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PubMed1992

Effects of different hepatic pathologies on disposition of alfentanil in anaesthetized patients.

We have studied the influence of different hepatic pathologies on the disposition of alfentanil in 23 unpremedicated patients (six healthy control subjects, six patients with liver dysfunction of alcoholic aetiology and 11 patients with non-alcohol related liver disease). All patients received a bolus of alfentanil 500 micrograms i.v. as supplement to 67% nitrous oxide and isoflurane in oxygen anaesthesia. Plasma drug concentrations were measured in venous blood samples at intervals up to 24 h by radio-immunoassay and protein binding was determined by equilibrium dialysis. Kinetic estimates were determined using non-compartmental analysis. Patients with non-alcoholic liver disease had lesser plasma clearance (114.8 (range 66.8-213.5) ml min-1) than the alcoholic group (158.8 (100.0-220.7) ml min-1) or controls (187.4 (125.2-269.5) ml min-1). In all three groups, there was considerable intersubject variability, with a bimodal distribution in the non-alcoholic group. This group also had a smaller apparent volume of distribution at steady state. Mean residence time was prolonged in the alcoholic group compared with controls (284.9 (217.8-362.2) min vs 226.8 (201.2-250) min). Protein binding was decreased in the alcoholic group compared with controls (84.9 (SD 4.2)% vs 89.3 (2.1)%); this was attributable to a lesser plasma alpha 1-acid glycoprotein concentration (0.55 (0.18) g litre-1 vs 0.89 (0.21) g litre-1). Free drug clearance was reduced in both liver dysfunction groups compared with controls.

Adult↗
PubMed1999

Risperidone-induced hepatotoxicity in children and adolescents? A chart review study.

Risperidone is an atypical antipsychotic drug that has been used in the treatment of numerous psychiatric disorders in children and adolescents. The question of whether risperidone-induced weight gain is associated with steatohepatitis has recently been raised. The purpose of this chart review was to ascertain: (1) the rate of liver dysfunction observed during risperidone treatment in children and adolescents; and (2) the clinical factors associated with liver dysfunction. For purposes of this chart review study, abnormal liver function was defined by serum transaminase or bilirubin values falling outside the normal laboratory ranges. Chart reviews were completed on 38 youths with ages ranging from 5-17 years with a variety of psychiatric diagnoses. The mean length of risperidone treatment was 15.2 months at a mean dose of 2.5 mg/day. It was found that 37 of the 38 youths treated with risperidone had no liver enzyme abnormalities at the end of study. One subject had an alanine aminotransferase (ALT) level of 46 U/L which was 7 U/L above the upper limit of normal for this laboratory test. This isolated value was not considered clinically significant. These data were noted in spite of weight gain and the use of numerous concomitant psychotropic medications. These findings suggest that risperidone in short term treatment does not commonly lead to evidence of abnormal liver function at therapeutic doses in children and adolescents. Larger-scale, prospective studies are needed in order to confirm these findings.

Adolescent↗
PubMed2006

Transient postpartum diabetes insipidus associated with HELLP syndrome.

Diabetes insipidus in pregnancy has different causes. The association of diabetes insipidus with disturbances of liver function has been reported, however, diabetes insipidus has rarely been reported in HELLP syndrome. We present a 23-year-old primigravida with a singleton gestation complicated by HELLP syndrome who developed postpartum diabetes insipidus. Labor was induced promptly to terminate pregnancy because of intrauterine fetal death and liver dysfunction. 1-deamino-8-D-arginine-vasopressin was administered. Diabetes insipidus and liver dysfunction resolved within 2 weeks. Development of diabetes insipidus may result from increased vasopressinase activity mainly caused by deterioration of liver functions caused by HELLP syndrome. In pregnant women with liver disease as a result of any cause, the development of diabetes insipidus should be assessed with particular attention.

Adult↗
PubMed2006

High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?

BACKGROUND: Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients. METHODS: 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one case. Laboratory, microbiological, imaging and histological evaluations were performed to identify the origin of graft dysfunction. The International Autoimmune Hepatitis scoring system was also applied. RESULTS: In all cases infections, anastomoses complications and rejection were excluded, whereas the autoimmune hepatitis score suggested a "probable autoimmune hepatitis" (score from 10 to 14). Three patients developed other definite autoimmune disorders (overlap anti-mitochondrial antibodies (AMA)-positive cholangitis, autoimmune thyroiditis and systemic lupus erythematosus, respectively). In all cases, pre-existing autoimmune hepatitis was excluded. Anti-lymphocyte antibodies in immunosuppressive induction treatment correlated with the development of the disorder, whereas the use of granulocyte colony-stimulating factor to treat interferon-induced neutropenia showed a protective role. Withdrawal of antiviral treatment and treatment with prednisone resulted in different outcomes (five remissions and four graft failures with two deaths). CONCLUSIONS: De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on treatment with interferon.

Aged↗
PubMed2003

Flutamide-induced hepatic dysfunction in relation to steady-state plasma concentrations of flutamide and its metabolites.

The frequency, severity, and outcome of flutamide-induced hepatic injury were prospectively evaluated in 55 patients with prostate cancer who received 125 mg of flutamide 3 times a day (daily dose: 375 mg) combined with an agonistic analogue of luteinizing hormone-releasing hormone. In addition, we examined plasma and urine concentrations of flutamide and its major metabolites 4 weeks after the beginning of flutamide therapy, and evaluated their significance in predicting flutamide-induced hepatic dysfunction. Hepatic function could be assessed in 50 patients and hepatic dysfunction during therapy was observed in 9 patients (18%); 3 patients (6%) were classified as having moderate liver dysfunction and 6 (12%) were classified as having mild liver dysfunction. The steady-state plasma levels of flutamide and its biologic active metabolite, hydroxyflutamide (OH-Flu), were not related to hepatic dysfunction. However, the concentration of another major metabolite, 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) was considerably higher in 2 patients who developed clinically significant hepatic dysfunction. These findings suggest that clinically significant hepatic dysfunction could be induced in patients with compromised flutamide metabolism, which leads to a high concentration of FLU-1. Based on results of this study, we propose that plasma FLU-1 levels are one of the predictive factors for flutamide-induced hepatic dysfunction. This hypothesis will be confirmed in a large-scale study.

Aged↗
PubMed2003

Transjugular liver biopsy effecting changes in clinical management.

Although transjugular liver biopsies are frequently performed in patients with impaired blood coagulation, their impact on effecting changes in clinical management has not been assessed. We reviewed our experience with 43 consecutive transjugular liver biopsies performed over 3 years (1998-2000) at Westmead Hospital, Sydney, Australia. The technical success, procedural complication rates and subsequent management of these patients were ascertained from the medical case records. Forty-two (28 men) patients were studied. The indications for liver biopsy were as follows: assessment of hepatitis/cirrhosis status (n = 21), evaluation of liver dysfunction following bone marrow transplantation (n = 19) and miscellaneous (n = 2). All liver biopsies were performed with a Cook 20-G transjugular cutting needle device. Adequate histological samples were obtained in 42 (98%) of the 43 biopsies performed. The pre-biopsy diagnoses were confirmed by histology in 28 cases (65%). A change in clinical diagnosis was observed in 12 (28%) patients, and there were changes to subsequent management in all 12 patients. Four patients developed procedural complications, including small neck haematomas in two patients and a self-limiting biliary fistula in one. The only major complication was an extracapsular bleed from a hepatic laceration. This patient required emergency surgery but recovered. Transjugular liver biopsies can be effectively and safely performed in high-risk patients with impaired coagulation. They aid accurate histological appraisal of liver dysfunction in these patients and influence clinical decision-making.

Adult↗
PubMed1989

Effect of liver disease on the kinetics of lactate removal after heavy exercise.

Recovery from heavy exercise requires clearance of lactic acid from the blood and body tissues. Although it has long been felt that the liver plays the major role in lactate removal, it has more recently been asserted that skeletal muscle plays the dominant role. We felt it relevant to this controversy to determine whether patients with liver dysfunction have slowed lactate removal following heavy exercise. Eight patients with alcoholic liver disease and 5 normal subjects were studied. Liver function was measured by the 14C-aminopyrine breath test; the results were expressed as the rate of appearance of 14CO2 in the breath two hours after ingestion, as a fraction of the ingested 14C dose (%.h-1). Each participant exercised on a cycle ergometer for 7 min at a work rate which was moderately heavy for that subject (mean peak lactate is 5.3 mmol.L-1). During, and for 45 minutes after exercise, blood was drawn from a hand vein catheter. The time required for blood lactate to decrease halfway toward resting levels (t1/2 LA) was determined. Compared to the normal subjects and historical controls, seven of the patients had distinctly slowed lactate removal. The t1/2 LA was as long as 46 min (as compared to approximately 15 min seen normally). Further, among the patients the 2 h breath excretion of 14C was well correlated with the rate constant of lactate removal (r 0.82, P less than 0.01). Four of the patients with severe liver dysfunction performed a second exercise test in which, instead of resting after heavy exercise, low level exercise was continued. The t1/2 LA of the averaged responses decreased by 29%.2+

Adult↗
PubMed1989

Acute abdominal pain: the value of liver function tests in suspected cholelithiasis.

Over a 4-year period, prospective data were collected on 311 patients with suspected acute cholecystitis. By identifying the diversity of conditions which can masquerade as acute cholecystitis, we have examined the role of biochemical liver function tests in the diagnosis and management of these patients. The initial clinical diagnosis of acute cholecystitis was confirmed in 229 patients (73.6%). Of those patients on whom liver function tests were performed, 76.3% (206/270) were confirmed to have cholecystitis and 69.9% (144/206) of these had some evidence of liver dysfunction. In the group of patients (64/270) with other diagnoses on whom liver function tests were performed, significantly fewer (57.8%, 37/64) had abnormal liver function tests (P less than 0.05). This is of little clinical value since normal liver function does not exclude cholecystitis (predictive value of negative test = 30.3%). In proven cases of cholecystitis, there was a significantly increased incidence of liver dysfunction when ductal calculi were present. Using the information obtained from this study, an investigative protocol is proposed which may substantially reduce the rate of misdiagnosis of patients with abdominal pain suggestive of cholelithiasis.

Abdomen, Acute↗
PubMed1999

Erythropoietic protoporphyria with fatal liver failure.

A 33-year-old woman with a history of photosensitivity, persistent abdominal pain, and liver dysfunction was admitted to our department because of abdominal pain and progression of liver dysfunction. On admission, levels of protoporphyrin and coproporphyrin within erythrocytes were markedly increased. Autofluorescent erythrocytes were also detected, leading to a diagnosis of erythropoietic protoporphyria. A liver biopsy specimen revealed cirrhosis with dark brown granules filling hepatocytes, bile canaliculi, and bile ductules. Transfusion of washed erythrocytes, hemodialysis, and administration of cholestyramine and beta-carotene transiently improved levels of porphyrins and liver function. The patient died of rupture of esophageal varices followed by multiple organ failure. However, the treatments were believed to have extended survival.

Adult↗
PubMed2006

Choline deficiency increases lymphocyte apoptosis and DNA damage in humans.

BACKGROUND: Whereas deficiency of the essential nutrient choline is associated with DNA damage and apoptosis in cell and rodent models, it has not been shown in humans. OBJECTIVE: The objective was to ascertain whether lymphocytes from choline-deficient humans had greater DNA damage and apoptosis than did those from choline-sufficient humans. DESIGN: Fifty-one men and women aged 18-70 y were fed a diet containing the recommended adequate intake of choline (control) for 10 d. They then were fed a choline-deficient diet for up to 42 d before repletion with 138-550 mg choline/d. Blood was collected at the end of each phase, and peripheral lymphocytes were isolated. DNA damage and apoptosis were then assessed by activation of caspase-3, terminal deoxynucleotide transferase-mediated dUTP nick end-labeling, and single-cell gel electrophoresis (COMET) assays. RESULTS: All subjects fed the choline-deficient diet had lymphocyte DNA damage, as assessed by COMET assay, twice that found when they were fed the control diet. The subjects who developed organ dysfunction (liver or muscle) when fed the choline-deficient diet had significantly more apoptotic lymphocytes, as assessed by the activated caspase-3 assay, than when fed the control diet. CONCLUSIONS: A choline-deficient diet increased DNA damage in humans. Subjects in whom these diets induced liver or muscle dysfunction also had higher rates of apoptosis in their peripheral lymphocytes than did subjects who did not develop organ dysfunction. Assessment of DNA damage and apoptosis in lymphocytes appears to be a clinically useful measure in humans (such as those receiving parenteral nutrition) in whom choline deficiency is suspected.

Adolescent↗
PubMed2004

Prenatally diagnosed portocaval shunt and postnatal outcome: a case report.

Congenital absence of the portal vein (CAPV) is a rare anomaly in the form of a portocaval shunt, whereby the intestinal and splenic venous drainage bypasses the liver and drains directly into the systemic circulation. We report a case of CAPV diagnosed prenatally after the recognition of a dilated umbilical vein draining directly into a large inferior vena cava (IVC). The IVC then drained into the right atrium of a dilated, hyperdynamic heart. The ductus venosus could not be identified. Repeated postnatal scans showed a gradual disappearance of venous lakes in the region of the porta hepatis and a clear drainage of the splenic vein to the left renal vein and the superior mesenteric vein to the IVC. From birth up to twelve months follow-up there was no evidence of liver dysfunction, encephalopathy or liver lesions.

Adult↗
PubMed1987

Drug disposition in patients with HBsAg-positive chronic liver disease.

Chronic infection with hepatitis B virus (HBV) results in a spectrum of hepatic abnormalities ranging from minimal liver dysfunction to severe liver failure. These patients provide an opportunity to examine the relationship between the evolution of the liver disease and the ability to metabolize drugs. We have examined hepatic drug disposition in patients with chronic persistent hepatitis, chronic active hepatitis, and cirrhosis due to HBV infection. Four model drugs were used: two low-extraction capacity-limited drugs (antipyrine and aminopyrine) and two high-extraction flow-limited drugs (ICG and lidocaine). The disposition of the four drugs tested was comparable to that of healthy controls in patients with chronic persistent hepatitis, chronic active hepatitis, and mild cirrhosis. In patients with severe cirrhosis (as defined by the presence of ascites, encephalopathy, or large esophageal varices), there was a significant impairment in the aminopyrine breath test (-31%) and in the clearance of antipyrine (-53%), lidocaine (-49%), and ICG (-54%). These results indicate that impairment of drug clearance occurs only late in the evolution of HBV-related chronic liver disease. This is in keeping with the known slow and insidious progression of the disease.

Adult↗
PubMed1993

Investigations into the effects of various hepatotoxic compounds on urinary and liver taurine levels in rats.

The effect of various hepatotoxicants on urinary taurine and urinary creatine has been studied in the rat. Several hepatotoxic agents, carbon tetrachloride, thioacetamide, galactosamine and allyl alcohol which all caused hepatic necrosis (sometimes accompanied by steatosis), resulted in a rise in urinary taurine and in some cases creatine, when administered to rats. Ethionine and hydrazine also raised urinary taurine but caused only steatosis and did not raise urinary creatine. Therefore urinary taurine and possibly creatine may be useful markers of liver injury and dysfunction. Liver taurine levels were also affected by some of the hepatotoxicants but in those cases where there was a rise in urinary taurine this could not be accounted for by the loss in liver taurine. It is suggested that the increase in urinary taurine is partly due to changes in protein synthesis and hence in sulphur amino acid metabolism caused by hepatotoxic agents. However, bromobenzene did not increase urinary taurine and alpha-naphthylisothiocyanate and lithocholate caused reduced levels. It is suggested that this lack of increase in urinary taurine may be due to depletion of glutathione or interference with the biliary system.

1-Naphthylisothiocyanate↗
PubMed2000

A case of erythropoietic protoporphyria with liver cirrhosis suggesting a therapeutic value of supplementation with alpha-tocopherol.

Erythropoietic protoporphyria (EPP) was diagnosed in a 27-year-old man based on a typical clinical history, and a marked increase in erythrocyte and fecal protoporphyrin concentrations. Although liver disease is not a common feature in EPP, he had slight liver dysfunction. A percutaneous liver biopsy was performed and it showed minimal hepatocellular damage and many reddish brown pigment deposits in hepatocytes, Kupffer cells, portal histiocytes, bile canaliculi and small biliary radicles. Electron microscopic findings confirmed that these deposits were composed of protoporphyrin crystals. Liver biochemistry remained well for >2 years, but deteriorated rapidly and second liver biopsy obtained 28 months after the first biopsy revealed the development of liver cirrhosis. We treated the patient with intravenous administration of dl-a-tocopherol acetate (vitamin E; 500 IU/body/day). Following the administration of vitamin E, the concentration of protoporphyrin in erythrocytes decreased significantly and the liver function tests were improved. Sixteen weeks later he showed the full clinical and biochemical recovery suggesting that vitamin E supplementation might be useful in treating patients with EPP who developed liver damage.

Journal Article↗
PubMed2000

Inhibition of transforming growth factor beta prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats.

We investigated whether anti-transforming growth factor beta (TGF-beta) molecular intervention can halt the progression of liver fibrosis in rats. To block TGF-beta action in a specific manner, we prepared an adenovirus expressing a truncated type II TGF-beta receptor (AdTbeta-TR), which specifically inhibits TGF-beta signaling as a dominant-negative receptor. We also used an adenovirus expressing bacterial beta-galactosidase (AdLacZ) as a control adenovirus. Rats were treated with dimethylnitrosamine (DMN) for 3 weeks; then, AdTbeta-TR, AdLacZ, or saline was intravenously applied once, followed by an additional 3-week DMN treatment. The ratio between the truncated receptor and the wild-type receptor at the mRNA level was 15 at 1 week and 10 at 3 weeks after gene transfer. Immunohistostaining analysis showed that the truncated receptor was expressed mainly in septal cells including hepatic stellate cells. Liver fibrosis, as assessed by histology, hydroxyproline content, and the serum level of hyaluronic acid, progressed during the additional 3-week DMN treatment. However, in rats infected with AdTbeta-TR, the fibrosis remained at the level seen in rats given DMN for only 3 weeks. All AdTbeta-TR-treated rats remained alive, whereas DMN-treated rats infused with either AdLacZ or saline died of liver dysfunction. In the livers of AdTbeta-TR-treated rats, electron microscopy showed: 1) less accumulation of extracellular matrix proteins in the Disse's spaces; 2) regenerated hepatocytes; and 3) fat droplet-rich "quiescent" hepatic stellate cells. Our results demonstrate that TGF-beta plays a critical role in the progression of liver fibrosis, and suggest that anti-TGF-beta intervention should be therapeutic in already-established fibrotic livers, not only by suppressing fibrosis, but by facilitating hepatocyte regeneration.

Animals↗
PubMedDate not supplied

[Valproate-associated hepatotoxicity--pathogenesis, clinical aspects, therapy and prevention].

The potential hepatotoxicity resulting in fatal liver failure is of major concern in treating patients with valproate (VPA). Until now there is no relevant laboratory parameter allowing early detection of impending liver failure. The major routes of VPA biotransformation are glucuronidation and beta-oxidation. There are several other pathways of degradation with formation of mono- und di-unsaturated derivates. VPA dose, patients age, co-medication (anticonvulsants, aspirin), fasting and glucose supply influence the VPA metabolism. The clinical spectrum of VPA-associated hepatotoxicity reaches from slight increases of liver enzymes without clinical manifestations over reversible slight to severe liver dysfunction to fatal liver failure. With respect to pathogenesis attention has focused on depletion of beta-oxidation and change of biotransformation to other pathways with increased synthesis of toxic unsaturated VPA derivates. Several inborn errors of metabolism, acute infections and status epilepticus seem to predispose to liver failure. Another hypothesis lies in the possible VPA-induced depression of free radical scavenging enzyme activities. On this basis N-acetylcysteine has been used successfully in treating children with severe hepatotoxicity. In the presence of certain risk factors VPA should be avoided.

Ammonia↗
PubMed1992

Brief communication: clinical experience with high branched-chain parenteral nutrition.

Patients who appear to respond best to high branched-chain amino acid (BCAA) solutions have been previously described by objective measurements such as total urinary nitrogen (TUN) excretion, oxygen consumption index (O2Cl), plasma lactate, plasma pyruvate, plasma glucose (PG) and urinary 3-methylhistidine. Use of these measurements in assessing possible candidates for high BCAA solutions may not be convenient for some institutions. The purpose of this study is to describe our clinical practice experience with patients receiving high BCAA parenteral nutrition (PN) and how we apply the criteria previously developed. Forty critically ill adult patients (19 males, 21 females; 50 +/- 19 years) who received BCAA-enriched PN were prospectively monitored for demographic information as well as objective biochemical measurements and current clinical status within a time window of 72 hours before or after beginning the high BCAA solution. Patients demonstrated marked elevations in O2Cl (168 +/- 44 ml/min/m2), TUN (18 +/- 6 g/day), and PG (157 +/- 63 mg/dl), and decreased serum albumin (2.4 +/- 0.6 g/dl) and transferrin (123 +/- 50 mg/dl). Patients were categorized according to primary diagnosis: malignant tumor (n = 10), organ transplant (n = 12), trauma (n = 1), chronic or acute disease (n = 1, n = 3), and chronic or acute disease requiring surgery (n = 7, n = 6). Clinical statuses within the 72-hour time window were as follows: infection (n = 26), renal dysfunction (n = 15), pulmonary dysfunction (n = 22), liver dysfunction (n = 14), and multiple organ failures (n = 14).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1977

Radioimmunoassay of serum bile acid levels in biopsy-proved cirrhosis.

Serum bile acid levels were determined by a radioimmunoassay for conjugates of cholic acid in 18 patients with biopsy-proved cirrhosis and compared to results of conventional liver function tests. Serum bile acid levels were abnormal in all 18 patients whereas results of the other tests were abnormal in only 50% to 72% of patients. In this group of patients with a well established diagnosis of cirrhosis, serum bile acid levels were a more sensitive indicator of liver dysfunction than standard liver function tests.

Bile Acids and Salts↗