A simple method for determination of antipyrine clearance.

Antipyrine clearance (Cl(AP)) is widely used for assessment of microsomal liver function. The usual procedure involves collection of 4 to 7 samples of plasma or saliva obtained during 24 to 48 hr. To determine whether this procedure could be simplified it was compared with one based on a single sample (sCl(AP)) and an estimated volume of distribution (V(D)) in 142 persons. VD was estimated from body weight, in kilograms (BW), height, in centimeters (BH), age in years, and sex, or assumed to be 40 l. The agreement between values of Cl(AP and sCl(AP) increased with the time of the single sample and the two clearance estimates were nearly identical in all cases when the sample was taken after 18 hr. The method used for assessment of V(D) had only a small influence on the agreement. It is suggested that antipyrine clearance (in ml/min) is estimated as (formula: see text) where D is the dose of antipyrine (in mg), c(t) the concentration of antipyrine (in mg/t) at sampling time t (in min), t should be about 1440 min (24hr), and V(D) (in l) is calculated as 0.2363 X BW + 0.1962 X BH - 0.0272 X age - 10.26 (women) or 0.3625 X BW + 0.2239 X BH - 0.1387 X age - 14.47 (men). Little information is lost, however, if a fixed volume of 40 l is used. Then, if the dose is l gm, c(t) is expressed in milligrams per liter, and the sampling time is 24 hr, sCl(AP) = (3.28 - ln c(t)) X 28 ml/min.

Use of a prognostic index in evaluation of liver transplantation for primary biliary cirrhosis.

In the Cambridge/King's College Hospital program, one of the main criteria for recommendation of a liver transplant for a patient with primary biliary cirrhosis (PBC), as in other types of end-stage liver disease, has been the overall assessment that survival was likely to be less than one year. In the present study, a recently developed prognostic model, based on six variables, was used retrospectively to estimate the likely survival without transplantation of the first 29 patients receiving a transplant for PBC. Median estimated survival time for the complete group of patients was five months and in only four patients was survival in the absence of transplantation estimated to be more than one year. Comparison of actual survival curves after transplantation with the estimated survival in the absence of such a procedure shows that, despite an initial higher mortality related to surgery and the immediate postoperative period, grafting was associated with a statistically significant improvement in overall survival. No correlation between the outcome after transplantation and the severity of preexisting liver disease, (as assessed by the expected survival) could be determined, but further assessment of preoperative variables is warranted.

Serial measurements of serum Gc-globulin in acetaminophen intoxication.

OBJECTIVES: To describe serum Gc-globulin and the extent to which it complexes with monomeric actin in the initial phase of acetaminophen (Paracetamol) intoxication and to relate this to the severity of liver necrosis and the clinical course. PATIENTS AND METHODS: Serial measurements of Gc-globulin and the proportion of Gc-globulin complexed to G-actin (complex ratio) were made on admission and every 3 h thereafter in eighteen consecutive patients with acetaminophen intoxication. Eight patients developed hepatic encephalopathy (HE) and two died. RESULTS: On admission, all patients had significantly reduced serum Gc-globulin levels compared with normal individuals (P < 0.0001); patients with HE had significantly lower values than patients without HE (P < 0.001). Gc-globulin levels in the two patients who died did not differ from those in patients who survived hepatic encephalopathy. Fourty-four of 52 serum samples with Gc-globulin levels below 120 mg/l were from patients with encephalopathy (all eight of these patients provided at least three samples). The complex ratio on admission did not differ significantly between patients with and those without HE and fluctuated considerably during the observation period. The peak complex ratio was, however, higher in patients with HE than in patients without HE (P < 0.01), and three of four patients with peak complex ratios above 75% had HE. In addition, the mean complex ratio was greater in the two patients who died than in those who survived HE (P < 0.05). CONCLUSION: Gc-globulin levels were decreased in individuals suffering from acetaminophen intoxication; this decrease correlated with the most severe sign of liver dysfunction, HE. Serum Gc-globulin levels below 120 mg/l and peak complex ratios above 75% may be critical values. However, as a result of considerable fluctuations in the complex ratio, serial measurements are needed to evaluate the Gc-globulin complexing capacity.

Systemic vascular resistance during high-volume plasmapheresis in patients with fulminant hepatic failure: relationship with oxygen consumption.

BACKGROUND: In patients with fulminant hepatic failure, systemic vascular resistance and blood pressure are often reduced. OBJECTIVE: To determine whether systemic vascular resistance increases during high-volume plasmapheresis, which is assumed to eliminate endogenous vasodilatory substances from the bloodstream. DESIGN: A prospective study. PATIENTS AND METHODS: Ten patients [median age 48 (range 21-53) years] were admitted for liver transplantation. Systemic haemodynamic variables were determined using a catheter in a radial artery and a thermodilution catheter placed in a pulmonary artery. Ten (range 8-15) litres of fresh frozen plasma were exchanged, while body temperature [37.6 (range 36.6-38.4) degrees C], blood partial pressure of carbon dioxide [3.75 (range 3.30-4.50) kPa] and peak inspiratory ventilatory pressure [24 (range 20-26) mmHg] were kept constant. RESULTS: Mean arterial pressure increased from 74 (range 61-110) to 96 (range 68-103) mmHg and cardiac index decreased from 5.2 (range 3.6-7.5) to 4.2 (range 3.4-6.6) l/min/m2. The systemic vascular resistance index increased from 662 (range 430-1270) to 1060 (range 621-1520) dyn s/cm5/m2. In contrast, the pulmonary vascular resistance index [42 (range 20-110) dyn s/cm5/m2) remained constant. As cardiac index decreased, oxygen delivery decreased from 939 (range 680-1496) to 745 (range 601-1189) ml/min/m2 with no effect on oxygen consumption [171 (87-231) ml/min/m2], as the arteriovenous oxygen extraction ratio increased from 17 (range 9-22) to 25 (range 8-31)% (P < 0.02). CONCLUSION: In patients with fulminant hepatic failure, cardiac output, systemic vascular resistance and arterial blood pressure improved during high-volume plasmapheresis.

Cerebral blood flow, oxygen metabolism and transcranial Doppler sonography during high-volume plasmapheresis in fulminant hepatic failure.

OBJECTIVE: The effect of high-volume plasmapheresis on hepatic encephalopathy, cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) was investigated in patients with fulminant hepatic failure (FHF). METHODS: Twelve consecutive patients (8 women, 4 men, median age 34 years (range 19-51), were studied before and after high-volume plasmapheresis with 10-16 litres fresh frozen plasma, while PaCO2 and body temperature were maintained at 30 (23-34) mmHg and 37.6 degrees C (36.6-38.4), respectively. Blood samples from the internal jugular vein and a radial artery allowed calculation of the cerebral arteriovenous oxygen difference (AVDO2) and oxygen extraction (AVDO2 divided by arterial oxygen content). CBF was determined by a xenon-133 clearance method in eight patients and CMRO2 calculated as AVDO2 times CBF. Cerebral perfusion pressure (CPP) was determined as the difference between mean arterial and subdural pressures in eight patients. RESULTS: High-volume plasmapheresis was initiated 22 (6-168) h after the development of hepatic encephalopathy and 11 patients had grade 4 encephalopathy. Following high-volume plasmapheresis the grade of encephalopathy improved in four patients. The CBF increased from a median of 31 (16-86) to 45 (18-97) ml/100 g/min and as oxygen extraction remained unchanged (32 (9-41) vs. 29 (7-39)%), CMRO2 increased from 1.24 (0.96-1.82) to 1.86 (1.00-2.07) ml/100 g/min (P < 0.05). The CPP increased from 62 (19-76) to 92 (50-105) mmHg (P < 0.01), whereas the intracranial pressure remained unchanged (19 (3-45) vs. 11 (5-33) mmHg). No statistical difference was found between the relative changes in the above parameters in survivors compared to non-survivors. CONCLUSION: Although the clinical status did not improve in all patients, both CBF and CMRO2 increased after high-volume plasmapheresis. The alleviation of brain oxygen metabolism by high-volume plasmapheresis may reflect partial removal of neuroinhibitory plasma factors.

Effects of a Brussels sprouts extract on oxidative DNA damage and metabolising enzymes in rat liver.

The apparent anticarcinogenic effect of cruciferous vegetables found in numerous epidemiological and experimental studies has been associated with their influence on phase I and phase II metabolising enzymes as well as on the antioxidant status. In the present study we investigated the effect of administration of a Brussels sprouts extract on the expression at the mRNA level and/or catalytic activity in rat liver of three phase I enzymes [cytochrome P450-1A2 (CYP1A2),-2B1/2 (CYP2B1/2) and-2E1 (CYP2E1)] and two phase II enzyme [NADPH:quinone reductase (QR) and glutathione S-transferase pi 7 (GSTpi)], all previously suggested to be induced by vegetables. We also examined the activity and/or expression of several important antioxidant enzymes: glutathione peroxidase (GPx), catalase and gamma-glutamyl-cysteine synthetase (GCS) and the activity of the repair enzyme 8-oxoguanine DNA glycosylase (OGG1). QR, GPx and catalase activity was also assessed in the kidneys. In order to examine a possible effect of the Brussels sprouts related to oxidative stress, we measured oxidative DNA damage in terms of 7-hydro-8-oxo-2'-deoxyguanosine (8-oxodG) and lipid peroxidation in terms of malondialdehyde (MDA) formation in the liver. Oral administration of an aqueous Brussels sprouts extract for 4 days was found to induce the expression of GST 1.3-fold (P < 0.05) and the activity of QR 2.6-fold in rat liver (P < 0.05). No significant differences were seen in the expression of the phase I enzymes. No differences in antioxidant enzyme activity/expression or OGG1 activity were observed. In a second experiment, administration of the Brussels sprouts extract for 3 or 7 days was found to increase the level of 8-oxodG in rat liver from 0.75 to 0.97 per 10(5) dG and from 0.81 to 0.97 per 10(5) dG, respectively (P < 0.05). No effects on MDA levels were found. The present results support the data obtained in several studies that consumption of cruciferous vegetables is capable of inducing various phase II enzyme systems. However, the observed increase in oxidative DNA damage raises the question of whether greatly increased ingestion of cruciferous vegetables is beneficial.

High volume plasma exchange in fulminant hepatic failure.

We investigated the effect of repeated high volume plasma exchange with fresh donor plasma in 11 patients with fulminant hepatic failure, all initially in stage 3 or 4 encephalopathy. A daily exchange of a volume equal to the extracellular volume (20% of body weight) on three consecutive days was intended. We obtained an average of 2.6 exchanges each with a mean volume equal to 16% of the body weight. Five patients (46%, 95% confidence limits 17%-77%) survived, all with acetaminophen induced liver failure. Four of the 6 non-survivors showed a temporary improvement in cerebral function. Two of the patients woke up completely. The 6 non-survivors maintained a stable condition with a systolic blood pressure > 110 mm Hg for a mean of 6.9 days after initiating plasma exchange. Plasma exchange may be considered in acute liver failure in patients with residual liver function before transplantation is finally decided. In addition, plasmapheresis may be used to keep patients with definite liver failure clinically stable until a transplant can be performed.

The Lugano statements on controlled clinical trials.

During a consensus conference in Lugano, Switzerland, 175 statements on controlled clinical trials were drafted by 47 representatives from academia, governmental registration agencies and industry in nine countries. Their opinion on these statements was similar to that of 47 'matched pairs' who did not attend the conference. Thus, the opinion of participants and non-participants appears to reflect the general opinion of those currently involved in designing, conducting and analysing controlled clinical trials. The Lugano statements give answers to the following questions: Is the controlled clinical trial in a crisis? What is the motivation to perform controlled clinical trials? Is it possible for a physician participating in a controlled clinical trial to act in the patient's best interest? Is it possible to obtain truly informed consent in a controlled clinical trial? When is it ethical to withhold active treatment in a controlled clinical trial? What are the controversial issues in the design of a good controlled clinical trial? Is there a double standard with respect to efficacy and adverse drug reactions in controlled clinical trials? What are the alternatives to controlled clinical trials and when should they be performed? How can sponsor bias be minimized? How should an ethics committee decide whether a controlled clinical trial is ethical? Should registration agencies become directly involved in the planning and conduct of controlled clinical trials? Do the declarations of Tokyo and Helsinki facilitate the conduct of ethically valid controlled clinical trials? Is it possible to create an international standard for the conduct and regulation of controlled clinical trials? Why do messages from controlled clinical trials filter into medicine so slowly? Is it possible to bridge the gap between controlled clinical trials and clinical reality? What are the costs of doing and not doing controlled clinical trials? When should drug companies decide to start a trial programme with a specific compound? Is there public hostility against controlled clinical trials? If so, how can it be reduced? The respondents almost unanimously felt that controlled clinical trials are a must: the public must be told that progress in medicine depends on controlled clinical trials, that patients often benefit from participating in them and that the alternative, practising in the face of constant uncertainty, is worse than the possible disadvantages related to the conduct of the trial.

[Gc-globulin in paracetamol poisoning]. / Gc-globulin ved paracetamolforgiftning.

Gc-globulin scavenges actin liberated from necrotic cells. We measured serum Gc-globulin and the degree of complexing with monomeric actin (complex ratio) in the initial phase of paracetamol (acetaminophen) intoxication and related this to the severity of liver necrosis and the clinical course. In eighteen patients with paracetamol intoxication serial measurements of serum Gc-globulin and complex ratio were determined from admission and every three hours thereafter. Eight patients developed hepatic encephalopathy (HE) and two of them died. On admission all patients had significantly reduced serum Gc-globulin levels compared to normal individuals, and patients with HE had significantly lower values than patients without HE. All patients with HE had at least three samples, where Gc-globulin was below 120 mg/l (35% of normal). Complex ratio on admission did not differ significantly in the patients with and those without HE. The peak complex ratio was higher in patients with HE than in patients without HE, and three of four patients with peak complex ratio above 75% had HE. In conclusion, Gc-globulin levels were found to be decreased in patients with paracetamol intoxication; this decrease correlated with the most severe sign of liver dysfunction, HE. Serum Gc-globulin below 120 mg/l and peak complex ratios above 75% may be critical values.

[Recurrent familial intrahepatic cholestasis in the Faroe Islands]. / Recidiverende familiaer intrahepatisk kolestase på Faerøerne.

Recurrent familial intrahepatic cholestasis is an autosomal recessive disorder characterized by episodes of severe pruritus and jaundice lasting for weeks to months without extrahepatic bile duct obstruction. Symptom-free intervals may last for months to years, and chronic liver damage does not develop. We recently studied four of the five patients from the Faeroe Islands described by us 30 years ago (one had recently died), and a further five patients who were identified after the initial report. The episodes of cholestasis were more frequent and severe in patients with early onset, but tended to reduce in frequency with age. The youngest patient, aged 25 years, who had had 16 episodes, each lasting about six months, had a liver transplant after which no further episodes were recorded (one year after surgery). Signs of chronic liver disease were absent in all patients. The FIC1 gene was investigated for mutations in the surviving patients. A single mutation (I661T) was found on both chromosomes in all 9 patients, indicating that they are genetically identical for the disease causing defect. Nevertheless, considerable differences between patients were observed clinically.