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PubMed2002

A role for chronic parvovirus B19 infection in liver dysfunction in renal transplant recipients?

BACKGROUND: Clinically, liver dysfunction in renal transplant recipients is related to hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. The contribution of parvovirus B19 (B19) to liver disease in renal transplant recipients has not been studied. Here we present the association of liver dysfunction with or without the coinfection of B19, HBV, and HCV after renal transplantation. METHODS: We used enzyme-linked immunosorbent assay to identify B19, HBV, and HCV infections in serum samples taken from 144 renal transplant recipients before transplantation and at 12 and 24 months after transplantation. After each patient had fasted for 12 hr, blood was taken for measurement of aspartate aminotransferase and alanine aminotransferase monthly for at least 6 months. RESULTS: Liver dysfunction developed at the significantly higher incidence of 47% in the anti-HCV(+) patients compared with 6% in the noninfected group (P<0.0001). HBV infection had no impact on the incidence of liver dysfunction in renal transplant recipients. A higher incidence of liver dysfunction was found in 42% of B19 IgG(+)IgM(-) group patients compared with 13% of the B19 IgG(+)IgM(+) group (P=0.0051) and 9.5% of the B19 IgG(-)IgM(-) group (P=0.0003). A B19 polymerase chain reaction (PCR) assay revealed significantly higher liver dysfunction in 29% of B19 PCR(+) group patients compared with 13.6% of B19 PCR(-) patients (P=0.0419). Patients who were anti-HCV(+) and B19 PCR(+) had a significantly higher incidence of liver dysfunction than B19 PCR(-) patients (P=0.002). CONCLUSIONS: Chronic B19 infection and HCV infection, both separately and in combination, increase the incidence of liver dysfunction in renal transplant recipients. HBV infection does not seem to be independently or synergistically associated with liver dysfunction.

Adolescent↗

PubMed1989

Comparison of anamnestic history, alcohol intake and smoking, nutritional status, and liver dysfunction between thorotrast patients who developed primary liver cancer and those who did not.

In order to clarify the differences in past history, nutritional condition and, consumption of alcohol and tobacco, and liver dysfunction between the thorotrast patients who developed primary liver cancer and those who did not, 103 persons who had no primary liver cancer in January 1980 were studied. All subjects were military men who had undergone angiography with thorotrast between 1943 and 1946. Twenty persons developed hepatocellular carcinoma and 16 developed intrahepatic bile duct carcinoma by April 1987, whereas 67 are still alive without any cancer. There was no difference in age or period after thorotrast infusion between those two groups of patients in January 1980. A difference in history of hepatitis and/or jaundice and presence of hepatic dysfunction was found between the subjects who developed primary liver cancers and those who did not. These findings suggest that an anamnestic history of hepatitis and liver dysfunction are risks for development of thorotrast-induced liver cancer. On the basis of the above findings, early detection of liver dysfunction offers a possibility of early diagnosis of primary liver cancer.

Aged↗

PubMed1986

Liver dysfunction in haemophilia.

Liver function was studied in 139 of 291 haemophiliacs known to a single Regional Haemophilia Centre including patients with classical haemophilia, Christmas disease and von Willebrand's disease. In 57 patients, six-monthly liver function tests over a five year period were also available. Thirty-nine of the 139 patients had had jaundice or hepatitis and 56 had a positive test for HBsAb in the blood although few of these had had an identifiable clinical illness. Fifty-eight haemophiliacs had elevated serum aminotransferases at the time of study, but the five year review revealed only six patients who had had persistently abnormal results, although none had clinically evident liver disease. Liver dysfunction was unrelated to a history of hepatitis, to a positive HBsAb test, or to age, type of haemophilia, factor level or frequency of factor replacement treatment. Abnormalities of liver function in haemophilia appear to be unrelated to past or present hepatitis B infection in most cases and may not be related to any single transmitted infectious agent.

Adult↗

PubMed1991

Low uracil concentration in the liver might be responsible for the decreased antineoplastic activity of fluoropyrimidines in mice with CCl4-induced chronic liver dysfunction.

Some fluoropyrimidines are considered to be metabolized in liver microsomes. The present study was designed to assess the effect of chronic liver dysfunction on the antineoplastic activity of fluoropyrimidines. Chronic liver dysfunction was induced in BALB/c mice by 8 weeks of CCl4 injections. The 5-fluorouracil (5-FU)-sensitive MOPC-104E and 5-FU-resistant Meth-A cells were inoculated subcutaneously into the mice and then various fluoropyrimidines were administered intragastrically. The antitumor activity of the fluoropyrimidines decreased in mice with chronic liver dysfunction, although the concentration of 5-FU in the tumor of normal mice did not differ from that of mice with liver dysfunction. However, the concentration of uracil in the liver was decreased in mice with chronic liver dysfunction. On the other hand, the percent conversion of Tegafur [1-(2-tetrahydrofuryl)-5-FU] to 5-FU in the normal liver did not differ from that in the dysfunctional liver. These results suggest that low uracil concentrations in the liver may result from chronic liver dysfunction and lead to decreased antitumor efficacy of fluoropyrimidines.

Animals↗

PubMed1977

Liver dysfunction in hypertension.

Liver-function tests measured routinely in hypertensive patients attending the Glasgow Blood Pressure Clinic were abnormal in 15-8% of men and 6-2% of women. The patients studied appeared to be representative of the whole clinic population. Liver dysfunction was related to alcohol consumption, heavy body-weight, male sex, young age, and higher diastolic blood-pressure. It is suggested that alcohol and obesity were the principal causal factors and that fatty infiltration of the liver was the probable pathology. Liver dysfunction was unrelated to treatment. Alcohol use was found to be heavy in 12% of male patients attending the clinic, and this was probably an underestimate. The possibility that alcohol abuse may have a causal role in hypertension needs further study.

Age Factors↗

PubMed1994

Monitoring of hepatic venous oxygen saturation for predicting acute liver dysfunction after Fontan operations.

Acute liver dysfunction after Fontan operations may result from inadequate hepatic perfusion along with low cardiac output and high central venous pressure. We monitored hepatic venous oxygen saturation in 15 patients after Fontan operations to determine whether oxygen saturation predicts the occurrence and severity of acute liver dysfunction. We measured oxygen saturation from hepatic venous blood samples every 4 to 5 hours for at least 24 hours after the operation and used the mean hepatic venous oxygen saturation value for the first 24 hours after the operation to analyze the relationship between oxygen saturation and hepatic function. As indices of hepatic function, we measured serum alanine aminotransferase, total bilirubin, blood lactate (arterial, hepatic venous, and the difference between them), and the arterial ketone body ratio (the ratio of aceto-acetate to beta-hydroxybutyrate). For alanine aminotransferase and bilirubin, we used the maximal values during the first week in the analysis, and for blood lactate and ketone body ratio, we used the mean values for the first 24 hours after the operation. Significant broken-line regression relationship existed between mean hepatic venous oxygen saturation and hepatic function indices (alanine aminotransferase, total bilirubin, and blood lactate). The interpretation of these relationships is that hepatic indices are constant above the critical mean hepatic venous oxygen saturation values but are correlated with mean hepatic venous oxygen saturation below critical points in the range of 21% to 26%. Thus a hepatic venous oxygen saturation value below about 25% during the first 24 hours after a Fontan operation predicts the occurrence and the severity of acute liver dysfunction. We suggest that monitoring hepatic venous oxygen saturation is useful for management of critically ill patients after Fontan operations.

Adolescent↗

PubMed1995

The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase.

1. We have investigated whether (i) endotoxaemia caused by E. coli lipopolysaccharide in the anaesthetized rat causes a multiple organ dysfunction syndrome (MODS; e.g. circulatory failure, renal failure, liver failure), and (ii) an enhanced formation of nitric oxide (NO) due to induction of inducible NO synthase (iNOS) contributes to the MODS. In addition, this study elucidates the beneficial and adverse effects of aminoethyl-isothiourea (AE-ITU), a relatively selective inhibitor of iNOS activity, and NG-methyl-L-arginine (L-NMMA), a non-selective inhibitor of NOS activity on the MODS caused by endotoxaemia. 2. In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 117 +/- 3 mmHg (time 0) to 97 +/- 4 mmHg at 2 h (P < 0.05, n = 15) and 84 +/- 4 mmHg at 6 h (P < 0.05, n = 15). The pressor effect of noradrenaline (NA, 1 micrograms kg-1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS-rats with AE-ITU (1 mg kg-1, i.v. plus 1 mg kg-1 h-1 starting at 2 h after LPS) caused only a transient rise in MAP, but significantly attenuated the delayed vascular hyporeactivity seen in LPS-rats. Infusion of L-NMMA (3 mg kg-1, i.v. plus 3 mg kg-1 h-1) caused a rapid and sustained rise in MAP and attenuated the delayed vascular hyporeactivity to NA. Neither AE-ITU nor L-NMMA had any effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 3. Endotoxaemia for 6 h was associated with a significant rise in the serum levels of aspartate or alanine aminotransferase (i.e. GOT or GPT), gamma-glutamyl-transferase (gamma GT), and bilirubin, and hence, liver dysfunction. Treatment of LPS-rats with AE-ITU significantly attenuated this liver dysfunction (rise in GOT, GPT, gamma GT and bilirubin) (P < 0.05, n = 10). In contrast, L-NMMA reduced the increase in the serum levels of gamma GT and bilirubin, but not in GOT and GPT (n = 5). Injection of LPS also caused a time-dependent, but rapid (almost maximal at 2 h), increase in the serum levels of urea and creatinine, and hence, renal dysfunction. This renal dysfunction was not affected by either AE-ITU (n = 10) or L-NMMA (n = 5). In rats infused with saline rather than LPS, neither AE-ITU (n = 4) nor L-NMMA (n = 4) had any significant effect on the serum levels of GOT, GPT, gamma GT, bilirubin, creatinine or urea. 4. Endotoxaemia for 6 h resulted in a 4.5 fold rise in the serum levels of nitrite (9.13 +/- 0.77 microM, P < 0.01, n = 15), which was significantly reduced by treatment with AE-ITU (6.32 +/- 0.48 microM, P < 0.05, n = 10) or L-NMMA (5.10 +/- 0.40 microM, P < 0.05, n = 5). In addition, endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver homogenates, which was significantly reduced in lung or liver homogenates obtained from LPS-rats treated with either AE-ITU or L-NMMA. 5. Thus, AE-ITU or L-NMMA (i) inhibits iNOS activity in LPS-rats without causing a significant increase in MAP in rats infused with saline and, hence inhibition of endothelial NOS activity, and (ii) attenuates the delayed circulatory failure as well as the liver dysfunction caused by endotoxaemia in the rat. Thus, an enhanced formation of NO may contribute to the development of liver failure in endotoxic shock.

Animals↗

PubMed2006

[Hepatitis B and C virus infection and liver dysfunction in patients receiving chemotherapy].

BACKGROUND/AIMS: Liver dysfunction and reactivation of hepatitis virus are well-described complications in cancer patients who receive cytotoxic chemotherapy and may result in varying degrees of liver damage. However, there has been just few reports on such complications and on the preemptive use of lamivudine in Korea. The aims of this study were to determine the prevalence of hepatitis B and C virus infection and the incidence of liver dysfunction in patients with malignancies who receive chemotherapy, to determine the reactivation rate of hepatitis B virus (HBV) in those patients, to evaluate the effect of preemptive use of lamivudine in patients with HBV infection. METHODS: Among 1,477 patients who received chemotherapy due to various malignancies from January 2000 to June 2005, 668 patients with incomplete viral studies or hepatitis related malignancy were excluded. A retrospective study was conducted by reviewing the medical records of remaining 809 patients. RESULTS: The overall prevalence rate of hepatitis B or C virus in patients receiving chemotherapy was 6.55% (53/809). The incidences of liver dysfunction was not significantly different between hepatitis virus positive group and negative group. Reactivation rate of hepatitis B or C virus after chemotherapy was 15% (6/40). In all patients who received lamivudine therapy, aspartate aminotransferase and alanine aminotransferase level were normalized and HBV DNA negativity achieved. CONCLUSIONS: The existence of hepatitis virus in patients receiving chemotherapy did not significantly influence the development of severe liver dysfunction, owing probably to the lamivudine therapy. Further prospective studies are required to ascertain the reactivation of hepatitis virus in patients receiving chemotherapy and the need for prophylactic lamivudine therapy in HBV positive patients.

Adult↗

PubMed2002

Prospective study of liver dysfunction in pregnancy in Southwest Wales.

BACKGROUND: Liver dysfunction in pregnancy has serious consequences. Its frequency and characteristics have not been systematically documented in Britain. We have prospectively determined incidence, causes, and outcome of liver dysfunction in pregnancy in an obstetric unit in Southwest Wales, UK. METHODS: A central laboratory identified all abnormal liver tests (bilirubin >25 micro mol/l, aspartate transaminase >40 U/l, or gamma glutamyl transpeptidase >35 U/l) from patients in antenatal clinics and wards of an obstetric unit serving a population of 250 000. Patients with abnormal liver tests were assessed and followed throughout and after pregnancy [corrected]. Medical advice was provided to obstetric teams. FINDINGS: There were 4377 deliveries during the 15 month study. A total of 142 patients had abnormal liver tests. There were 206 contributing diagnoses, the great majority being pregnancy specific. Among the most important were pre-eclampsia (68), HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome (30), obstetric cholestasis (23), hyperemesis gravidarum (11), acute fatty liver of pregnancy (five), and hepatic infarct (one). Sepsis, postoperative factors, and placental pathology (51) were not uncommonly responsible but incidental or pre-existing hepatobiliary disease was infrequent (17). Sixty five patients were delivered early by induction or caesarean section because of liver dysfunction. Despite substantial liver related morbidity, there were no maternal deaths and only two intrauterine deaths. CONCLUSIONS: Liver dysfunction was seen in 3% of deliveries during a 15 month prospective study and was usually directly related to pregnancy with spontaneous recovery in the puerperium. Incidence of the most serious conditions, acute fatty liver of pregnancy and HELLP syndrome, was much greater than previously reported. Profound effects on maternal and infant health were observed but close medical and obstetric collaboration ensured low mortality.

Adult↗

PubMed2001

Serum leptin concentrations in liver cirrhosis: relationship to the severity of liver dysfunction and their characteristic diurnal profiles.

Liver cirrhosis is often associated with malnutrition status, and while leptin, which reduces food intake, appears to contribute to it, there have been few detailed studies of serum leptin concentrations in cases of liver cirrhosis. We therefore measured serum leptin concentrations in liver cirrhosis and investigated its relationship with gender, body composition analysis, and the severity of liver dysfunction and the patterns of diurnal profiles in serum leptin. There were no significant differences between the serum leptin concentrations in the healthy controls and patients with liver cirrhosis. The serum leptin concentrations in liver cirrhosis cases were significantly higher in females than in males. Significant positive correlations were observed between the serum leptin and the body composition analysis data such as body mass index (BMI), arm circumference (AC), and triceps skin fold thickness (TSF). There was no correlations between BMI and arm muscle circumference (AMC). No changes in leptin levels were observed in association with the progression of liver dysfunction, according to the Child-Pugh classification. The diurnal profiles showed different patterns in liver cirrhosis and diabetes mellitus. In diabetes, a nocturnal rise was seen beginning around 21:00, but in liver cirrhosis, the rise in serum leptin started around 12:00, peaked at 13:00, and remained elevated until 03:00 in the morning. No associations were observed between the variations in serum leptin concentrations and variations in blood glucose or plasma insulin levels. In summary, serum leptin concentrations in liver cirrhosis are higher in women, positively correlated with the body composition analysis data, but not correlated with the severity of liver dysfunction. The diurnal profiles in serum leptin concentrations in liver cirrhosis also showed a different pattern from the profiles in diabetes with the values starting to increase earlier, during the daytime. Further study regarding the relation of leptin to nutrition and metabolic abnormalities in liver cirrhosis appears to be necessary.

Journal Article↗

PubMed2000

Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection.

Liver toxicity is a common side effect of antituberculosis (anti-TB) drugs. We studied the differences in liver dysfunction observed during anti-TB treatment between hepatitis B virus carriers (HBV) and noncarriers. Three hundred twenty-four patients on anti-TB drugs were recruited and followed up for 1 year. Forty-three patients with HBV and 276 non-HBV patients were included for analysis. Liver function tests and viral markers were monitored monthly. Liver biopsy was requested whenever the alanine transaminase (ALT) was persistently abnormal. Eighty-six HBV carriers who were not given anti-TB drugs were chosen as a second control and evaluated prospectively. The incidence of liver dysfunction was significantly higher in HBV carriers given anti-TB drugs (34.9%) when compared to noncarriers (9.4%, P <.001) and with HBV carriers not given anti-TB drugs (8.1%, P <.001). For patients given anti-TB drugs, HBV carriers who developed liver dysfunction were younger (P =.011) and had more severe liver injury compared with noncarriers (P =.008). By multiple logistic regression analysis, age (P =.002) and hepatitis B infection (P <.001) were the only 2 significant risk factors for hepatotoxicity related to anti-TB therapy.

Adult↗

PubMed1996

Liver dysfunction in allogeneic bone marrow transplantation recipients.

Liver dysfunction is common in allogeneic bone marrow graft recipients, but no systematic studies of pre- and posttransplantation liver biopsies have been performed to identify and compare hepatic lesions. This study involved 25 consecutive patients who had undergone serial viral screening tests, liver tests, and pre- and posttransplantation liver biopsy. The aims were to ascertain the origin of liver disorders prior to bone marrow transplantation, to determine the mechanism and severity of liver dysfunction occurring early after transplantation, and to identify a possible relationship between pre-existing liver lesions and the frequency and nature of early liver dysfunction after transplantation. Pretransplantation biochemical liver tests were abnormal in 72% of patients, despite the absence of clinical liver disease. Eleven patients had chronic viral hepatitis B or C. Mild or moderate histological lesions were present in all the patients, with bile duct abnormalities in 48%, central vein abnormalities in 24%, sinusoidal fibrosis in 52%, portal fibrosis in 88%, portal necrosis in 52%, and parenchymal siderosis in 76%. After transplantation, fatal veno-occlusive disease occurred in two patients and biochemical abnormalities occurred in 24. Coded review of needle biopsy specimens failed to provide a single diagnosis. Histological lesions differed between pre- and posttransplantation biopsy specimens only by increased iron overload (96%, P<0.01). We conclude that pretransplant liver lesions contribute to hepatic dysfunction early after bone marrow transplantation, being very similar in nature and degree to lesions observed posttransplantation.

Adolescent↗

PubMed1989

[Anti-tumor effect of fluoropyrimidines on human tumor cell lines transplanted in nude mice with CCl4-induced liver dysfunction].

Tegafur (FT) is a masked compound of 5-fluorouracil (5-FU) and supposed to be activated in the liver. The present study was designed to estimate anti-tumor effect of FT on human tumors transplanted in nude mice with liver dysfunction induced by CCl4. Histologically, cirrhotic changes of liver were observed after injection with 1ml/kg 10% CCl4 twice a week for 8 weeks. Mice were transplanted with human gastric (GC-SF) or colonic cancer (CC-ZK) lines, and daily administered intragastrically with 5-FU (15mg/kg), FT (100mg/kg) or UFT (FT 20mg/kg + Uracil 44.8mg/kg) for 4 weeks. The growth of GC-SF was enhanced by liver dysfunction, but that of CC-ZK was not affected. The mean growth inhibition rates (MGIR) of CC-ZK by 5-FU, FT or UFT were 18.3, 33.1 and 54.2%, respectively, in mice without liver dysfunction, and 14.0, 50.0 and 59.5%, respectively, in mice with liver dysfunction. The MGIRs of GC-SF were 39.0, 63.8 and 48.0%, respectively, in mice without liver dysfunction, and 12.6, 53.6 and 50.0%, respectively, in mice with liver dysfunction. In both lines effect of 5-FU was reduced in liver dysfunction, but those of FT and UFT was not. These results suggest that FT and UFT can be used for cancer patients with liver dysfunction.

Animals↗

PubMedDate not supplied

Predictive value of preoperative serum cholinesterase concentration in patients with liver dysfunction undergoing cardiac surgery.

OBJECTIVE: There are an increasing number of patients with severe liver dysfunction subjected to open heart surgery. This retrospective study was designed to assess operative results and clarify the degree of liver injury in patients with liver dysfunction undergoing open heart surgery. In addition, determinants influencing their prognosis were assessed. METHODS: In a 9-year period from 1988 to 1996, we operated on 31 patients with posthepatitis liver dysfunction and 16 with chronic passive congestion of the liver. This group was 2.3% and 1.6% of the 1368 patients undergoing cardiac surgery in the same period. We compared several perioperative factors between survivors and nonsurvivors to determine risk factors affecting mortality. RESULTS: In the group with posthepatitis liver dysfunction, the postoperative course of 5 patients among 31 (16.1%) was poor. Serum cholinesterase concentration was lower only in the nonsurvivor group (nonsurvivor vs survivor: 1979+/-949 vs 3515+/-1424 IU/I, p < 0.05). All patients with cholinesterase < 2000 IU/L died. The duration of CPB (212+/-53 vs 150+/-54 minutes, p < 0.03) and ACC time (151+/-38 vs 96+/-40 minutes, p < 0.02) was longer in the nonsurvivor group. In the group with chronic passive congestion, the postoperative course of 5 of 16 (31.3%) patients with valvular disease was poor. Serum cholinesterase concentration was lower only in the nonsurvivor group (nonsurvivor vs survivors: 2006+/-435 vs 3483+/-1442 IU/L, p < 0.02), and all patients with cholinesterase < 2000 IU/L died. Postoperative bleeding was greater in the nonsurvivor group (3327+/-2106 vs 1428+/-643 mL, p < 0.05). Multivariate logistic regression analysis including the described pre- and intraoperative factors identified only serum cholinesterase concentration (F = 9.18) as significant. CONCLUSIONS: A low value of preoperative serum cholinesterase (< 2,000 IU/L) is thought to be the predictor of prognosis after open heart surgery in patients with severe posthepatitis and congestive liver dysfunction. Operative factors (cardiopulmonary time in posthepatitis liver dysfunction and postoperative bleeding in the congestive liver dysfunction) also influenced the prognosis.

Adolescent↗

PubMed1988

Acute liver dysfunction after modified Fontan operation for complex cardiac lesions. Analysis of the contributing factors and its relation to the early prognosis.

Acute liver dysfunction was analyzed in 15 patients who received a modified Fontan operation for single ventricle in nine (atrial isomerism, seven) and tricuspid or mitral atresia in six. Nine patients had elevation of serum glutamic-pyruvic transaminase levels above 1000 U/L during the first week. As an analysis of postoperative liver function during the first week, the highest values of serum glutamic-pyruvic transaminase and total bilirubin and the lowest prothrombin time were scored from 0 to 4 within each parameter, and totaled to give a liver dysfunction score. The liver dysfunction score was 0 to 2 (no or trivial injury) in five patients, 3 to 5 (mild) in two, and 6 to 11 (moderate or severe) in eight (53.3%). The group operated on for single ventricle had a higher incidence (67%) of a liver dysfunction score of 6 or higher than the other group (33%). A multivariate analysis for the prediction of the liver dysfunction score mainly from early postoperative hemodynamics showed the highest correlation with cardiac index, followed by urine output, systolic arterial pressure, and central venous pressure. One patient required plasmapheresis. Four died early (less than 1 month); three of these had a liver dysfunction score of 6 or higher. Those with scores of 6 or above had higher serum glutamic-pyruvic transaminase levels at 1 month after operation than those with scores less than 5. In three patients (single ventricle), hepatic venous oxygen saturation was monitored and showed a marked decrease to below 20% with subsequent acute liver dysfunction. These results indicate that acute liver dysfunction appears to occur in patients with complex lesions after a modified Fontan operation from possible hepatic hypoperfusion and that low cardiac output may be more crucial than high central venous pressure alone.

Acute Disease↗

PubMed2003

Liver-specific reactivation of the inactivated Hnf-1alpha gene: elimination of liver dysfunction to establish a mouse MODY3 model.

Mice deficient in hepatocyte nuclear factor 1 alpha (HNF-1alpha) develop dwarfism, liver dysfunction, and type 2 diabetes mellitus. Liver dysfunction in HNF-1alpha-null mice includes severe hepatic glycogen accumulation and dyslipidemia. The liver dysfunction may appear as soon as 2 weeks after birth. Since the HNF-1alpha-null mice become diabetic 2 weeks after birth, the early onset of the liver dysfunction is unlikely to be due to the diabetic status of the mice. More likely, it is due directly to the deficiency of HNF-1alpha in liver. Although the HNF-1alpha-null mice have an average life span of 1 year, the severe liver phenotype has thwarted attempts to study the pathogenesis of maturity-onset diabetes of the young type 3 (MODY3) and to examine therapeutic strategies for diabetes prevention and treatment in these mice. To circumvent this problem, we have generated a new Hnf-1alpha mutant mouse line, Hnf-1alpha(kin/kin), using gene targeting to inactivate the Hnf-1alpha gene and at the same time, to incorporate the Cre-loxP DNA recombination system into the locus for later revival of the Hnf-1alpha gene in tissues by tissue-specifically expressed Cre recombinase. The Hnf-1alpha(kin/kin) mice in which the expression of HNF-1alpha was inactivated in germ line cells were indistinguishable from the HNF-1alpha-null mice with regard to both the diabetes and liver phenotypes. Intriguingly, when the inactivated Hnf-1alpha gene was revived in liver (hepatic Hnf-1alpha revived) by the Cre recombinase driven by an albumin promoter, the Hnf-1alpha(kin/kin) mice, although severely diabetic, grew normally and did not develop any of the liver dysfunctions. In addition, we showed that the expression of numerous genes in pancreas, including a marker gene for pancreas injury, was affected by liver dysfunction but not by the deficiency of HNF-1alpha in pancreas. Thus, our hepatic-Hnf-1alpha-revived mice may serve as a useful mouse model to study the human MODY3 disorder.

Alleles↗

PubMed2003

Bacterial lipopolysaccharide decreases thrombomodulin expression in the sinusoidal endothelial cells of rats -- a possible mechanism of intrasinusoidal microthrombus formation and liver dysfunction.

BACKGROUND/AIMS: To elucidate the mechanism of liver dysfunction occurring in patients with sepsis, we evaluated the effect of bacterial lipopolysaccharide (LPS) on the expression of thrombomodulin (TM) in rat sinusoidal endothelial cells (SECs) and the therapeutic efficacy of exogenous recombinant TM. METHODS: We induced endotoxemia in rats by bolus intraperitoneal injection of LPS. TM antigen levels within tissues were assessed by immunohistochemistry. We measured TM in cultured SECs by enzyme immunoassay, functional analysis and real-time polymerase chain reaction (PCR). RESULTS: TM antigen and activity levels were significantly decreased in SECs isolated from LPS-treated rats after 3 and 6 h treatment, and recovered after 12 h treatment, correlating with immunohistochemical observations. In contrast, TM messenger RNA was decreased after 6 and 12 h treatment, and slightly recovered after 24 h treatment. TM expression in cultured SECs isolated from normal rats was also reduced after treatment with LPS and tumor necrosis factor (TNF)-alpha in vitro. The increased levels of serum fibrin degradation products (FDP), fibrin deposition within liver sinusoids, injury of SECs and liver dysfunction induced by LPS in our rat model was improved by recombinant TM treatment. CONCLUSIONS: Decreased TM expression in SECs of LPS-treated rats may result in intrasinusoidal microthrombus formation and subsequent liver dysfunction during sepsis.

Animals↗

PubMed1994

Liver dysfunction in spontaneous intracerebral hemorrhage.

The purpose of this study was to investigate the relationship between mild degrees of liver dysfunction and spontaneous intracerebral hemorrhage (ICH) from the hemostatic standpoint. A detailed study of hemostatic systems was made in 462 patients with ICH. To compare ICH with the other cerebrovascular diseases, data from 120 patients with subarachnoid hemorrhage and 114 others with cerebral infarction were reviewed. At admission, the medical histories of the patients, including information about previous alcohol consumption, was taken, and blood samples were collected to perform the following studies: platelet count, fibrinogen level, prothrombin time, activated partial thromboplastin time, antithrombin III, plasminogen and alpha 2-antiplasmin activity, platelet aggregability, and liver function tests. The incidence of liver dysfunction and alcohol consumption in patients with ICH was significantly (P < 0.05) higher than in patients with subarachnoid hemorrhage and in those with cerebral infarction. Hematoma volume, mortality rate, and past alcohol consumption in patients with ICH significantly increased with worsening severity of liver dysfunction. Although almost all hemostatic parameters became worse with increasing severity of liver dysfunction, they changed within the normal limits. Platelet aggregability and alpha 2-antiplasmin activity in patients with liver dysfunction were remarkably deteriorated beyond normal limits. In conclusion, liver dysfunction associated with alcohol consumption appears to be an important factor in the deterioration of the clinical status of patients with ICH and may be one of the causative factors in the development of ICH. Although mildly impaired hemostatic systems may be partially responsible for these adverse effects of liver dysfunction on ICH, it seems probable that nonhemostatic mechanisms are attributed to the effects.

Adult↗