Lipid metabolism in the liver studied in vivo with two isomers of labeled fatty acid analogs.

UNLABELLED: The two radioiodinated fatty acid analogs 15-(para-131 I-phenylpentadecanoic acid (pPPA) and 15-(ortho-131I-phenyl)-pentadecanoic acid (oPPA) are isomers with individually different routes in lipid metabolism but with near equal transport kinetics into tissue. METHODS: Normal adult male Wistar rats (n = 79) and those with liver cell damage from adriamycin treatment (n = 84) received 1.48- 1.85 MBq 131I-pPPA or 131I-oPPA (specific activity, 33.3-46.3 GBq/microM) into the jugular vein. At 1, 2, 3, 5, 7, 10 and 20 min, livers of up to five animals per group were examined for total tracer uptake and tracer incorporation into various lipid fractions. RESULTS: Uptake of both isomers into the total liver plateaued at about 2 min; the ratio oPPA/pPPA in normal liver averaged 2.63 and was significantly higher than the average ratio of 1.50 after adriamycin treatment. This fall in ratio was mainly due to an increase of pPPA uptake. Significant differences of the respective ratios were found in the plateau for the phospholipids (9.7 versus 3.0), cholesterol (2.4 versus 0.7) and triglycerides (2.0 versus 0.4). CONCLUSION: The dual-tracer technique with pPPA and oPPA promises to be clinically useful for the diagnosis of liver disease by imaging the ratios of tracer uptake in the total liver and by in vitro analysis of the uptake ratio in serum triglycerides.

Radiation exposure from long-lived beta emitters in clinical investigation.

Potential hazards restrict the use of 14C in clinical investigation. Nevertheless, 14C, in readily metabolized compounds, continues to be administered and in relatively large doses. The compounds are converted to intermediates and products with longer half-lives than their half-lives. These longer biological half-lives have not always been taken into account, although calculations of radiation exposure can be markedly altered by their inclusion. The minimum dose of 14C needed to accomplish a study must also be considered, and benefits relative to risks in the administration must be assessed in terms of the kind and total number of subjects required. Similar considerations apply to the administration of 3H-labeled compounds. Furthermore, in assessing risks, the limited information available on the localization and concentration of the isotopes in the body should be taken into account. There are also concerns with regard to administrations in growth situations and to an individual on multiple occasions. Within those constraints, 14C and 3H can be given with relative safety.

Orbital pseudotumor imaged with Ga-67 citrate.

An orbital pseudotumor causing proptosis, diplopia, and gaze palsy was imaged with Ga-67 citrate and showed persistent intense activity for five days. This may be the first case of gallium uptake into an orbital pseudotumor to be reported in the literature. This case report demonstrates the use of Ga-67 citrate imaging in the early diagnostic workup of this disorder.

Impaired oxidation of carbon-labeled galactose by alcoholic or diabetic liver in vivo.

Because of the organ and enzyme specificity of the metabolism of galactose, evaluation of various kinds of liver disease can be done by measuring the formation of labeled breath CO2 from carbon-labeled galactose in vivo. As shown earlier with uniformly 14C- or 13C-labeled galactose, a further study of alcoholic cirrhotic patients and controls with cheaper 1-14C-galactose indicates a superior discriminatory value of this test compared with common liver function tests. The oxidation test is easier to perform and more acceptable to patients than the standard galactose tolerance blood test. Output of 14CO2 showed slight correlations with serum albumin and 99mTc-sulfur colloid scan grade, but not with other function tests (SGOT, alkaline phosphatase, bilirubin). Comparison with five-year clinical outcome (two groups: with or without known liver-related death) in 29 of 43 total cirrhotic patients (U-14C or 1-14C-galactose) showed a low (75% probability) significance of prognosis for the galactose oxidation test, but none for any of the other tests. A two-part test of oxidation of 14C-galactose (with and without an acute dose of ethanol) in 19 possibly or likely alcoholic (but non-cirrhotic) persons indicated, by correlation with other liver function tests and drinking history, some possibly enhanced sensitivity of the two-part versus the single test for recognizing early liver damage. A preliminary study of the single galactose oxidation test in 7 patients with Type II diabetes suggests moderate impairment of oxidation, which might be applied to evaluate the hepatic disorder in diabetes.

Phantom gallbladder. A variant of the rim sign.

Nonvisualization of the gallbladder is the primary finding in cholescintigraphy for acute cholecystitis. Recent investigators have described a useful secondary finding of increased pericholecystic hepatic activity (PCHA). A case of acute cholecystitis is presented in which the PCHA was round in configuration and appeared in the first 5 minutes of the study. This may be a source of diagnostic error if it is interpreted as visualization of the normal gallbladder. Appearance of the PCHA has not been previously described before 30 minutes. This case of early appearance raises the possibility that hyperemia may play a role as the cause in some forms of the PCHA. The phantom gallbladder was correctly identified as PCHA by observing the peak of activity of the PCHA occurring before the appearance of intrahepatic biliary radicals.

17-Iodine-123 iodoheptadecanoic acid for metabolic liver studies in humans.

(17-123I)-Iodoheptadecanoic acid ([123I]HA) was used for dynamic planar scintigraphy of the liver in normal individuals (control I), in patients without liver disease but with elevated serum cholesterol and/or triglycerides (control II), and in patient groups with alcohol-induced fatty liver (PG I), fatty liver not due to alcohol (PG II), alcohol-induced liver cirrhosis (PG III), or liver cirrhosis of the posthepatitic type (PG IV). Tracer uptake and elimination time were assayed in different liver regions; mean elimination time was expressed for total liver. In control I, tracer uptake was homogeneous, and mean elimination time was 20.7 +/- 5.3 min without significant local variations. In control II, tracer uptake was reduced but homogeneous and mean elimination time was 59.4 +/- 35.8 min with some local variations. In PG I, uptake was reduced and inhomogeneous and elimination time was the same as in control I, irrespective of cholesterol and triglyceride values. In PG II, uptake was the same as in PG I but mean elimination time was 48 +/- 8.1 min with some local variations. In PG III, uptake was extremely reduced and spotty and elimination time correlated with the severity of disease from 19 to 881 min in different liver regions.

15-(ortho-123I-phenyl)-pentadecanoic acid, a new myocardial imaging agent for clinical use.

The result of previous experiments in rodents indicated different kinetics for the para- and ortho-isomers of 15-(iodophenyl)-pentadecanoic acid (p-IPPA, o-IPPA), with o-IPPA showing an enhanced rate of washout. To test the relevance of this phenomenon for clinical diagnosis, 15 fasting male patients with confirmed coronary heart disease (1-VD/7, 2-VD/4, 3-VD/4) were investigated under exercise. Serial images were recorded at a rate of 3 frames min-1 for 70 to 90 min, corrected for tracer in blood and compared with thallium-201 images obtained from these patients within less than 2 weeks. Time-activity curves were also taken from the peripheral blood. Ortho-IPPA was well taken up by healthy myocardium and, contrary to rodents, retained with elimination half times longer than 200 min. A decreased myocardial uptake was seen which was very similar to the pattern obtained with thallium. Ortho-IPPA was eliminated from the blood to less than 10% at 4 min. Almost all radioactivity was in the organic phase (greater than 95% at 5 min) and chromatography showed only one major peak (o-IPPA) indicative of minimal organic catabolism.

Myocardial fatty acid metabolism after acute ethanol consumption.

This study was undertaken to assess the effect of ethanol ingestion on myocardial fatty acid metabolism in man. Nine individuals with informed consent and with a habitual ethanol consumption of approximately 40 g per day, but without any clinical signs of heart and metabolic disease, were examined after i.v. injection of omega-123I-heptadecanoic acid (IHA). Eight days later, these individuals were similarly examined after 2 h of continuous ingestion of a body weight dependent amount of ethanol, which was calculated to produce a blood level of 100 mg per 100 ml (1%). Then the subjects had been asked to reduce their ethanol consumption rigorously for 15 months. Subsequently after 2 weeks of abstinence a follow-up investigation without ethanol loading was carried out. The investigations were performed with an Anger scintillation camera in LAO-45 degrees projection. The measurement period was 40 min. Tracer accumulation and regional elimination half-times of IHA were analysed. In all patients, acute ethanol loading produced significant changes in pattern of accumulation and/or regional elimination half-times. Ethanol-induced alterations in segmental accumulation did not appear to be predictably correlated with changes in segmental elimination half-times. After rigorous reduction of ethanol consumption followed by 2 weeks of abstinence a normalization of the tracer uptake was observed; the distribution pattern was almost homogeneous. Also the regional elimination half-times became normal. The data demonstrate the significant effects of both chronic ethanol consumption and particularly acute ethanol loading on myocardial fatty acid metabolism and the reversibility of the effects.

Kinetics of different 123I- and 14C-labelled fatty acids in normal and diabetic rat myocardium in vivo.

Terminally radioiodinated long-chain fatty acids (FA) or phenyl-FA have shown promise for external myocardial imaging and detection of metabolic disorders with changes like those seen with radiocarbon-labelled natural FA. Yet, questions remain about the correlation of these changes to the biochemical forms of radioiodine within the cell. We have measured the distribution of label from 123I-heptadecanoic acid (HA), 123I-para-phenyl- and ortho-phenylpentadecanoic acid (pPPA and oPPA), 1-14C-stearic acid (SA) and 1-14C-palmitic acid (PA) into complex lipids (CL) (i.e. triacylglycerols (TG) and phospholipids (PL)), aqueous phase (AP) and solid residue (SR) of myocardium of normal (N) and streptozotocin-diabetic (D) rats at 1,2, 3, 5 and 10 min after i.v. injection. For the total heart (TH) all FA have similar initial peak heights in % dose (pPPA highest) at 1 to 2 min in N and D. Tracer kinetics for CL, TG and PL were similar for PA and pPPA and for SA and HA. For PA and pPPA 2/3 of CL tracer were in TG and 1/3 in PL, whereas it was 1/2 in each for SA and HA. In D rats turnover of CL was enhanced and tracer uptake into TG reduced for all FA. Tracer kinetics in SR and AP were similar, with highest values for HA; relationship between peak times for CL and AP indicates rapid formation of catabolite and its early cell exit. Unlike pPPA, oPPA was little converted to TG or PL and equally in N and D rats showed rapid decline.

Uptake of Ga-67 in the cardiac region in hypersensitivity angiitis.

Although Ga-67 can be used to recognize various inflammations of the heart and pericardium, it is seldom used to evaluate the inflammatory process of a myocardial infarction because of lack of specificity, lack of early uptake, and other factors. However, inadvertent recognition on routine Ga-67 scans is always a possibility and has been reported once before. Here described is another case of silent, multiple myocardial infarction seen by Ga-67 scan as a consequence of multiple organ involvement with hypersensitivity angiitis. This incidental finding was the only indication of direct cardiac involvement at the time of the patient's death by cardiac arrest on the same day as the Da-67 scan.

Test for alcoholic cirrhosis by conversion of [14C]- or [13C]galactose to expired CO2.

After ingestion of galactose (10 g per m2) labeled with 14C or 13C, breath was collected from subjects at intervals for 4 hr followed by measurement of 14CO2 by liquid scintillation counting or of 13CO2 by mass spectrometry. Nine subjects without liver disease and 21 "cirrhotic" patients were tested with 14C; 8 control subjects and 4 patients with diagnosis of cirrhosis were tested with 13C. The mean rates of expiration of labeled CO2 by the patients with "cirrhosis" were one-third to one-half of mean normal rates during the first 90 min. The time of peak concentration of tracer CO2 for cirrhotic patients (150 to 180 min) was later than for normal subjects (90 to 120 min). There was distinctly greater separation between control and liver disease groups by test of 14CO2 radioactivity at 1 hr than by serum alkaline phosphatase, total bilirubin, and transaminase, but only slightly better separation than by serum albumin concentration (which was highly correlated with 14CO2 output). The [14C]galactose test is simpler than the standard intravenous galactose tolerance test, and , like the latter, appears superior to some other tests for recognition of cirrhosis. The use of 13C provides an example of a new direction for clinical application of this stable, nonradioactive nuclide.

Pituitary-testicular axis in patients on lithium therapy.

Plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels were studied in 10 patients undergoing lithium therapy. Testosterone levels were below the normal range in 7 of the 10 patients. FSH levels were high in two patients and LH levels were high in one. The effects of lithium on the pituitary-testicular axis are discussed.

Radiorespirometric study of carbohydrate metabolism in childhood liver disease.

The need for a suitable parameter to evaluate patients with chronic liver disease has been felt for some time, especially in order to judge the response to surgical shunts and the influence of certain drugs and diets on the liver. Since the liver is a major organ for carbohydrate metabolism, it was decided to analyze the in vivo oxidation of such substrates as glucose and galactose labeled with 14C. Moderately advanced "Indian childhood cirrhosis" and idiopathic fatty hepatic infiltration were selected to represent diffuse chronic liver disease. Oral administration of 14C-U-glucose or 14C-1-galactose was followed by analyses of 14CO2 in breath by liquid scintillation counting. Conversion of 14C-glucose to 14CO2 was accelerated by both diseases. On the other hand, oxidation of 14C-galactose was slowed in fatty infiltration and was markedly subnormal in Indian childhood cirrhosis.

Human plasma triglyceride labeling after high sucrose feeding. II. Study on triglyceride kinetics and postheparin lipolytic activity.

Kinetic studies of the very-low-density lipoprotein triglycerides (VLDL-TG) turnover by endogenous labeling with glycerol-2-3-H were performed in 13 patients in the postabsorptive state, first after 10-14 days on a low-sucrose high-starch diet, then again after 10-14 days of isocaloric high-sucrose low-starch diet (HSD). After HSD, a significant decrease in the fractional turnover rates of VLDL-TG was observed, as well as a modest but significant increase in its pool size, but the net turnover rates remained unchanged. Using Michaelis-Menten formulation, we have further calculated the Vmax and Km's of the removal system for VLDL-TG and found that the Vmax and Km's do not differ significantly between the two dietary periods. These results suggest that the removal mechanism for VLDL-TG has not changed after 10-14 days on the HSD, at least when the patients are studied in the postabsorptive state. Measurements of postheparin lipolytic acitivty under fed condition in 17 patients (including the 13 patients above) have shown a decrease after HSD. However, a defect in the removal of plasma-TG related to decreased activity of tissue-lipoprotein lipase in the fed state has not been conclusively uncovered by the kinetic studies performed in the postabsorptive state, and cannot contribute significantly to the expansion of VLDL-TG pool.