Heikki Pirttiaho

Histological changes in the liver and indices of drug metabolism in alcoholics

SummaryThe drug metabolizing capacity of the liver was investigated in 27 consecutive alcoholics by comparison of in vivo (antipyrine kinetics) and in vitro (cytochrome P-450) indices of drug metabolism with quantitative histological determinations of fat, trabeculae and non-fatty parenchyma in liver biopsies, and with biochemical liver function tests. The reduced amount of hepatic parenchyma in the biopsies was related to diminished drug metabolizing capacity, both in vivo and in vitro. The accumulation of fat alone did not significantly alter the kinetics of antipyrine, although it was associated with reduced cytochrome P-450 content. The replacement of parenchyma by fibrous tissue resulted in a decrease both in antipyrine clearance rate and cytochrome P-450 content. There was a logarithmic correlation between the kinetic parameters of antipyrine and cytochrome P-450 in the entire series, whereas a linear relationship was found in the alcoholic subjects in the various diagnostic groups. A non-linear relationship was also found between biochemical liver function tests and the in vivo and in vitro indices of drug metabolism. The results demonstrate that drug metabolizing capacity in alcoholics is related to ethanol-induced changes in the liver. quantitative evaluation of hepatic parenchymal changes, together with tests of the functional capacity of the liver, might be of significance value in predicting the ability of alcoholics to metabolize drugs.

Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants.

SummaryLiver blood flow and indices of hepatic drug metabolism (antipyrine elimination rate and cytochrome P-450 concentration in liver biopsy specimens) were studied in 19 epileptics on long-term anticonvulsant treatment, and in 18 controls. The size of the liver and the total estimated liver blood flow were greater in the epileptics than in the controls, whereas the relative liver blood flow (per unit weight of the liver) was not significantly different. The epileptics had higher cytochrome P-450 levels and they eliminated antipyrine faster than the controls. It was concluded that long-term ingestion of enzyme-inducing anticonvulsants is associated with an increase in the total hepatic blood flow in parallel with the increase in liver size, and not as an independent phenomenon. Since the relative perfusion rate of the hepatocytes was unchanged, the enhanced activity of drug metabolizing enzymes is presumed to be mainly responsible for the increased drug clearance observed in epileptic subjects.

Augmentation of Atrial Contribution to Left Ventricular Filling in IDDM Subjects as Assessed by Doppler Echocardiography

Left ventricular diastolic function was assessed by pulsed Doppler echocardiography in 21 subjects (mean age 48 yr) with insulin-dependent diabetes mellitus (IDDM) and without evidence of ischemic heart disease and in 21 healthy control subjects of similar age and sex distribution. The peak mitral valve flow velocities during the early rapid filling phase (E) and during late atrial filling (A) were measured, and the ratio of these peak flow velocities (E:A) was calculated. E was similar in both groups, but A was higher (P < .01) in the diabetic group. Thus, E A was lower (1.19 ± 0.24 vs. 1.65 ± 0.67; P <.01) in the diabetic subjects than in the control subjects. On subgroup analysis, 6 patients with cardiac autonomic neuropathy had lower E:A than the patients with no such disorder (0.99 ± 0.15 vs. 1.29 ± 0.25; P < .05). E A was not related to the duration of diabetes, presence of retinopathy, HbA,, or blood glucose levels. In conclusion, the atrial contribution to left ventricular filling seems to be augmented in diabetic subjects. This finding indirectly supports the view that left ventricular compliance is already reduced in asymptomatic diabetic subjects.

Relationship between in vivo and in vitro drug metabolism in man

SummaryRelationship between in vivo and in vitro drug metabolism was investigated in 200 consecutive patients with diagnostic liver needle biopsy by comparing the cytochrome P-450 (P-450) content in biopsies with the elimination kinetics of antipyrine. P-450 level in livers varied from 0.5 to 32.5 nmole/g, it was increased in subjects treated with enzyme inducing drugs and reduced in patients with degenerative parenchymal changes in the liver. Antipyrine metabolism also varied markledy, the half-life ranged from 2.2 to 54.4 hrs and the clearance from 3.5 to 142.4 ml/min. Rapid drug metabolism was associated with subjects with normal liver or with slight liver changes in case they were also treated with known inducers whereas reduced antipyrine metabolism was seen in subjects with degenerative liver changes. P-450 content in biopsies was related to the kinetic parameters of antipyrine: correlation between P-450 in livers and the drug clearance was linear whereas a non-linear relationship between P-450 and plasma half-life was obtained. The results demonstrate a relationship between in vivo and in vitro parameters of drug metabolism in man and show the importance of liver parenchymal changes and drug therapy as factors influencing hepatic drug metabolism.

Liver size and indices of drug metabolism in alcoholics.

SummaryThe role of liver size in drug metabolism was investigated in 34 chronic alcoholics and 28 controls by comparing antipyrine half-life with biopsy content and total amount of hepatic cytochrome P-450 (P-450) and liver weight. Liver size was significantly greater in alcoholics than in controls. Total P-450 was increased and antipyrine metabolism was enhanced in alcoholics with normal histology of the liver. In subjects with alcoholic hepatitis or cirrhosis, the antipyrine half-life was prolonged and P-450 was decreased. Alcoholics with fatty liver had a reduced P-450 content, but the total amount of P-450 and the antipyrine half-life were normal. The results demonstrate in alcoholics that an enlarged liver of normal histological appearance is associated with enhanced drug metabolism. In subjects with fatty liver the drug metabolizing capacity per unit weight of liver is often impaired, but the increase in liver size leads to undisturbed total oxidizing capacity and normal in vivo metabolism. In alcoholic hepatitis drug metabolism is impaired in spite of hepatomegaly. In cirrhosis the enlargement of the liver appears to compensate for the decreased P-450 content resulting in only slightly decreased total P-450, and the severely impaired in vivo drug metabolism may be due to derangement of blood flow.

Serum low-density lipoprotein and high-density lipoprotein cholesterol, and liver size in subjects on drugs inducing hepatic microsomal enzymes

SummarySerum low-density lipoprotein cholesterol and high-density lipoprotein cholesterol concentration and the ratio between them, major risk factors of coronary heart disease, and liver size were investigated in 18 subjects who were on enzyme-inducing anti-convulsants, phenytoin alone or in combination with phenobarbital and/or carbamazepine. The subjects with a high liver cytochrome P-450, indicating hepatic microsomal enzyme induction, who showed an increase in liver size, had an elevated high-density lipoprotein concentration and high-density lipoprotein cholesterol/total cholesterol ratio, and a reduced low/high-density lipoprotein cholesterol ratio. The high-density lipoprotein cholesterol concentration and its ratio to total cholesterol were directly and related to the ratio between low and high-density lipoprotein cholesterol were inversely related to the extent of liver enlargement. The serum cholesterol distribution profile associated with an increase in liver size was typical of subjects with a low risk of coronary heart disease. The results suggest that enzyme-inducers, such as phenytoin and phenobarbital, induce structural and functional changes in hepatocellular membranes associated with liver enlargement and cholesterol distribution characteristic of low susceptibility to atherosclerotic vascular disease.

Effect of Coronary Artery Disease on Parasympathetic Cardiovascular Reflexes in NIDDM Patients

To evaluate the effect of coronary artery disease on parasympathetic cardiac reflexes in patients with noninsulin- dependent diabetes mellitus (NIDDM), we studied standard cardiovascular reflexes in 27 NIDDM patients with coronary artery disease (group 1) and in 21 NIDDM patients with no signs of coronary artery disease (group 2). Groups did not differ with respect to age, duration of diabetes, or presence of retinopathy. The mean ± SD heart-rate variation in deep breathing was lower in group 1 than in group 2 (11.6 ± 6.5 vs. 17.1 ± 9.0 beats/min, P < 0.05). Heart-rate variation was more often abnormally low (<10 beats/min) in group 1 than in group 2 (48 vs. 19%, P < 0.05). Thus, the presence of coronary artery disease appears to modify cardiac parasympathetic reflexes in patients with diabetes mellitus and must be kept in mind when interpreting test results.

Asymptomatic coronary artery disease in diabetes: associated with autonomic neuropaphy?

To elucidate the potential association of diabetic autonomic neuropathy with increased prevalence of silent coronary artery disease (CAD), 138 asymptomatic diabetic subjects were screened using exercise ECG. 24-h ambulatory ECG and dynamic thallium scintigraphy. Fourteen patients with exercise-induced myocardial ischaemia and angiographically confirmed CAD (≥50% coronary artery narrowing) were found using this protocol. Their autonomic nervous function was assessed using standard cardiovascular tests and compared with that of 23 consecutive diabetic patients catheterised because of symptomatic CAD (mean New York Heart Association class 3.0). The diabetic patients with symptomatic CAD had more severe coronary atherosclerosis than the diabetic patients with asymptomatic CAD assessed by jeopardy score (P<0.01). The groups did not, however, differ with respect to autonomic function tests. Five patients (22%) with symptomatic CAD and 3 patients (21%) with asymptomatic CAD had definite autonomic dysfunction, i.e. two or more abnormal tests. Thus, our results suggest that the frequency of autonomic neuropathy is not increased in diabetic patients with asymptomatic CAD. The contribution of diabetic autonomic neuropathy to the absence of cardiac pain needs further clinical and pathological studies.

Influence of liver size on the relationship between in vivo and in vitro studies of drug metabolism

SummaryOne hundred and twelve subjects were investigated to elucidate the influence of liver size on the relationship between in vivo (antipyrine kinetics) and in vitro (cytochrome P-450) studies of drug metabolism. The correlation between these variables appeared to be linear in 20 subjects with normal parenchyma and nonlinear in 92 subjects with slight or severe histological alterations in liver biopsy specimens. When liver size was taken into account by calculating the total amount of cytochrome P-450/liver (liver weight g x cytochrome P-450 concentration nmol/g), the relationship between in vivo and vitro studies improved in normal controls. In subjects with changed liver structure the correlation showed no improvement and remained nonlinear.