Hepatic Hypoxia Research Articles

Ethanol and tobacco smoke increase hepatic steatosis and hypoxia in the hypercholesterolemic apoE −/− mouse: Implications for a “multihit” hypothesis of fatty liver disease

Although epidemiologic studies indicate that combined exposure to cigarette smoke and alcohol increase the risk and severity of liver diseases, the molecular mechanisms responsible for hepatotoxicity are unknown. Similarly, emerging evidence indicates a linkage among hepatic steatosis and cardiovascular disease. Herein, we hypothesize that combined exposure to alcohol and environmental tobacco smoke (ETS) on a hypercholesterolemic background increases liver injury through oxidative/nitrative stress, hypoxia, and mitochondrial damage. To test this, male apoE −/− mice were exposed to an ethanol-containing diet, ETS alone, or a combination of the two, and histology and functional endpoints were compared to filtered-air-exposed, ethanol-naïve controls. Whereas ethanol consumption induced a mild steatosis, combined exposure to ethanol + ETS resulted in increased hepatic steatosis, inflammation, α-smooth muscle actin, and collagen. Exposure to ethanol + ETS induced the largest increase in CYP2E1 and iNOS protein, as well as increased 3-nitrotyrosine, mtDNA damage, and decreased cytochrome c oxidase protein, compared to all other groups. Similarly, the largest increase in HIF1α expression was observed in the ethanol + ETS group, indicating enhanced hypoxia. These studies demonstrate that ETS increases alcohol-dependent steatosis and hypoxic stress. Therefore, ETS may be a key environmental “hit” that accelerates and exacerbates alcoholic liver disease in hypercholesterolemic apoE −/− mice.

Hepatotoxic Interaction of Sulindac with Lipopolysaccharide: Role of the Hemostatic System

Sulindac (SLD) is a nonsteroidal anti-inflammatory drug (NSAID) that has been associated with a greater incidence of idiosyncratic hepatotoxicity in human patients than other NSAIDs. One hypothesis regarding idiosyncratic adverse drug reactions is that interaction of a drug with a modest inflammatory episode precipitates liver injury. In this study, we tested the hypothesis that lipopolysaccharide (LPS) interacts with SLD to cause liver injury in rats. SLD (50 mg/kg) or its vehicle was administered to rats by gavage 15.5 h before LPS (8.3 x 10(5) endotoxin unit/kg) or its saline vehicle (i.v.). Thirty minutes after LPS treatment, SLD or vehicle administration was repeated. Rats were killed at various times after treatment, and serum, plasma, and liver samples were taken. Neither SLD nor LPS alone caused liver injury. Cotreatment with SLD/LPS led to increases in serum biomarkers of both hepatocellular injury and cholestasis. Histological evidence of liver damage was found only after SLD/LPS cotreatment. As a result of activation of hemostasis induced by SLD/LPS cotreatment, fibrin and hypoxia were present in liver tissue before the onset of hepatotoxicity. Heparin treatment reduced hepatic fibrin deposition and hypoxia and protected against liver injury induced by SLD/LPS cotreatment. These results indicate that cotreatment with nontoxic doses of LPS and SLD causes liver injury in rats, and this could serve as a model of human idiosyncratic liver injury. The hemostatic system is activated by SLD/LPS cotreatment and plays an important role in the development of SLD/LPS-induced liver injury.

Portosystemic Encephalopathy in a Patient Treated With Peritoneal Dialysis

We present a case of a 75-year-old man with end-stage renal disease caused by immunoglobulin A nephropathy who developed hepatic encephalopathy 15 months after starting continuous ambulatory peritoneal dialysis therapy. Liver test results were normal except for hyperammonemia (ammonia, 317 microg/dL [186 micromol/L]) and mildly increased alkaline phosphatase and gamma-glutamyl transpeptidase levels. Abdominal ultrasonography showed normal liver architecture, and color Doppler ultrasonography showed a normal splenic-portal axis with hepatopetal blood flow. Histological examination of a laparoscopic liver biopsy specimen showed moderate fibrosis limited to portal tracts without necrosis or inflammation. Magnetic resonance angiography and percutaneous transhepatic portal angiography showed a large shunt between the left gastric and azygous veins, with blood flowing from the portal vein to the superior vena cava. The patient was transferred to hemodialysis treatment, and although his condition improved slightly, episodes of encephalopathy did not disappear. Surgical ligation of the left gastric vein was performed. In the 8 months after surgery, he has experienced no further episodes of hepatic encephalopathy or hyperammonemia. We speculate that increased intra-abdominal pressure and vasodilation caused by peritoneal dialysis solutions in a patient with a spontaneous portosystemic shunt resulted in ammonia-rich blood flow from the portal vein to the superior vena cava and encephalopathy. In addition, it is possible that chronic hepatic hypoxia caused by hypoperfusion from portosystemic shunting contributed to the development of liver fibrosis. To our knowledge, this is the first report of spontaneous portosystemic shunt encephalopathy in a patient with a noncirrhotic liver undergoing peritoneal dialysis.

Anticoagulation and inhibition of nitric oxide synthase influence hepatic hypoxia after monocrotaline exposure

Monocrotaline (MCT) is a pyrrolizidine alkaloid plant toxin that produces hepatotoxicity in humans and animals. Administration of MCT to rats causes rapid sinusoidal endothelial cell (SEC) injury, hemorrhage, pooling of blood and fibrin deposition in centrilobular regions of liver. These events precede hepatic parenchymal cell (HPC) injury and produce marked changes in the microvasculature of the liver, which could interrupt blood flow and produce hypoxia in affected regions. To test the hypothesis that hypoxia occurs in liver after MCT exposure, rats were treated with 300 mg MCT/kg, and hypoxia was detected immunohistochemically. MCT produced significant hypoxia in centrilobular regions of livers by 8 h after treatment. Inasmuch as fibrin deposition can impair oxygen delivery by reducing blood flow, the effect of anticoagulant treatment on MCT-induced hypoxia was determined. Administration of warfarin to MCT-treated rats reduced hypoxia in the liver by approximately 70%, suggesting that fibrin deposition plays a causal role in the development of hypoxia in the liver. Conversely, administration of l-NAME, a nonspecific inhibitor of nitric oxide synthases (NOSs), enhanced MCT-induced hypoxia and HPC injury. l-NAME did not, however, affect SEC injury or coagulation system activation. Results from these studies show that hypoxia occurs in the liver after MCT exposure. Furthermore, hypoxia precedes HPC injury, and manipulations that modify hypoxia also modulate HPC injury.

Heterozygous Bile Salt Export Pump Deficiency: A Possible Genetic Predisposition to Transient Neonatal Cholestasis

Heterozygous Bile Salt Export Pump Deficiency: A Possible Genetic Predisposition to Transient Neonatal Cholestasis

Molecular Pathogenesis of Alcohol‐Induced Hepatic Fibrosis

Alcohol abuse is a main cause of liver fibrosis and cirrhosis in the western world. Although the major mechanisms of fibrogenesis are independent of the origin of liver injury, alcoholic liver fibrosis features distinctive characteristics, including the pronounced inflammatory response of immune cells due to elevated gut-derived endotoxin plasma levels, increased formation of reactive oxygen species (ROS), ethanol-induced pericentral hepatic hypoxia or formation of cell-toxic and pro-fibrogenic ethanol metabolites (e.g., acetaldehyde or lipid oxidation products). These factors are together responsible for increased hepatocellular cell death and activation of hepatic stellate cells (HSCs), the key cell type of liver fibrogenesis. To date, removing the causative agent is the most effective intervention to prevent the manifestation of liver cirrhosis. A novel experimental approach in fibrosis therapy is the selective induction of cell death in HSCs. Substances such as gliotoxin, anandamide or antibody against tissue inhibitor of metalloproteinase (TIMP)-1 can selectively induce cell death in activated HSCs. These new results in basic science are encouraging for the search of new antifibrotic treatment.

Analysis of safe limit of human hepatic warm ischemic time by microarray

目的 探讨人肝不同缺血时限细胞凋亡相关基因的多基因表达模式和差异表达,为掌握肝缺血安全时限提供科学依据.方法应用基因芯片表达谱技术观测正常人肝组织与肝缺血15 min(组一)、30 min(组二)及肝缺血15 min与30 min(组三)相比较细胞基因表达状况,对200点特异性凋亡相关基因差异表达进行分析比较.结果肝缺血0～15 min,凋亡相关基因的表达基本处于低表达或正常表达水平,表达明显上调的的差异表达基因主要为调节细胞内环境稳定的基因;而至肝缺血30 min,各种维系细胞和细胞器内环境稳定的调控基因表达水平明显下降,多种促凋亡发生的相关基因、诱导凋亡发生的核转录因子则明显活化、表达上调.结论一般而言,人肝一次热缺血时限以尽量不超过30 min为宜。

Protective effects of moderate hypothermia on phosphoenergetic metabolism in rat liver during gradual hypoxia studied by in vivo31P nuclear magnetic resonance spectroscopy

Background Hepatic hypoxia during resuscitation and other critically ill conditions is a serious cause of acute hepatic failure. Measurement of the ATP concentration is a sensitive method to evaluate the extent of hypoxic damage in the liver. Hypothermia has been shown to attenuate organ injury in hypoxia. Our aim was to evaluate the effects of moderate hypothermia on the hepatic energy metabolism in rats during gradual hypoxia using 31P nuclear magnetic resonance (NMR) spectroscopy. Materials and methods The rats were divided into two groups: a normothermia group ( n = 8, rectal temperature at 37–37.5°C) and a hypothermia group ( n = 8, rectal temperature at 30–32°C). The fraction of inhaled oxygen (F IO 2) was reduced gradually (0.5, 0.2, 0.15, 0.125, 0.1, 1.0) and rectal temperature was regulated using a water perfusion mat under the rat body. Phosphoenergetic metabolism of the liver was evaluated from the changes in peak areas of β-adenosine triphosphate (ATP) and inorganic phosphate (P i) in 31P NMR spectra. Intracellular pH (pH i) was calculated from the chemical shifts between P i and α-ATP peaks. Results In the normothermia group, β-ATP decreased markedly and P i increased during hypoxia, while in the hypothermia group, both β-ATP and P i changed only slightly from the initial state during hypoxia. During hypoxia, the minimal changes in β-ATP were 18% and 80%, and the maximal changes in P i were 270% and 160% in the normothermia and hypothermia groups, respectively. Significant difference between the two groups was observed during hypoxia. The recoveries of β-ATP and P i were more complete in the hypothermia group. The decrease in pH i during hypoxia was less in the hypothermia group. Conclusions During gradual hypoxia, β-ATP decreased, P i increased, and pH i decreased in the rat liver, depending on the oxygen concentration. These changes were more prominent in the NT group than in the HT group. We conclude that moderate hypothermia effectively protects high energy phosphoenergetic metabolites in rat liver during gradual hypoxia as compared to normothermia.

Multiple gene differential expression patterns in human ischemic liver: safe limit of warm ischemic time.

To investigate the multiple gene differential expression patterns in human ischemic liver and to produce the evidence about the hepatic ischemic safety time. The responses of cells to hepatic ischemia and hypoxia at hepatic ischemia were analyzed by cDNA microarrary representing 4 000 different human genes containing 200 apoptotic correlative genes. There were lower or normal expression levels of apoptotic correlative genes during the periods of hepatic ischemia for 0-15 min, the maintenance homostatic genes were expressed significantly higher at the same time. But at the hepatic ischemia for 30 min, the expression levels of maintenance homeostatic genes were down-regulated, the expressions of many apoptotic correlative genes and nuclear transcription factors were activated and up-regulated. HIF-1, APAF-1, PCDC10, FBX5, DFF40, DFFA XIAP, survivin may be regarded as the signal genes to judge the degree of hepatic ischemic-hypoxic injure, and the apoptotic liver cell injury due to ischemia in different time limits. The safe limit of human hepatic warm ischemic time appears to be generally less then 30 min.

A retrospective analysis of hepatic injury in horses with proximal enteritis (1984-2002).

The purpose of this study was to test the hypothesis that horses with proximal enteritis (PE) are predisposed to hepatic injury. We also determined whether the presence of liver injury in horses with PE was associated with other clinicopathologic abnormalities or affected outcome. The medical records of all horses admitted for evaluation of colic and gastric reflux between 1984 and 2002 were reviewed. Horses were considered to have PE if the diagnosis was made at surgery or postmortem examination or if they had clinical findings consistent with PE. Horses with a small intestinal strangulating obstruction (SISO) were used as the control group. Historic and clinicopathologic data were collected for each horse. The data were analyzed by descriptive statistics, parametric and nonparametric analyses, and logistic regression. Horses with PE had significantly higher serum gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) activities than horses with SISO (P < .05). Horses with PE were 12.1 times more likely to have high GGT activities than were horses with SISO. Horses with PE had an increased risk of at least 1 hepatic enzyme being increased if a high anion gap or large volume of reflux was present. Our conclusion is that horses with PE are more likely to have hepatic injury than horses with SISO. The mechanism of hepatic injury may involve ascending infection from the common bile duct, absorption of endotoxin or inflammatory mediators from the portal circulation, or hepatic hypoxia resulting from systemic inflammation and endotoxemic shock.

Carbon monoxide paradoxically protects against hypoxia

Background: Tissue hypoxia is fundamental to the development of cellular injury caused by multiple processes, including hemorrhagic shock. Others and we have previously demonstrated that endogenous production of carbon monoxide (CO) by heme oxygenase or exogenous administration of CO can protect against organ injury induced by hemorrhage. The purpose of these experiments was to test the hypotheses that CO abrogates the development of tissue hypoxia in vivo and diminishes effects of hypoxia in vitro.Methods: Male C57/BL6 mice were hemorrhaged to a mean arterial pressure of 25 mmHg. Control animals underwent the same procedure but were not hemorrhaged (sham). Inhalational CO exposure (250 ppm) was initiated concurrently with hemorrhage Mice were administered EF5 (10 μl/g; ip), which is an agent that irreversibly binds to intracellular proteins under hypoxic conditions and can then be detected by immunohistochemistry. Mice were sacrificed after 75 minutes of shock and livers were harvested. For in vitro experiments, primary mouse hepatocytes were exposed to normoxia (21% O2) or hypoxia 1% O2) with and without CO (250 ppm). Cells were harvested and assayed for viability, ATP content, or VEGF production. Results: Untreated hemorrhaged mice had a 17-fold increase in EF5 staining compared to shams. Hepatic hypoxia was most pronounced around the central veins. CO-treated hemorrhaged mice had a 79±13% reduction in EF5 staining compared to untreated hemorrhaged mice (P < 0.05). Additionally, CO-treated sham mice demonstrated no significant liver hypoxia. In vitro, CO significantly protected against hypoxia-induced cell death (P < 0.05). Hepatocytes exposed to hypoxia demonstrated a 54 ± 4% reduction in intracellular ATP levels after 6 hours, whereas CO treatment of hypoxic cells resulted in only a 9 ± 3% reduction in ATP (P < 0.01). Likewise, CO significantly inhibited VEGF elaboration by hypoxic hepatocytes. Conclusions: Inhaled low dose CO can paradoxically abrogate liver hypoxia during hemorrhage. Additionally, CO diminishes the consequences of hypoxia in vitro. CO may exert these effects by decreasing cellular metabolic activity and oxygen requirements, though further investigation is required. CO may prove to be a useful clinical adjunct in the treatment of hemorrhagic shock.

Hepatic cold hypoxia and oxidative stress: implications for ICAM-1 expression and modulation by glutathione during experimental isolated liver preservation

Cold preservation and reperfusion of liver during transplantation are necessary steps in the procedure but which are also associated with damage to the organ. One aspect of this damage is thought to concern up-regulation of inflammatory markers, such as the adhesion molecule intercellular adhesion molecule 1 (ICAM-1) on target cells in the liver. This aids sequestration of activated leucocytes, which promote inflammation, by a complex sequence of events, including free radical mediated damage. We have studied changes in ICAM-1 in rat liver as a consequence of cold preservation for various times, and also after warm reperfusion during isolated liver perfusion. We have also investigated the effects of the free radical scavenging agent (reduced glutathione—GSH) on the modulation of ICAM-1 expression after cold hypoxia and reperfusion. Livers were subjected to various regimes of cold preservation and reperfusion. Liver biopsies were taken at three time points (initial baseline on liver exposure; after organ flushing and post-storage at 0, 8, 16, and 24 h cold hypoxia in University of Wisconsin solution; in the same livers after 1 h warm reperfusion). The tissues were processed for frozen biopsy work, and frozen sections were stained using immunohistochemical methods, for blinded scoring by an independent observer. Positive controls were obtained by exposure to endotoxin lipopolysaccharide before liver flushing. ICAM-1 expression was low in control livers (0.33 ± 0.21), and increased to near maximal (2.83 ± 0.17) after endotoxin exposure. ICAM-1 expression increased progressively with cold preservation, reaching values of 1.17 ± 0.31 and 1.83 ± 0.31 after 16 and 24 h, respectively ( P<0.05 and 0.02 versus controls). Warm reperfusuion increased ICAM-1 expression in all flushed groups and with longer cold preservation was close to maximal (2.67 ± 0.21 after 16 h and 2.98 ± 0.02 after 24 h; P<0.001 in both cases). Addition of the free radical scavenger GSH prevented up-regulation of ICAM-1 in livers reperfused after flushing and cold storage for up to 8 h; beyond this time, ICAM-1 expression still increased, such that by 24 h cold preservation and reperfusion absence (2.98 ± 0.02) or presence (2.67 ± 0.21) made no difference. We conclude that liver ICAM-1 expression is demonstrably increased by progressive cold preservation and reperfusion, and is only marginally affected by addition of GSH during reperfusion. The model can be used to investigate other agents which might be more successful in preventing post-storage inflammatory damage.

L’hépatite ischémique

Ischemic hepatitis is defined as an acute reversible elevation in either the serum alanine or aspartate aminotransferase level of at least 20 times the upper normal limit, excluding known causes of acute hepatitis or hepatocellular injury (viral or toxic). Histopathologic examination reveals a centrolobular liver cell necrosis. The pathophysiology of ischemic hepatitis is poorly understood. At present, the pathophysiologic hypotheses most often proposed are an ischemic/reperfusion injury of the liver and a selective hypersensitivity of the mesenteric vasculature to the renin–angiotensin axis. In ischemic hepatitis an hepatic venous congestion and a hypoxia hepatitis should be present. An underlying cardiac disease is the factor that often leads to hepatic venous congestion. The hepatic hypoxia is the result of the decrease in systemic blood pressure leading to a reduction in hepatic blood pressure or the result of a severe arterial hypoxemia. The causes of a low cardiac output are more often cardiogenic, but hypovolemia or toxic causes are possible. More rarely, a hypoxemia, without shock, is responsible for ischemic hepatitis. The incidence of ischemic hepatitis in patients admitted to intensive care unit is unknown. The mortality rate, six months after the ischemic hepatitis is 50%. The prognosis is primarily related to cardiac function.

Use of hyperbaric oxygen for hepatic artery thrombosis following adult orthotopic liver transplantation

Use of hyperbaric oxygen for hepatic artery thrombosis following adult orthotopic liver transplantation

Hepatocyte Growth Factor and c-Met Inhibition by Hepatic Cell Hypoxia: A Potential Mechanism for Liver Regeneration Failure in Experimental Cirrhosis

Hepatic resection in cirrhotic patients is associated with impaired liver regeneration and poor clinical outcome. Because experimental cirrhosis is associated with hepatic cell hypoxia, we herein investigated whether hypoxia might alter the mechanisms of liver regeneration in the cirrhotic liver. Cirrhosis was induced by diethylnitrosamine in rats. Immunohistochemistry was performed to assess hepatocellular hypoxia and proliferation 24 hours after a two-thirds partial hepatectomy (PH) in cirrhotic and control rats. Cultured hepatocytes and myofibroblastic hepatic stellate cells were submitted to hypoxia using anaerobic jars. Hepatocyte growth factor (HGF) and c-Met expressions were determined by reverse transcriptase-polymerase chain reaction, Northern blot, and Western blot. In control rats, hypoxia was restricted to perivenular hepatocytes, and PH induced a marked increase in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression remained unchanged. In cirrhotic rats, hypoxia was detected virtually in all of the hepatocytes, and PH induced no significant change in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression was decreased as compared to normal livers. In vitro, the expression of HGF in myofibroblastic hepatic stellate cells and of c-Met in hepatocytes underwent a dramatic decrease under hypoxia. Our results suggest that hepatocellular hypoxia causes inhibition of HGF (and of c-Met)-mediated proliferation and thereby might contribute to liver regeneration failure in cirrhotic liver.

Autonomic nervous system and gut-derived endotoxin: involvement in activation of Kupffer cells after in situ organ manipulation.

Gentle in situ organ manipulation rapidly causes disturbances in the hepatic microcirculation, hypoxia, and activation of Kupffer cells. Because the mechanisms of Kupffer cell activation after organ manipulation remain unclear, the possible role of the autonomic nervous system and gut-derived endotoxin were assessed. To mimic what occurs with major abdominal surgery, livers from female Sprague-Dawley rats (200-230 g) underwent minimal dissection for 12 minutes and were manipulated gently or were left alone for 13 subsequent minutes. Kupffer cells were activated 2 hours after manipulation, reflected by a significant increase in intracellular calcium ([Ca2+]i) from about 90 nM in unmanipulated controls to more than 180 nM in response to lipopolysaccharide (LPS 100 ng/ml). Furthermore, Kupffer cells from manipulated rats produced about threefold more tumor necrosis factor-alpha after LPS (100 ng/ml) than did the unmanipulated controls. Moreover, O2 uptake of ex situ perfused liver was increased from about 110 micromol/g/hr in unmanipulated controls to more than 160 micromol/g/hr 2 hours after organ manipulation. Binding of pimonidazole (120 mg/kg IV), a 2-nitroimidazole hypoxia marker given 2 hours after manipulation, increased about 2.5-fold, and hepatic glycogen was depleted. Two hours after organ manipulation gut permeability to horseradish peroxidase was elevated and endotoxin in the portal venous blood was increased twofold. Microsurgical hepatic denervation, ganglionic blockade, adrenalectomy, and antibiotics to sterilize the gut before manipulation prevented activation of Kupffer cells by organ manipulation. Hexamethonium and adrenalectomy prevented increases in gut permeability caused by manipulation. Although antibiotics blunted the increase in portal venous endotoxin significantly, there was no effect on gut permeability. These data indicate for the first time that both the autonomic nervous system and gut-derived endotoxin are involved in activation of Kupffer cells after organ manipulation.

Acute Fulminant Lactic Acidosis Complicating Metastatic Cholangiocarcinoma

A patient with cholangiocarcinoma, metastatic to the liver and lungs, developed acute fulminant lactic acidosis in the absence of overt hepatic failure, sepsis, hypoxia, or circulatory failure. Despite extensive tumor replacement of hepatic parenchyma, no acidbase disorder was present during initial evaluation. The onset of acute lactic acidosis was temporally associated with the development of otherwise asymptomatic episodes of intermittent atrial arrhythmias. Once established, lactic acidosis was inexorably progressive, despite resolution of arrhythmias. Extensive areas of acute necrosis within the large hepatiC metastases were demonstrated on postmortem examination, suggesting that local tissue ischemia, precipitated by cardiac arrhythmias, lead to excessive lactic acid production.

A prospective study of the causes of notably raised aspartate aminotransferase of liver origin

BACKGROUND AND AIMSTo ascertain the causes of raised aspartate aminotransferase (AST) presumed to be of hepatic origin in two hospitals and the local community served by a centralised biochemistry laboratory.METHODSFrom...

II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin.

It is well known that females show a greater susceptibility to alcohol-induced liver injury than males. Additionally, females who consume alcohol regularly and have been obese for 10 years or more are at greater risk for both hepatitis and cirrhosis. Female rats on an enteral alcohol protocol exhibit injury more quickly than males, with widespread fatty changes over a larger portion of the liver lobule. Levels of plasma endotoxin, intercellular adhesion molecule-1, free radical adducts, infiltrating neutrophils, and nuclear factor-kappaB are increased about twofold more in livers from female than male rats after enteral alcohol treatment. Estrogen treatment in vivo increases the sensitivity of Kupffer cells to endotoxin. Evidence has been presented that Kupffer cells are pivotal in the development of alcohol-induced liver injury. Destruction of Kupffer cells with gadolinium chloride (GdCl3) or reduction of bacterial endotoxin by sterilization of the gut with antibiotics blocks early inflammation due to alcohol. Similar results have been obtained with anti-tumor necrosis factor-alpha antibody. These findings led to the hypothesis that alcohol-induced liver injury involves increases in circulating endotoxin, leading to activation of Kupffer cells, which causes a hypoxia-reoxygenation injury. This idea has been tested using pimonidazole, a nitroimidazole marker, to quantitate hypoxia in downstream pericentral regions of the liver lobule. After chronic enteral alcohol, pimonidazole binding increases twofold. Enteral alcohol also increases free radicals detected with electron spin resonance. Importantly, hepatic hypoxia and radical production detected in bile are decreased by destruction of Kupffer cells with GdCl3. These data are consistent with the hypothesis that Kupffer cells participate in important gender differences in liver injury caused by alcohol.

Transient neonatal cholestasis: origin and outcome.

We studied, retrospectively, 92 children who were first seen with neonatal cholestasis and who were followed up until liver test results normalized. Among the 92 children, 81 displayed factors responsible for chronic and/or acute perinatal distress. Onset of jaundice was recorded at a mean age of 7 days, and mean duration was 3.5 months. Stools, initially discolored in 39 children, were normally colored at a mean age of 1.7 months. Hepatomegaly present in 90 children resolved at a mean age of 13 months. Liver test results were normal at the age of 1 year in 83 children and normalized at a mean age of 10 months. Liver histologic examination, performed in 70 children, showed moderate portal and lobular fibrosis, multinucleated giant hepatocytes, and hematopoietic foci; findings in follow-up liver biopsy specimens from 15 children were normal or improved. Spontaneously resolving forms of neonatal cholestasis may result from the association of several factors, including immaturity of bile secretion and perinatal disease leading to hepatic hypoxia or ischemia.