Objective: To study the effects of GH treatment for up to 42 months on bone mineral density (BMD) and bone turnover. Design and methods: BMD with dual energy X-ray absorptiometry, serum type I procollagen carboxyterminal propeptide (PICP), serum type I collagen carboxy-terminal telopeptide (ICTP) and serum IGF-I were assessed in 71 adults with GH deficiency. There were 44 men and 27 women, aged 20 to 59 (median 43) years. Thirty-two patients completed 36 months and 20 patients 42 months of treatment. Results:The BMD increased for up to 30-36 months and plateaued thereafter. In the whole study group, the maximum increase of BMD was 5.0% in the lumbar spine (P < 0.001), 5.9% (P < 0.01) in the femoral neck, 4.9% (NS, P > 0.05) in the Ward's triangle and 8.2% (P < 0.001) in the trochanter area. The serum concentrations of PICP (202.6 Ϯ 11.5 vs 116.3 Ϯ 5.4 mg/l; mean -Ϯ S.E.M.) and ICTP (10.5 Ϯ 0.6 vs 4.4 Ϯ 0.3 mg/l) doubled (P < 0.001) during the first 6 months of GH treatment but returned to baseline by the end of the study (130.0 Ϯ 10.4 and 5.6 Ϯ 0.7 mg/l respectively), despite constantly elevated serum IGF-I levels (39.6 Ϯ 4.1 nmol/l at 42 months vs 11.9 Ϯ 0.9 nmol/l at baseline; P < 0.001). The responses to GH treatment of serum IGF-I, PICP, ICTP (P < 0.001 for all; ANOVA) and of the BMD in the lumbar spine (P < 0.05), in the femoral neck and the trochanter (P < 0.001 for both) were more marked in men than in women. At the end of the study the BMD had increased at the four measurement sites by 5.7-10.6% (P < 0.01-0.001) in patients with at least osteopenia at baseline and by 0.1-5.3% (NS P < 0.05) in those with normal bone status (P < 0.001 for differences between groups; ANOVA). Among patients who completed 36-42 months of treatment, the number of those with at least osteopenia was reduced to more than a half. The response of BMD to GH treatment was more marked in young than in old patients at three measurement sites (P < 0.05-<0.001; ANOVA). In the multiple regression analysis the gender and the pretreatment bone mass appeared to be independent predictors of three measurement sites, whereas the age independently determined only the vertebral BMD. Conclusions: GH treatment in GH-deficient adults increased BMD for up to 30-36 months, with a plateau thereafter. Concurrently with the plateau in BMD the bone turnover rate normalized. From the skeletal point of view GH-deficient patients exhibiting osteopenia or osteoporosis should be considered as candidates for GH supplementation of at least 3-4 years.
Hepatic drug-metabolizing capacity was investigated in 56 diabetics. The antipyrine test was selected as an in vivo index, since its kinetics indirectly reflect the metabolically active liver mass. Hepatic cytochrome P-450 (P-450), determined from the biopsy samples, was used as an in vitro parameter, since it is a direct measure of microsomal drug-metabolizing enzyme activity. There was a wide interindividual variation in the indexes of drug metabolism in the diabetics: 40 fold in P-450 content and eightfold in antipyrine metabolism. P-450 levels were higher and antipyrine metabolism faster in the subjects with normal liver than in those with fatty liver, parenchymal inflammatory changes, or cirrhosis. Thus the in vivo and in vitro parameters of drug metabolism were related to the alterations in liver histology. On the other hand, the diabetes per se did not seem to alter the drug-metabolizing capacity of the liver. Also, drug metabolism in diabetics classified by treatment regimen did not differ significantly.
1 The effect of fatty degeneration of liver parenchyma on drug metabolism was investigated in 21 obese non-insulin-dependent diabetic subjects by measuring plasma antipyrine kinetics, hepatic cytochrome P-450, liver size and the extent of fatty infiltration. 2 The hepatic drug metabolising capacity, as measured by total antipyrine clearance and the estimated total amount of cytochrome P-450, was at the same level as in nondiabetic control subjects with normal livers. 3 Relative antipyrine clearance (per unit weight of liver) and cytochrome P-450 concentrations were significantly lower in the diabetics than in controls. 4 The extent of fatty infiltration correlated poorly with the indices of drug metabolism. 5 In non-insulin-dependent diabetics, slight to moderate hepatic fatty infiltration, without more serious structural distortion interfering with hepatic blood flow or hepatocellular function, seems to have only a minor influence on drug metabolism.
The associations between liver histological changes and hepatic cytochrome P-450 content (P-450) and the activities of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin O-de-ethylase (ECD) have been investigated in 30 diabetics undergoing diagnostic liver biopsy. There were more than 10-fold interindividual variations in P-450 contents and AHH and ECD activities in the diabetics. P-450 content decreased with increasing severity of liver histological changes, whereas AHH and ECD activities were significantly reduced only in biopsies with severe histological changes. However, despite differential effects of liver disorders on P-450 and AHH and ECD activities there were highly significant correlations between these three parameters with each other.
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