Noninvasive ratio indexes to evaluate fibrosis staging in chronic hepatitis C: role of platelet count/spleen diameter ratio index

OBJECTIVES: Noninvasive evaluation of fibrosis is an on-going effort in the management of chronic hepatitis C. This study was planned to noninvasively evaluate fibrosis staging. DESIGN: We evaluated the biochemical, functional [aminopyrine breath test (ABT)] and ultrasonographic variables of 75 chronic hepatitis C patients. RESULTS: Clinical [body mass index (BMI)], biochemical [aspartate aminotransferase (AST), alanine aminotransferase (ALT) and platelets (PLT)] and ratio indexes, together with the ABT, showed a higher relationship with fibrosis: initial (score2) fibrosis: BMI (24+/-2 vs. 26+/-2, P=0.0007), AST (56+/-36 vs. 88+/-65, P=0.0159), ALT (92+/-54 vs. 139+/-108, P=0.0290), PLT (220+/-64 vs. 173+/-61, P=0.0007), PLT/spleen diameter ratio (PLT/SPD) (2133+/-786 vs. 1540+/-681, P=0.0003), AST/platelet count ratio index (APRI) (0.80+/-0.87 vs. 1.51+/-1.47, P=0.0010), ABT%d/h30 min (10.8+/-4.5 vs. 7.6+/-3.8, P=0.0007), ABT%d/cum120 min (8.9+/-3.3 vs. 6.5+/-3.1, P=0.0007). Considering the differences between fibrosis score 2 and 3 patients, BMI, ABT and PLT/SPD ratio proved to be statistically significant. Multivariate stepwise analysis (with and without BMI) identified two models for distinguishing between initial and evident fibrosis: Model 1: -0.569+(BMIx0.107)+(APRIx0.169)-(PLT/SPDx0.304), and Model 2: 2.376+( APRIx0.152)-(ABTd/h30x0.043)-(PLT/SPDx0.249). These models showed concordance in identifying or ruling out evident fibrosis in 76% and 78.7% of the patients respectively. The PLT/SPD ratio also showed 78.7% concordance with the histological score. CONCLUSION: These results suggest that noninvasive evaluation of fibrosis in chronic hepatitis C may be considered an effective tool thanks to the use of an inexpensive, reproducible ratio index.     

Assessment of drug metabolism in hepatic disease: Comparison of plasma kinetics of oral cyclobarbital and the intravenous aminopyrine breath test

Summary The exhalation of ¹⁴CO₂ derived from an i.v. tracer dose of [dimethylamine-¹⁴C]aminopyrine has been investigated in normal controls and patients. They subsequently ingested 200 mg cyclobarbital calcium in the evening and the decline in the plasma drug level over the following 2 days was measured by thin-layer chromatography. The peak specific activity of exhaled ¹⁴CO₂ occurred 0.5–2 h after ¹⁴C-aminopyrine injection in the absence of liver disease and in non-cirrhotic liver disorders. It was delayed in certain patients with cirrhosis. Compared to 8 medically healthy subjects, 10 patients with acute viral hepatitis, 8 with cirrhosis and 10 with fatty liver exhibited a significantly increased half-life of ¹⁴CO₂ exhalation. Normal mean values were found in 12 patients with non-cirrhotic alcoholic liver disease and in 14 patients with non-hepatic diseases. The cyclobarbital (CB) half-life was prolonged and the clearance reduced in patients with viral hepatitis, cirrhosis, or alcoholic liver damage as compared to data from 17 control subjects. Due to a larger apparent volume of distribution, patients with fatty liver disease had an increased CB half-life, although its clearance was normal. A close negative correlation was detected between the clearance and the logarithm of the CB level measured 36 h after drug ingestion. The oral CB test evaluated from a single blood sample taken about 36 h after drug administration appears to be a useful indicator of human drug metabolising capacity. Discrimination between patients with and without disordered liver function was similar in the two drug elimination tests.     

Patient age is a strong independent predictor of 13C-aminopyrine breath test results: a comparative study with histology, duplex-Doppler and a laboratory index in patients with chronic hepatitis C virus infection

1. Noninvasive tests for the staging of chronic hepatitis C virus (HCV) infection would be an attractive alternative to liver biopsy. The 13C-aminopyrine breath test (ABT) has been proposed for the noninvasive assessment of hepatic function and partly correlates with fibrosis. We aimed to investigate causes for the lack of discriminatory power for different degrees of hepatic fibrosis. 2. Eighty-three patients (median age 49 years (28-78 years)) with chronic HCV infection underwent the ABT after an oral load of 75 mg N,N-dimethyl-13C-aminopyrine. Portal vein flow was assessed by duplex-Doppler and a laboratory index (aspartate aminotransferase to platelet ratio index or APRI) was calculated. Parameters were compared with liver histology. 3. The cumulative 13C-recovery differed significantly between patients without relevant fibrosis (fibrosis score 0-2) and cirrhosis (5-6), beginning after 30 min of sampling (P < 0.05). The ABT did not discriminate patients with fibrosis scores 3-4 from the remaining two patient groups. Sensitivity and specificity for the prediction of cirrhosis was 73.4-82.8% and 63.2-68.4%, depending on the sampling time. Compared with the fibrosis score (P = 0.04), patient age was a highly significant independent predictor for the 13C-recovery (P < 0.0001). Aspartate aminotransferase to platelet ratio index and duplex-Doppler predicted cirrhosis with 76.6%vs. 87.5% sensitivity and 63.2%vs. 68.4% specificity. 4. Our data suggest an age-dependent decrease of cytochrome P450 activity which probably accounts for the large overlap of ABT results that preclude clear differentiation. This is also consistent with former pharmacodynamic trials. Age-adapted reference ranges could improve ABT results.     

Pharmacokinetics of isradipine in patients with chronic liver disease

Summary The pharmacokinetics of the dihydropyridine calcium antagonist isradipine has been examined in 8 healthy volunteers, 7 patients with non-cirrhotic chronic liver disease (CLD), and 8 patients with biopsy-proven cirrhosis (CIR). Isradipine was simultaneously given orally (¹²C 5 mg) and i.v. (¹³C 1 mg).Systemic availability was significantly increased from 17% and 16% in controls and CLD, respectively, to 37% in CIR. The corresponding systemic clearances averaged 1.1, 0.9 and 0.61 · min^–1, the reduction in cirrhotics being significant.Both aminopyrine demethylation capcity, a measure of hepatic microsomal function, and indocyanine green disappearance, a measure of hepatic perfusion, were correlated with the reduction in systemic clearance, and the reduction in oral clearance was correlated with the reciprocal of the serum bile acid concentration.The loss of first-pass extraction should be considered when this calcium antagonist is given perorally in patients with hepatic cirrhosis.     

Placental transfer and pharmacokinetics of primidone and its metabolites phenobarbital,PEMA and hydroxyphenobarbital in neonates and infants of epileptic mothers

Summary The placental transfer of primidone and its metabolites phenobarbital, phenylethylmalondiamide (PEMA) and p-hydroxyphenobarbital (free and conjugated) has been investigated at birth in 14 epileptic women who had been treated with primidone throughout pregnancy. All drugs studied were found in similar concentrations in maternal and cord blood. In seven of the newborns the pharmacokinetics of these drugs were studied during the first postnatal weeks. Primidone and phenobarbital were eliminated with mean half-lives of 23±10 h and 113±40 h, respectively, PEMA with 35±6 h. In some neonates the serum concentrations of phenobarbital and PEMA increased during the first few days due to their formation by neonatal primidone metabolism. Some babies showed a biphasic elimination pattern with elimination rates increasing after a few days. Although half-lives varied greatly, they corresponded well with renal clearance values and aminopyrine demethylase activities as measured by¹³CO₂-exhalation from¹³C-labelled aminopyrine. Two newborns whose mothers had been treated with phenytoin in addition to primidone, showed half-lives, renal clearance values and aminopyrine demethylase activities well within the corresponding ranges for adults, thus demonstrating prenatal induction. Newborns whose mothers had been treated with valproate as comedication, did not exhibit elevated excretion rates as compared to newborns of mothers who were treated with primidone alone. Withdrawal symptoms developed in two newborns at times when primidone had been essentially excreted, and in spite of the presence of elevated phenobarbital and PEMA levels. All drugs studied were also present in mothers' milk. During breast feeding, drugs ingested with the milk contributed to the neonate's blood levels, particularly in the case of phenobarbital.Presented at the International Workshop on Perinatal and Pediatric Aspects of Clinical Pharmacology, Heidelberg, Federal Republic of Germany, 27–29 February 1980     

N-Demethylation of Aminopyrine by the Nasal Mucosa in Mice and Rats

Abstract: N-demethylation of aminopyrine was demonstrated in the nasal mucosa of C57 B1 mice and Sprague-Dawley rats by measurements of the ¹⁴CO₂ formed at incubation of ¹⁴C-aminopyrine with tissue-slices. The metabolism of aminopyrine by the nasal mucosa was induced by phenobarbital pretreatment and susceptible to inhibition with metyrapone and SKF 525 A suggesting the presence of a cytochrome P-450-dependent enzyme system in the tissue. Immediately after injection of ¹⁴C-aminopyrine in rats a uniform distribution of radioactivity in the body was recorded. After thirty minutes, however, a preferential localization of radioactivity was found in the nasal mucosa and in the liver. By pretreatment with metyrapone the uptake of radioactivity in the nasal mucosa and in the liver was blocked suggesting that the observed accumulation of radioactivity is due to metabolites.     

氨基比林和亚硝酸钠诱发的肝内胆管癌动物模型

目的 用氨基比林和亚硝酸钠诱发叙利亚地鼠肝内胆管癌（ICC）动物模型,观察胆管癌发生的病理变化。方法 以800mg／L的氨基比林和亚硝酸钠溶液作为50只6周龄利亚地鼠的饮用水,每周饮用6d,连续饮用24周,定期分批处死动物,观察肝脏组织的病理学改变。结果 诱癌早期出现卵圆细胞增生、管六增生及小胆管的囊性增生,中期主要病变为肝内胆管上皮乳头状增生、化生、不典型增生和胆管纤维化,晚期可见肝内胆管腺瘤和腺癌。晚期肝内管癌的发生率达50．0％（10／20）。结论 该动物模型与人类肝内胆管癌发生发展的过程相似,方法简便、经济、可重复性好,具有良好的应用前景。肝内胆管的各种增生发生性病变与ICC密切相关,尤其是不典型增生和胆管腺瘤,应视为ICC的高危性癌前病变。     

Long-term effect of nadolol on quantitative liver function tests in patients with cirrhosis

Summary Nadolol, a non-cardioselective beta adrenoreceptor blocking agent, has been reported to decrease portal pressure without affecting liver function in cirrhotic patients treated for 1 month. There were no data about the long-term effects of nadolol on liver function.In 11 patients with cirrhosis and portal hypertension galactose eliminating capacity, aminopyrine metabolic capacity, ICG clearance and IGC intrinsic hepatic clearance according to the parallel tube model were measured before and after 6 months of treatment with nadolol at a dose reducing resting heart rate by approximately 25%. No significant variation in any of these parameters was found.Thus 6 months of continuous oral administration of nadolol did not further impair liver function in cirrhotics.     

姜酚对小鼠肝药酶活性的影响

目的:研究姜酚对小鼠肝脏细胞色素氧化酶P450(CYP450)含量及其亚型CYP2E1与CYP3A活性的影响。方法:小鼠口服给药姜酚(200,100,50 mg.kg-1.d-1),5 d后钙沉淀法制备肝微粒体,测定并考察姜酚对小鼠肝重、微粒体蛋白、CYP450及CYPb5含量的影响;氨基比林法和红霉素法测定肝微粒体CYP亚型CYP2E1与CYP3A的活性。结果:姜酚高、中、低剂量(200,100,50 mg.kg-1.d-1)对小鼠肝重、蛋白含量无影响,能显著降低CYP450的含量以及增加CYPb5的含量(P<0.01);3种剂量姜酚均可抑制CYP2E1的活性(P<0.05),且随着剂量增加抑制作用增强,高剂量姜酚可以抑制CYP3A的活性(P<0.05)。结论:姜酚对小鼠CYP450含量及亚型CYP2E1,CYP3A活性有抑制作用,抑制程度与剂量有关。     

The determination of aminopyrin elimination for control of the metabolic capacity of the liver in man

Abstract. The kinetics of plasma and breath elimination of aminopyrine after ¹⁴C-aminopyrine given orally were studied using an open one-compartment model and first order rates of elimination. The study comprises eight healthy volunteers and two groups with histologically verified chronic liver diseases (cirrhosis, n = 12, and chronic aggressive hepatitis, n = 12). Elimination rates from plasma and breath were significantly reduced in the group with cirrhosis, but only so in chronic aggressive hepatitis when they were expressed relative to each other.
Monomethylaminopyrine was eliminated more rapidly compared to aminopyrine, and the rate of formaldehyde formation was positively correlated to the excretion rate of CO₂ ( r = 0.53, P <0.002). No correlation was found with clinical or other laboratory data in the groups of liver diseases studied.
The test is a quantitative indicator of the drug metabolizing mixed function oxidases of the endoplasmatic reticulum of the liver, and may reflect the degree of damage to this system in chronic liver disease.