Assessment and monitoring of liver function by ¹³C-aminopyrine breath test after selective transarterial chemoembolisation of hepatocellular carcinoma.

BACKGROUND: Liver function and tumor staging are essential parameters for selection of treatment modalities in patients with hepatocellular carcinoma (HCC). Transarterial chemoembolization (TACE) is associated with a risk of deterioration of liver function. In clinical routine hepatic function in patients with liver cirrhosis is assessed by the Child-Pugh-classification. Dynamic breath tests allow the assessment of the hepatic functional mass and have the potential to give more accurate information on hepatic function periinterventionally. PATIENTS AND METHODS: A prospective clinical study was performed in 13 patients receiving a total of 18 TACE sessions. (13)C-aminopyrine breath test was performed the day before TACE, 2 days and 30 days after TACE and correlated with standard laboratory work-up of the patients. RESULTS: Fourteen TACE sessions were performed in Child A liver cirrhosis, 4 in Child B cirrhosis. All patients presented with impaired aminopyrine metabolism at baseline. No significant changes in the (13)C aminopyrine breath test following TACE were observed. Two patients treated in Child A cirrhosis decompensated to Child B, one of them recovered. No further decompensation was observed in patients treated in Child B cirrhosis. DISCUSSION AND CONCLUSION: Liver function assessment with (13)C-aminopyrine breath test and Child-Pugh-classification following TACE was discordant in a large proportion of patients. Whether a quantification of mitochondrial liver function in patients planned to undergo locoregional treatment of HCC in liver cirrhosis is helpful in the prediction of postprocedural liver decompensation needs to be addressed in larger prospective clinical trials.

Non-invasive methods for the assessment of hepatic fibrosis: transient elastography, hyaluronic acid, 13C-aminopyrine breath test and cytokeratin 18 fragment.

BACKGROUND. In the management of chronic hepatitis C (CHC) patients, liver biopsy is the gold standard for liver fibrosis assessment despite some technical limits and risks. Non-invasive approaches have been proposed as alternative methods to evaluate structural liver damage. AIM. To investigate the diagnostic accuracy of transient elastography, 13C-aminopyrine breath test (13C-ABT), serum hyaluronic acid (HA) and cytokeratin 18 Asp396 fragment (CK-18) as non-invasive methods of liver fibrosis assessment ad their correlation to METAVIR score. MATERIAL AND METHODS. In a cohort of 57 CHC patients, liver stiffness, cumulative percentage of administered dose of 13C-aminopyrine at 120 min, serum HA and serum CK-18 concentration were determined. Diagnostic accuracy in detecting significant fibrosis (F ≥ 2), severe fibrosis (F ≥ 3) and cirrhosis (F = 4) was assessed by the area under the receiver operating characteristic curve. RESULTS. Liver fibrosis score showed a strong correlation with liver stiffness (r = 0.667; p < 0.0001) and a significant inverse correlation with 13C-ABT results (r = -0.418; p = 0.0012). A weaker correlation was found with CK18 (r = 0.329; p = 0.0126) and no correlation with HA. Areas under the curve of elastography, 13C-ABT, HA and CK18 were: 0.98, 0.75, 0.69, 0.64, respectively, for F ≥ 2; 0.97, 0.69, 0.80, 0.66, respectively, for F ≥ 3; 0.95, 0.64, 0.70, 0.56, respectively, for F = 4. CONCLUSION. Elastography has the best diagnostic accuracy for the assessment of the degree of liver fibrosis in CHC patients. Its application can provide an alternative useful tool for monitoring the disease evolution.

A comparison of the reproducibility of the parameters of the ¹³C-aminopyrine breath test for the assessment of hepatic function.

This study determined the within-subject and between-subject variability of different ways of expressing the results of the (13)C-aminopyrine breath test ((13)C-ABT) and the effect of shortening the test duration. The (13)C-ABT was conducted on three separate occasions in 10 healthy volunteers and on a single occasion in 22 patients with established liver cirrhosis. The within-subject variability of cumulative percentage dose recovered (cPDR), using measured CO(2) production rate (VCO(2)), in the reference group over three trials was 15% over 120 min. Higher within-subject variability in cPDR would have been evident if the test was terminated at either 30 or 60 min. Substitution of predicted VCO(2) to calculate cPDR yielded comparable values at all time points. Significant differences between cirrhotics and reference group were evident after just 10 min using PDR/h, cPDR or enrichment (all P<0.05). The ABT demonstrates clinically acceptable reproducibility. Shortening of the duration may make the test more acceptable clinically, but it is associated with increasing imprecision.

Could metabolic liver function tests predict mortality on waiting list for liver transplantation? A study on 560 patients.

BACKGROUND: Allocation of graft in liver transplantation (LT) depends mainly on Model for End Stage Liver Disease (MELD) score. We studied the prognostic ability of three metabolic liver function tests in 560 cirrhotic patients listed for transplantation, in comparison with MELD and Child-Turcotte-Pugh (CTP) scores. METHODS: Indocyanine green retention rate (ICG), aminopyrine breath test (ABT), and galactose elimination capacity were performed at the time of listing in addition to standard biological parameters. Seventy-three patients died on waiting list, 438 were transplanted, and 73 died after LT. Cox regression analysis and receiver operating characteristic curves with c-statistics were calculated after stratification according to CTP and MELD score. RESULTS: For the mortality before transplantation, c-statistics showed that ICG and ABT had a slightly better prognostic ability (0.73 and 0.68, respectively) than MELD score (0.66), and similar to CTP score (0.70). ABT's prognostic ability remained significant once the MELD score (below and above 20) had already been taken into account. Only ICG had a prognostic ability to predict the survival after LT, even after stratification according to MELD and CTP score. CONCLUSIONS: Our results strongly support that ABT and ICG may be useful in the ranking of the patients in LT list, adding prognosis information in association with MELD score.

Aminopyrine breath test: development of a 13C-breath test for quantitative assessment of liver function in humans.

BACKGROUND/AIM: 14C-aminopyrine breath test (ABT) has been shown to be well correlated to the severity of liver diseases, but its use is limited in countries where radioactive isotopes are severely controlled. The goal of this study was to develop a 13C-ABT based on a highly sensitive method to measure 13CO2 in breath samples. MATERIALS AND METHODS: The relevant parameters were studied in 26 controls and 27 patients: the 13CO2 enrichment of expired breath between t-10 and t+60 minutes was determined as the most simple and clinically useful parameter. The 13C-ABT was then prospectively compared to clinico-biological data and the galactose elimination capacity (GEC) in 82 patients. RESULTS: The 13C-ABT was well correlated to: i) the Child-Pugh classification; ii) GEC results; iii) the hepatic volume. The presence of ascites or alcoholic consumption did not alter significantly the results of the test. 13C-ABT appeared more sensitive than GEC to evaluate minor liver dysfunctions. CONCLUSIONS: The 13C-ABT is a simple and sensitive test to measure liver function. The use of the stable isotope 13C ensures the harmlessness of the test and the possibility to repeat it in a given patient.

Microsomal function in hepatitis B surface antigen healthy carriers: assessment of cytochrome P450 1A2 activity by the 14C-caffeine breath test.

The hepatitis B surface antigen (HBsAg) carrier state is associated with changes in hepatocellular function involving the cytochrome P450 (CYP) system. Among this system, CYP1A2 enzyme plays an important role in chemical carcinogenesis and in the metabolism of several drugs. We have thus investigated CYP1A2 function using two 14C-caffeine breath tests (3-methyl-14C; C3BT and 7-methyl-14C caffeine; C7BT) in 12 HBsAg healthy carriers and 8 healthy volunteers matched for 14C-aminopyrine breath test values. HBsAg carriers exhibited lower C3- and C7BT values than normal controls. This difference, however, did not reach statistical significance except for C7BT values normalised for aminopyrine breath test values. Our data thus do not support the association between viral presence and CYP1A2 dysfunction.

A device for automatic measurement of writhing and its application to the assessment of analgesic agents.

A device was developed for automatically measuring writhing in mice so as to be applied to the assessment of analgesic agents. The device was composed of a specially designed container equipped with a detector, namely, a mechanoelectro transducer for writhing. The detector was made up of units of a string, two plates, and two strain gauges. In the unit, each end of the string was connected to either of the plates to which either of the strain gauges was attached. The change in tension of the string due to writhing was converted into the mechanical strain of the plates and then the resistance change of the strain gauges. The resistance change was amplified by a Wheatstone bridge circuit that was connected to a differential amplifier, a high-pass filter, comparator(s), and a monostable multivibrator to obtain the electrical signal for writhing. Using this device, writhing was continuously measured, and evaluation of various types of analgesic agents was performed. The result suggests that this device has sufficient accuracy both for the detection of writhing and the evaluation of analgesics. It has the advantage of automatic measurement of writhing in contrast to the conventional visual observation method.

Hepatic function during general hypothermia in the pig: assessment by aminopyrine breath test.

We investigated the influence of pre-harvesting general hypothermia on liver metabolic activity by means of Aminopyrine Breath Test (ABT). This study was conducted in pigs which were anesthetized, curarised and cooled on an ice bed. Each animal received labelled aminopyrine and 14CO2 in expired air was measured between 37.5 and 25.5 degrees C. The liver metabolic activity at 31.5 degrees C represents 53.3% of the normothermic value. At 25.5 degrees C, this activity is reduced by 75.1%. The mean decreasing rate is 6.2%/degrees C for a fall in temperature of 12 degrees C. A change of slope occurred at 31.5 degrees C. The first decreasing rate is 7.47 +/- 1.62%/degrees C and the second one is 4.48 +/- 2.27%/degrees C. Thus, use of general hypothermia during liver harvesting should improve the quality of organ preservation: the important reduction of metabolism should decrease the oxygen debt resulting from anaerobic cold perfusion.

Assessment of lidocaine metabolite formation in comparison with other quantitative liver function tests.

In clinical practice, the seriousness of liver disease is assessed based on the combined information from clinical examination, routine biochemical tests, and liver histology. Recently, the assessment of hepatic lidocaine metabolism has been proposed as a quantitative liver function test offering valuable additional information. To evaluate whether this new liver function test reflects the combined clinical assessment, we prospectively measured lidocaine metabolism in 111 patients with well characterized liver disease. In addition, lidocaine test results were compared with the aminopyrine breath test and the galactose elimination capacity. Lidocaine (1 mg/kg) was injected i.v. and serum concentrations of its main metabolite monoethylglycinexylidide were determined after 15 min. The results varied widely and the means (+/- S.D.) were similar among patients with mild liver disease (46 +/- 23 ng/ml), but significantly (P < 0.05) lower among patients with Child class A cirrhosis (19 +/- 11 ng/ml) or Child class B or C cirrhosis (21 +/- 19 ng/ml). The [13C]aminopyrine breath test, however, gave a better discrimination among patients with increasing severity of liver disease than lidocaine metabolite formation. The galactose elimination capacity finally best separated patients with mild liver disease from those with cirrhosis. The correlations between any two of the different quantitative liver function tests were weak (R2 consistently < 0.2). We conclude that lidocaine metabolite formation, like other quantitative liver function tests that are based on the microsomal metabolism of model compounds, quantitates a very particular enzymatic reaction which may not be representative for the functional reserve of the entire organ.

[Assessment of microsomal enzyme function in liver of patients with duodenal ulcer treated with famotidine]. / Ocena czynnosci enzymów mikrosomalnych watroby u osób z choroba wrzodow a dwunastnicy leczonych famotydyna.

The liver microsomal enzymes activity was measured by aminopyrine breath test in 20 subjects with duodenal ulcer disease treated with famotidine for 8 weeks. Aminopyrine breath test was performed, before treatment (group I), after 4 weeks of therapy (group II) and after 8 weeks of treatment with famotidine (group III). The mean aminopyrine breath test value before treatment was 5.32% dose/h. After 4 weeks of treatment with famotidine statistically significant decrease of breath test values (x = 4.79% dose/h) was found. More strong microsomal enzymes inhibition was found after 8 weeks of famotidine therapy (x = 4.46% dose/h). These data indicate an inhibitory effect of famotidine on liver monooxygenases activity. In patients taking this drug, treatment with other drugs metabolised in liver and with drugs inhibiting the microsomal system must be very cautions.

An in vivo 31P MRS study of patients with liver cirrhosis: progress towards a non-invasive assessment of disease severity.

Fourteen patients with liver cirrhosis of differing severity participated in a one-dimensional chemical shift imaging 31P MRS study of the liver. Patients were divided into two groups according to the severity of their liver disease using Child's classification and the aminopyrine breath test (AB test). Seven normal volunteers without liver disease acted as controls. The phosphomonester (PME) peak in normal subjects was 4.77% (95% confidence interval, CI: 4.11-5.42) of total phosphorus. The PME peak was significantly elevated in both mild cirrhosis [5.80% (95% CI: 5.46-6.14), p = 0.0051, vs normal subjects] and severe cirrhosis [9.64% (95% CI: 8.71-10.57), p = 0.0002, vs normal subjects and p = 0.001, vs mild cirrhosis]. There was a significant negative linear correlation (r = 0.88, p < 0.01) of PME with the percentage dose of 14CO2 excreted over 2 h in the AB test. pH values in patients with mild cirrhosis [7.45 (95% CI: 7.35-7.55)] but not severe cirrhosis [7.36 (95% CI: 7.25-7.47)] were significantly elevated (p = 0.04) compared to normal subjects [7.29 (95% CI: 7.17-7.41)]. Comparison of the peak area of PME at TR = 0.5 s against that using TR = 5.0 s in cirrhotic liver suggested no reduction in T1 of phosphorus metabolites in cirrhosis. A relationship between the severity of liver cirrhosis and a relative increase in PME was demonstrated and this was not due to a reduction of T1. This study highlights the clinical potential of 31P MRS as a non-invasive means of assessing the severity of liver cirrhosis.

Emission tomography for assessment of diffuse alcoholic liver disease.

A method of quantitative liver tomoscintigraphy (SPECT) was compared for accuracy with planar scintigraphy (PS) in a group of patients with diffuse alcoholic liver disease. SPECT sensitivity was also compared with that of transmission computed tomography (CT), US, aminopyrine breath test (ABT) and liver chemistries (LC). One hundred and fourteen alcoholic patients with proven liver disease and 17 patients free of liver disease were included. Seven quantitative scintigraphic features and a score, including all criteria were considered. With a specificity of 95%, the sensitivity was 79% in steatosis and 97% in cirrhosis. SPECT showed a better sensitivity than PS (SPECT 89%, PS 66%), especially in patients with steatosis. In the same subsets of patients, SPECT sensitivity also compared favorably with that of transmission CT (SPECT 92%, CT 65%), ultrasonography (SPECT 88%, US 53%) and ABT (SPECT 90%, ABT 63%).

Assessment of hepatic function. Comparison of caffeine clearance in serum and saliva during the day and at night.

Hepatic microsomal function was assessed by a caffeine clearance test at night and during the day using saliva and serum samples obtained simultaneously. In 26 patients with cirrhosis, 21 patients with noncirrhotic liver disease and 15 control subjects caffeine elimination correlated well during the day and at night (r = 0.915 for serum and 0.917 for saliva). The correlation coefficients for caffeine clearance in saliva and serum were 0.940 during the day and 0.963 overnight. In the cirrhotic patients, clearance differed significantly from noncirrhotic liver disease and controls in saliva samples overnight: 0.51 +/- 0.45 ml/min per kg versus 0.91 +/- 0.44 and 1.41 +/- 0.56, respectively. Comparable results were obtained for serum clearance overnight and clearances during the day. Serum and saliva clearances at night correlated well with the aminopyrine breath test (rs = 0.884 and 0.907, respectively). Overnight caffeine clearance in saliva might be a simple useful method for assessing progression and prognosis of liver disease.

Liver function assessment by drug metabolism.

Liver function can be assessed by administering an exogenous substance to quantify changes in hepatic blood flow, uptake, biotransformation, and excretion. Characterization of drug half-life, clearance, and product formation rates are possible methods for measuring hepatic efficiency. Allopurinol and caffeine have been used to measure metabolite formation followed by renal elimination of both parent substance and metabolite. Sorbitol, a substance with high intrinsic clearance, can reflect liver blood flow, while trimethadione, a low-extraction drug, has been used to measure liver enzyme capacity. Metabolites from lidocaine, methacetin, and aminopyrine have been measured in serum, urine, and breath tests. Salivary clearance measurements of caffeine and antipyrine are reported as suitable for routine use. Genetic diversity of isoenzymes and the many metabolic processes used by hepatocytes make it extremely difficult to quantify functional changes with one substance. Combinations of model substrates have been suggested to assess the many hepatic processes.

[UV-spectrophotometric analysis of the component of antondin injection by the Monte Carlo method of area fitting].

The Monte Carlo method is a kind of unique calculation method. It can resolve not only the question of define evaluation, but also that of random evaluation. The Monte Carlo area fitting method was applied to UV-spectrophotometry of the multicomponent complex preparations without previous separation. The area of each component of complex preparation within a suitable wavelength range of standard spectrogram was multiplied by certain coefficients, and then the products were obtained to fit the area of the measured multicomponent complex preparations. The method was used to simultaneous determination of barbital, amidopyrine and antipyrine in antondin injection. The experimental data were measured and treated by UV-190 spectrophotometer and microcomputer IBM-PC. The average recoveries of barbital, amidopyrine and antipyrine were 99.1 +/- 1.1% (CV), 99.6 +/- 1.3% (CV), and 99.7 +/- 1.0% (CV), respectively.

[Assessment of the degree of carcinogenicity of small doses of nitrites]. / Otsenka stepeni kantserogennoi opasnosti malykh doz nitritov.

Chronic experiments on CBA and C57B1 mice and acute experiments on CBA mice established: (a) carcinogenic effect of sodium nitrite given continuously with drinking water (0.1; 1.0 and 10.0 maximum allowable concentration) in combination with morpholine fed with bread, and (b) endogenous synthesis of nitrosomorpholine as a result of simultaneous intragastric administration of same doses of sodium nitrite and morpholine. Also, nitrosomorpholine and N-nitrosodimethylamine synthesis was observed in vitro following addition of low-dose sodium nitrite, morpholine and amidopyrine to human gastric juice. Carcinogenic hazard associated with low-dose nitrite consumption in humans is discussed.