The major risk factors for HCC are outlined in Table 2. Each factor may contribute to the multistep process of hepatocarcinogenesis. Hepatitis B virus and aflatoxins are the principal aetiological candidates and may be considered as initiators of the malignant state (see Figure 1). The majority of HCC arises via the cirrhotic pathway; the associated changes in the hormonal milieu may alter the handling of environmental carcinogens and the rounds of cell proliferation may increase sensitivity to sub-threshold doses of carcinogens. Exogenous androgens and oestrogens may operate through a similar mechanism to promote clonal expansion of preneoplastic cells. The importance of identifying the major aetiological factors lies in the possibility of prevention. The prognosis of HCC is dismal and it represents a major scourge in developing Third World countries. It is encouraging to think that the majority of cases could be prevented by the widespread use of hepatitis B vaccines and the development of intervention programmes against aflatoxin contamination of foodstuffs.

The 20-year period since the discovery of AFP by Abelev has seen the introduction of a wide range of new tumour markers and it is now clear that PLC is biologically heterogeneous. Hepatoblastomas, fibrolamellar carcinomas, hepatocellular carcinomas and cholangiocarcinomas may secrete a variety of distinctive markers which are predominantly glycoproteins, and may resemble those found in placenta or fetal liver. Diagnostically, AFP remains the best marker for HCC, both in sensitivity and specificity; it is known to consist of isoforms. In patients with elevated serum AFP and filling defects on liver scan, Con A reactive AFP may differentiate PLC from hepatic metastases, whilst fucosylated AFP may distinguish PLC from benign disorders when AFP is non-diagnostically elevated. With this recognition of tumour heterogeneity the value of a multiple-marker approach has become apparent. The measurement of vitamin B12 binding protein and neurotensin should lead to the detection of most patients with the fibrolamellar variant of HCC and many of these should be resectable. In patients with normal serum AFP levels, HCC-associated GGTP is of major value whilst in low-incidence areas for HCC, patients should also be screened for H-ALP; using a multiple marker approach in high-risk groups, 90% of clinically diagnosed hepatocellular carcinomas are serologically positive. The Chinese and Alaskan studies, in which small, potentially resectable tumours were detected, suggest that it is now possible to achieve 5-year survival figures of up to 60% in HCC patients detected by screening. The value of such a strategy in low-incidence countries is currently under study. In patient monitoring, as in diagnosis, AFP remains the outstanding marker. In AFP-negative patients, other markers including vitamin B12-binding protein, neurotensin, HCC-specific isoenzymes, des-gamma-carboxy-prothrombin and alpha-fucosidase, are of undoubted diagnostic value, but their value as indicants of disease progression remains to be established. In monitoring the response of hepatic metastases, CEA remains the least unsatisfactory marker but should always be used in conjunction with serial ultrasound scans. Tumour markers now play an important role in the diagnosis and monitoring of PLC but a role is also emerging in tumour imaging and drug targeting. The next 20 years should see the introduction of tumour markers of high sensitivity and specificity which make a fundamental contribution not only to detection and monitoring, but also to the effective treatment of liver cancer.

Findings by several groups of investigators have provided a reliable data base that supports a nonoperative approach toward the management of so-called silent gallstones. Considerable progress has been made in the medical dissolution treatment of selected patients with cholesterol gallstones. Ursodeoxycholic acid, and, more recently, a combination of ursodeoxycholic and chenodeoxycholic acids have been shown to be both effective and safe in dissolving gallstones that are predominantly composed of cholesterol. A drawback of the bile acid dissolution therapy lies in a significant recurrence rate after treatment is discontinued. Currently, several new methods of gallstone treatment are under study, which involve either the injection of a cholelitholytic solution, such as methyl tert-butyl ether, into the gallbladder or the use of mechanical means, such as excorporeally induced shock waves, to disintegrate gallstones. These treatments, however, are effective only if the stones are composed mainly of cholesterol without significant admixtures of calcium salts, pigment, or mucus. Most of the treatment failures are probably related to the presence of calcifications that are not visible on conventional radiographs. Future improvements of gallstone dissolution therapy can be expected from the following possible developments: improvement in ability to predict gallstone composition; dissolution of calcium salt-, pigment-, and mucus-containing stones; early treatment, before calcifications occur; combination of chemical and mechanical methods of treatment; stimulation of gallbladder contraction; prevention of stone recurrence after dissolution; and synthesis of new cholelitholytic agents.

Orally administered UDCA dramatically reduces the secretion of cholesterol into the bile. During UDCA therapy cholesterol balance is maintained by a reduction in both the relative and absolute absorption of cholesterol and, perhaps, by a combined moderate enhancement of bile acid synthesis and a suppression of cholesterol production. The percentage of UDCA in the bile is limited by the inability of UDCA to suppress bile acid synthesis from cholesterol and by the conversion of UDCA to CDCA by the intestinal bacteria.

The previous sections illustrate that we are still defining (a) which sets of lymphoid cells are present in the intestine and which are not, (b) which sets are peculiar to the intestine, and (c) how the sets that are there function in the intestinal microenvironment. An understanding of the latter point is going to require knowledge of how these sets communicate with and regulate one another via cell surface molecules such as MHC class I and class II molecules, and via soluble mediators or lymphokines. The recent advances in various technologies make this a particularly exciting time in this field because the tools are now available to address and answer some of these basic and important questions in mucosal immunology. At the same time these advances hold great promise for our eventual understanding of chronic inflammatory diseases of the intestine. As was mentioned at the outset, the immune system has considerable power for both protection and destruction. It remains a puzzle how this latter potential is contained and controlled in the intestine of most individuals, such that they do not have inflammatory disease even in the setting of intense stimulation by substances, such as endotoxin, that are phlogistic elsewhere in the body. An answer to the question of why everyone does not have intestinal inflammation could provide new insights into the mechanisms involved in chronic intestinal inflammatory diseases. The recent advances just detailed, as well as others sure to come, suggest that it is only a matter of time before such questions are answered.

This paper reviews the literature reports concerning sickle cell disease and the hepatobiliary system. Sickle cell disease can cause progressive injury to the liver with significant fibrosis, often cirrhosis, and decreased liver function by adulthood. Asymptomatic patients commonly have hepatomegaly and elevated liver enzyme levels. The presence of sickle cell disease obscures features otherwise useful in differential diagnosis. Acute episodes of the disease selectively affect the liver in 10% of patients, causing hepatic crisis with abdominal pain, nausea, fever, jaundice, and transaminase elevation. Viral hepatitis is often clinically indistinguishable from hepatic crisis, but in viral hepatitis the abdominal pain is usually less, the jaundice tends to be more severe, and the transaminase elevation more prolonged. The two can be distinguished by serology and liver biopsy. Furthermore, acute cholecystitis or choledocholithiasis may have clinical and laboratory features similar to sickle cell hepatic crisis or viral hepatitis. By adulthood, 50%-70% of sickle cell patients have gallstones. Elective cholecystectomy is indicated for those who are symptomatic, but, because of operative mortality, there is disagreement concerning surgery for asymptomatic patients. The literature contains nine well-documented cases of acute hepatic failure related to sickle cell disease. The mechanism is unclear; however, as the necrosis is often not severe, a metabolic problem is suggested.

It is apparent that renal water retention in patients with advanced liver disease constitutes a fascinating clinical constellation with numerous and diverse causes and an elusive pathophysiology. The dissociation between elevated AVP levels and the attendant changes in renal water handling under diverse experimental conditions, and the demonstration of an impairment in renal water excretion in response to prostaglandin synthetase inhibition, underscore the multifactorial nature of the derangement. It is likely that the development of impaired renal water handling is attributable to a panoply of several hormonal or neural mediators, or both, acting in concert. Additional insight into this fascinating problem must await further characterization of some of the mediators and a delineation of their pathophysiologic role.

In 1971 interest in the role of prostaglandins in the gastrointestinal tract was stimulated by the publication of two hypotheses--that aspirin damaged the gastric mucosa by inhibiting prostaglandin synthesis (1) and that cholera toxin caused diarrhea by stimulating it (2). Subsequent research into the gastrointestinal actions of prostaglandins has been considerable and now impinges on clinical practice. This paper reviews the involvement of prostaglandins and related compounds in mucosal protection, in ulcer healing, in diarrhea, and in gastrointestinal inflammation, with particular reference to the growing body of human data.

Most of the gastrointestinal tract and the biliary tract have a cyclic motor activity. The electric counterpart of this motor activity is called cyclic myoelectric activity. A typical motor cycle in the LES, stomach, and small intestine is composed of a quiescent state, followed by progressively increasing amplitude and frequency of contractions culminating in a state of maximal contractile activity. The colonic motor cycle has only the quiescent and the contractile states. In the small intestine, these motor complexes migrate in an aborad direction, and in the colon in both orad and aborad directions. The mechanisms of initiation and migration of these complexes are best understood in the small intestine. Both the initiation and migration of these complexes seem to be controlled by enteric neural mechanisms. The functions of the enteric mechanisms may be modulated by the central nervous system and by circulating endogenous substances. The mechanisms of initiation of these complexes are not completely understood in the rest of the gastrointestinal tract and in the biliary tract. The physiologic function of these motor complexes that occur only after several hours of fast in the upper gastrointestinal tract of nonruminants may be to clean the digestive tract of residual food, secretions, and cellular debris. This function is aided by a coordinated secretion of enzymes, acid, and bicarbonate. In ruminants, phase III activity is associated with the distal propulsion of ingested food. The function of colonic motor complexes that are not coordinated with the cyclic motor activities of the rest of the gastrointestinal tract may be only to move contents back and forth for optimal absorption.

The primary function of the SC-pIg system is to secrete pIgs into various external secretions. The cellular mechanism responsible for this transport is schematically depicted in Figure 5. Polymeric immunoglobulin A, which is synthesized by plasma cells that are part of the mucosa-associated lymphoid tissue, gains access to the SC on the abluminal surface of epithelial cells by diffusion from sites of synthesis in mucosae or enters the blood circulation and is cleared, largely by hepatic transport, into bile. The pIgA binds to SC on the abluminal surface of the epithelial cells (and probably hepatocytes) initially by noncovalent interactions that are saturable, reversible, and specific for pIgA and IgM. Subsequently, covalent interaction between SC and its ligand occurs to a variable degree in different species. The SC-IgA complex is endocytosed by the epithelial cell or hepatocyte and is transported across the cell into the external secretions by a microtubule-dependent vesicular transport mechanism. At some point during the transport, the complex is rendered soluble by proteolytic cleavage of the membrane-associated SC molecule to release the soluble sIgA into the gland lumen or the canaliculus. In the intestinal lumen, SC helps protect the sIgA molecule from proteolytic degradation. The sIgA may play a major role in the mucosal defense against pathogenic organisms or harmful antigens. The SC-pIg system differs from many of the other known receptor-ligand interactions in several important ways. First, the synthesis or expression of the receptor (SC), or both, are not regulated by the concentration of the ligand. Second, SC probably is not dissociated from its ligand or recycled to the cell surface as it is secreted in complex with its ligand (pIg) into the external secretions. Third, the interaction of pIgs with their receptor does not function to regulate an intracellular process, but results in transcellular transport of the ligand, which acts in the external environment. Fourth, after initial noncovalent, reversible binding between the receptor and its ligand, the interaction becomes covalent by the formation of disulfide linkages between SC and the pIg. Finally, SC is initially inserted into the abluminal domain of epithelial cells as an integral membrane protein and subsequently is proteolytically cleaved to a soluble molecule which is secreted by the cell. Thus, in contrast to many cell-surface receptor-ligand interactions in which the ligand is ultimately degraded and the receptor is conserved, the SC-pIgA interaction results in partial proteolytic degradation of the receptor and conservation of the ligand.(ABSTRACT TRUNCATED AT 400 WORDS)

The author reviews the literature on occult blood surveillance for colorectal carcinoma. The guaiac-based Hemoccult (SmithKline Diagnostics, Sunnyvale, Calif.) test is the most reliable and widely used. However, testing is complicated by several technical issues that can affect clinical results, and even successful screening programs will miss a high proportion of tumors. Public compliance is often poor, and a number of indirect and "hidden" costs make surveillance programs much more expensive than is usually claimed. Almost all published screening trials are uncontrolled. They generally detect about 3-20 colorectal malignancies for every 10,000 people enrolled, but only about 5%-10% of occult blood reactions are due to cancer. Though screen-detected tumors tend to be at a relatively early stage, this does not imply any benefit of surveillance because of lead time and length biases inherent in the screening process. Only controlled trials can answer the central question of whether screening decreases mortality from bowel cancer. Two such trials are underway, but mortality data are not yet available from either.