Sarcoidosis Presenting as Necrotizing Sarcoid Granulomatosis of the Liver, Sclerosing Cholangitis, and Gastric Ulcer.

Sarcoidosis is a multisystem granulomatous disease. The liver is affected in up to 50-90% of cases. Sarcoidosis typically presents as non-necrotizing epithelioid granuloma.

Microarray gene analysis of the liver in a rat model of chronic, voluntary alcohol intake.

The mechanisms underlying alcoholic liver disease are not fully understood. It has been established that alcohol interferes with transcriptional and translational regulatory steps of cell function. To understand such an effect, assessment of alcohol-induced changes in the simultaneous expression of a large number of genes may prove very useful.

Elevation of ceramide in serum lipoproteins during acute phase response in humans and mice: role of serine-palmitoyl transferase.

Recent studies have indicated that ceramide generated in the liver is secreted into the bloodstream as component of very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL). This manuscript investigates the effect of host acute phase response to inflammation on lipoprotein ceramide levels. In humans, two different patterns of responses were found.

Transjugular intrahepatic portosystemic shunt migration in patients undergoing liver transplantation.

Transjugular intrahepatic portosystemic shunt (TIPS) is a useful procedure for patients with variceal bleeding and refractory ascites. Migration of TIPS can potentially complicate the subsequent transplant procedure. The aim of this study was to compare survival, operating time, and blood transfusion requirements in patients with migrated and nonmigrated TIPS undergoing liver transplantation.

The effect of endotoxin on hepatocyte nuclear factor 1 nuclear protein binding: potential implications on CYP2E1 expression in the rat.

The purpose of this study was to determine if changes in nuclear protein binding of hepatocyte nuclear factor 1 (HNF-1) occur after lipopolysaccharide (LPS) administration. In addition, the time-course of alterations in CYP2E1 regulation were evaluated. Rats were injected with 2.

Acetaminophen hepatotoxicity: An update.

Acetaminophen is a widely used nonprescription analgesic and antipyretic agent. It is also a dose-related hepatotoxin that can cause fulminant liver failure when taken in massive overdoses or, much less commonly, at therapeutic doses in susceptible individuals. Persons who regularly consume alcohol or persons who have been fasting may be more susceptible to this hepatotoxicity.

Depression of constitutive murine cytochromes P450 by staphylococcal enterotoxin B.

Most in vivo studies demonstrating decreased activities of hepatic cytochromes P450 with inflammation have used Gram-negative bacterial lipopolysaccharide (LPS) as the inflammatory stimulant. But products of Gram-positive bacteria, such as staphylococcal enterotoxin B (SEB), also stimulate inflammatory mediators, albeit with a different pattern than LPS. Therefore, effects of SEB on the regulation of murine constitutive P450s were determined in this study and compared with those of LPS.

The effect of endotoxin administration on the pharmacokinetics of chlorzoxazone in humans.

Objective: Inflammation induced by Escherichia coli lipopolysaccharide alters the clearance of several hepatically eliminated drugs. Extensive rat liver research has shown CYP2E1 down-regulation after lipopolysaccharide administration. To further investigate this phenomenon in humans, lipopolysaccharide was administered to healthy male volunteers and chlorzoxazone was used as a CYP2E1 probe drug.

Activities of conjugating and antioxidant enzymes following endotoxin exposure.

Endotoxin exposure elicits various responses in mammals including the acute phase response that has been shown to cause changes in the activity of several forms of cytochrome P450s and other enzymes. Therefore, the hepatic conjugating enzyme, glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UDPGT), the antioxidant enzymes, glutathione peroxidase (GSHPx), catalase, and superoxide dismutase (SOD), as well as lipid peroxidation were investigated following the administration of endotoxin to male Sprague-Dawley rats (8 mg/kg body weight). Rats were euthanized at various times following endotoxin administration and the livers removed and processed to assess various enzyme activities.

The effect of high dose endotoxin on CYP3A2 expression in the rat.

Purpose: The purpose of our research was two-fold: 1) to further characterize the downregulation of CYP3A2 mRNA, protein, and activity during an acute phase response (APR); 2) most importantly, to relate the time-dependent activation of nuclear proteins to putative DNA binding sequences within the CYP3A2 5'-flanking region, with the loss in CYP3A2 expression.

Methods: Rats were injected (2.0 mg/animal, i.

Stability of cephalosporin prodrug esters in human intestinal juice: implications for oral bioavailability.

The levels of degradation of cefetamet pivoxil (CAT), cefuroxime axetil (CAE), and cefpodoxime proxetil (CPD) in 0.6 M phosphate buffer (pH 7.4) and human intestinal juice (pH 7.

Role of iron in the natural history and clinical course of hepatitis C disease.

The following review evaluates the current data implicating a role for hepatic iron in enhancing the liver injury in patients with chronic hepatitis C infection. Iron removal lowers transaminases, but doesn't appear to improve responsiveness to interferon-alpha therapy. An important effect of iron removal might be to delay progression of liver injury to fibrosis and cirrhosis.

Ascorbic acid deficiency in porphyria cutanea tarda.

Porphyria cutanea tarda (PCT), the most common form of porphyria, is manifested as skin photosensitivity caused by excess hepatic production of uroporphyrin and heptacarboxylporphyrin. In experimental animal models, ascorbic acid modulates chemically induced uroporphyrin accumulation. The purpose of this study was to determine whether ascorbic acid is decreased in the plasma of patients with PCT.

Effects of endotoxin on zinc metabolism in human volunteers.

After stress or trauma, the serum zinc concentration decreases. This study evaluated possible mechanisms for hypozincemia with the use of a human endotoxemia model. Two doses of endotoxin [lipopolysaccharide (LPS)] were administered on consecutive mornings to 12 healthy volunteers, and each subject was also studied after saline injection.

Endotoxin depresses hepatic cytochrome P450-mediated drug metabolism in women.

Aims: In men, the inflammatory response to intravenous endotoxin depresses apparent oral clearances of antipyrine, hexobarbitone, and theophylline. The aim of this study was to investigate whether there might be gender differences in the regulation of hepatic cytochromes P450.

Methods: Experiments were carried out in seven healthy women volunteers (ages 19-51, median 22 years).

Cytokines and alcoholic liver disease.

Chemical messengers called cytokines play an important role during the body's initial response to infection (i.e., acute inflammation).

In vitro tumor necrosis factor cytotoxicity in Hep G2 liver cells.

Tumor necrosis factor-alpha (TNF-alpha) is a mediator of liver injury. The objective of this study was to develop an in vitro model of TNF-mediated liver cell injury using the Hep G2 cell line. Hep G2 cells normally are insensitive to TNF cytotoxicity, but they were rendered susceptible, or sensitized, to TNF cytotoxicity by inhibitors of RNA and protein synthesis.

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections.

Head injury and cytochrome P-450 enzymes. Differential effect on mRNA and protein expression in the Fischer-344 rat.

Head trauma produces debilitating injuries that affect millions of people each year. Such injuries lead to a cascade of physiologic sequelae resulting in a hypercatabolic/hypermetabolic state. Current information describing changes in hepatic drug metabolism as a result of head trauma is limited.

Effects of interferon-alpha monotherapy on hepatic drug metabolism in cancer patients.

1. The influence of interferon-alpha (IFN alpha) on the clearances of theophylline (TH), antipyrine (AP) and hexobarbitone (HB) was studied in seven cancer patients given IFN alpha as their only treatment. In addition, IFN alpha effects on drug clearance were correlated with changes in serum inflammatory cytokines and acute phase proteins.

Tumor necrosis factor in alcohol enhanced endotoxin liver injury.

Endotoxin administration causes liver injury. Patients with alcoholic liver disease frequently have portal vein and systemic endotoxemia, and some investigators have suggested that endotoxin plays an etiologic role in alcoholic liver injury. Many of the metabolic effects of endotoxin are mediated by the cytokine tumor necrosis factor (TNF).

Increased plasma interleukin-6 concentrations in alcoholic hepatitis.

Interleukin-6 (hepatocyte stimulating factor) is a 26 kd cytokine that plays a major role in the acute phase response, especially the hepatic aspects of the acute phase response. Patients with alcoholic hepatitis manifest many aspects of the acute phase response. In this 6-month study we evaluated serial plasma interleukin-6 levels in 30 consecutive patients with moderate to severe alcoholic hepatitis.

The calcium channel blocker nisoldipine minimizes the release of tumor necrosis factor and interleukin-6 following rat liver transplantation.

Kupffer cells, when activated, release toxic cytokines such as tumor necrosis factor (TNF), which can cause tissue injury. Takei et al. have reported that nisoldipine, a calcium channel blocker which decreases phagocytotic activity by Kupffer cells, also diminishes liver and lung injury and dramatically improves survival following liver transplantation.