Gastric cancer is among the most prevalent malignant disorders in the world. Mortality has remained high because disease is often advanced at the time of diagnosis. In Japan, where gastric cancer is particularly common, nationwide screening programs have lead to increased early detection rates and potentially decreased mortality. In lower incidence regions like the West, population screening is not a realistic option, but surveillance of individuals at risk might be a more useful strategy. Adopting and optimal surveillance strategy requires careful quantification of cancer risk in patients with potentially premalignant gastric lesions such as gastritis, intestinal metaplasia, and dysplasia. In this issue of Gastroenterology, De Vries et al report their analysis of progression rates of premalignant gastric conditions to gastric cancer in a Western population. The authors used a national database of histopathology and cytopathology reports in the Netherlands to identify 90,316 patients with histologically confirmed first diagnoses of premalignant gastric lesions (atrophic gastritis, intestinal metaplasia, or dysplasia; excluding Barrett’s esophagus) between 1991 and 2005. There were equal numbers of men and women and the mean age at initial diagnosis increased with increasing severity of the lesions (from 60 for atrophic gastritis to 75 for severe dysplasia), and was higher in women than in men. For each patient, diagnostic codes concerning gastric biopsies after the first diagnosis of a premalignant gastric lesion to the end of the study period were retrieved. Reevaluation biopsies were present in only a subset of the patients (26% for atrophic gastritis to 61% for severe dysplasia), and these were younger than those without follow-up biopsies. Histologic follow-up data from 26,538 patients showed significantly more progression to more severe lesions in severe dysplasia compared with the less severe lesions. During follow-up, 1470 patients developed gastric cancer at a median age of 73.5 years. The median interval between initial diagnosis and gastric cancer was 1.6 years in patients with atrophic gastritis, 0.9 years for patients with intestinal metaplasia, 0.5 years in patients with mild to moderate dysplasia, and 0.1 year in patients with severe dysplasia (P < .001). Within 5 years’ follow-up, the annual incidence of gastric cancer in our Western population was 0.1% for patients with atrophic gastritis, 0.25% for intestinal metaplasia, 0.6% for mild to moderate dysplasia, and 6% for severe dysplasia. These numbers agree with the multistep model of gastric carcinogenesis where Helicobacter pylori causes chronic gastritis, which may progress through the premalignant stages of atrophic gastritis, intestinal metaplasia, and dysplasia to gastric adenocarcinomas. The progression of premalignant lesions to gastric cancer over the follow-up period is summarized in Figure 1. Based on these findings, early reexamination seems warranted in patients with severe dysplasia, and periodical surveillance seems indicated in all patients with dysplasia, but the risk of progression to cancer seems low for intestinal metaplasia and atrophic gastritis. In these groups, surveillance could be limited to young patients only. In multivariate analysis, age at diagnosis, severity of the premalignant lesion and male gender were all associated with increased risk for disease progression. The present data set provides important insights in cancer risk and approaches to better management of patients with premalignant gastric lesions. They suggest that systematic follow-up with endoscopy and biopsy sampling is indicated in patients with mild to moderate and with severe dysplasia on gastric biopsies. Strict surveillance with repeated multiple biopsy sampling should lead to early detection of cancer and better survival, through surgery or endoscopic resection of early neoplastic lesions. See page 945. Liver fibrosis occurs in the advanced stages of liver injury of varies etiologies. A precise estimation of the degree of liver fibrosis is important in determining the prognosis, surveillance, and treatment decisions in patients with chronic liver disease. Liver biopsy is the current reference standard for the assessment of liver fibrosis, but the method is invasive and not devoid of complications. A number of noninvasive methods for the assessment of liver fibrosis are under evaluation, including hematologic and biochemical tests, serum surrogate fibrosis markers and panels, extracellular matrix markers and panels, specialized tests for liver function, glycomics, proteomics, radiological imaging, and transient elastography (FibroScan). In transient elastography, a vibration is transmitted from a vibrator probe toward the tissue, which induces an elastic shear wave that propagates through the tissue. These, whose velocity is directly related to tissue stiffness, are followed by pulse-echo ultrasound acquisitions. Using this approach to estimate liver fibrosis, the method was reported to be easy to learn and highly reproducible, but its exact place in clinical management remains to be determined. In this issue of Gastroenterology, Friedrich-Rust et al report on a meta-analysis of studies that evaluated the performance of transient elastography for the diagnosis of liver fibrosis. The authors identified 15 full papers and 35 abstracts for inclusion in the analysis. Using the area under the receiver operating characteristic curve (AUROC), transient elastography performed best at differentiating cirrhosis from no cirrhosis (mean AUROC 94%). The AUROC for the detection of severe fibrosis was 89%. The method was less accurate (mean AUROC 84%) for the detection of significant fibrosis, a hallmark of progressive liver disease (Figure 2). Heterogeneity of AUROC for the detection of significant fibrosis decreased when distinctions were made between different underlying liver diseases. These results support the use of transient elastography in clinical practice for the confirmation of liver cirrhosis, for instance when other clinical signs and examinations are not decisive. They also suggest that transient elastography alone is insufficient for the detection of significant fibrosis, but may contribute to decision making when taking into account other clinical and diagnostic results. See page 960. Serum low-density lipoprotein (LDL) cholesterol levels are influenced by cholesterol synthesis, intestinal absorption, and biliary elimination. Hypopituitarism is associated with obesity, and in hypophysectomized rats, serum LDL cholesterol is dramatically increased when any cholesterol is ingested. The mechanism for the increased cholesterol absorption when pituitary function is disturbed was not known. In the study by Galman et al, hypophysectomized rats were used as a model to decipher the mechanism for pituitary cholesterol regulation. Hypophysectomized rats showed a 2- to 4-fold increase in serum and hepatic cholesterol after feeding when compared with pituitary-intact animals without any change in hepatic cholesterol 7α-hydrolase enzymatic activity, the rate-limiting enzyme in bile acid production. Increased intestinal absorption was through the Niemann-Pick C1-Like 1 (NPC1L1) protein; blockage of NPC1L1 with ezetimibe reversed the serum cholesterol increase in the hypophysectomized rats. The increased intestinal cholesterol absorption in hypophysectomized rats was reversed with l-thyroxine, but not growth hormone or cortisone (Figure 3), but there were no observed changes in expression of the intestinal cholesterol transporters NPC1L1 or ABCG5 and ABCG8. However, hepatic expression of ABCG5 and ABCG8 was strongly suppressed in hypophysectomized rats, and treatment with l-thyroxine dramatically increased the expression of these 2 cholesterol transporters (60- and 186-fold, respectively), with subsequent increase in biliary secretion of cholesterol that was in parity with an observed increase in the fecal excretion of cholesterol. Surprisingly, cholesterol feeding of the hypophysectomized rats normalized ABCG5 and ABCG8 expression, suggesting faulty regulation with feeding. Pituitary-intact rats treated with l-thyroxine increased ABCG5 and ABCG8 4- and 2.5-fold, respectively. The study indicates that thyroid hormone exerts a strong dampening effect on intestinal cholesterol absorption by controlling gatekeepers of hepatobiliary cholesterol transport. These findings may have implications for the regulation of cholesterol absorption in humans. See page 1127. Some patients with progressive familial intrahepatic cholestasis, a heterogeneous group of disorders with disrupted bile formation, have bile salt export pump (BSEP) deficiency. Patients often present as infants, and may have high serum bile salts, pruritis, and malabsorption, and can progress to jaundice, end-stage liver disease, and failure to thrive, often necessitating liver transplantation. BSEP is caused by mutations in ABCB11 (located on chromosome 2q24-31), a member of the ATP-binding cassette/multidrug resistance (ABC/MDR) family of transporters. Analysis of mutations of ABCB11 may provide clues that can predict genotype–phenotype correlations. In the study by Strautnieks et al, 109 families obtained from multiple sites around the world were analyzed for germline mutations in ABCB11 and hepatic expression of ABCB11, and were correlated with the occurrence of hepatocellular carcinoma (HCC) or cholangiocarcinoma. A total of 82 mutations in ABCB11 were identified, with the majority (55%) as missense mutations, but also nonsense, whole gene deletions, splice site alterations, and insertion/deletion mutations were identified. Biallelic mutations were identified in 93% of families. The mutations predicted to prematurely truncate the ABCB11 protein (comprising 45% of all mutations) were distributed throughout the protein, whereas most missense mutations clustered in 2 highly conserved nucleotide binding fold domains (Figure 4). Immunohistochemical detection of ABCB11 showed that 93% of patient’s livers had abnormal or absent BSEP. In the 15% of patients who developed HCC or cholangiocarcinoma, those with 2 protein-truncating mutations showed the highest risk (38% developed malignancy versus 10% of patients without truncating mutations). This study indicates the genetic distribution of ABCB11 mutations in patients with BSEP deficiency. Abnormal immunohistochemical detection of BSEP correlates well with the presence of mutation, and those with protein truncating mutations are at highest risk for hepatobiliary malignancy. See page 1203. Gastric Cancer Risk in Patients With Premalignant Gastric Lesions: A Nationwide Cohort Study in the NetherlandsGastroenterologyVol. 134Issue 4PreviewBackground & Aims: A cascade of precursor lesions (eg, atrophic gastritis, intestinal metaplasia, and dysplasia) precedes most gastric adenocarcinomas. Quantification of gastric cancer risk in patients with premalignant gastric lesions is unclear, however. Consequently, endoscopic surveillance is controversial, especially in Western populations. Methods: To analyze current surveillance practice and gastric cancer risk in patients with premalignant gastric lesions, all patients with a first diagnosis between 1991 and 2004 were identified in the Dutch nationwide histopathology registry (PALGA); follow-up data were evaluated until December 2005. Full-Text PDF Performance of Transient Elastography for the Staging of Liver Fibrosis: A Meta-AnalysisGastroenterologyVol. 134Issue 4PreviewBackground & Aims: Transient elastography has been studied in a multitude of liver diseases for the staging of liver fibrosis with variable results. A meta-analysis was performed to assess the overall performance of transient elastography for the diagnosis of liver fibrosis and to analyze factors influencing the diagnostic accuracy. Methods: Literature databases and international conference abstracts were searched. Inclusion criteria were as follows: evaluation of transient elastography, liver biopsy as reference, and assessment of the area under the receiver operating characteristic curve (AUROC). Full-Text PDF Dramatically Increased Intestinal Absorption of Cholesterol Following Hypophysectomy Is Normalized by Thyroid HormoneGastroenterologyVol. 134Issue 4PreviewBackground & Aims: Hypopituitarism is associated with dyslipidemia, and feeding hypophysectomized rats cholesterol induces severe hypercholesterolemia. This study aimed to unravel further how hypophysectomy alters cholesterol and bile acid metabolism. Methods: Intact and hypophysectomized rats were studied during challenge with dietary cholesterol and ezetimibe and upon hormonal substitution with growth hormone, cortisone, and thyroid hormone. Results: Five findings were established in hypophysectomized rats: (1) The intestinal absorption of cholesterol is doubled. Full-Text PDF Severe Bile Salt Export Pump Deficiency: 82 Different ABCB11 Mutations in 109 FamiliesGastroenterologyVol. 134Issue 4PreviewBackground & Aims: Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. Methods: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. Full-Text PDF