Serum Aminotransferase Concentrations Research Articles

Reduced urinary 6β-hydroxycortisol to cortisol ratios in patients with liver cirrhosis

While the urinary concentration ratio of 6β-hydroxycortisol (6β-HC) to cortisol (C) in 24-h urine samples is an established parameter for the induction of hepatic cytochrome P450 (CYP) 3A activity, it remains unclear whether it would be reduced in association with chronic liver damages. To clarify this issue we measured this parameter in 12 patients with chronic hepatitis, 15 patients with liver cirrhosis and 12 healthy subjects. Urinary 6β-HC and C were assayed with high-performance liquid chromatography with ultraviolet absorption. Multiple regression analysis was performed to search for which biochemical or demographic parameter(s) would be associated with the overall variability of urinary 6β-HC/C ratios. Results showed that the mean (±S.D.) 6β-HC/C ratio obtained from the patients with liver cirrhosis (4.3±2.6), but not that from patients with chronic hepatitis (7.4±7.2), was significantly ( P<0.05) lower than that obtained from the healthy controls (11.8±8.3). It was also revealed that among the clinical parameters examined (e.g. serum transaminases concentrations) only serum albumin concentrations were correlated significantly ( R=0.61, P<0.05) with the urinary 6β-HC/C ratio. In conclusion, the present study implies that that the reduced urinary 6β-HC/C ratios in patients with liver cirrhosis may be associated with attenuated hepatic CYP3A activity in these patients.

Health Risks of Selected Performance-Enhancing Drugs

This article reviews adverse effects of and the difficulty of attributing toxic effects to selected drugs and dietary supplements that purportedly enhance athletic performance. On surveys estimating the extent of performance-enhancing drug use, 5% of high school students indicated anabolic-adrenergic steroid use, and approximately 28% of collegiate athletes and 5.6% of middle and high school athletes admitted creatine use. Many adverse health effects from the abuse of androgenic-anabolic steroids and androstenedione (a prodrug) are exaggerations of excessive testosterone on hepatic, cardiovascular, reproductive, and behavioral functions that can produce permanent changes. With creatine use, nausea, vomiting, diarrhea, elevated serum transaminase concentrations, hypertension, fluid retention, muscle cramping, and muscle strains have been reported. Ephedra stimulates adrenergic receptors, leading to tachycardia and hypertension, with central nervous system effects of anxiety, tremor, and hyperactivity. From 1997 to 1999, 10 people died and 13 suffered permanent disabilities due to ephedra. γ-Hydroxybutyrate and several prodrugs (γ-butyrolactone and 1,4-butanediol) can produce alternating agitation and coma, amnesia, hypotonia, ataxia, nystagmus, tremors, bradycardia, respiratory depression, and apnea. Although γ-hydroxybutyrate abuse began as a bodybuilding aid, most serious adverse effects are from acute overdoses. Adverse effects from performance-enhancing drugs do occur, but their extent and frequency are unknown.

Association between hepatitis C virus core protein and carotid atherosclerosis.

A link between certain infectious microorganisms and an increased risk of atherosclerotic disease has been suggested. By analyzing the data of subjects who had undergone general health-screening tests, a possible association between carotid atherosclerosis and seropositivity of antibody against hepatitis C virus (HCV) has been previously reported. In the present study, a possible link between carotid atherosclerosis and HCV core protein positivity was assessed, because it is postulated to be a better marker of viremia and thus persistent infection. Of the 1992 enrolled subjects, 496 (25%) had carotid artery plaque, and 25 (1.3%) were positive for HCV core protein. Carotid artery plaque was positive in 480/1967 (24%) and 16/25 (64%) of the core protein-negative and core protein-positive subjects, respectively (p<0.0001 by chi(2) test). Serum concentrations of transaminases were higher in core protein-positive subjects, but albumin concentrations were not significantly different between the 2 groups. Multivariate logistic regression analysis showed that HCV core protein positivity is an independent predictor of carotid plaque with an odds ratio of 5.61 (95% confidence interval 2.06-15.26, p<0.001). These data further support the possible link between persistent HCV infection and carotid atherosclerosis in the subjects without severe liver dysfunction.

Hepatic involvement in lepromatous leprosy

Hepatic involvement in a lepromatous leprosy (LL) patient is reported. The serum concentrations of aminotransferases were much higher than previously described in the leprosy literature. Other causes for hepatic damage were ruled out. Such hepatic involvement and elevation of aminotransferases have never been described in leprosy.

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

Lack of susceptibility of Chacma baboons (Papio ursinus orientalis) to hepatitis C virus infection.

The main reason to ascertain whether baboons are susceptible to infection with hepatitis C virus (HCV) is the need to replace chimpanzees, which are endangered, as an animal model for undertaking research into the biology and host-virus interactions of HCV, and for developing a vaccine against this virus. A second reason is that baboons are a possible source of xenografts for human liver transplantation. We inoculated serum containing HCV into four Chacma baboons and monitored them for 52 weeks for evidence of infection. Serum was tested for antibody to HCV, HCV RNA, and aminotransferase concentrations at 2-week intervals for 26 weeks and thereafter at 4-week intervals. Liver tissue was examined at 28 and 52 weeks for histopathological changes and viral RNA, and at 52 weeks for viral particles using electron microscopy. Reverse transcription-polymerase chain reaction assay was used to detect HCV RNA, and the results were confirmed by Southern hybridization. Serum aminotransferase concentrations remained within the normal range and liver histology was normal during the follow-up period. Passive transmission of anti-HCV to the baboons was observed during the first 4 weeks. HCV RNA was not detectable in any serum or liver sample and electron microscopy failed to reveal viral particles in liver tissue. In conclusion, we did not find Chacma baboons to be susceptible to infection with HCV, although we cannot deny that in an immunosuppressed liver transplant recipient, infection of a baboon xenograft might occur. Another animal model for HCV infection must be sought.

Chronic acetaminophen overdosing in children: risk assessment and management.

Acetaminophen is currently the pediatric analgesic and antipyretic of choice. Although children appear to tolerate single, high-dose ingestions well, the literature is replete with reports of significant morbidity and mortality after repeated supra-therapeutic dosing. Proposed risk factors for injury with chronic use include age, total dose, duration, presence of intercurrent febrile illness, starvation, co-administration of cytochrome P450-inducing drugs, underlying hepatic disease, and unique genetic makeup. Evaluation of these children should include serum acetaminophen concentration, prothrombin time, and serum bilirubin and transaminase concentrations. The Rumack-Mathew nomogram should not be used to estimate the risk of hepatotoxicity in cases of chronic ingestion. Based on history, clinical examination, and laboratory findings, patients may be placed in three categories: those without hepatic injury and with no residual acetaminophen to be metabolized, those without injury but with some acetaminophen to be metabolized, and those with hepatotoxicity. Those without injury and no residual acetaminophen need not be treated or followed. Patients with hepatotoxicity or potential for hepatotoxicity based on residual acetaminophen should be treated with N-acetylcysteine. Most importantly, because so many parents are unaware of the potential risk of inappropriate dosing, education is the key to preventing future cases.

Interferon Therapy in Liver Cirrhosis Type C

Objective: To review current information on the role of interferon (IFN) therapy in patients with liver cirrhosis type C. Data Sources: All relevant articles from 1989 to December 1998 were identified by a MEDLINE search using the terms interferon treatment and liver cirrhosis. Some studies were identified from bibliographies of selected articles. Study Selection: More than 97 articles were identified. Reports were included if they contained new or relevant information on the hepatitis C virus (HCV), IFN therapy in liver fibrosis and cirrhosis, outcome of cirrhosis, hepatocellular carcinoma (HCC), or adverse effects related to IFN. Abstracts were included only when they added information not otherwise available in the literature. Data Synthesis: Response to IFN is unfavorably influenced by the presence of cirrhosis; there are several other predictors of response. IFN therapy can decrease the risk of development of HCC in some patients. In patients with compensated cirrhosis type C, a higher dosage of IFN-alfa and longer duration of therapy are associated with a better response. Combined therapy with IFN-alfa 2b and ribavirin is more effective than therapy with IFN-alfa alone. Therapy with human lymphoblastoid IFN (L-IFN) produces sustained response rates equivalent to those of recombinant IFN-alfa. Consensus IFN (CIFN) is more effective than IFN-alfa 2b. Larger dosages of CIFN are associated with better results. Normal alanine transaminase concentration and the absence of serum HCV RNA after treatment and again after 24 weeks of observation indicate a successful end point of IFN therapy. Adverse effects related to IFN treatment are usually minor. Conclusions: Although the presence of cirrhosis predicts a poor response to IFN treatment, some patients benefit from this therapy. Reasonable treatment regimens for patients with compensated HCV cirrhosis include IFN-alfa therapy, 6 MU subcutaneously three times weekly for 12 months, L-IFN 3 MU intramuscularly three times weekly for six months, or CIFN 9 or 12 μg subcutaneously three times weekly for six months. Patients receiving IFN should be seen every two to four weeks, with frequent monitoring of complete blood count and serum transaminase concentrations.

Modulation of the inflammatory properties and hepatotoxicity of recombinant adenovirus vectors by the viral E4 gene products.

Liver toxicity and inflammation were assessed in C57BL/6, CBA, and BALB/c mice injected intravenously with a series of recombinant adenoviruses deleted simultaneously in E1/E3, in E1/E3/E2A, or in E1/E3/E4. All vectors were either devoid of transgenes or carried in E1 the human CFTR cDNA under the control of the CMV promoter. Injection of the E1/E3-deleted vector induced a significant liver dystrophy and inflammatory responses that were accompanied by an increased serum transaminase concentration. The vector toxicity remained elevated on additional deletion of the E2A gene and was further enhanced when hCFTR was expressed. In contrast, additional deletion of E4 led to a reduction in hepatotoxicity, suggesting an active role of E4 gene products in liver injury. However, deletion of E4 also led to a loss of transgene expression. To identify the individual E4 product(s) involved in liver toxicity and in the regulation of transgene expression, a series of isogenic E1/E3-deleted vectors, with or without the hCFTR transgene, and containing various combinations of functional E4 open reading frames (ORFs), were evaluated in vitro and in vivo. We demonstrate that liver injury was markedly reduced with vectors containing either ORF3 alone or ORF3,4 while vectors containing ORF4, ORF6,7 or ORF3,6,7 still displayed elevated hepatotoxicity and inflammatory responses. Moreover, transgene expression was restored when ORF3,4 or ORF3,6,7 was retained in the vector. These results highlight the importance of the E4 gene products in the design of improved in vivo gene transfer vectors.

Serum aminotransferase concentration as evidence of hepatocellular damage

Because the liver has a variety of biochemical, synthetic, and excretory functions, several biochemical tests are used in the diagnosis and management of liver diseases. These tests are commonly referred to collectively as liver-function tests, even though the investigation most frequently requested and of greatest use in clinical practice—namely, serum aminotransferase concentrations—is an indicator not of hepatocellular dysfunction but of hepatocellular damage. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are present in high concentration in hepatocytes, where they catalyse the transfer of alpha-amino groups from alanine and aspartate to the alpha-keto group of ketoglutaric acid, to produce pyruvic acid and oxaloacetic acid, respectively.

The evaluation of the therapeutic effect of tao-shang-tsao on alpha-naphthylisothiocyanate and carbon tetrachloride-induced acute liver damage in rats.

The hepatoprotective effects of Tao-shang-tsao, Ixeris laevigata Sch.-Bip. var. oldhami Kitam., were studied on cholestatic hepatitis induced by alpha-naphthylisothiocyanate (ANIT, 100 mg/10 ml/kg, in olive oil, i.p.) and acute hepatitis induced by carbon tetrachloride (20% CCl4/olive oil, 1.5 ml/kg, i.p.) in rats by post-treatment with the crude methanolic extracts of I. laevigata (0.3, 1.0, and 2.0 g/kg) orally in the therapeutic model. Hepatoprotective activity was monitored by estimating the serum transaminases concentrations and histopathological changes in the livers of experimental rats. It was found that the I. laevigata extract significantly decreased the acute elevation of serum transaminases by biochemical examination. According to pathohistological studies in the liver of experimental rats, the crude I. laevigata extract ameliorates the central necrosis, fatty change or proliferation of bile duct epithelium focal necrosis caused by ANIT or CCl4-induced hepatitis rats.

Gabexate mesilate, a synthetic protease inhibitor, reduces ischemia/reperfusion injury of rat liver by inhibiting leukocyte activation.

To investigate whether gabexate mesilate, a synthetic protease inhibitor with anticoagulant properties, prevents hepatic damage by inhibiting leukocyte activation, we examined its effect on ischemia/reperfusion injury of rat liver in which activated leukocytes play a critical role. Prospective, randomized, controlled study. Research laboratory at a university medical center. Male Wistar rats weighing 220 to 280 g. Hepatic damage was evaluated by changes in bile flow and serum transaminase concentrations after ischemia/ reperfusion. Rats received continuous intravenous infusions of gabexate mesilate (10 mg/kg/hr) or intravenous administration of an inactive derivative of activated factor X (Xa), a selective inhibitor of thrombin generation (3 mg/kg), immediately before the induction of ischemia in the median and left lobes of the liver. To determine whether gabexate mesilate inhibits leukocyte activation, we examined the effects of gabexate mesilate on hepatic concentrations of tumor necrosis factor-alpha and rat interleukin-8 and on hepatic myeloperoxidase activity after ischemia/reperfusion. Hepatic dysfunction, observed after 60 mins of ischemia/reperfusion, showed a reduction in bile flow. The ischemia/reperfusion-induced decrease in bile flow was prevented by administration of gabexate mesilate. Serum transaminase concentrations increased after hepatic ischemia/reperfusion, peaking 12 hrs after reperfusion. Gabexate mesilate significantly inhibited the ischemia/reperfusion-induced increase in serum transaminase levels seen 12 hrs after reperfusion. Although an inactive derivative of factor Xa inhibited the increases in serum levels of fibrin and fibrinogen degradation products 6 hrs after reperfusion, it did not prevent ischemia/ reperfusion-induced liver injury. Hepatic levels of tumor necrosis factor-alpha, rat interleukin-8, and myeloperoxidase were significantly increased after ischemia/reperfusion. These increases were significantly inhibited by gabexate mesilate but unaffected by an inactive derivative of factor Xa. Gabexate mesilate reduced ischemia/reperfusion-induced hepatic injury not by inhibiting coagulation, but by inhibiting leukocyte activation.

Folate Nutriture Alters Choline Status of Women and Men Fed Low Choline Diets

Choline and folate share methylation pathways and, in studies of rats, were shown to be metabolically inter-related. To determine whether choline status is related to folate intake in humans, we measured the effect of controlled folate depletion and repletion on the plasma choline and phosphatidylcholine concentrations of 11 healthy men (33–46 y) and 10 healthy women (49–63 y) fed low-choline diets in two separate metabolic unit studies. Total folate intake was varied by supplementing low folate (25 and 56 μg/d for men and women, respectively) and low choline (238 and 147 mg/d for men and women, respectively) diets with pteroylglutamic acid for 2–6 wk following folate-depletion periods of 4–5 wk. The low folate/choline intakes resulted in subclinical folate deficiencies; mean plasma choline decreases of 28 and 25% in the men and women, respectively; and a plasma phosphatidylcholine decrease of 26% in the men (P < 0.05). No functional choline deficiency occurred, as measured by serum transaminase and lipid concentrations. The decreases in choline status measures returned to baseline or higher upon moderate folate repletion and were more responsive to folate repletion than plasma folate and homocysteine. Feeding methionine supplements to the men did not prevent plasma choline depletion, indicating that folate is a more limiting nutrient for these methylation pathways. The results indicate that 1) choline is utilized as a methyl donor when folate intake is low, 2) the de novo synthesis of phosphatidylcholine is insufficient to maintain choline status when intakes of folate and choline are low, and 3) dietary choline is required by adults in an amount > 250 mg/d to maintain plasma choline and phosphatidylcholine when folate intake is low.

Safety and Efficacy of Cefoperazone Plus Sulbactam versus Ceftazidime in the Empiric Treatment of Febrile Neutropenia

Objective: To compare the safety and efficacy of cefoperazone plus sulbactam (CPZ + SB) (3 g [2:1] every 8 h) and ceftazidime (CTZ) (2 g every 8 h) as monotherapy in the empiric treatment of febrile neutropenia in patients with cancer. Patients: One hundred eighteen cancer patients with chemotherapy-associated neutropenia and fever. Most patients (82) received norfloxacin and fluconazole as prophylaxis. Results: Fifty-nine patients were enrolled in the CPZ + SB group, and 59 were enrolled in the CTZ group. The mean duration of antibiotic therapy was less than 10 days in both groups. Forty-three patients (19 in the CPZ + SB group and 24 in the CTZ group) were bacteremic, and 7 others had cellulitis. Of the 56 microorganisms producing bacteremia, 51 were gram-positive bacteria, mostly staphylococci (28 isolates) and streptococci (22 isolates). Gram-positive cocci were more frequently resistant to CTZ than to CPZ + SB (77% vs. 40%, respectively; p &lt; 0.002). However, the clinical response rate at 72 hours of therapy was 53% in the CPZ + SB group and 52% in the CTZ group (p = 1.0). At the end of therapy, clinical responses were similar in the two groups (p = 0.19). Clinical success with antibiotic modification was seen in 42% of the CPZ + SB recipients and in 58% of CTZ recipients (p = 0.10). Bacteriologic eradication among bacteremic patients appeared to be slightly better in the CPZ + SB group (79% vs. 54%; p = 0.09). Except for rashes in 3 patients (1 in the CPZ + SB group and 2 in the CTZ group), both drugs were well tolerated. Adverse events included superinfections, transient elevation of serum transaminase concentrations, diarrhea, and chills. Conclusions: CPZ + SB was superior to CTZ in its in vitro activity against aerobic gram-positive cocci encountered in the study; however, the clinical efficacy and safety of the two drug treatments were similar in the empiric therapy for febrile neutropenia.

Hepatic expression of c-Myb in chronic human liver disease

C-Myb is a sequence-specific DNA binding protein that regulates the expression of genes involved in cell proliferation and differentiation. The present study was designed to elucidate the role of c-Myb in the pathogenesis of chronic liver disease by an immunohistochemical approach. In normal (control) livers, few or no hepatic cells were positive for c-Myb. In livers from patients with chronic viral hepatitis, positive staining for c-Myb was found not only in spindle-shaped mesenchymal cells in expanded portal areas, but also in perisinusoidal cells (PSCs) within liver lobules. In cirrhotic livers, a few PSCs within lobules were positive for c-Myb, while no staining was seen in fibrous septa. Immunoelectron microscopy revealed that c-Myb-positive PSCs displayed morphological features of hepatic stellate cells. Other sinusoidal lining cells including Kupffer cells and sinusoidal endothelial cells, as well as hepatocytes, were all negative for c-Myb. Dual c-Myb/alpha-smooth muscle actin (alphaSMA) staining revealed that more than 97% of c-Myb-positive cells were alphaSMA-positive. Moreover, dual c-Myb/proliferating cell nuclear antigen (PCNA) staining showed that approximately 70% of c-Myb-positive cells also expressed PCNA. The labeling index (LI) (number of c-Myb-positive cells/0.1 mm2) significantly correlated with serum transaminase concentrations and increased in parallel with the disease activity. However, the LI showed no correlation with the degree of fibrosis. These results suggest that c-Myb may be involved in stellate cell activation and proliferation in chronically diseased human livers, and that the level of c-Myb expression is associated with the activity of chronic hepatitis. (Hepatology 1997 Dec;26(6):1506-12)

Sexual Transmission of the Hepatitis C Virus and Efficacy of Prophylaxis With Intramuscular Immune Serum Globulin

To estimate the risk of sexual transmission of hepatitis C and to assess the value of prophylaxis with periodic intramuscular immune serum globulin administration. Of 1102 steady heterosexual partners of patients with antibodies to the hepatitis C virus (HCV), 899 were enrolled in a single-blind, randomized, controlled trial. All the partners tested negative for antibodies to HCV and had normal baseline serum aminotransferase concentrations. The partners were assigned to receive 4 mL of 16% polyvalent immune serum globulin prepared from unscreened donors every 2 months (n = 450) or a placebo (n = 449). Tests for HCV infection were performed every 4 months. Eight hundred eighty-four partners completed the study. Seven partners became infected with HCV: 6 in the control group (incidence density, 12.00 per 1000 person-years; 95% confidence interval, 3.0 21.61) and 1 in the immune serum globulin group (incidence density, 1.98 per 1000 person-years; 95% confidence interval, 0-5.86). The risk of infection was significantly higher for partners in the control group (P = .03): for each year approximately 1% of the partners became infected. Sequence homology studies strongly suggest the sexual transmission of HCV. All immune serum globulin lots used had high enzyme-linked immunosorbent assay titers of neutralizing antibodies to HCV envelope glycoproteins and high neutralization titers in the neutralization of binding assay. Hepatitis C can be sexually transmitted. Immune serum globulin prepared from unscreened donors significantly reduced the risk. The treatment was safe and well tolerated. Because only immune serum globulin from unscreened donors (and not from those screened for HCV) contain anti-HCV neutralizing antibodies, hyperimmune anti-HCV immune serum globulin should be prepared from blood testing positive for antibodies to HCV, which is currently discarded.

GB virus C (GBV-C)/hepatitis G virus (HGV) infection among intravenous drug users in Japan

A sero-epidemiologic survey of 74 IVDUs and 86 age-matched controls was performed to investigate the prevalence, clinical significance, and genetic distribution of GB virus C (GBV-C)/hepatitis G virus (HGV) infection among intravenous drug users (IVDUs) in Japan. GBV-C/HGV RNA was detected by reverse transcriptase-hemi-nested polymerase chain reaction (RT-hemi-nested PCR) for the 5′-untranslated region (5′-UTR) in 43.2% (32/79) of the IVDUs compared with 1.2% (1/86) of the controls (P<0.001). The duration of drug use did not correlate with the prevalence of GBV-C/HGV. Thirteen subjects positive for GBV-C/HGV RNA without HCV RNA had normal serum aminotransferase concentrations. Phylogenetic tree showed that the 32 GBV-C/HGV-positive isolates from IVDUs were classified within a new GBV-C/HGV group, which has been identified mainly in Asian subjects (type 3). The present study illustrated, (1) the high incidence of GBV-C/HGV infection among Japanese IVDUs, (2) GBV-C/HGV alone may not be an important pathogenic factor for hepatic injury, and (3) type 3 GBV-C/HGV was the most prevalent among IVDUs in Japan.

Vesnarinone inhibits immune-mediated but not fas (CD95) agonist-mediated hepatic injury

Previous studies have shown that the administration of concanavalin A (ConA) into mice induces immune-mediated liver injury, which can be largely abrogated by neutralizing tumor necrosis factor(TNF)α. Vesnarinone is an experimental drug which is known to inhibit TNFα release. Here we demonstrate that vesnarinone inhibits ConA-induced hepatic injury. In a dose-dependent manner, vesnarinone inhibits in several mouse strains the increase of serum aminotransferase concentrations. Additional experiments show that vesnarinone inhibits ConA-mediated accumulation of DNA fragmentation in the liver. Furthermore, the drug significantly reduces the levels of circulating TNFα and interleukin-6 (IL-6). Vesnarinone does not modulate TNFα and IL-6 action on hepatic cells, as shown by its failure to reduce the cytokine specific-stimulation of acute phase plasma proteins in the rat hepatoma H-35 cell line. Neither vesnarinone nor anti-TNFα protect against direct liver injury induced by a sublethal dose of agonist anti-Fas (CD95) antibody. Taken together, these results suggest that vesnarinone blocks hepatic injury, in part by inhibiting the release of TNFα in vivo.

HGV: hepatitis G virus or harmless G virus?

The discovery of the hepatitis G virus (HGV) has given hepatologists a new lease on life. Just when they were becoming frustrated with the slow rate of progress in unravelling the pathobiological consequences of hepatitis B and C virus infections, along comes another candidate virus. HGV, a single-stranded ribonucleic acid (RNA) virus that belongs to the Flaviviridae family, has a global distribution. The virus is present in 1–2% of blood donors in the USA, a frequency higher than that of either HCV or hepatitis B virus (HBV) (Alter). Even more striking is the seroprevalence of 15.2% reported in West African residents (J Med Virol 1996; 50: 97). HGV exists in a chronic carrier state. The virus is transmitted parenterally and is often present in patients who have received multiple transfusions or who are on haemodialysis (N Engl J Med 1996; 334: 1485), and in intravenous drug users. There is preliminary evidence for perinatal transmission (Lancet 1996; 347: 615). HGV RNA sequences have been identified in serum from patients with non-A-E acute and chronic hepatitis and cirrhosis. Impressive data comes from Brescia, Italy, where 35% of patients with acute hepatitis and 39% of those with chronic hepatitis were positive for HGV RNA (Fiordalisi). Among blood donors the virus is more common in those with raised serum amino transferase concentrations (3.9%) than in those with normal concentrations (0.8%) (J Med Virol 1996; 50: 97). These findings imply that HGV is a human pathogen, but is it? Other information is more consistent with HGV being an innocent passenger. The great majority of individuals who become HGV-RNA positive after blood transfusion have normal serum amino transperase concentrations and neither they, nor those found positive for HGV RNA in other circumstances, develop liver disease during prolonged follow-up (Alter). Moreover, when serum enzyme concentrations are raised they seldom accord with levels of viraemia. HGV and HCV are often, and HGV and HBV less often, found together in serum. In those coinfected with HGV and HCV, amino transterases run parallel to HCV rather than HGV, and the presence of the latter seems to have no effect on outcome. HGV usually accounts for only a minority of cases of acute non-A-E hepatitis, and there is no evidence yet of progression over time to chronic hepatitis, cirrhosis, or hepatocellular carcinoma, as occurs with HBV and HCV. Although severe (even fulminant) cases of community-acquired acute hepatitis G have been reported, some of the patients had histories suggestive of earlier exposure to HGV and HGV RNA has persisted for a long time after clinical and biochemical recovery, so one possibility is that they were chronic carriers of the virus and the acute liver injury had another cause. HGV positivity rates in patients with chronic non-A-E hepatitis are not usually higher than in patients with non-viral hepatitis. Inclusion of HGV among the hepatitis viruses may have been premature. Furthermore, it is obvious that at least one virus that causes clinically significant liver disease is still out there waiting to be identified. Several other important observations appeared during 1996. Ursodeoxycholic acid, long known to improve the symptoms and disturbed biochemistry in patients with primary biliary cirrhosis, was finally shown to improve long-term survival as well. Ecstasy (3,4 methyl-enedioxymethamphetamine) unsurprisingly proved to be hepatotoxic. Eight patients with severe acute liver failure were reported: all but one required liver transplantation and six died.

Role of granulocyte elastase in ischemia/reperfusion injury of rat liver.

To investigate the role of granulocyte elastase in ischemia/reperfusion injury of liver, the effect of ONO-5046, a granulocyte elastase inhibitor, was examined in ischemia/reperfusion-induced liver injury in rats. Prospective, randomized, controlled study. Research laboratory at a university medical center. Male Wistar rats, weighing 220 to 280 g. Animals receiving continuous intravenous infusion of ONO-5046 (50 mg/kg/hr) were subjected to hepatic ischemia/reperfusion. Hepatic damage was evaluated by effects on bile formation capacity, plasma clearance of indocyanine green, and serum aminotransferase concentrations after ischemia/reperfusion. Hepatic dysfunction, observed after 60 mins of ischemia/reperfusion, led to a reduction in bile flow and to a decrease in the plasma clearance of indocyanine green. These indicators of hepatic dysfunction were prevented, to a large extent, by administration of ONO-5046. Serum concentrations of aminotransferases increased after hepatic ischemia/reperfusion, peaking at 12 hrs of reperfusion. Increases in serum concentrations of aminotransferases were significantly inhibited by ONO-5046. Granulocyte elastase derived from activated leukocytes may play a critical role in hepatic dysfunction and the subsequent hepatic injury induced by ischemia/reperfusion.