter, long-term follow-up will be necessary to deal with any recurrence. The place of non-selective beta-blockers is still contentious, but they do reduce portal pressure and may lessen the chance of rebleeding. There is also a growing role for hepatic transplantation, which not only eliminates the varices but also restores liver function to normal and greatly reduces the risk of subsequent hepatoma development.

A continuous IV infusion of vasopressin was administrated to a patient with cirrhosis of the liver and acute gastrointestinal bleeding from esophageal varices. In the first 24 hours, the patient developed rhabdomyolysis and cutaneous necrosis. Stopping vasopressin infusion resulted in relief of these lesions. The rarity of these complications suggests an idiosyncratic reaction of susceptible individuals that may be related to previous vascular disease or a failure in baroreceptor regulation.

Continuation of linear growth late into the third decade of life is rarely observed. This report describes a 27-year-old man with delayed growth and sexual maturation secondary to glycogen storage disease type I who grew 5.3 cm after orthotopic liver transplantation. Sequential improvement in selected measures of metabolic control (blood glucose, lactate, and bicarbonate concentrations) and growth-promoting peptides (testosterone and insulinlike growth factor I) were documented after transplantation and before the increase in height. Potential increases in final stature may be present in adult patients with underlying metabolic disease and delayed skeletal maturation.

As yet, there is limited information about the relationship of colonic motility to colonic flow or transit. The overall flow in the colon is slow and highly variable. The measurement of total and segmental transit time is essential for the differentiation of motor disorders associated with delayed transit. Rapid movements of colonic contents (mass movements) occur only a few times during the day. Their motor equivalent is the giant contraction which migrates in the aborad direction at relatively high velocity. Motor activity in the colon is highly variable, with periods of contraction and motor quiescence. Contractions occur at different frequencies ranging from 2 to 13 cycles per minute. High frequency contractions are stationary. Their myoelectrical equivalent is short spike bursts. Long spike bursts result in sustained, low frequency contractions, which may migrate in both directions. Technological advances now make it possible to obtain ambulant manometric recordings from the colon for 24 h. Such studies show a circadian variation in colonic motility with increases of activity after meals and after awakening. Motor disorders of the colon are not associated with specific abnormal motor patterns. Rather, they are due to changes in the occurrence of motor patterns seen in health. In constipated patients with slow colonic transit the suppression of strong peristaltic activity is the most plausible common pathogenetic mechanism. In diarrhoeal states, propulsive activity such as the giant migrating contractions may be a major mechanism which promotes the passage of stools. There is no agreement that there is disordered basal colonic motor activity in IBS. There is, however, increasing evidence that in IBS the colon responds abnormally to eating, certain forms of stress and distension, and that this may relate to symptoms. The psychopathology of IBS patients is apparently the most important factor in the health care-seeking behaviour of the patients. No specific therapy has yet been shown to be convincingly effective.

Disorders of small intestinal motility and transit are becoming increasingly recognized partly as a result of a greater awareness of their existence and partly because suitable diagnostic methods are more widely available. Usually, the neuropathic and myopathic forms can be separated, and gut disease secondary to a generalized neuromuscular disorder can be identified by the clinician. The availability of better non-invasive methods for the diagnosis of disorders of motility and transit would greatly facilitate their management. Treatment must include the restoration and maintenance of nutrition, attempts to improve intestinal motor function and resection of any segments of localized disease. Regrettably, all such measures are ineffective in the severest cases. In the future, a greater understanding of the enteric neural control of the smooth muscle and an ability to manipulate it with novel, specific drugs or peptidergic receptor agonists and antagonists, or electrical pacing, may lead to more effective therapies.

Gallbladder and sphincter of Oddi motility regulates the flow of bile from the liver to the duodenum. During the interdigestive period most secreted bile is diverted into the gallbladder where it is concentrated, but a significant minority of the biliary secretion passes directly into the duodenum. Regulation of this flow is mainly via the phasic contractions of the sphincter of Oddi and the sphincter basal tone. The phasic contractions expel small volumes of fluid into the duodenum, but most of the flow occurs between the contractions and is therefore not dependent on peristaltic pumping, but rather on a small pressure gradient. During fasting, just prior to duodenal phase III activity, the gallbladder expels up to 40% of its volume and the sphincter phasic contractions increase. Following a meal, the gallbladder empties its contents, and the sphincter of Oddi resistance is reduced via a fall in basal pressure and inhibition of the amplitude of phasic contractions. Control of this activity is via an interplay of both neuronal and hormonal factors which together have an effect on both gallbladder and sphincter of Oddi motility. Abnormalities in motility are recognized for both the gallbladder and the sphincter of Oddi. Gallbladder dyskinesia is objectively diagnosed using the radionuclide GBEF. In patients with a GBEF less than 40% cholecystectomy results in relief of symptoms. In postcholecystectomy patients sphincter of Oddi dysfunction presents as either biliary-like pain or idiopathic recurrent pancreatitis. Endoscopic sphincter of Oddi manometry provides the most objective diagnostic information. In patients with a sphincter of Oddi stenosis, characterized manometrically as an elevated basal pressure, division of the sphincter results in relief of symptoms. For patients with biliary-like pain, division is performed as an endoscopic sphincterotomy, whereas for patients with idiopathic recurrent pancreatitis, a sphincteroplasty and pancreatic duct septectomy are required.

Achalasia is the best understood of the motor disorders described in this chapter. The pathogenesis involves loss of intramural neurones, a process that subsequently results in poor lower sphincter relaxation and atony of the oesophageal body. Treatment is appropriately focused on mechanical or pharmacological alleviation of LOS obstruction. In contrast, the pathophysiology of DOS and the non-specific disorders remains poorly understood. Some of the non-specific disorders, such as the vigorous contraction wave abnormalities (including 'nutcracker oesophagus'), appear closely related to DOS. Treatment for patients with these findings has been based on assumptions about mechanisms of symptom production. The non-specific disorders are common in referred patients with oesophageal symptoms, and the importance of these findings deserves further study. We use a method for categorization of these manometric abnormalities which aids understanding of this difficult area and recommend its more widespread use.

Recurring substernal chest pain is an important clinical problem, causing anxiety for patients and their physicians because of the fear of possible cardiac disease. The differential diagnosis includes coronary artery disease, oesophageal disorders such as acid reflux disease and motility disturbances, musculoskeletal problems, psychological disorders including panic attacks, and a new 'fly in the ointment'--microvascular angina. History alone usually cannot distinguish cardiac from non-cardiac chest pain. After exclusion of significant coronary artery disease, attention must be turned to oesophageal disorders, which may be seen in as many as 50% of these patients. Oesophageal motility disorders, particularly the nutcracker oesophagus, are common, but the relationship between pain and abnormal contraction pressures is not well established. Provocative tests such as edrophonium (Tensilon) and balloon distension help to identify the oesophagus as the source of chest pain but do not direct therapy. Recent studies with ambulatory oesophageal monitoring suggest that gastro-oesophageal reflux may be a more common cause of chest pain than motility disorders. This is an important finding as acid reflux is a treatable problem, while therapies for motility disorders may only worsen reflux disease. The recent observation that oesophageal disorders are frequently associated and interact with psychological disorders such as anxiety, depression, somatization and panic attacks complicates the evaluation and understanding of chest pain. How these various abnormalities may be linked is an unresolved issue. Increased central nervous system stimulation and altered visceral and/or central pain sensitivity could be the common factors. It is hoped that further research into these areas will lead to new understandings of and possible solutions to the complex problem of non-cardiac chest pain.

Management of disordered oropharyngeal swallowing begins with careful assessment of the patient's oropharyngeal anatomy and physiology, medical status and cognitive, language and behavioural characteristics. More often, videofluoroscopic studies are performed which enable observation of bolus movement and movements of the oral cavity, pharynx and larynx throughout the swallow. Treatment for oropharyngeal dysphagia may take the form of compensatory strategies, direct therapy or indirect therapy. Compensatory strategies include postural changes and modification of bolus volume and consistency as well as rate of food presentation. These strategies are designed to eliminate the symptoms of the swallowing problem but may not directly change swallow physiology. Direct therapy techniques are designed to change swallow physiology and consist of oral sensory stimulation techniques and swallow manoeuvres, as well as maxillofacial prosthetics, medication and surgical procedures. Indirect therapy procedures are designed to improve the neuromuscular controls necessary for the swallow without actually producing a swallow. Specific swallowing treatment strategies within each category are described. In addition to assessing the patient's swallow physiology, the videofluoroscopic study of the swallow can be used as a treatment efficacy trial in which selected compensatory strategies or direct therapy techniques are used by the patient to improve their swallow safety and efficiency. Factors to be considered in the design of an overall treatment plan for a patient with disordered swallowing are defined.

Swallowing is a complex sequence of integrated motor events which is programmed entirely within a 'pattern generator', the medullary swallow centre. The swallow is not a reflex but rather a programmed response which is only initiated given the right combination of cortical and peripheral sensory cues to the medulla. Interruption of these afferent pathways profoundly influences the ability to initiate a swallow. While the basic sequence of motor events that constitutes a swallow is constant, the temporal relationships among component events are modifiable according to the characteristics of the swallowed bolus. The pathophysiology of dysphagia can be categorized on the basis of dysfunction of one or more of seven broad mechanisms that make up the swallow: bolus preparation, lubrication, oral delivery, palatal closure, airway closure, pharyngeal propulsion and UOS opening. This mechanistic approach originates directly from the videoradiographic observations and provides a rational basis for treatment. Videoradiography is the single most valuable technique in the evaluation of oral pharyngeal dysphagia. Oesophagoscopy and laryngoscopy should be performed in most cases because small tumours in the region can mimic pharyngeal motor disorders and may be easily overlooked. Manometry is providing valuable physiological and pathophysiological information about swallowing but, as an adjunct to videoradiography, only provides additional important information in the minority of patients undergoing investigation.

The molecular and biophysical characterization of Ca2+ channels in smooth muscle has lagged behind that in cardiac and skeletal muscles. This is caused by the difficulties in isolating viable cells and applying electrophysiological techniques to smooth muscle cells. The heterogeneity of smooth muscle cells from different organs also adds to the complexity. In spite of these problems there has been an increasing number of reports on Ca2+ channels in smooth muscle. This review provides an overview of this area. As in skeletal muscles, L (long-acting) and T (transient) voltage-dependent Ca2+ channels are found in smooth muscle; the former is better characterized. L channel is regulated by voltage, Ca2+, cyclic nucleotides, and protein kinase C. Ca2+ also influxes through receptor-operated channels that are voltage insensitive. The receptor-operated and T channels are insensitive to dihydropyridine. Clinically, Ca2+ blockers are extensively used for diseases of the cardiovascular system, with more limited use in the gastrointestinal tract. Further understanding of the properties of Ca2+ channels could lead to development of selective Ca2+ channel blockers for the gastrointestinal tract.

Primary biliary cirrhosis has been classified as a model autoimmune disease based on striking defects in immune regulation and the presence of autoantibodies to mitochondria. Until recently the significance and definition of mitochondrial autoreactivity was unknown. Since 1987, there has been a vast improvement in the understanding and definition of the biochemical and molecular target autoantigens. The cloning of complementary DNAs for mitochondrial antigens has led to the identification of three enzymes of the 2-oxo-acid dehydrogenase family as the targets of the autoantibodies to mitochondria in patients with primary biliary cirrhosis. The major reactive autoantigen is the E2 subunit of pyruvate dehydrogenase. Immunodominant sites on pyruvate dehydrogenase E2 (autoepitopes) have been mapped and have been shown to be the site of attachment of the functionally important lipoic acid prosthetic group. The autoepitope for the other enzymes probably occupies an equivalent site on the enzyme. The availability and definition of these mitochondrial autoepitopes have allowed specific questions to be addressed relating to the processing and targeting of these autoantigens as well as further studies on mechanisms of immunopathology. Similarly, the availability of well-defined autoantigens could contribute to the development of valid animal models in addition to the already described reproduction of the biliary ductular lesions by transfer of peripheral blood lymphocytes from patients with primary biliary cirrhosis into severe combined immunodeficient mice. Such models will facilitate specific study of the role of major histocompatibility complex expression and the characterization of T-cell reactivity. Thus, primary biliary cirrhosis is a key example of significant progress in autoimmunity being made by use of recombinant DNA technology.