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Pituitary aplasia or hypoplasia occurs in anencephalic and normocephalic infants. Two infants with hypopituitarism are described; in each the diagnosis was made clinically. The infants had frank clinical and histologic evidence of the neonatal hepatitis syndrome. There may be more than a chance relationship between the clinicopathologic findings of neonatal hypopituitarism and hepatitis.
Patients who have undergone a Fontan-type operation usually have an elevated systemic venous pressure. To determine the sequelae of this nonphysiologic condition, we evaluated 66 patients 1 to 14 years after a Fontan-type operation. Fifty-one patients were apparently in good clinical condition, and 15 patients had symptoms and were restricted in their daily life. Bicycle exercise capacity, tested in 41 patients, ranged from 50% to 110% (mean 85%) of the predicted value for length. In 16 patients, a decreased capacity (< 85%) was, among others, related to arrhythmias and the presence of protein-losing enteropathy. A 24-hour ambulatory electrocardiogram was available in 56 patients and found to be normal in 32 (57%) patients. Arrhythmias were present in 21 patients, six of whom had symptoms. Three patients had previous pacemaker implantation. One or more abnormalities in liver enzyme and function tests were present in 40 patients (61%) and in coagulation factors in 46 patients (69%). The most pronounced was a protein C deficiency, a known thrombotic risk factor, present in 41 patients. The occurrence of arrhythmias increased with time of follow-up (p < 0.004), the occurrence of protein C deficiency decreased with time (p < 0.0001), and the occurrence of abnormal liver enzyme and function tests was not related to time of follow-up. With regard to age at operation, arrhythmias did not occur in patients who underwent operation at a mean age of 4 +/- 1.9 years (standard deviation), in contrast to patients who underwent operation at a mean age of 7.6 +/- 4 years (standard deviation) (p < 0.001). The occurrence of the two other types of sequelae was not related to the age at operation. With regard to the type of operation, only patients with a valved right atrium-to-pulmonary artery connection had a higher prevalence of arrhythmias than patients with a nonvalved or direct right atrium-to-pulmonary artery connection (p < or = 0.001). The latter patients also had a higher prevalence of protein C deficiency (p < or = 0.001). No relationship was found among the other types of operation, the underlying structure, or the hemodynamic condition measured at rest and the presence of arrhythmias, abnormal liver enzyme and function tests, or protein C deficiency. This point survey shows that even patients with an apparently good clinical condition are at risk for arrhythmias, abnormal liver enzyme and function tests, and coagulation factor abnormalities. Serial statement of affairs is recommended to ensure that adequate preventive measures can be taken.
Levodopa is the cornerstone of idiopathic Parkinson's disease (PD) treatment. However, after long-term use of levodopa, a significant percentage of patients experience motor fluctuations, which worsen their quality of life. Catechol-O-methyltransferase (COMT) inhibitors reduce levodopa metabolism and enhance the respective plasma levels, resulting in improvements in symptoms and overall quality of life. Tolcapone was the first drug of this class to be marketed, but was withdrawn in the European Union due to its implication in the deaths of three PD patients due to hepatic failure. Three deaths from fulminant hepatic failure in 40000 patient-years is a number that is 10-100 times higher than the expected incidence in the general population and, according to the manufacturer's own information, the number is probably underestimated due to under-reporting of cases. In the US, tolcapone was not withdrawn, but restrictive liver enzyme monitoring measures were issued by authorities, which severely limited its use. No further deaths from hepatic failure were reported since these measures were implemented. The mechanisms by which tolcapone may induce liver toxicity are still under debate. It was thought that mitochondrial uncoupling of oxidative phosphorylation by tolcapone, and consequent impairment of energy production by hepatocytes, could be responsible for the observed effects. Some experts consider that the restrictive guidelines issued in the US regarding tolcapone use may be loosened with no consequential reductions in safety. It was suggested that ongoing clinical information about safety should be considered and periodical revisions of the restrictions made accordingly. The identification of the molecular and biochemical basis of tolcapone hepatotoxicity, when completed, should also provide important indications for the clinical use of this drug. In conclusion, appropriate monitoring of liver function can ensure adequate safety in PD patients receiving tolcapone, who can therefore benefit from the symptomatic improvements obtained with this drug.
AIM: to reduction the TPN-related hepatic toxicity with an anaerobicidal therapy (ornidazole in our case). PATIENT: a 24-year-old male surgically treated for intestinal occlusion. He had been treated with abdominal radiotherapy for rabdomyosarcoma of embryonic urogenital sinus when he was five months old. It was found a great abdominal radiotherapy sequelae and occluded and perforated small-bowel loop that was resected. Postoperative time developed pelvic abscess and reoperation was performed. Severe intraabdominal inflammatory-adhesive process was noticed which included all the intestinal loops with multiple perforations. Attempts to release this situation was unsuccessful and several anastomoses, with some loop exclusions and a diverting loop jejunostomy were performed. In postoperative period he developed an enterocutaneous fistula and TPN was initiated. Higher and higher hepatic marker values were detected suggesting a progressive hepatotoxicity. METHODS: anaerobicidal agent (ornidazole) and cyclic total parenteral nutrition as a therapy design were prescribed. RESULTS: there were satisfactory showing a reduction in hepatic marker values (72.5% fall in alanine aminotransferase). CONCLUSIONS: bearing in mind that some theories suggest that total parenteral nutrition may cause atrophic changes in the gut mucosa so giving rise to bacterial translocation, this anaerobicidal treatment designed could be assumed effective for attenuating TPN-related liver damage.
Low adiponectin levels are associated with elevated plasma alanine aminotransferase, a marker of reduced hepatic insulin sensitivity and a risk factor for type 2 diabetes. This study aims to determine the relationship between serum adiponectin level and alanine aminotransferase in diabetic and non-diabetic subjects. Fifty-six type 2 diabetic patients and 33 non-diabetic subjects participate in the study. Baseline plasma concentrations of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and glucose are measured on a chemistry analyser. Insulin and adiponectin are measured using enzyme-linked immunoassay techniques and insulin resistance is determined using the homeostatic model assessment method. Diabetic patients showed significantly lower levels of serum adiponectin than did the non-diabetic subjects, whereas levels of alanine aminotransferase and alkaline phosphatase were similar in both groups. While female non-diabetic subjects showed higher serum adiponectin levels than did female diabetic patients, alanine aminotransferase level did not differ (P>0.05). No significant relationship was seen between adiponectin and alanine aminotransferase in diabetic and non-diabetic subjects (P>0.05). Serum adiponectin levels were higher in non-diabetic subjects but there was no significant correlation between adiponectin and alanine aminotransferase in both groups of subjects. The data suggest that low serum adiponectin level may not be a suitable marker for impaired liver function in diabetic patients.
Clindamycin was used to treat six patients with endocarditis because of allergy to penicillin in five, and an unfavorable clinical response to methicillin in one. Only one patient had an uneventful cure with clindamycin. Two had hepatotoxicity which resolved rapidly after clindamycin was stopped. Two patients, one of whom had an aortic prosthesis, had completed four to six weeks of clindamycin therapy when clinical relapse occurred and blood cultures were again positive for a clindamycin-sensitive isolate. A fifth patient had peptostreptococcal endocarditis. Despite a favorable initial clinical and bacteriologic response, blood cultures taken on the 20th day of therapy again grew the Peptostreptococcus. This relapse pathogen had become resistant to clindamycin and was 100-fold less sensitive than the initial isolate. The few conditions in which clindamycin is indicated for therapy of bacterial endocarditis are outlined.
UNLABELLED: A cholestatic 6-mo-old girl was admitted to our department because she recently presented with hypotonia and lethargy, apparently due to moderate and transient hypoglycaemia. Her urine contained 3-hydroxy-dicarboxylic acids of 12 to 14 carbons in length and her plasma acylcarnitine profile was consistent with long-chain 3-hydroxyacylCoA dehydrogenase deficiency. This diagnosis was confirmed by enzyme studies. This deficiency was due to a G1528C mutation on the paternal allele (mutation on the maternal allele as yet not identified). The patient improved dramatically with medium-chain triglyceride supplementation. CONCLUSION: Early cholestasis and hepatic fibrosis must lead to search for long-chain 3-hydroxyacylCoA dehydrogenase deficiency, particularly when hypoketotic hypoglycaemia is present.
Hepatic sinusoidal uptake of bile acids is mediated by defined carrier proteins against unfavourable concentration and electrical gradients. Putative carrier proteins have been identified using bile acid photoaffinity labels and more recently using immunological probes, such as monoclonal antibodies. At the sinusoidal domain, proteins with molecular weights of 49 and 54 kDa have been shown to be carriers for bile acid transport. The 49 kDa protein has been associated with the Na(+)-dependent uptake of conjugated bile acids, while the 54 kDa carrier has been involved in the Na(+)-independent bile acid uptake process. Within the hepatocyte, cytosolic proteins, such as the glutathione S-transferase (also designated the Y protein), the Y binders and the fatty acid binding proteins, are able to bind bile acids and possibly facilitate their movement to the canalicular domain. At the canalicular domain a 100 kDa carrier protein has been isolated and it has been shown by several laboratories that this particular protein is concerned with canalicular bile acid transport. The system is ATP-dependent and follows Michaelis-Menten kinetics. Interference with bile acid transport has been demonstrated by several chemicals. The mechanisms by which these chemicals inhibit bile acid transport may explain the apparent cholestatic properties observed in patients and experimental animals treated with these agents. Several studies have shown that Na+/K(+)-ATPase activity is markedly decreased in cholestasis induced by ethinyloestradiol, taurolithocholate and chlorpromazine. However, other types of interference have been described and the cholestatic effects may be the result of several mechanisms. Cholestasis is associated with several adaptive changes that may be responsible for the accumulation of bile acids and other cholephilic compounds in the blood of these patients. It may be speculated that the nature of these changes is to protect liver parenchymal cells from an accumulation of bile acids to toxic levels. However, more detailed quantitative experiments are necessary to answer questions with regard to the significance of these changes and the effect of various hepatobiliary disorders in modifying these mechanisms. It is expected that the mechanisms by which bile acid transport is regulated and efforts to understand the molecular basis for these processes will be among the areas of future research.
The determination of carbohydrate-deficient transferrin (CDT) in serum has been suggested as a marker of alcohol abuse. We evaluated serum CDT in 199 patients admitted to our Department of Medicine using a commercially available radioimmunoassay kit for CDT. A history of alcohol consumption was obtained quantitatively by a self-administered questionnaire and qualitatively by the Munich Alcoholism Test. Using a cut-off level of 60 g ethanol per day according to the information from the questionnaire. CDT had a sensitivity of 70% and a specificity of 84%. False-positive values were primarily encountered in cases of hepatic malignoma, primary biliary cirrhosis and chronic hepatitis C. The sensitivity and specificity of CDT was superior to two other markers of chronic ethanol consumption, serum gamma-glutamyltransferase and mean cell volume, and thus proved to be the best single laboratory test for the detection of alcohol abuse.
Rats with chronic experimental portocaval anastomosis were hypoactive as indicated by diminished activity in the home cage, during habituation in red light to an observation box and during exposure in white light to an open-field. Food intake and responsiveness to electric shock were also decreased. However, there was an abnormally high frequency of social activity when anastomosed rats were paired together after having been caged singly for 3 weeks. Also, sham-operated rats interacted more with anastomosed rats than they did with other sham-operated animals. Anastomosis also raised brain concentrations of tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. Administration of tryptophan to sham-operated rats increased shock threshold and decreased ambulation in an open-field. Thus, while anastomosed rats are not comatose they do have considerable behavioural abnormalities for which brain tryptophan changes may be in part responsible.
A 42-year-old woman was admitted because of cough, sputum, and fever. A chest roentgenogram revealed a nodular density in the left upper lung field with satellite lesions compatible with tuberculoma. Mycobacterium tuberculosis was detected from sputum. Five weeks after starting the treatment with 0.4 g/day of isoniazid, 0.45 g/day of rifampicin, and 0.75 g/day of streptomycin, she showed itching erythema in the trunk. The white blood cell count was 4,500/mm3 with 14% eosinophils, and serum transaminases were slightly increased (GOT 101 U/L, GPT 74 U/L). Although isoniazid and rifampicin were stopped, the erythema with exfoliation spread to her extremities, suggesting exfoliative dermatitis. The white blood cell count reached 15,990/mm3 with 68% eosinophils (10,810/mm3). Stimulation indices measured with the lymphocyte stimulation test (LST) were 109% with rifampicin, 140% with isoniazid, and 275% with streptomycin, suggesting streptomycin-induced allergy. After cessation of streptomycin, the symptoms gradually improved. After the reaction had subsided, the treatment with isoniazid, rifampicin, and ethambutol was resumed, but she showed no further adverse reactions. LST seems to be very useful to identify the drug or drugs responsible for the reactions occurred during the treatment by antituberculosis drugs.
Transaminase values [alanine amino transferase (ALT) and aspartate amino transferase (AST)] and markers for hepatitis B were serially determined in 558 hemophiliacs exposed to blood products. Hepatitis B surface antigen (HBsAg) persistent for over 12 months was present in 6% of the patients. Antibody to hepatitis B surface antigen (anti-HBs) was noted in 90% of the 259 patients treated with factor VIII or IX concentrates but in only 49% of the 43 patients treated with fresh frozen plasma (FFP) or cryoprecipitate. Persistently abnormal transaminase values were noted in 31% of the patients treated with commercial concentrates but in only one (2%) of the patients exposed to cryoprecipitate or FFP. This difference continued even when the two groups of patients were matched for the amount of blood products, up to 50,000 units, which they had received in the study period. In the concentrate-treated patients, no correlation could be found between transaminase values and the number of units of factor VIII or IX they had received during the six years of the study (1973-1978).
AIM: To induce intrahepatic cholestasis in rats using lomustine 1(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU). METHODS: Doses of 10 mg, 20 mg and 30 mg/Kg body weight of CCNU were injected intraperitoneally in separate groups of animals. RESULTS: With 10 mg/Kg body weight of CCNU, serum bilirubin levels increased for up to 72 hours and then slowly returned to normal. With a dose of 20 mg/Kg body weight of CCNU, serum bilirubin, AST, ALT and alkaline phosphatase levels increased for 72 hours and then returned to normal over 4-5 weeks. With a dose of 30 mg/Kg body weight peak levels of serum bilirubin were reached on day 17. Pathological studies were carried out after injection of 30 mg/Kg body weight of CCNU. After 72 hours hepatocytes were normal, with minimal nonspecific inflammation and bile duct proliferation. After 16 days, triaditis was observed with deposition of collagen. Focal fibrosis was also noticed. There was no significant abnormality of hepatocytes. After 75 days, hepatocytes showed focal ballooning. Bile duct proliferation was seen invading the parenchyma. Nodules of hepatocytes separated by irregular fibrous bands indicated cirrhosis. CONCLUSIONS: An animal model of intrahepatic cholestasis has been developed using CCNU; this model may be used to assess the utility of hepatobiliary radiopharmaceuticals.
The disposition of total and non-protein-bound etoposide was investigated in 21 cancer patients receiving etoposide and cisplatin combination chemotherapy. Etoposide plasma concentrations were determined using a specific high-performance liquid chromatography (HPLC) method, and etoposide plasma protein binding was determined by equilibrium dialysis. The patients had a wide range of renal function (creatinine clearance, 32 to 159 mL/min/m2) and hepatic function (total bilirubin range, 0.3 to 21.5 mg/dL; aspartate aminotransferase [AST] range, 14 to 415 IU/L; serum albumin range, 2.7 to 4.1 g/dL). The mean etoposide total systemic clearance was not different in 15 patients with total bilirubin less than 1.0 mg/dL versus six patients with total bilirubin 1.1 to 21.5 mg/dL (18.7 +/- 5.9 mL/min/m2 v 26.4 +/- 10.7 mL/min/m2; t-test P = .06), with a trend toward higher total clearance in the patients with abnormal bilirubin values. However, the mean clearance of unbound etoposide was significantly lower in patients with increased total bilirubin (220 +/- 90 mL/min/m2 v 135 +/- 61 mL/min/m2; t-test P = .027). The fraction of etoposide unbound (fu) in plasma was significantly higher in patients with increased bilirubin (9% +/- 3% v 27% +/- 15%; t-test P = .002), explaining the trend toward higher total clearance in these patients. Etoposide clearance (total or unbound) in the 14 patients with measurable hepatic metastases was not different from the clearance in the seven patients without hepatic metastases. This study provides an explanation for why patients with increased bilirubin do not have lower total systemic clearance of etoposide, and indicates that such patients have a higher exposure to unbound etoposide. The results of ongoing pharmacodynamic studies of total and unbound etoposide in patients with increased bilirubin will determine the clinical relevance of altered etoposide protein binding.
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We investigated the effect of sodium tauroursodeoxycholate (UR-906) on cholestasis in common bile duct-ligated rats in comparison with the effect of dehydrocholic acid. UR-906 (30-180 mumol/kg) and dehydrocholic acid (180 mumol/kg) were intravenously given once daily for consecutive 20 days in rats and the common bile duct was ligated for the last 10 days. On the next day after the last test drug administration, serum biochemical and plasma hemostatic variables were determined. UR-906 significantly ameliorated the elevation of serum cholesterol, phospholipid, bilirubin and bile acid concentrations in bile duct-ligated rats. UR-906 significantly suppressed the prolongation of plasma prothrombin time and activated partial thromboplastin time. Furthermore, UR-906 significantly suppressed the decreases in plasma coagulation factor II and X activities. However, dehydrocholic acid did not cause significant changes in any of the variables examined in this model. These results suggest that UR-906 has a beneficial effect against cholestasis induced by bile duct ligation in rats and that this drug may be useful in the treatment of clinical cholestatic disorders.
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