Disturbed Liver Function Research Articles

Non-narcotic analgesics. Problems of overdosage.

The first cases of fulminant hepatic failure due to paracetamol poisoning were reported in 1966, and in the United Kingdom this condition is now responsible for more cases of acute hepatic failure than any other cause. Adults account for the majority of serious and fatal cases of paracetamol poisoning and it is extremely rare for young children to ingest sufficient paracetamol to cause more than minimal liver damage. A single measurement of the plasma paracetamol concentration is an accurate predictor of liver damage provided that it is taken not earlier than 4 hours after ingestion of the overdose. Peak disturbance of liver function occurs 2 to 4 days after the overdose, often accompanied by mild jaundice, after which recovery is usually rapid and complete. In a few patients, fulminant hepatic failure, manifested by increasing jaundice and encephalopathy, may develop by the third to fifth day. Acute renal failure may complicate paracetamol poisoning, often in the context of severe liver damage. Renal failure, which is often non-oliguric, typically becomes apparent 24 to 72 hours after overdosage. The treatment of paracetamol intoxication should include gastric lavage, which has been shown to be of value for up to 6 hours after ingestion of a paracetamol overdose. Further general treatment may include parenteral fluid replacement and a prophylactic infusion of dextrose (5-10%) in patients at risk of hepatic failure. Specific protective agents in those patients at risk of paracetamol-induced liver damage include N-acetylcysteine and methionine which are most effective if given within 8 to 10 hours of ingestion of the overdose. Hepatic and renal failure should be managed conventionally. In recent years in the United Kingdom there has been a gradual decline in the number of hospital admissions and the number of deaths from aspirin poisoning. Salicylates in overdose directly stimulate the respiratory centre and so cause a respiratory alkalosis. Metabolic acidosis occurs in severe poisoning because of impairment of the oxidative metabolism of energy substrates. At very high salicylate concentrations respiratory depression may occur, possibly associated with neuroglycopenia, adding respiratory acidosis to the worsening metabolic acidosis. In addition to a mixed acid-base disturbance, hypokalaemia and hypoglycaemia may be present. Nausea and vomiting increase the fluid deficit. If dehydration is sufficiently severe, decreasing cardiac output may hasten development of lactic acidosis and acute renal failure.(ABSTRACT TRUNCATED AT 400 WORDS)

Experimental acute sodium fluoride poisoning in sheep: Renal, hepatic, and metabolic effects

Sheep received a single intragastric dose of 0.5, 1.0, 1.5, or 2.0 mmol F −/kg. Mild signs occurred at 1.5 mmol F −/kg and the animals recovered 2 days later. With the 2.0 mmol F −/kg dose all animals showed dullness, anorexia, and mild diarrhea which decreased from the third day. Dose-related congestion of duodenum, liver, kidney, and lung was observed in all animals. For the two higher doses kidney degeneration and tubular necrosis were associated with glomerular inflammation. Serum fluoride had a dose-related increase and was still significantly elevated on Day 7 for sheep given doses higher than or equal to 1.0 mmol F −/kg. Serum calcium and glucose levels were significantly lowered for all doses on the first day and the decrease was dose-related. In sheep given 2.0 mmol F −/kg total proteins and sodium were significantly lowered, whereas potassium and urea were increased ( p < 0.05); alkaline phosphatase (ALP) and lactic dehydrogenase (LDH) were both lowered ( p < 0.01) on the first day and ALP was still lowered on Day 7. For the highest dose glutamate dehydrogenase (GDH) was increased on Days 1 and 7 and γ-glutamyl transferase (GGT) was increased on Day 1 and lowered on Day 7. Diuresis was increased for the two higher doses in Day 3 or 4 following dosage. A dose-related increase of daily fluoride excretion occurred for all doses on Day 1 and fluoride excretion was still significantly elevated on Day 7 except for the lowest dose. Daily urine GGT excretion was increased on the first day for all doses higher than or equal to 1.0 mmol F −/kg; GDH and LDH showed similar variations but less significant for LDH. On Day 7, SDH, GDH, ALP, and GGT in liver, GGT and LDH in kidney, and LDH in muscle were all lowered for the two higher doses. These data demonstrate that acute fluoride poisoning in sheep induces severe disturbances of kidney and liver function as reflected by altered activity of many enzymes.

Morphological basis for hepatic failure in the early period of the crush syndrome

Disturbances of liver function are of great importance in the clinical management of the crush syndrome (CS). The results of including the allogenic and xenogenic liver in the perfusion circuit of the crushed limb under clinical and experimental conditions indicate that the state of the liver can largely determine both the victim's recovery from shock and the development of acute renal failure [5]. Depression of many functions of the liver during crushing of the soft tissues has been observed during the first few hours of decompression, and may continue for a long time after trauma [3, 7, 12, 13]. For instance, disturbanceofantitoxic function was described even 3 months after trauma [i0] and depression of the protein forming function 5 years after trauma [ii]. The mechanism of the disturbances of liver function in CS and itsmorphological basis have been inadequately studied. Nonspecific changes in the liver have been described, in the form of congestion and stasis of blood in the sinusoids, disappearance of glycogen from the hepatocytes, and microfocal necrosis [3, 4]. Insufficient attention has been paid in the pathogenesis of liver damage to the effect of the decompression factor, and no data are available on the state of the reticuloendothelial system (RES) of the liver in CS. In the investigation described below the morphological basis and possible mechanisms of liver damage in the early period of CS were studied. EXPERIMENTAL MET}IOD The liver of rats and dogs with a severe form of CS, reproduced in animals with different typological features of their nervous system was studied; this was done in order to achieve the closest possible similarity between the model and CS in man, which is characterized by diversity of its clinical manifestations. Both hind limbs of 45 rats, under open ether anesthesia, were crushed with a force of 30 kg for 6 h. The soft tissues of one thigh of 20 dogs were crushed under thiopental anesthesia by metal forceps for 9 h. Morphological changes in the liver were studied at the end of the period of decompression and 2-7 h after decompression. Paraffin sections stained with hematoxylin and eosin and after the PAS reaction were examined. Pieces of liver for electron microscopy were fixed in 1% osmic acid and sections were stained with uranyl acetate and lead and studied in the JEM-100B electron microscope.

A Case of Carbimazole-Induced Intrahepatic Cholestasis

A patient is described with cholestatic hepatitis following the use of carbimazole. A liver biopsy specimen showed intracanalicular cholestasis and some mononuclear cell infiltrate in the portal triades, consistent with drug toxicity; indications of an autoimmune or viral pathogenesis were absent. Rechallenge with the drug precipitated jaundice and disturbed liver function once more. Carbimazole induced a blastogenic response of patient lymphocytes in vitro. Both may suggest the involvement of an immune-mediated reaction, especially as it has been shown that sensitized lymphocytes may produce a cholestatic factor on stimulation with antigen.

Prenatal diagnosis of the cerebro-hepato-renal (Zellweger) syndrome by detection of an impaired plasmalogen biosynthesis.

The cerebro-hepato-renal (Zellweger) syndrome (ZS, McKusick 21410) is an autosomal recessive disease characterised clinically by severe hypotonia, typical craniofacial dysmorphism, hepatomegaly, disturbances in liver function, renal cysts, failure to thrive and severe psychomotor and sensorial retardation. The disease is usually lethal within the first year of life; no effective treatment is available. Biochemical characteristics are the absence of morphologically distinct peroxisomes (microbodies) in liver and kidney (Goldfischer et al., 1973), an accumulation of very long chain fatty acids (Brown et ai, 1982), trihydroxycoprostanoic acid (Hanson et al., 1979) and pipecolic acid (Danks et al., 1975) in blood and urine and the virtual absence of plasmalogens in tissues (Heymans, 1984). Furthermore, we found that the peroxisomal enzyme dihydroxy-acetone phosphate acyltransferase (DHAP-AT; EC 2.3.1.42), which catalyzes the first step in the biosynthetic route of ether phospholipids, is deficient in tissues and cultured skin fibroblasts of ZS patients (Schutgens et al, 1984).

Gamma-glutamyltransferase and its isoenzymes: progress and problems.

Because of its sensitivity to disturbances of excretory liver function, gamma-glutamyltransferase (GGT; EC 2.3.2.2) assay has become one of the most important diagnostic tests for hepatobiliary disorders. However, its value in the differential diagnosis of liver diseases is limited. It is present in kidney, liver, pancreas, and intestine in electrophoretically distinct but not necessarily organ-specific forms. Much effort has been expended to relate diseases of these organs to isoenzyme findings in serum. Although the activities of GGT isoenzymes in disease differ from those in health, the existence of disease-specific patterns is controversial. Much is known about the biochemistry, structure, and immunochemistry of GGT, but more work is needed on methods, standardization of terminology, and correlation of isoenzyme findings with diseases. Further progress in the last area should improve the clinical applicability of the isoenzyme activities.

Hepatic sequestration in sickle cell anaemia.

Several episodes of acute hepatic enlargement associated with a dramatic fall in haemoglobin concentration were observed in two patients with sickle cell anaemia. No appreciable disturbances of liver function or signs of cardiac failure were evident. The most likely mechanism was sequestration of sickled erythrocytes in the liver. This complication, which may have a basis similar to that of splenic sequestration and the sickle lung syndrome, may be easily overlooked unless the size of the liver is regularly monitored in patients with sickle cell crisis.

Blood analysis for liver fibrosis

Liver fibrosis is one of the most important factors of disturbed liver function, but could not be measured by simple blood tests until recently. Among several parameters used for this purpose, the aminoterminal procollagen type III peptide (PIIIP) appears to be the most widely accepted. Studies conducted in several clinical groups have shown that PIIIP effectively distinguishes between non-fibrotic and fibrotic liver disease. A reliable commercial kit is available and a wide application possible to evaluate the clinical meaning of serum PIIIP for the long-term outcome of chronic liver disease. With this novel blood test we can now assess liver fibrosis as we can measure the hepato-biliary function.

Influence of long-term anticonvulsant treatment on liver ultrastructure in man.

In 35 patients on long-term anticonvulsant treatment (7-35 years, means = 19.6 years), various liver enzymes were measured. In 32 cases (91.4%), elevated levels of serum-gamma-glutamyl-transpeptidase (GGT) were found. Liver biopsy was performed in five of 13 patients with GGT levels of greater than 60 U/l (75-257, means = 123 U/l). Light microscopy showed a minimal steatosis and fine granular appearance of hepatocytes in two cases, and a slight portal fibrosis in one case. Two cases showed an unremarkable histology. Electron microscopy revealed signs of enzyme induction as overall swelling of the smooth endoplasmic reticulum and additionally a dilatation of the rough endoplasmic reticulum in all five specimens. No signs of liver damage or disturbance of liver function could be observed.

Erfolgreiche Therapie einer Verbrauchskoagulopathie bei EPH-Gestose mit mehrfachem Organversagen

A 23 year old primipara with EPH gestosis after caesarean section suffered massive disseminated intravascular coagulation resulting in anuria, respiratory failure, gastrointestinal bleeding and disturbance of liver function. By treatment with antithrombin-III concentrates, fresh blood and fresh frozen plasma we were able to normalise coagulation disorders and to restore organ functions. Causes and therapeutical management of these diseases are discussed.

Fulminant Hepatic Failure After Open Heart Surgery: A Case Report

Reports on fulminant hepatic failure after open heart surgery are very few. We recently experienced a 38-year-old female with fulminant hepatic failure accompanying encephalopathy after open heart surgery, and possible etiology of this syndrome was discussed. The patient having undergone open mitral commissurotomy for mitral stenosis died on the 27th postoperative day following the postoperative course of a fulminant type of liver failure. No other possible causes of hepatic dysfunction were identified except slight preoperative disturbance in liver function probably due to congestion. We conclude that preoperative congestive heart failure may cause a fulmi nant type of liver dysfunction after open heart surgery.

Antithrombin III levels in preeclampsia correlate with maternal and fetal morbidity

In 57 patients with pregnancy-induced or aggravated hypertension, antithrombin III levels correlated inversely with maternal morbidity. Morbidity was determined by the maximal diastolic blood pressure, disturbance of renal and liver function, and thrombocytopenia. Antithrombin III levels and platelet counts correlated inversely with the degree of placental infarction. Proteinuria (grams per 24 hours) was most predictive of fetal outcome, which was considered to be either favorable if a healthy baby could be discharged with its mother or unfavorable in case of perinatal death or a prolonged stay in the neonatal intensive care unit. Plasma antithrombin III and serum glutamic oxaloacetic transaminase levels, in that order, augmented the number of correct predictions. Antithrombin III inhibits blood coagulation by forming irreversible complexes with activated clotting enzymes, notably with factor Xa and thrombin. Evidence is presented which suggests that antithrombin III levels in preeclampsia are depressed as a result of increased consumption in the maternal vascular tree, rather than decreased synthesis or increased urinary loss.

Cardiovascular effects of sulmazol administered intravenously to patients with severe heart failure.

Ten patients with severe heart failure (NYHA class IV) received sulmazol intravenously under haemodynamic and electrocardiographic surveillance. All patients were on maintenance doses of digitalis and diuretics. At 30 min intervals we increased the infusion rate of sulmazol from 1 to 2, 4, 6, and 8 mg min-1, to a total of 630 mg of sulmazol administered over 150 min. Statistically significant changes (P less than 0.001) were found for heart rate (from 97 to 103 min-1); right atrial pressure (from 9.5 to 1.5 mmHg); pulmonary artery diastolic pressure (from 25.0 to 9.0 mmHg); pulmonary capillary wedge pressure (from 22.0 to 9.0 mmHg); aortic diastolic pressure (from 62.5 to 52.5 mmHg); pulmonary artery oxygen saturation (from 53.0 to 68.5%); cardiac output (from 2.83 to 4.38 l min-1), and for indices derived from these measurements. No correlation was found between the improvement in cardiac performance and sulmazol plasma concentrations. Haemodynamic improvement persisted for more than 7.5 h after cessation of sulmazol administration. Renal function was measured before and after sulmazol administration; creatinine clearance (from 47.5 to 52.0 ml min-1) and p-amino hippuric acid clearance (from 146 to 125 ml min-1) were unchanged. Side-effects included yellow-colored vision, ventricular extrasystoles, and possibly sulmazol-induced liver function disturbances. Even in severe heart failure sulmazol improved cardiac performance in patients who were treated with the maximum tolerated dose of digoxin.

Impaired hormonal stimulation in isolated hepatocytes of phosphorous depleted rats.

Clinical evidence has been presented for disturbed liver function in patients with phosphorous depletion and hypophosphatemia 1. Rajan et al.2 emphasized that hypophosphatemic patients with cirrhosis tend to undergo greater hepatic decompensation than do patients with normal blood phosphorous. Furthermore, Klock et al.3 found a defective hyperglycemic response to glucagon in alcoholic patients with hypophosphatemia. This abnormality was completely normalized after restoration of serum phosphorous levels. These observations were made in intact organism. Consequently, it cannot be decided whether hepatic cell function is altered or whether these changes are secondary to circulatory problems, altered tissue oxygenation 4 or altered hormone metabolism.KeywordsGlucose ProductionHepatic ComaSerum Phosphorous LevelcAMP ContentPhosphate DepletionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Nine years' experience of physiological correction of tricuspid atresia: long-term results and current surgical approach.

Fontan's correction has been performed without early death in 24 consecutive patients with tricuspid atresia. Eighteen patients had ventriculoarterial concordance (group I) and six discordance (group II). Late death related to infections occurred in three patients. The follow-up time in group I (16 survivors) ranges from 1 year 10 months to 7 years 5 months (mean 3 years 8 months) and in group II (five survivors) from 2 years 1 month to 5 years 6 months (mean 3 years 6 months). Early postoperative cardiac catheterisation showed arterial pulsatile pressure recordings in the pulmonary artery only in two patients in group I, in whom a valved conduit was used to connect the right atrial appendage with the outlet chamber. Patients with a valved conduit connected with either the pulmonary artery (group II) or the outlet chamber (two patients of group I) showed better preservation of right atrial contractions angiocardiographically and scored better in exercise tests than did patients with a non-valved conduit (14 patients of group I). In the latter patients evidence of regurgitant bloodflow from the outlet chamber into the right atrium was found. Reoperation was necessary in two patients. The outlet chambers showed a substantial increase in diameter after operation. No disturbances of kidney or liver function were found up to seven years after operation. The clinical condition has improved considerably in all survivors. It is concluded that the use of a valved conduit is preferable for connecting the pulmonary artery directly in cases of tricuspid atresia with ventriculoarterial discordance or the outlet chamber when there is ventriculoarterial concordance.

Plasma levels of parent drug and metabolites in the intravenous aminopyrine breath test

[Dimethylamine-14C]-aminopyrine was given i.v. to 5 healthy volunteers and 5 medical patients in a dose of 1.67 mg/kg, containing 0.02 micro Ci/kg 14C. In 4 volunteers the experiment was repeated using oral administration of aminopyrine. Exhalation of 14CO2 was followed for 6-10 h and plasma levels of the drug and of its metabolites 4-methylamino-antipyrine, 4-amino-antipyrine, 4-acetylamino-antipyrine, 4-formylamino-antipyrine, were measured by thin-layer chromatography. The concentration-time profiles of the metabolites mostly failed to conform to a Bateman function. Areas under the curves from 1 to 6 h after dosing indicated distinct interindividual differences in metabolite patterns even in the absence of disturbed liver function, whereas the intraindividual data were closely reproducible. In most subjects, the area of formylamino-antipyrine exceeded that of the acetyl analogue. The metabolite patterns did not exhibit a consistent relationship to the ratios between 14CO2 half-life in breath and aminopyrine half-life in plasma, which varied from 1.4 to 3.2.

Biliary lipids, faecal steroids, and liver function in patients with chronic active hepatitis and primary biliary cirrhosis: significance of hepatic orcein-stained complexes.

Biliary lipids, faecal steroids, and serum bile acids were studied in patients with chronic active hepatitis and primary biliary cirrhosis. The results were correlated with excretory and parenchymal liver function tests and with the presence or absence of orcein-positive copper-protein complexes in histological liver specimens. In general, faecal bile acids, but not neutral and total sterols, correlated negatively with the percentage of biliary cholic acid, serum cholesterol, and serum bile acids and positively with the percentage of biliary deoxycholic acid. In orcein-positive subjects-indicative of long-standing cholestasis-the bile was undersaturated with cholesterol, biliary deoxycholic acid was subnormal, cholic acid correspondingly increased, and serum cholesterol and bile acids were raised. Only patients with marked impairment of both excretory and parenchymal liver functions had a decreased output of neutral sterols, bile acids, and total steroids, and, thus, low bile acid and cholesterol synthesis. The findings indicate that mild disturbances in parenchymal liver function infrequently cause major changes in cholesterol metabolism, while abnormalities in secretory liver function-in orcein-positive subjects especially-are frequently associated with proportionate changes in parameters of cholesterol metabolism.

じん臓培養組織由来ウロキナーゼ（ＴＣＵＫ）による脳血せん症治療効果の評価に関する二重盲検試験

A multi-center double blind study for the clinical evaluation of TCUK was carried out on 115 patients with cerebral thrombosis.The administration of TCUK was done continuously in doses of 60, 000 I. U. for 7 days under comparison with negative placebo.The study was performed according to the protocol, shown in Table 1-6 and the effects of TCUK were judged by the grade of improvement of apparent subjective complaints, disturbances of consciousness, motorius and sensorial disorders of extremities and comprehensive daily life activities. The total scoring of improvements in individual disorders and their comprehensive evaluation were made for judgement of the global improvement and availability of the drugs, obtaining the following conclusions:(1) The availability, particularly the global improvement of TCUK were better than those of placebo in their statistical significance (Table 10).(2) In the serial evaluations, the clinical effects were more significant in patient groups of mild or moderate grades in the severity of disorders, of ages between 40-69, without histories of brain damages and without simultaneous infusions of large amount of solutions.(3) The side effects of TCUK were rare (Table 11) with only two exceptional cases with disturbance of liver functions (Table 18), but the relationship between this liver function disturbance and administration of TCUK was obscure and no cases of hemorrhagic infarction were found in connection with TCUK administration in this study.

Cefoperazone in the treatment of severe or complicated infections.

We report the use of cefoperazone in 62 cases of serious infection, most of which occurred in patients with renal impairment. 43 severe or complicated urinary tract infections, 11 cases of pneumonia and 8 with other severe sepsis were treated with cefoperazone 1 to 2 g twice daily usually for 5 to 10 days. Of the patients with urinary tract infection, all who were symptomatic showed a rapid clinical response; 26 (61%) were cured including 11 of 16 with chronic renal failure; 12 relapsed and 5 were reinfected with a different pathogen. All of these patients were infected by organisms sensitive to cefoperazone by disc testing but in 5 of those who relapsed the cefoperazone MIC was in fact greater than or equal to 50 microgram/ml. Ten of 11 cases with radiologically confirmed pneumonia were cured with cefoperazone. 7 episodes of pneumonia were in patients with end-stage chronic renal failure (6 were on dialysis) and 1 was in a patient with acute renal failure. Seven of 8 cases with severe sepsis were cured with cefoperazone. 1 patient was withdrawn from the study when acute bronchospasm followed a 2 g intravenous dose. 2 of the successfully treated patients had functioning renal transplants, 2 of 3 with severe chronic renal failure were on dialysis and 1 had acute renal failure. Side effects included minor disturbances of liver function in 6 patients (11%), diarrhoea in 7 (13%) and marked alcohol intolerance in one, 4 patients with chronic renal failure developed a coagulation disorder which was corrected with vitamin K. None of the patients showed deterioration in renal function while receiving cefoperazone. Cefoperazone promises to be an effective drug for the treatment of a wide spectrum of severe infections in hospitalised patients including those with impaired renal function.

Ribonuclease as a tumour marker for pancreatic carcinoma.

Serum ribonuclease has been measured in 61 patients with a variety of inflammatory and malignant conditions. Serum activity is elevated in pancreatic carcinoma but it is not restricted to this condition. Levels were significantly elevated in cases of disturbed liver function.