Hepatocellular carcinoma (HCC), the most common primary hepatic malignancy, usually develops in patients with cirrhosis, growing sequentially from low-grade dysplastic nodules to frank malignant HCC. Its recognition is critical because curative treatment and prognosis require early diagnosis. Survival in patients with HCC relates directly to the number, size, and extent of lesions at diagnosis. Imaging of HCC is complicated because the tumor has a varied imaging appearance and frequently coexists with other cirrhotic nodules. Magnetic resonance imaging (MRI), the best available diagnostic technique, offers good contrast resolution and diagnostic sensitivity ranging from 33% to 77%. The main difficulty is not in diagnosing large tumors, but rather small tumors (<2 cm), because of considerable overlap on imaging between benign (regenerative), borderline (dysplastic), and malignant nodules. Increasing degrees of histological malignancy are associated with increasing arterialization and loss of portal blood supply; therefore, recognition of HCC requires dynamic imaging with gadolinium-enhanced T1-weighted sequence. Typically, HCC is a focal lesion with high signal intensity on T2-weighted images, variable signal intensity on T1-weighted images, intense arterial phase enhancement after gadolinium injection, and isointensity or hypointensity at the portal venous phase. The sensitivity of MRI for detecting small lesions is low, and improvement is still needed. Newer contrast agents, higher field strength (3 Tesla) imaging, and perfusion and diffusion MRI techniques possibly will provide greater sensitivity and specificity for detecting small HCCs in the future.

The ability of x-ray computed tomography (CT) to detect and characterize liver lesions has been one of the most studied issues in radiology during the past 20 years. Technological advances, combined with increased knowledge about the pathophysiological characteristics of these tumors, have dramatically increased the ability to detect and characterize large hepatocellular carcinomas (HCCs). Nonetheless, detection and characterization of early and small HCC lesions remains a difficult task. We review the imaging appearances of HCC on CT and discuss the sensitivity and specificity of computed tomographic imaging in screening patients with cirrhosis for HCC.

The diagnosis of hepatocellular carcinoma (HCC) includes detection of the index lesion, staging of the lesion within the liver, and assessment for extrahepatic metastasis. HCC is a highly vascular neoplasm usually arising in a cirrhotic liver. Based on this concept, consensus criteria have been developed for the radiographic diagnosis of HCC. These include: (1) identification of a mass >2 cm in diameter in a cirrhotic liver in 2 imaging modalities, and (2) contrast enhancement on computed tomography, magnetic resonance, or angiography. A mass lesion within a cirrhotic liver in the presence of a serum alpha-fetoprotein level >400 ng/mL also is diagnostic. For lesions <2 cm in diameter, histological confirmation is required. Serum markers for the diagnosis of early HCC (<2 cm in diameter) have not been established. Staging HCC for metastases is insensitive and is based on conventional criteria (eg, pulmonary nodules, skeletal metastases, and lymphadenopathy). Additional diagnostic techniques based on cytological advances, genomics, and proteomics are needed for the diagnosis and staging of this highly malignant neoplasm.

Refinements of serological markers and screening of patients at high risk for developing hepatocellular carcinoma (HCC) may lead to better HCC detection, earlier intervention, and successful treatment, improving long-term outcomes. Proteomics promises the discovery of biomarkers for early HCC detection and diagnosis. Proteomic-based profiling uniquely allows delineation of global changes in expression patterns resulting from transcriptional and posttranscriptional control, posttranslational modifications, and shifts in proteins between cellular compartments. Approaches to that effect include direct serum protein profiling and comparative analysis of protein expression in normal, precancerous, and early-stage tumor tissues. Identification of panels of tumor antigens that elicit a humoral response also may contribute to the discovery of new markers for HCC screening and diagnosis. Today, 2-dimensional polyacrylamide gel electrophoresis, multidimensional liquid chromatography, mass spectrometry, and protein microarrays are among the proteomic tools available for biomarker and drug target discovery. We review these technologies and their application to the study of HCC. Our objective is to provide a framework for appreciating the promise, while at the same time understanding the challenges behind translating proteomics discovery into novel diagnostic tests.

The incidence of hepatocellular carcinoma (HCC) is increasing worldwide; the overall survival of patients with HCC is grim because most patients are diagnosed late, when curative treatment is not possible. Cirrhosis is the strongest risk factor for the development of HCC. HCC surveillance with alpha-fetoprotein (AFP) and ultrasonography has been recommended for persons with cirrhosis. However, AFP level is insensitive for the early detection of HCC, and ultrasonography is expensive and operator dependent. Clearly, there is a need for novel strategies for the early detection of HCC. The ideal biomarker assay for HCC would be sensitive, specific, noninvasive, reproducible, inexpensive, and acceptable to patients. The Early Detection Research Network of the National Cancer Institute has proposed 5 phases for biomarker validation: preclinical exploratory studies, clinical assay development for disease, retrospective longitudinal study to detect preclinical disease, prospective screening study, and cancer control studies. Several biomarkers, such as des-gamma carboxyprothrombin, lens culinaris agglutinin-reactive AFP, human hepatocyte growth factor, and insulin-like growth factor-1, are promising, but none of these markers has been validated for clinical use. Limitations of the current literature include inadequate sample size, heterogeneity in biomarker assay methods and result reporting, limited analysis of demographics and cause of liver disease as covariates in the expression of these markers, and a scarcity of longitudinal studies evaluating the ability of biomarkers to detect preclinical disease. There is an urgent need for novel biomarkers for the detection of early HCC; the National Cancer Institute proposal provides a framework for future validation studies.

Although there is no definitive evidence that hepatocellular carcinoma (HCC) screening in high-risk groups improves survival, many physicians screen high-risk populations with various strategies. alpha-fetoprotein (AFP) and liver ultrasonography (US) are the most widely used tools. AFP sensitivity and specificity depend on the cut-off value chosen. In cirrhotic patients, using a cut-off level of 20 ng/mL, sensitivity is only around 60% and positive predictive value ranges from 9% to 50%, depending on HCC prevalence. Sensitivity and specificity are much higher (94.1% and 99.9%, respectively) in hepatitis B carriers, but positive predictive value is only 5%. The performance of US as a screening tool varies widely depending on the experience of the examiner and the technology used. Recent studies generally indicate a 60% sensitivity or higher, a specificity greater than 90%, and a positive predictive value of 70%. The cost effectiveness of screening strategies using AFP, US, or both have been estimated retrospectively or using decision models. In general, HCC screening using both AFP and US appears to be of borderline cost effectiveness or not cost effective at all. Based on the estimated HCC doubling time, the recommended screening interval is 6 months, although a 1-year interval seems as effective. Currently, HCC screening with AFP only is not recommended except when US is either not available or of poor quality. US seems more efficient as a screening tool. Pathology assessment of liver explants in living-donor transplantation programs will provide more precise and reliable information regarding the value of AFP and US as HCC screening tools.

Individuals with chronic viral hepatitis and other forms of liver disease are at risk for developing hepatocellular carcinoma (HCC). When HCC presents with clinical symptoms, the tumor is typically very far advanced and the patient has few therapeutic options. Thus, screening and surveillance for HCC would appear to very appropriate. However, there is no definitive evidence that surveillance improves patient outcomes and current techniques lack sensitivity and specificity. Nonetheless, serial measurement of alpha-fetoprotein (AFP) levels in serum and hepatic ultrasound have become routine practice, despite a lack of evidence of their overall benefit. Clearly, better methods are needed for early diagnosis of HCC. Improved technology will ultimately have to be tested for improved patient outcome before becoming widely recommended.

Computed tomographic colonography (CTC) was first described more than a decade ago. Recent advances in imaging hardware and software and results of clinical trials based on new methods for performing and interpreting images suggest that CTC may now be assessed as a method for colorectal cancer screening.

The existence of high- and low-affinity cholecystokinin (CCK)-A receptors on rodent pancreatic acini is well established. Until recently, CCK was believed to act directly on pancreatic acini to stimulate pancreatic secretion in both rodents and humans. However, conclusive evidence that human pancreatic acini lack functional CCK-A receptors has been presented. Despite substantial differences in rodent and human pancreatic physiology, CCK appears to act via vagal cholinergic pathways to mediate pancreatic secretion in both species. Structural and functional evidence suggests that CCK acts on vagal afferent fibers, which may explain how CCK doses that produce physiologic plasma CCK levels act via vagal cholinergic pathways to stimulate pancreatic secretion. Although most knowledge of vagal CCK-A receptors comes from research on rodents, physiologic studies suggest that this information is applicable to humans. In contrast to its effect on satiety, which is mediated by low-affinity vagal CCK-A receptors, CCK acts through high-affinity CCK-A receptors to evoke pancreatic secretion, suggesting that different affinity states of the vagal CCK receptors mediate different digestive functions. Vagal afferent pathways also transmit sensory information about the mechanical and physiochemical state of the digestive tract, mediated in part by serotonin, which, in turn, influences pancreatic secretion. A synergistic interaction between CCK and serotonin at the level of the nodose ganglia may explain the robust postprandial pancreatic secretion despite a modest postprandial increase in plasma CCK. Important physiologically, these findings not only explain discrepancies in previous in vivo vs. in vitro studies, but they revolutionize our current concept of the mechanism of CCK on pancreatic exocrine secretion.

Minute-to-minute behavior of the bowel, whether it is normal or disordered, is determined by integrative functions of the enteric nervous system (ENS). Information input processed by the ENS is derived from local sensory receptors, the central nervous system, and immune/inflammatory cells including mast cells. Enteric mast cells use the power of the immune system for detection of antigenic threats and for long-term memory of the identity of the specific antigens. Specific antibodies attach to the mast cells and enable the mast cell to detect sensitizing antigens when they reappear in the gut lumen. Should the sensitizing antigen reappear, mast cells detect it and signal its presence to the ENS. The ENS interprets the mast cell signal as a threat and calls up from its program library secretory and propulsive motor behavior that is organized to eliminate the threat rapidly and effectively. Operation of the alarm program protects the individual, but at the expense of symptoms that include cramping abdominal pain, fecal urgency, and diarrhea. Enteric mast cells use immunologic memory functions to detect foreign antigens as they appear and reappear throughout the life of the individual. Mast cells use paracrine signaling for the transfer of chemical information to the neural networks of the ENS. Integrative circuits in the ENS receive and interpret the chemical signals from the mast cells. Signals from the mast cells are interpreted by the ENS as a labeled code for the presence of a threat in the intestinal lumen.

Health economic analyses are increasingly common in the digestive diseases literature and often are cited to frame practice guidelines. Although clinical trials are subjected routinely to critical appraisal, there has been no attempt to appraise the quality of health economic analyses with a validated instrument. We sought to appraise the quality of health economic analyses in digestive diseases, and to identify predictors of study quality.

The diagnosis and management of Barrett's esophagus (BE) are controversial. We conducted a critical review of the literature in BE to provide guidance on clinically relevant issues.