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The article discusses the increasing evidence regarding the association between nonalcoholic fatty liver disease and a risk of cardiovascular disease in the case of such patients. The different treatment methodologies and management regime for the same are highlighted.

A study was conducted to evaluate whether certain gene modifiers were associated with severe liver disease in patients with cystic fibrosis (CF). Results indicated that the SERPINA1 Z allele was associated with risk of developing the disease.

Environmental heat stress is associated with an age-related increase in hepatic oxidative damage and an exaggerated state of oxidative stress. The purpose of this investigation was to evaluate the regulation of hepatic iron after heat stress. A secondary aim was to determine a potential role for iron in heat stress-induced liver injury. Hyperthermia-induced alterations in hepatic iron were evaluated in young (6 mo) and old (24 mo) Fischer 344 rats by exposing them to a two-heat stress protocol. Livers were harvested at several time points after the second heating and assayed for labile and nonheme iron. In the control condition, there was no difference in labile iron between age groups. Both labile iron and storage iron were not altered by hyperthermia in young rats, but both were increased immediately after heating in old rats. To evaluate a role for iron in liver injury, hepatic iron content was manipulated in young and old rats, and then both groups were exposed to heat stress. Iron administration to young rats significantly increased hepatic iron content and ferritin but did not affect markers of lipid peroxidation under control conditions or after heat stress. In old rats, iron chelation with deferoxamine prevented the increase in nonheme iron, labile iron, ferritin, and lipid peroxidation after heat stress. These results suggest that iron may play a role in hepatic injury after hyperthermia. Thus, dysregulation of iron may contribute to the gradual decline in cellular and physiological function that occurs with aging. reactive oxygen species; deferoxamine; hyperthermia; electron paramagnetic resonance spectroscopy; inflammation

Recent studies have implicated dysregulation of the endocannabinoid system in various liver diseases and their complications (e.g., hepatitis, fibrosis, cirrhosis, cirrhotic cardiomyopathy, and ischemia-reperfusion), and demonstrated that its modulation by either cannabinoid 2 ([CB.sub.2]) receptor agonists or [CB.sub.1] antagonists may be of significant therapeutic benefits. This review is aimed to focus on the triggers and sources of endocannabinoids during liver inflammation and on the novel role of [CB.sub.2] receptors in the interplay between the activated endothelium and various inflammatory cells (leukocytes, lymphocytes, etc.), which play pivotal role in the early development and progression of inflammatory and other liver diseases. ischemia-reperfusion; endocannabinoids; cannabinoid 2 receptor; inflammation; endothelium

Iron deficiency seems to deteriorate vitamin A metabolism leading to a reduction in serum retinol and an increase in hepatic retinol and retinyl ester. These alterations probably result from an increase in retinol sequestration to the liver and/or impairment in the activity of hepatic retinyl ester hydrolases decreasing vitamin A mobilization.

CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is a key component in endoplasmic reticulum (ER) stress-mediated apoptosis. The goal of the study was to investigate the role of CHOP in cholestatic liver injury. Acute liver injury and liver fibrosis were assessed in wild-type (WT) and CHOP-deficient mice following bile duct ligation (BDL). In WT livers, BDL induced overexpression of CHOP and Bax, a downstream target in the CHOP-mediated ER stress pathway. Liver fibrosis was attenuated in CHOP-knockout mice. Expression levels of co-smooth muscle actin and transforming growth factor-[beta]1 were reduced, and apoptotic and necrotic hepatocyte death were both attenuated in CHOP-deficient mice. Hepatocytes were isolated from WT and CHOP-deficient mice and treated with 400 [micro]M glycochenodeoxycholic acid (GCDCA) for 8 h to examine bile acid-induced apoptosis and necrosis. GCDCA induced overexpression of CHOP and Bax in isolated WT hepatocytes, whereas CHOP-deficient hepatocytes had reduced cleaved caspase-3 expression and a lower propidium iodide index after GCDCA treatment. In conclusion, cholestasis induces CHOP-mediated ER stress and triggers hepatocyte cell death, and CHOP deficiency attenuates this cell death and subsequent liver fibrosis. The results demonstrate an essential role of CHOP in development of liver fibrosis due to cholestatic liver damage. apoptosis; necrosis; endoplasmic reticulum stress; transforming growth factor-[beta]1; bile duct ligation

Alterations in mitochondrial function have been implicated in the pathogenesis of insulin resistance and type 2 diabetes. However, it is unclear whether the reduced mitochondrial function is a primary or acquired defect in this process. To determine whether primary defects in mitochondrial [beta]-oxidation can cause insulin resistance, we studied mice with a deficiency of long-chain acyl-CoA dehydrogenase (LCAD), a key enzyme in mitochondrial fatty acid oxidation. Here, we show that LCAD knockout mice develop hepatic steatosis, which is associated with hepatic insulin resistance, as reflected by reduced insulin suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. The defects in insulin action were associated with an [approximately equal to] 40% reduction in insulin-stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity and an [approximately equal to] 50% decrease in Akt2 activation. These changes were associated with increased PKC[epsilon] activity and an aberrant 4-fold increase in diacylglycerol content after insulin stimulation. The increase in diacylglycerol concentration was found to be caused by de novo synthesis of diacylglycerol from medium-chain acyl-CoA after insulin stimulation. These data demonstrate that primary defects in mitochondrial fatty acid oxidation capacity can lead to diacylglycerol accumulation, PKC[epsilon] activation, and hepatic insulin resistance. diacylglycerol | mitochondria | nonalcoholic fatty liver disease | PKC[epsilon]

Sepsis is associated with an activation of the coagulation system and multiorgan failure. The aim of the study was to examine the effects of selective thrombin inhibition with melagatran on renal hemodynamics and function, and liver integrity, during early endotoxemia. Endotoxemia was induced in thiobutabarbital-anesthetized rats by an intravenous bolus dose of lipopolysaccharide (LPS; 6 mg/kg). Sham-Saline, LPS-Saline, and LPS-Melagatran study groups received isotonic saline or melagatran immediately before (0.75 [micro]mol/kg iv) and continuously during (0.75 [micro]mol*[kg.sup.-1] iv) 4.5 h of endotoxemia. Kidney function, renal blood flow (RBF), and intrarenal cortical and outer medullary perfusion (OMLDF) measured by laser-Doppler flowmetry were analyzed throughout. Markers of liver injury and tumor necrosis factor (TNF)-[alpha] were measured in plasma after 4.5 h of endotoxemia. In addition, liver histology and gene expression were examined. Melagatran treatment prevented the decline in OMLDF observed in the LPS-Saline group (P < 0.05, LPS-Melagatran vs. LPS-Saline). However, melagatran did not ameliorate reductions in mean arterial pressure, RBF, renal cortical perfusion, and glomerular filtration rate or attenuate tubular dysfunctions during endotoxemia. Melagatran reduced the elevated plasma concentrations of aspartate aminotransferase (-34 [+ or -] 11%, P < 0.05), alanine aminotransferase (-21 [+ or -] 7%, P < 0.05), bilirubin (-44 [+ or -] q%, P < 0.05), and TNF-[alpha][(-32 [+ or -] 14%, P < 0.05) in endotoxemia. Melagatran did not diminish histological abnormalities in the liver or the elevated hepatic gene expression of TNF-[alpha], intercellular adhesion molecule-1, and inducible nitric oxide synthase in endotoxemic rats. In summary, thrombin inhibition with melagatran preserved renal OMLDF, attenuated liver dysfunction, and reduced plasma TNF-[alpha] levels during early endotoxemia. acute kidney failure; acute liver failure; coagulation; multiple organ failure; sepsis

We used a congenic C57B1/6J cystic fibrosis transmembrane conductance regulator [(Cftr).sup.-/-] mouse model, which develops cystic fibrosis (CF)-like pathology in all organs, to evaluate the short- and long-term therapeutic effects of dietary docosahexaenoic acid (DHA). Thirty-day-old [(Cftr).sup.-/-] mice and wild-type littermates were randomized to receive a liquid diet with or without DHA (40 mg/day). Animals were killed for histological and lipid analysis after 7, 30, and 60 days of therapy. DHA had no significant therapeutic or harmful effect on the lung, pancreas, or ileum of the [(Cftr).sup.-/-] mice or their wild-type littermates. In contrast, dietary DHA resulted in highly significant amelioration of the severity of liver disease in the [(Cftr).sup.-/-] mice, primarily a reduction in the degree of peri-portal inflammation. Additionally, these detailed measurements confirm our previous findings that [(Cftr).sup.-/-] mice have significant alterations in the pancreas (except external acinar diameter), ileum, liver, lung, and salivary (except sublingual) glands at all ages compared with their age-matched wild-type littermates. In conclusion, inhibition of cytokines and/or eicosanoid metabolism and release of endogenous inhibitors of inflammation by DHA may account for the anti-inflammatory effects in the liver of this congenic murine model of CF. The potential therapeutic benefits of DHA in severe CF-associated liver disease remain to be explored. cystic fibrosis transmembrane conductance regulator; postnatal organ development; anti-inflammatory effect; cystic fibrosis-associated liver disease

Liver injury secondary to blunt abdominal trauma is a well-defined entity in emergency medicine. A challenge exists in the diagnosis of liver trauma in the stable, well-appearing patient with a [...]

Cryptogenic liver disease (CLD) is defined as persistently elevated aminotransferases levels in the absence of Hepatitis C and/or B viruses replication and of other common causes of liver disease. An analysis concluded that CLD is an uncommon condition in HIV-positive individuals and might be associated with prolonged didanosine.

Nonalcoholic fatty liver disease is the most common reason for abnormal liver chemistries in the United States. The factors that lead from benign steatosis to nonalcoholic steatohepatitis are poorly understood. Transthyretin-Abcb11 (TTR-Abcb11) transgenic mice overexpress the bile salt transporter Abcb11 and hypersecrete biliary lipids. Thus the aim of this study is to employ feeding of the methionine-choline-deficient (MCD) diet to TTR-Abcb11 transgenic mice to further determine the mechanisms responsible for the development of steatohepatitis. FVB/NJ and TTR-Abcb11 mice were fed control or MCD diets for up to 30 days. Serum aminotransferase levels, serum and hepatic triglyceride content, cytokines, markers of oxidative stress, and expression of selective genes were examined. MCD diet-fed TTR-Abcb11, but not wild-type, mice have elevated serum aminotransferase levels when compared after 7 days. They also have significantly lower hepatic triglyceride levels at all time points studied. After 14 days on the MCD diet, TTR-Abcb11 mice have 3-fold increases in TNF-[alpha] mRNA and 3.9-fold increases in IL-6 mRNA compared with FVB/NJ mice. TTR-Abcb11 mice also had a greater increase in cytochrome P-450 2E1 expression. A greater decrease in sterol regulatory element binding protein-1c and fatty acid synthase mRNA expression was also seen in TTR-Abcb11 compared with wild-type mice fed an MCD diet. They also have enhanced TNF-[alpha] IL-6, and cytochrome P-450 2E1 expression. We conclude that TTR-Abcb11 mice develop a more rapid hepatitis with less steatosis. nonalcoholic steatohepatitis; oxidative stress; cytokines

Cholestasis is associated with accumulation of bile acids and lipids, and liver injury. The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic nuclear receptors that coordinate protective hepatic responses to potentially toxic stimuli, including bile acids. We investigated the role of these receptors in the regulation of bile acid and lipid metabolism in a bile duct ligation (BDL) model of cholestasis applied to receptor knockout mice. Hepatic damage from bile acid accumulation was increased in both CAR knockout (CARKO) and PXR knockout mice, but bile acid concentrations were lower in CARKO mice. High-density lipoprotein (HDL) cholesterol was elevated in CARKO mice, and serum total cholesterol increased less in CARKO or PXR knockout mice than WT mice after BDL. Gene expression analysis of the BDL knockout animals demonstrated that, in response to cholestasis, PXR and CAR both repressed and induced the specific hepatic membrane transporters Oatp-c (organic anion transporting polypeptide C) and Oatp2 ([Na.sup.+]-dependent organic anion transporter 2), respectively. Induction of the xenobiotic transporter multidrug resistance protein 1 in cholestasis was independent of either PXR or CAR, in contrast to the known pattern of induction of multidrug resistance protein 1 by xenobiotics. These results demonstrate that CAR and PXR influence cholesterol metabolism and bile acid synthesis, as well as multiple detoxification pathways, and suggest their potential role as therapeutic targets for the treatment of cholestasis and lipid disorders. bile acid | cholestasis | high-density lipoprotein | cholesterol

Byline: Carlos Abramowsky (1,2), Rene Romero (2), Thomas Heffron (2,3) Keywords: children; noncirrhotic liver; portal hypertension Abstract: From 1995--2002, 14 patients with predominantly prehepatic, noncirrhotic portal hypertension were evaluated. At presentation, the eight females and six males had a mean age of 9 years (range 2--18). Seven were admitted with gastrointestinal, mostly esophageal bleeding, three with splenomegaly, three with hepato-pulmonary syndrome, and one with hyperammonemia. Imaging studies showed portal vein obstruction in six patients and nonobstructed but frequently anomalous vascular patterns, including hypoplasia of the portal vein, in the remaining eight patients. At the onset, liver function was marginally abnormal in all patients, but thrombocytopenia of approximately 100 x 10.sup.9/L was consistently observed, probably reflecting chronic mild consumption coagulopathy and hypersplenism. The most striking and frequent histopathologic finding in 25 liver samples, was the presence of hypoplastic portal triads with collapsed portal vein radicles. In contrast, other triads showed markedly distended and misshapen portal vein radicles and likely lymphatics. These two patterns of collapse and distention presumably reflect areas of impaired versus overloaded intrahepatic portal venous flow. Some of the biopsies showed variable portal/sinusoidal fibrosis. Four patients (two with intestinal bleeding, two with hepato-pulmonary syndrome) required liver transplants and are doing well. Eight patients are doing well clinically after surgical or spontaneous vascular shunting. Two patients with intestinal bleeding and hepato-pulmonary syndrome, respectively) who had congenital dyskeratosis, underwent bone marrow transplantation and died of nonhepatic-related complications. It is possible to suggest prehepatic causes of portal hypertension even in needle biopsies when collapsed portal vein radicles are present in portal triads, but more than one biopsy sample with larger bore bioptomes may be required to see the changes. Conversely, identifying these changes may suggest to the clinicians the need to work-up a patient for portal hypertension. Author Affiliation: (1) Department of Pathology, Emory University School of Medicine, Egleston Children's Hospital, 1405 Clifton Road, Atlanta, GA 30322, USA (2) Department of Pediatrics, Emory University School of Medicine, Egleston Children's Hospital, 1405 Clifton Road, Atlanta, GA 30322, USA (3) Department of Surgery, Emory University School of Medicine, Egleston Children's Hospital, 1405 Clifton Road, Atlanta, GA 30322, USA Article History: Received Date: 09/01/2003 Accepted Date: 22/05/2003 Online Date: 21/08/2003 Article note: This study was presented in abstract form at the annual meeting of the Society for Pediatric Pathology, Chicago, Illinois, USA, February 2002.

The mechanisms by which some drugs damage the liver are reviewed. Topics include hepatic biotransformation, types of reactions, targets of cell injury, clinical consequences, acetaminophen toxicity, drug-related liver damage in patients with liver disease, and the diagnosis and treatment of drug-induced liver damage. In the late 1990s, Duract and Rezulin were both withdrawn from the market because they caused liver damage in some patients.

In a series of experiments, the effects of soy protein isolate (SPI), defatted soy (DFS) or SPI supplemented with L-methionine (SPIM) were examined in the Long-Evans rat with a cinnamon coat color (LEC rat), a model animal of Wilson's disease with a hereditary defect in the Atp7b gene resulting in defective copper metabolism and copper accumulation in hepatocytes. Milk casein in the control AIN-93G diet (20 g/100 g) was totally or 60% replaced by the soy products, SPI, DFS or SPIM (L-Met added to be equal to that in the control diet) beginning when rats were 6 wk old. Copper and iron concentrations in SPI and DFS were measured and the concentrations of these metals in the salt mix were adjusted so that test and the control diets had the same final concentrations. Food intake did not differ among groups. Rats were euthanized when they became moribund with jaundice. Survival time in the SPI diet group was shorter (14.0 [+ or -] 0.8 wk) than in the control group (19.1 [+ or -] 1.7 wk) (P < 0.001), and that in the DFS diet group was intermediate (16.0 [+ or -] 1.7 wk). Survival time in the SPIM diet group did not differ from that of the SPI diet group. Copper concentrations in the livers of rats in the SPI and SPIM diet groups were ~80% higher than in rats fed the control diet. Liver iron concentrations did not differ among the groups. The results, including histological analyses, indicate that SPI enhances copper uptake into the liver cells and promotes liver cell damage in LEC rats. However, this did not occur in the livers of F344 rats with wild-type Atp7b. Recommendations to individuals suffering from Wilson's disease to avoid consuming soy protein may be warranted. KEY WORDS: * LEC rats * soy protein isolate * copper * Wilson's disease * liver cell damage

Mutations in the genes for keratin 8 might cause some types of liver disease, according to a study of 55 patients with cryptogenic liver disease. Five had keratin 8 gene mutations that were not detected in patients with other types of liver disease. Keratins are proteins found in epithelial cells of the liver, pancreas, and intestines.

A 17-year-old girl with jaundice and weight loss was diagnosed with liver damage caused by 3,4-methylenedioxy-methamphphetamine (MDMA), a drug commonly known as ecstasy. Jaundice is a yellowing of the skin and mucous membranes caused by liver damage.

Patients with hepatitis C liver disease who do not respond to interferon therapy may have a hidden hepatitis B infection. Hepatitis B is considered occult, or hidden, when a patient tests negative for the hepatitis B surface antigen, yet has other markers for the disease. Researchers tested 200 patients with hepatitis C-associated cirrhosis, chronic hepatitis, or other liver disease. Half of the patients had antibodies to the core antigen of the hepatitis B virus. Nearly half of the patients who did not respond to interferon alfa therapy had hepatitis B markers, while only 7 of 28 responsive patients had such markers.

The metabolic derangements that occur in adenosine deaminase deficiency may cause liver dysfunction. Adenosine deaminase deficiency is a genetic disorder that leads to immune system abnormalities. A newborn baby developed oral Candida infection, an enlarged liver and jaundice by the time he was three weeks old. At seven weeks, he weighed less than he had at birth and was below the fifth percentile in length and head circumference. Analysis of a sample of blood cells revealed undetectable activity of adenosine deaminase, which led to elevated levels of deoxyadenosine nucleotides. He was diagnosed with adenosine deaminase deficiency. A liver biopsy revealed enlarged liver cells but no evidence of viral infection was found. No other cause of liver disease was identified. He was treated with PEG-ADA, which replaces the missing enzyme. His liver function returned to normal and at the age of 23 months, he had attained normal height and weight for his age.

The case of a 34-year-old HIV-infected man who died of drug-induced liver disease indicates that physicians should not overlook the obvious. He was admitted to a hospital with jaundice, which is a symptom of liver dysfunction. His doctors assumed that it was a result of some kind of opportunistic infection, which is common in people with suppressed immune systems. However, extensive diagnostic tests revealed no evidence of infection. They briefly speculated that his liver dysfunction might be caused by some of the drugs he was taking, including an herbal preparation called PCM4. A liver biopsy confirmed that the liver damage was caused by a drug. His antibiotics were discontinued, but he continued taking trimethoprim-sulfamethoxazole, which is given to HIV patients to prevent Pneumocystis carinii pneumonia. This drug was eventually stopped, but the patient died. This drug appears to have been responsible for his liver disease.