Form Of Liver Disease Research Articles

Detection of Liver Disease in Injection Drug Users

Detection of liver disease among injection drug users is an important challenge because liver disease is common, usually unrecognized, and treatable in early stages. Many forms of liver disease occur in injection drug users (IDUs). However, commensurate with its exceedingly high prevalence among IDUs, much of the published literature (and accordingly the focus of this review) regards liver disease caused by chronic hepatitis C. Existing guidelines for detection of liver disease are presented in the context of the current standard of care. Since recent research shows these guidelines rarely contribute to the medical management of IDUs, special emphasis is given to novel approaches that, when coupled with advances in treatment, the authors believe could substantially reduce the medical and psychological consequences of injection drug use.

Stemming the Tide of Hepatitis B Virus–Related Hepatocellular Carcinoma?

Infection with hepatitis B virus (HBV) is a major global public health problem, with an estimated prevalence of 350 million chronic carriers worldwide, and 1.5 million in the United States. The majority of HBV-infected individuals are concentrated in Asia and subSaharan Africa, but the incidence is rising is Western countries as a result of changing migration patterns. Chronic HBV infection can lead to liver cirrhosis, hepatic decompensation, and premature death. As many as 25% of HBV-infected patients will develop hepatocellular carcinoma (HCC), which is the fourth most common solid tumor worldwide. As much as a 50% reduction in the incidence of HBV transmission has been achieved in certain countries through widespread vaccination programs. Reduction in the morbidity and mortality of HBV-related HCC has been achieved as a result of intensive screening programs and through antiviral treatment with agents such as lamivudine and interferon. Because the majority of HCC cases worldwide are HBV-associated, HCC is truly a preventable malignancy. Given the considerable number of patients who are at risk for developing chronic HBV infection and its deadly sequelae, the costs associated with screening and treatment are similarly enormous. The challenge, therefore, is to select those patients most likely to benefit from HBV treatment and HCC screening to maximize the benefit-cost ratio of such programs. Any opportunity to optimize selection of patients for HBV treatment and HCC screening, and thereby reduce the incidence of HCC, should result in a significant public health benefit. HBV has been classified into eight genotypes, designated by capital letters A through H. HBV genotypes have distinct geographic distributions, with genotypes B and C being the most prevalent in Asia. Several studies have demonstrated that genotype C is associated with a higher prevalence of hepatitis B e antigen (HBeAg), more active hepatitis, and more advanced liver disease than genotype B. In a cross-sectional study of 270 Taiwanese HBV carriers with various forms of liver disease, genotype C was more prevalent in patients with cirrhosis and in those with HCC older than 50 years compared with age-matched asymptomatic carriers. Furthermore, HBV genotype C has been shown to be an independent risk factor for development of HCC. In a study of 426 Chinese patients infected with HBV, 25 patients developed HCC during a median follow-up of 121 weeks. Cirrhosis and HBV genotype C infection were independently associated with HCC development. In a study of 4,841 Taiwanese male hepatitis B s antigen (HBsAg) carriers, there were 154 cases of HCC diagnosed during a 14-year follow-up period. HBV DNA levels and HBV genotypes were determined for all patients with HCC and 316 control subjects. Results indicated that the risk of HCC increased with increasing HBV viral load. Moreover, genotype C was associated with an increased risk of HCC compared with other HBV genotypes (adjusted odds ratio [OR] 5.11; 95% CI, 3.20 to 8.18). In that study, the association of HBV genotype C and HBV viral load with HCC risk appeared to be additive. The adjusted OR of HCC for those carrying genotype C and with viral load in the highest quintile was 26.49 (95% CI, 10.41 to 67.42) compared with those carrying other HBV genotypes and lower viral loads. These and other recent studies have been paramount in our understanding of the factors that influence clinical outcome in HBV infection. However, it appears that HBV genotype is only one of the elements associated with hepatocarcinogenesis. Mutations in the basic core promoter (BCP) and precore regions carry an increased risk of HCC. In a cross-sectional, retrospective study of 160 chronic HBV carriers and 200 patients with HCC, advanced age, male sex, the precore A1896 mutation, the BCP T1762/A1764 mutation, and a high HBV load were significantly associated with development of HCC. There has also been recent interest in studying the relationship among HBV genotypes, subgenotypes, and mutations encountered in HBV carriers. Whether these have additive or synergistic effects on the risk of HCC development remains unclear. It has been reported that patients with genotype B have a higher chance of harboring precore mutations when compared with patients with genotype C. In the same study, core promoter mutations, T1653 mutations, HBV DNA levels of at least 4 log10 copies/mL, and cirrhosis were shown on to be independent risk factors for HCC. HBV genotype C has been classified into four subgenotypes: HBV/C1-C4. The designation of the two most widely disseminated subgenotypes is controversial. HBV/C1 (or Cs) is commonly found in Southeast Asia. HBV/C2 (or Ce) is found in East Asia including Japan and China. There are limited data on the clinical implications and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 2 JANUARY 1

Nutritional management of acute and chronic liver disease

Malnutrition is prevalent in all forms of liver diseases. A number of factors contribute to malnutrition in patients with hepatic failure. Early diagnosis of malnutrition is essential to allow appropriate treatment, since malnutrition is an important predictor of complications of liver disease and mortality. Disease-specific nutritional therapy should be considered for acute liver failure, sepsis, transplantation, and encephalopathy. This article provides an overview of the nutritional management of acute and chronic liver disease and discusses the need for further intervention studies before appropriate rational treatment guidelines can be formulated.

Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis

Alpha-1 antitrypsin (alpha1-AT) deficiency is the most common genetic cause of liver disease in children. The homozygous alpha1-ATZ mutation (PiZZ) results in significant liver disease in 10% of all affected patients. The alpha1-ATZ mutation also may lead to worse liver injury in the setting of other liver diseases such as cystic fibrosis, nonalcoholic fatty liver disease, and hepatitis C. Although cholestatic injury is common to many forms of liver disease, its effect on the PiZZ phenotype is unknown. To elucidate the interplay of cholestasis and the PiZZ phenotype, we performed bile duct ligation (BDL) on C57BL/6 mice possessing a transgenic alpha1-ATZ mutation and littermate controls. PiZ transgenic mice undergoing BDL developed more liver fibrosis by quantification of Sirius red staining (P = 0.0003) and hydroxyproline (P = 0.007) than wild-type mice after BDL. More activated hepatic stellate cells (HSCs) and apoptotic cells also were observed in the PiZ BDL model. Quantitative real time polymerase chain reaction (PCR) of the endoplasmic reticulum (ER) stress markers CHOP and GRP78 were 4-fold and 2-fold more up-regulated, respectively, in PiZ BDL mice when compared with wild-type BDL mice (P = 0.02, P = 0.02). Increased apoptosis was also noted in PiZ BDL mice by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and cleaved caspase-3 histological staining. PiZ transgenic mice are more susceptible to liver fibrosis induced by cholestasis from BDL. Cholestasis therefore may lead to increased fibrosis in alpha1-AT deficiency, and the alpha1-ATZ mutation may act as a modifier gene in patients with concurrent cholestatic liver diseases such as cystic fibrosis.

Combining ursodeoxycholic acid or its NO-releasing derivative NCX-1000 with lipophilic antioxidants better protects mouse hepatocytes against amiodarone toxicity

Nonalcoholic steatohepatitis (NASH) is a common and potentially severe form of liver disease. This study aimed to determine the effect of ursodeoxycholic acid and its NO-releasing derivative NCX-1000 alone or in combination with antioxidants on cultured mouse hepatocytes treated with amiodarone to mimic certain aspects of hepatocyte injury found in NASH. Isolated mouse hepatocytes were incubated with ursodeoxycholic acid or NCX-1000 (0-100 micromol/L) combined or not combined with the hydrophilic antioxidants butylated hydroxytoluene and ascorbic acid (0-100 micromol/L) or with the lipophilic antioxidant alpha-tocopherol (0-100 micromol/L) 15 min before adding amiodarone (50 micromol/L) to the culture medium. Twenty hours later, necrosis, apoptosis, superoxide anion production, and malondialdehyde levels were assessed in cultured cells. Amiodarone led to a dose-dependent decrease in cell viability with an LD50 of 50 micromol/L and increased production of superoxide anion and lipid peroxidation. NCX-1000 showed a better protective potential than ursodeoxycholic acid against the toxic effects of amiodarone. The hydrophilic antioxidants had no effect on the toxicity of amiodarone, whereas alpha-tocopherol at a concentration >100 micromol/L almost completely suppressed it. Ursodeoxycholic acid and NCX-1000 protection was additive only when they were combined with alpha-tocopherol, not with butylated hydroxytoluene or ascorbic acid. In addition, all the antioxidants tested reduced the superoxide anion detected, but only alpha-tocopherol prevented lipid peroxidation induced by amiodarone. The combination of lipophilic antioxidants with ursodeoxycholic acid or NCX-1000 enhances their protective potential and could represent an interesting therapeutic approach to explore for the treatment of NASH.

Impact of Viral Hepatitis on Apo- and Lipoprotein Status in Blood

Objectives:To investigate the effect of viral hepatitis on serum levels of apo- and lipoproteins in different forms of liver diseases. Materials and Methods: One hundred and thirty adult patients and 100 healthy age- and gender-matched control individuals participated in this study. Patients were grouped according to four types of liver disease: acute viral hepatitis, chronic active hepatitis (CAH), cirrhosis of the liver and fulminant hepatic failure. Results: Hepatitis B virus, C virus and E virus (HEV) infections were recorded in different combinations in these patients, but viral infections of hepatitis A and D were not seen in any of the patient groups. The results of lipo- and apoprotein analysis showed different patterns. The low-density lipoprotein value was high in the CAH group. In the other three groups, low-density lipoprotein level was comparable to the control value. The high-density lipoprotein level (p = 0.02) was significantly low in all groups except in the cirrhosis group. Apo-A was significantly reduced in the acute viral hepatitis and fulminant hepatic failure groups, whereas Apo-B level was low in the CAH and cirrhosis groups. The lipoprotein (a) level in these groups was low, compared to control. Conclusion: No apparent relationship was observed between etiological viruses and ensuing changes in lipid/lipoprotein profile.

Transiente Elastografie zur Diagnose der Leberzirrhose

Detection of liver cirrhosis has numerous implications because of the potential sequelae of cirrhosis. Transient elastography (Fibroscan), was evaluated as a novel, non-invasive means of assessing cirrhosis by measuring liver stiffness. 147 consecutive patients with different forms of liver disease and histologically determined stages of liver fibrosis were prospectively studied by transient elastography. 48 patients had liver cirrhosis. The number of transient elastographic measurements per patient was 12+/-4 (range 6 - 30). Valid elastography measurements were available for 135 out of 147 patients (92 %). The results of transient elastography correlated positively with the histological score of liver fibrosis (r = 0.8; 95 % CI: 0.72 - 0.85; p < 0.001). Areas under the receiver operating characteristic curve (AUROC) were 0.91 for > or = F3 fibrosis (95 % CI: 0.85 - 0.96) and 0.94 for cirrhosis (95 % CI: 0.90 - 0.98). Using a cut-off value of 13 kPa for detection of liver cirrhosis a sensitivity of 90 %, a specificity of 82 %, a positive predictive value of 71 % and a negative predictive value of 95 % were obtained. Measuring liver stiffness by transient elastography proved to be an easy method to assess liver cirrhosis. In combination with clinical signs, ultrasound and biochemical markers noninvasive diagnosis of liver cirrhosis will be further improved.

Natural History of Patients Hospitalized for Management of Cirrhotic Ascites

Since the International Ascites Club published the diagnostic criteria of refractory ascites (RA) and hepatorenal syndrome (HRS), there have been few studies assessing the natural history of ascites. The aims of this study were to define the natural history of cirrhotic ascites and to identify prognostic factors for dilutional hyponatremia (DH), RA, HRS, and survival. Two hundred sixty-three consecutive cirrhotic patients were followed for 40.9 +/- 2.6 months after their first significant ascites. During follow-up 74 (28.1%) patients developed DH, 30 (11.4%) RA (diuretic-resistant in 2 cases and diuretic-intractable because of the development of diuretic-induced complications in 28 cases), and 20 (7.6%) HRS (type 1, 7; type 2, 13). The 5-year probability of DH, RA, and HRS development was 37.1%, 11.4%, and 11.4%, respectively. The probability of survival at 1 and 5 years was 85% and 56.5%, respectively. The independent predictors for survival were baseline age, baseline Child-Pugh score, and DH development. The 1-year probability of survival after developing DH, RA, and type 2 HRS was 25.6%, 31.6%, and 38.5%, respectively. In contrast, the mean survival was only 7 +/- 2 days in those patients developing type 1 HRS. (1) The survival of cirrhotic patients with first episode of ascites is relatively high, and it is mainly influenced by age and Child-Pugh score at the time of ascites decompensation, as well as by DH development. (2) The probability of RA and HRS development is relatively low, but they are associated with a poor prognosis.

Apoptosis in liver disease

The description of the morphological hallmarks of programmed cell death, apoptosis, in 1972 by Kerr, Wyllie and Currie started a field of research that revolutionized our understanding of cellular proliferation, tissue homeostasis and pathophysiology of many diseases. In the following years, a series of proteins involved in signaling and intracellular death pathways were identified and 30 years later the Noble Prize for physiology and medicine was awarded to S. Brenner, H. R. Horvitz and J. E. Sulston for their discoveries related to describing the mechanisms of cell death (apoptosis). The delineation of the signaling pathways that mediate apoptosis changed the paradigms of understanding in many liver diseases. The most detailed analyzed mode of apoptosis involves a cell surface-based receptor-ligand system. Death receptors are typically members of the tumor necrosis factor-receptor superfamily and comprise an intracellular death domain. Following ligand binding to the receptor, intracellular adapter molecules are recruited to the receptor and subsequently transmit the apoptotic signal. Intracellular organelle-dependent signaling occurs, and effector molecules then augment the receptor-initiated apoptosis process. Cell death and degradation follows the activation of a highly regulated set of cytosolic and nuclear proteases and DNAses. Receptor-independent activation of the apoptotic process can occur as part of the cytotoxicity related to UV radiation, chemotherapeuticals or other DNA-damaging agents through activation of intracellular sensors of cellular integrity, e.g. the tumor suppressor gene p53. In contrast to necrosis, apoptosis is not commonly accompanied by an inflammatory response that causes collateral cell damage. The apoptotic program is highly effective in eliciting cell death and thus must be tightly controlled. This is achieved through continuous integration of pro- and antiapoptotic signals at the individual cell level. Dysregulation of the apoptotic process, resulting in too much or too little cell death, has potentially devastating effects and has been implicated in many forms of liver disease like acute liver failure or hepatocellular carcinoma. This review will focus initially on recent progress in signaling events of hepatocellular apoptosis and subsequently discuss the consequences for the hepatic pathophysiology that involves disarrangement of hepatocellular apoptosis.

Viral hepatitis and proteinuria in an area endemic for hepatitis B and C infections: another chain of link?

Virus hepatitis may lead to nephropathy as one of its multiple extrahepatic manifestations. Proteinuria by dipstick, a simple test in practice, is a useful and cardinal sign of underlying renal abnormalities. The aim of this study was to elucidate the impact of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections on the occurrence of proteinuria amongst adults. A prospective, cross-sectional, community-based study was conducted in an HBV/HCV endemic area of southern Taiwan. Eligible subjects aged 40-65 years (n=9934) underwent testing of hepatitis B surface antigen (HBsAg), HCV antibody (anti-HCV) and other related biochemical profiles. Urinalysis with repeated dipstick for proteinuria detection was performed. Anti-HCV-positive rate amongst proteinuria subjects was significantly higher than nonproteinuria subjects (9.6% vs. 6.2%, P<0.001). By contrast, HBsAg-positive rate did not differ between subjects with and without proteinuria (13.0% vs. 13.8%, P=0.57). Prevalence of proteinuria amongst anti-HCV-positive subjects (10.2%) was significantly higher than that in HBsAg-positive subjects (6.4%, P=0.004) and in HBsAg-negative or anti-HCV-negative subjects (7.0%, P=0.004). The difference persisted even after excluding diabetics. Multivariate logistic regression analyses showed that diabetes was the most important significant factor associated with proteinuria, followed by hypertension, anti-HCV seropositivity, body mass index, age and triglyceride levels. We demonstrated the significant association between proteinuria and HCV, but not HBV, infection in this HBV/HCV-endemic area.

Transfusion-transmitted virus in association with hepatitis A-E viral infections in various forms of liver diseases in India

To describe the prevalence of transfusion-transmitted virus (TTV) infection in association with hepatitis A-E viral infections in different forms of liver diseases in North India. Sera from a total number of 137 patients, including 37 patients with acute viral hepatitis (AVH), 37 patients with chronic viral hepatitis (CVH), 31 patients with cirrhosis of liver and 32 patients with fulminant hepatic failure (FHF), were analyzed both for TTV-DNA and hepatitis A-E viral markers. Presence of hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis E virus (HEV) infections was detected in different proportions in different groups. Moreover, TTV-DNA was simultaneously tested in 100 healthy blood donors also. None of the patients had hepatitis A virus (HAV) and hepatitis D virus (HDV) infections. Overall prevalence of TTV-DNA was detected in 27.1% cases with AVH, 18.9% cases with CVH, 48.4% cases with cirrhosis and 9.4% cases with FHF. TTV-DNA simultaneously tested in 100 healthy blood donors showed 27% positivity. On establishing a relation between TTV infection with other hepatitis viral infections, TTV demonstrated co-infection with HBV, HCV and HEV in these disease groups. Correlation of TTV with ALT level in sera did not demonstrate high ALT level in TTV-infected patients, suggesting that TTV does not cause severe liver damage. TTV infection is prevalent both in patients and healthy individuals in India. However, it does not have any significant correlation with other hepatitis viral infections, nor does it produce an evidence of severe liver damage in patients with liver diseases.

Apoptosis and Necrosis in the Liver: A Tale of Two Deaths?

Death of hepatocytes and other hepatic cell types is a characteristic feature of liver diseases as diverse as cholestasis, viral hepatitis, ischemia/reperfusion, liver preservation for transplantation and drug/toxicant-induced injury. Cell death typically follows one of two patterns: oncotic necrosis and apoptosis. Necrosis is typically the consequence of acute metabolic perturbation with ATP depletion as occurs in ischemia/reperfusion and acute drug-induced hepatotoxicity. Apoptosis, in contrast, represents the execution of an ATP-dependent death program often initiated by death ligand/death receptor interactions, such as Fas ligand with Fas, which leads to a caspase activation cascade. A common event leading to both apoptosis and necrosis is mitochondrial permeabilization and dysfunction, although the mechanistic basis of mitochondrial injury may vary in different settings. Prevention of these modes of cell death is an important target of therapy, but controversies still exist regarding which mode of cell death predominates in various forms of liver disease and injury. Resolution of these controversies may come with the recognition that apoptosis and necrosis frequently represent alternate outcomes of the same cellular pathways to cell death, especially for cell death mediated by mitochondrial permeabilization. An understanding of processes leading to liver cell death will be important for development of effective interventions to prevent hepatocellular death leading to liver failure and to promote cancer and stellate cell death in malignancy and fibrotic disease.

Growing importance of liver disease in HIV-infected persons

Liver disease is a growing problem in HIV-infected persons. In those who are able to take antiretroviral therapy, the forms of liver disease have changed and their relative importance has increased. This review focuses on liver disease in HIV-infected persons, caused by hepatitis C virus, hepatitis B virus, or treatment of HIV infection.

Heterotopically Transplanted Hepatocyte Survival Depends on Extracellular Matrix Components

The novel approach of tissue engineering to treat many forms of liver diseases using hepatocytes requires sufficient numbers and sustained survival of the transplanted cells. It has been shown that providing extracellular matrix components extracted from Engelbreth-Holm-Swarm cells (EHS-ECMs) to heterotopically transplanted hepatocytes allows significantly greater hepatocyte survival. We investigated the survival and morphology of hepatocytes and EHS-ECMs transplanted under the kidney capsule compared with hepatocytes with growth factor-reduced EHS-ECMs in mice. Both the EHS-ECMs and growth factor-reduced EHS-ECMs showed a large number of surviving hepatocytes under the kidney capsule without any intergroup differences. Histologically, transplanted hepatocytes in both groups retained their characteristic morphologies and formed small liver tissues. These data indicate that extracellular matrix components are the predominant factor in EHS-ECMs required to maintain hepatocytes at heterotopic sites.

Lebertransplantation – Perspektiven und praktische Aspekte 2005

Orthotopic liver transplantation (OLT) has become the method of choice for many forms of endstage liver disease and is generally associated with a good long-term outcome. Morbidity and mortality for this routine procedure have become acceptable provided the procedure is carried out with a correct and timely indication. It is important for the general practitioner to recognize the various early clinical signs of liver failure and portal hypertension in due course in order to reach a comprehensive planning of all necessary medical steps ahead. The most frequent indications for OLT such as chronic hepatitis C related cirrhosis, cholostatic forms of liver disease, limited liver tumours and metabolic disorders (haemochromatosis) are discussed in detail and major practical problems that a general practitioner might encounter in the follow-up of patients with OLT are highlighted in this review.

Arsenite decreases CYP3A23 induction in cultured rat hepatocytes by transcriptional and translational mechanisms

Arsenic is a naturally occurring, worldwide contaminant implicated in numerous pathological conditions in humans, including cancer and several forms of liver disease. One of the contributing factors to these disorders may be the alteration of cytochrome P450 (CYP) levels by arsenic. In rat and human hepatocyte cultures, arsenic, in the form of arsenite, decreases the induction of several CYPs. The present study investigated whether arsenite utilizes transcriptional or post-transcriptional mechanisms to decrease CYP3A23 in primary cultures of rat hepatocytes. In these cultures, a 6-h treatment with 5 μM arsenite abolished dexamethasone (DEX)-mediated induction of CYP3A23 protein and activity, but did not inhibit general protein synthesis. However, arsenite treatment only reduced DEX-induced levels of CYP3A23 mRNA by 30%. The effects of arsenite on CYP3A23 transcription were examined using a luciferase reporter construct containing 1.4 kb of the CYP3A23 promoter. Arsenite caused a 30% decrease in DEX-induced luciferase expression of this reporter. Since arsenite abolished induction of CYP3A23 protein, but caused only a small decrease in CYP3A23 mRNA, the effects of arsenite on translation of CYP3A23 mRNA were investigated. Polysomal distribution analysis showed that arsenite decreased translation by decreasing the DEX-mediated increase in CYP3A23 mRNA association with polyribosomes. Arsenite did not decrease intracellular glutathione or increase lipid peroxidation, suggesting that the effect of arsenite on CYP3A23 does not involve oxidative stress. Overall, the results suggest that low-level arsenite decreases both transcription and translation of CYP3A23 in primary rat hepatocyte cultures.

ARSENITE DECREASES CYP3A4 AND RXRα IN PRIMARY HUMAN HEPATOCYTES

Arsenic is a naturally occurring, worldwide contaminant implicated in numerous pathological conditions in humans, including cancer and several forms of liver disease. One of the contributing factors to these disorders may be the alteration of cytochrome P450 (P450) levels by arsenic. P450s are involved in the oxidative metabolism and elimination of numerous toxic chemicals. CYP3A4, a major P450 in humans, is involved in the metabolism of half of all currently used drugs. Acute exposure to arsenite decreases the induction of CYP1A1/2 proteins and activities in cultured human hepatocytes, as well as CYP3A23 in cultured rat hepatocytes. Here, in primary cultures of human hepatocytes, we assessed the effects of acute arsenite exposure on CYP3A4 and several transcription factors involved in CYP3A4 expression. The concentrations of arsenite used in these studies were nontoxic to the hepatocytes and failed to elicit an oxidative response. Treatment with arsenite in the presence of CYP3A4 inducers, rifampicin (Rif) or phenobarbital, caused major decreases in CYP3A4 mRNA, protein, and activity. In addition, the levels of CYP3A4 in untreated cells were decreased following arsenite treatment. Transcription of the CYP3A4 gene is primarily regulated by heterodimers of the retinoid X receptor alpha (RXRalpha) and the pregnane X receptor (PXR). We found that arsenite failed to affect expression of PXR or the transcription factor Sp1, yet caused a significant decrease in PXR responsiveness to Rif. Arsenite caused a large decrease in nuclear RXRalpha protein and, to a lesser extent, RXRalpha mRNA. These results suggest that arsenite inhibits both untreated and induced CYP3A4 transcription in primary human hepatocytes by decreasing the activity of PXR, as well as expression of the nuclear receptor RXRalpha.

Abnormal aminotransferase activity in women with polycystic ovary syndrome

Alanine aminotransferase (ALT) activity was abnormal in 30% of 70 female infertility patients with polycystic ovary syndrome in whom causes other than nonalcoholic fatty liver disease were excluded by history and serum testing. Women with elevated ALT had significantly higher body mass index, waist circumference, serum triglycerides, total cholesterol-to-HDL-cholesterol ratio, and degree of insulin resistance.

Cholesterol Accumulation and Liver Cell Death in Mice With Niemann-Pick Type C Disease *

Niemann-Pick type C (NPC) disease develops as a result of mutations in the NPC1 gene that encodes a protein involved in the net movement of unesterified cholesterol from the late endosomal/lysosomal compartment to the metabolically active pool of sterol in the cytosol of virtually every cell in the body. Although early publications emphasized the neurodegeneration occurring in children with this mutation, more recent clinical information suggests that serious liver disease also is an important part of this syndrome. These studies, therefore, were undertaken to characterize the liver dysfunction seen in mice with this same mutation. The NPC mouse develops significant hepatomegaly that reaches 8% of body weight at 5 to 6 weeks of age. This increase in liver size is associated with a linear increase in cholesterol content and with accumulation of amorphous cellular inclusions in both hepatocytes and macrophages. During the few weeks after birth, significant elevation of the plasma alkaline phosphatase level occurs, as also is seen in the human infant with this disease. At 4 to 5 weeks of age, plasma aminotransferase levels also rise abruptly. Histologically, at this time there is apoptosis, but no excess deposition of collagen or glycogen. mRNA expression is elevated for caspase 1, caspase 6, and several enzymes associated with sterol biosynthesis and bile acid formation. In conclusion, the NPC mouse has liver disease similar to that seen in the NPC infant and represents a relevant model for exploring the molecular events occurring in this form of liver disease.

Pathology of Hepatic Iron Overload

The role of liver biopsy in all chronic liver diseases continues to evolve with the emergence of new laboratory and imaging tests. However, the value of histologic examination for fibrosis, parenchymal architectural remodeling, and possible concurrent disease remains relatively unchallenged, including in patients with suspected iron overload. In addition, only histologic evaluation allows detailed analysis of cellular and acinar localization of iron. Routine use of an iron stain for all liver biopsy analysis enables detection of iron when not otherwise suspected. The broad classifications of iron overload include parenchymal ("primary") or reticuloendothelial ("secondary"), and mixed. These classifications, however, serve only as guidelines to differential diagnoses, as will be noted in the following review of pathology of iron overload. Ultimately, the role of the pathologist is to document cellular and acinar localization of iron and to provide a semiquantitative assessment of amount to alert the clinician to the possibility of a significant condition. In this article, histopathologic findings in conditions of iron overload and in several forms of liver disease are discussed.