Positron emission tomography of hepatic first-pass metabolism of ammonia in pig.

Hepatic first-pass metabolism plays a key role in metabolic regulation and drug metabolism. Metabolic processes can be quantified in vivo by positron emission tomography scanning (PET). We wished to develop a PET technique to measure hepatic first-pass metabolism of ammonia. Seven anaesthetised pigs were given positron-labelled ammonia, (13)NH(3), into the portal vein and into the vena cava as successive 2-min infusions followed by 22-min dynamic liver scanning. Vena cava infusion data were used to account for recirculation of tracer and metabolites following the portal vein infusion. The scan data were analysed by a model of sinusoidal zonation of ammonia metabolism with periportal urea formation and perivenous formation of glutamine. The hepatic extraction fraction of (13)NH(3) was 0.73+/-0.16 (mean+/-SD, n=7 pigs). Values of clearance of ammonia to urea and to glutamine were obtained, as were rate constants for washout of these two metabolites. Overall, the modelling showed half of the ammonia uptake to be converted to urea and half to glutamine. The washout rate constant for glutamine was about one-tenth of that for urea. We conclude that hepatic first-pass metabolism of ammonia was successfully assessed by PET.

Liver kinetics of glucose analogs measured in pigs by PET: importance of dual-input blood sampling.

UNLABELLED: Metabolic processes studied by PET are quantified traditionally using compartmental models, which relate the time course of the tracer concentration in tissue to that in arterial blood. For liver studies, the use of arterial input may, however, cause systematic errors to the estimated kinetic parameters, because of ignorance of the dual blood supply from the hepatic artery and the portal vein to the liver. METHODS: Six pigs underwent PET after [15O]carbon monoxide inhalation, 3-O-[11C]methylglucose (MG) injection, and [18F]FDG injection. For the glucose scans, PET data were acquired for 90 min. Hepatic arterial and portal venous blood samples and flows were measured during the scan. The dual-input function was calculated as the flow-weighted input. RESULTS: For both MG and FDG, the compartmental analysis using arterial input led to systematic underestimation of the rate constants for rapid blood-tissue exchange. Furthermore, the arterial input led to absurdly low estimates for the extracellular volume compared with the independently measured hepatic blood volume of 0.25 +/- 0.01 mL/mL (milliliter blood per milliliter liver tissue). In contrast, the use of a dual-input function provided parameter estimates that were in agreement with liver physiology. Using the dual-input function, the clearances into the liver cells (K1 = 1.11 +/- 0.11 mL/min/mL for MG; K1 = 1.07 +/- 0.19 mL/min/mL for FDG) were comparable with the liver blood flow (F = 1.02 +/- 0.05 mL/min/mL). As required physiologically, the extracellular volumes estimated using the dual-input function were larger than the hepatic blood volume. The linear Gjedde-Patlak analysis produced parameter estimates that were unaffected by the choice of input function, because this analysis was confined to time scales for which the arterial-input and dual-input functions were very similar. CONCLUSION: Compartmental analysis of MG and FDG kinetics using dynamic PET data requires measurements of dual-input activity concentrations. Using the dual-input function, physiologically reasonable parameter estimates of K1, k2, and Vp were obtained, whereas the use of conventional arterial sampling underestimated these parameters compared with independent measurements of hepatic flow and hepatic blood volume. In contrast, the linear Gjedde-Patlak analysis, being less informative but more robust, gave similar parameter estimates (K, V) with both input functions.

[Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography]. / Detektion af kolangiokarcinom ved primaer skleroserende cholangitis ved hjaelp af positron-emissionstomografi.

Primary sclerosing cholangitis (PSC) predisposes to cholangiocarcinoma (CC). PET scanning can assess metabolism in vivo. The glucose analogue [18 F]fluoro-2-deoxy-D-glucose (FDG) accumulates in malignant tumours because of high glucose metabolism. PET scanning of the liver was performed after intravenous FDG in nine patients with PSC, six with PSC + CC, and five controls. "Hot spots" with radioactivity accumulation were seen in each PSC + CC patient, but not in the two other groups. Values of net metabolic clearance of FDG, K (ml min-1 100 ml-1 tissue), was in CC hot spots 1.59 to 4.17 (median, 2.34; n = 6); in reference liver tissues of these patients 0.40 to 0.69 (0.49); in PSC 0.23 to 0.53 (0.36); in controls 0.20 to 0.34 (0.31). The difference between K in CC hot spots and the other groups was statistically significant (P < 0.001). FDG-PET may detect small CC tumours and be useful in therapeutic management of PSC.

Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography.

Primary sclerosing cholangitis (PSC) predisposes to cholangiocarcinoma (CC), which usually is widespread in the liver at the time of the diagnosis and which has a median survival of approximately 6 months. Positron emission tomography (PET) is a noninvasive scanning method that allows the assessment of metabolism in vivo by means of positron-emitting radiolabeled tracers. [18F]Fluoro-2-deoxy-D-glucose (FDG) is a glucose analogue that accumulates in various malignant tumors because of their high glucose metabolic rates. The purpose of the study was to develop a PET method to detect small CC tumors in patients with PSC. PET scanning of the liver was performed after intravenous injection of 200 MBq FDG in 9 patients with PSC, 6 patients with PSC + CC, and 5 controls. The scanning was performed at successive time intervals for a total of 90 minutes with simultaneous successive arterial blood sampling for radioactivity concentration determination. In each of the PSC + CC patients, 2 to 7 "hot spots" were seen, with volumes of 1.0 to 45 mL (median, 4.4 mL). There were no hot spots in the two other patient groups. The localization of hot spots was confirmed by single-blind evaluation. Data were analyzed by the Gjedde-Patlak plot, yielding values of the net metabolic clearance of FDG, K [mL min(-1) 100 mL(-1) tissue]. In the CC hot spots, maximum K values were 1.59 to 4.17 (median, 2.34; n = 6); in the reference liver tissues of these patients, K values were 0.40 to 0.69 (median, 0.49); in PSC patients, they were 0.23 to 0.53 (median, 0.36); and in controls, they were 0.20 to 0.34 (median, 0.31). The difference between K in CC hot spots and the other groups was statistically significant (P < .001). We conclude that FDG-PET seems to be able to detect small CC tumors and may be useful in the therapeutic management of PSC.

Effects of brain death and glucose infusion on hepatic glycogen and blood hormones in the pig.

We wished to study the effects of intravenous glucose/ insulin infusion to brain-dead pigs on the hepatic glycogen content. Four groups of 40-kg pigs were studied: brain-dead and control pigs given isotonic saline or glucose/insulin (7.5 mg glucose/kg/min, 1.25 mU insulin/kg/ min) (n = 5 to 10 in each group). Brain death was induced by inflating a balloon placed in the epidural space. In brain-dead pigs given saline, liver glycogen decreased from 45 +/- 11 mmol/g DNA (mean +/- SEM) to 7 +/- 3 mmol/ g DNA after 6 hours. Thereafter, it increased to 28 +/- 9 mmol/g DNA after 9 hours (P = .05 compared with the 6-hour measurement). These changes were accompanied by transient increases in plasma adrenaline, glucose, free fatty acids (FFA), and glucagon. Following glucose/ insulin infusion, hepatic glycogen increased steadily and was approximately double after 12 hours (P < .01) in both brain-dead and in non-brain-dead pigs. In brain-dead pigs, the increases in the aforementioned blood measurements were smaller following glucose/insulin infusion than following saline infusion. However, studies of longer duration will be needed to examine these effects on a time scale that is relevant to human organ donors. In conclusion, the decrease in hepatic glycogen content after brain death could be prevented by intravenous glucose/insulin infusion probably because of a reduction of the adrenaline response to the induction of brain death.

Non-invasive investigation of parenchymal liver disease using 31P NMR spectroscopy.

Four 31P NMR spectroscopy parameters were measured non-invasively in the liver of 11 healthy pigs and 9 pigs with CCl4-induced liver disease: (i) absolute molar concentration of phosphorous metabolites; (ii) pH based on the chemical shift of the P(i) peak; (iii) T1 of the peaks in the 31P NMR spectrum; and (iv) changes in ATP, P1 and phosphomonoester after fructose administration. Liver disease was verified by histology and blood chemistry. The concentration of ATP decreased from 3.0(2.8-3.1) to 2.0(2.0-2.4) mM (median and quartiles) when liver disease was induced (p < 0.05). The concentration of phosphodiesters (PDEs) decreased from 14.8(11.4-19.5) to 8.7(7.4-11.6) mM (p < 0.05). pH increased by 0.1 unit. T1 relaxation times for the gamma-, alpha- and beta-ATP peaks increased from 320(249-471) to 577(506-638) ms (p < 0.01), from 765(611-786) to 906(820-1058) ms (p < 0.05) and from 402(327-509) to 579(543-743) ms (p < 0.01), respectively, while T1 for the PDE peak decreased from 2204(1909-2404) to 1758(1502-1894) ms (p < 0.05). In the healthy animals injection of fructose was followed by a reduction of ATP (beta-ATP). In diseased livers this reduction was significantly smaller. In conclusion, it was possible non-invasively to show differences between healthy and diseased livers in all NMR parameters evaluated. This means that 31P NMR spectroscopy may have a potential as a non-invasive diagnostic method for studying liver disease.