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Gastrointestinal lesions (in both the upper gastrointestinal tract and the colon) are frequently found in patients with iron-deficiency anemia. Since site-specific symptoms are predictive of abnormalities in the corresponding portion of the bowel, the initial evaluation should be directed by the location of the symptoms. Concomitant lesions of the upper and lower gastrointestinal tract are rare; thus, detection of a likely source of blood loss during the initial examination may obviate the need for further procedures.

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Drug-induced liver injury (DILI) is largely a diagnosis of exclusion and is therefore challenging. The US Drug-Induced Liver Injury Network (DILIN) prospective study used two methods to assess DILI causality: a structured expert opinion process and the Roussel-Uclaf Causality Assessment Method (RUCAM). Causality assessment focused on detailed clinical and laboratory data from patients with suspected DILI. The adjudication process used standardized numerical and descriptive definitions and scored cases as definite, highly likely, probable, possible, or unlikely. Results of the structured expert opinion procedure were compared with those derived by the RUCAM approach. Among 250 patients with suspected DILI, the expert opinion adjudication process scored 78 patients (31%) as definite, 102 (41%) as highly likely, 37 (15%) as probable, 25 (10%) as possible, and 8 (3%) as unlikely. Among 187 enrollees who had received a single implicated drug, initial complete agreement was reached for 50 (27%) with the expert opinion process and for 34 (19%) with a five-category RUCAM scale (P = 0.08), and the two methods demonstrated a modest correlation with each other (Spearman's r = 0.42, P = 0.0001). Importantly, the RUCAM approach substantially shifted the causality likelihood toward lower probabilities in comparison with the DILIN expert opinion process. Conclusion The structured DILIN expert opinion process produced higher agreement rates and likelihood scores than RUCAM in assessing causality, but there was still considerable interobserver variability in both. Accordingly, a more objective, reliable, and reproducible means of assessing DILI causality is still needed.

Leptin is a 16-kd hormone that mediates a range of metabolic effects by using a transduction pathway from the long form of the leptin receptor, OB-R L, through Janus kinase-signal transducer and activator of transcription (Jak-Stat) signaling components. Leptin is produced by hepatic stellate cells (HSCs) but only following their "activation." Because activation of stellate cells is a central event in the fibrotic response to liver injury, we hypothesized that leptin may directly stimulate fibrogenesis in activated stellate cells via OB-R L . We analyzed leptin receptors and their signaling partners in a stellate cell line (HSC-T6) as well as in primary stellate cell isolates. We also examined the effect of leptin on stellate cell expression of ␣ 2 (I) collagen messenger RNA (mRNA) levels by ribonuclease protection analysis (RPA). L eptin, a 16-kd peptide product of the ob gene, 1 is a potent adipocyte-derived hormone that plays a key role in the control of energy balance and food intake. [2][3][4] Leptin receptors, initially found primarily in central nervous tissues such as the hypothalamus, 5 have also been localized to other tissues, including the liver. 6 Leptin signaling is mediated by the leptin receptor (OB-R), a member of the hematopoietin receptor family that is most closely related to the signal-transducing subunits of the interleukin 6 -type cytokine receptors. 5,7,8 In humans and rodents, at least 2 predominant forms of OB-R are detected. Both isoforms have identical extracellular domains and ligand-binding affinity but differ in the intracellular domains, which represent alternative splice products. The major OB-R short form (OB-R S ), a 34 -amino acid cytoplasmic domain, is found in many organs. However, despite normal ligand-binding activity, OB-R S is considered incapable of signaling. 9,10 In contrast, the long form (OB-R L ) is the signaling-competent receptor isoform and contains a 302-amino acid cytoplasmic domain. 9-11 Reversetranscription polymerase chain reaction (RT-PCR) and ribonuclease protection analysis (RPA) show that various peripheral organs, including the liver, have detectable levels of messenger RNA (mRNA) encoding OB-R L , 9 imply-

Abstract. We have examined the cell-specific expression of two fibronectin isoforms, EIIIA and EIHB, during experimental hepatic fibrosis induced by ligation of the biliary duct. At the mRNA level, EIIIA and EIIIB were undetectable in normal liver but expressed early in injury, preceding fibrosis. The cellular sources of these changes were determined by fractionating the liver at various time points after bile duct ligation into its constituent cell populations and extracting RNA from the fresh isolates. EIllA-containing fibronectin mRNA was undetectable in normal sinusoidal endothelial cells but increased rapidly within 12 h of injury. By contrast, the EIIIB form was restricted to hepatic lipocytes (Ito or fat-storing cells) and appeared only after a lag of 12-24 h: it was minimal in sinusoidal endothelial cells. Both forms were minimal in hepatocytes. At the protein level, EIIIA-containing fibronectin was markedly increased within two days of injury and exhibited a sinusoidal distribution. Secretion of this form by endothelial cells was confirmed in primary culture. Matrices deposited in situ by endothelial cells from injured liver accelerated the conversion ("activation") of normal lipocytes to myofibroblast-like cells, and pretreatment of matrices with monoclonal antibody to the EIIIA segment blocked this response. Finally, recombinant fibronectin peptide containing the EIIIA segment was stimulatory to lipocytes in culture. We conclude that expression of EIIIA fibronectin by sinusoidal endothelial cells is a critical early event in the liver's response to injury and that the EIIIA segment is biologically active, mediating the conversion of lipocytes to myofibroblasts.

Pyogenic liver abscess (PLA) is an important entity with a changing clinical spectrum and may be more prevalent than previously reported. PLA remains most common in older patients, although we found a trend in age range downward. In contrast to earlier reports, PLA affected male and female patients with equal frequency. The most common known cause of PLA remains biliary tract disease, but the majority of patients with PLA were those in whom no underlying cause of PLA could be identified. Single PLA was more common than multiple PLA regardless of etiology. The clinical presentation of patients with PLA ia nonspecific and emphasizes the fact that a high index of suspicion is often required to make the diagnosis. Jaundice and a markedly elevated alkaline phosphatase are clues to the possibility of biliary tract involvement, but may not distinguish patients with liver abscess from those with other hepatic processes. While plain chest and abdominal X-rays were often abnormal and may point to the right upper quadrant as a source of abnormality, ultrasound (US) and abdominal computed tomography (CT) play a central role in this disease. Not only are they often paramount in elucidating the diagnosis of PLA, but US and CT are critical because of their ability to provide other useful information that may address the cause of PLA (that is the biliary tract, and in the case of abdominal CT, other structures). Further, our data suggest that in patients without clinical or imaging evidence of biliary tract disease or pylephlebitis, aggressive random evaluation of the intestinal tract is unwarranted. Percutaneous drainage combined with intravenous antibiotics was the most common therapeutic modality and resulted in cure in 76% of all patients in which it was used (compared to 65% with antibiotics alone and 61% with surgery) and has been successful in 90% of patients over the last 5 years (n = 50). In this study, percutaneous catheter drainage (PCD) appeared to result in a higher cure rate than percutaneous needle aspiration (PNA) but comparative studies are required to further address and determine their relative efficacies. Intravenous antibiotics alone are an important option in carefully selected patients. Surgical intervention as a primary mode of therapy has been almost completely replaced by less invasive approaches such as PCD/PNA, but remains an important consideration in patients who fail these therapies. Although PLA was once considered a fatal disease, the prognosis is now excellent. We have identified a subgroup of patients with no or low-level elevations in bilirubin and alkaline phosphatase and most often single right-sided PLA who do not have a readily identifiable cause of PLA (that is, cryptogenic), as having a particularly favorable prognosis. Death due to PLA is now limited primarily to those patients with severe underlying disease processes, including malignancy.