 |
 |
| Home | People | Research | Free software:iFit | Free e-book: Imaging In Hepatology |
|
Liver Physiology and Pathophysiology Investigated by PET/CT The work of the Liver PET Group at Aarhus University Hospital focus on the development of physiologically based PET/CT methods for studying the liver. The aim is to improve our understanding of liver physiology and pathophysiology and optimise human PET/CT studies. Clinical implementation of physiologically based PET/CT will improve the diagnosis and treatment of patients with liver diseases. Study designs are translational: New tracers are developed, such as 2-[18F]fluoro-2-deoxy-D-galactose (18F-FDGal) and [N-methyl-11C]cholylsarcosine (11C-CSar). Non-invasive PET/CT methods are developed using invasive studies in pigs. Then the novel PET/CT methods are tested in experimental studies in human subjects and implemented in clinical work with patients with liver diseases, including primary and secondary liver cancer and the clinical impact assessed. Our work takes greatest possible account of the liver's special anatomy, physiology and patho-physiology. The location of the liver between the gastrointestinal circulation and the systemic circulation is the basis for its filter function, including detoxification of harmful substances absorbed from the gut. In our modelling work we take into account the liver's blood supply from both the hepatic artery and portal vein, liver microcirculation, hepatocellular metabolism and hepatobiliary excretion. We integrate the power of data acquisition by contemporary PET/CT and mathematical-physiological modelling in the development of our physiological approach to liver PET. Physiological and technical background The liver plays a vital role in the metabolism of endogenous and exogenous substances. It's location between the gastrointestinal tract and the systemic circulation means that food and other consumed substances have to pass through the liver before reaching the systemic circulation. The liver receives blood from the gut via the portal vein (approx. 75%) and from the hepatic artery (approx. 25%) (Fig. 1). The blood from these two vessels mixes proportionally to the flow ratio at the entrance to the liver sinusoids - small fenestrated blood vessels through which the majority of substances can pass directly from the blood to the hepatocytes (Fig. 2). The sinusoidal membrane of the hepatocytes is lined with innumerable microvilli that project into the extended plasma volume, the space of Dissé between the hepatocytes and the endothelial cells lining the sinusoids. The structure of the liver is thus optimal for the exchange of substances with the blood. From the sinusoids the blood flows into the liver veins and is subsequently returned to the caval vein and to the systemic circulation.  In Dynamic Positron Emission Tomography PET, biological processes are recorded externally in three dimensions following administration of radiolabelled tracers by intravenous administration or inhalation. Compared to other functional imaging techniques such as SPECT, contemporary PET has better spatial and temporal resolutions. Moreover, specific PET tracers can be synthesized for studies of specific metabolic processes by radiolabelling naturally occurring substances (e.g. 11C-glucose and 13N-ammonia) and analogues hereof (e.g. 18F-deoxy-2-glucose (18F-FDG), 18F-FDGal, 11C-CSar and pharmaceuticals. During and following tracer administration the time course of the concentration of radioactivity in the tissue is recorded by the PET tomograph and the time course of the concentration of radioactivity in the inflowing blood is measured in successive blood samples. The resulting data are then analysed using a kinetic model for turnover of the tracer used (Fig. 3).  Publications Keiding S, Sørensen S, eds. Functional Molecular Imaging in Hepatology. Sharjah, UAE: Bentham Science Publishers 2012 Keiding S. Bringing physiology into PET of the liver. J Nucl Med 2012; 53: 425—433. Sørensen M, Keiding S, Positron emission tomography of the liver. In Textbook of Hepatology: From Basic Science to Clinical Practice, 3. ed. (eds. Rodés J, Benhamou JP, Blei A, Reichen J and Rizzetto M), Blackwell, 2007, pp. 561—566. Bass L, Keiding S. Physiologically based models and strategic experiments in hepatic pharmacology. Biochem Pharmacol 1988; 37: 1425—1431. . The Liver PET Group's projects encompass four areas
. [Projects] [Top] 1. The liver's blood supply and exchange of substances with the blood Dual blood supply. Following an intravenous bolus injection of tracer, the time-dependent concentration profile of the tracer in arterial CHA and portal venous blood CPV differs markedly (Fig. 4). Assuming that the blood from the two vessels mixes completely at the entry to reaching the liver sinusoids, the flow-weighted dual-input concentration CDual can be calculated as:   In man the portal vein is inaccessible to blood sampling. For substances that are not metabolized in the gut or the transfer from the intestinal arteries to the PV is delayed beyond the scan time, tracer input via the portal vein can be ignored if the net hepatic uptake is to be measured. This is for example the case for the 18F-FDGal and 11C-CSar (Section 2). However, if a considerable proportion of the substance is metabolized in the gut or if one wants to calculate more specific rate constants and parameters for uptake and turnover of the substance it is necessary to know the flow-weighted mixed tracer input to the liver. In return, though, this enables differential measurement of the liver blood perfusion, transport of the tracer across the cell membrane and its turnover in the cell and/or excretion via the bile. We are therefore developing PET/CT methods to obtain the flow-weighted mixed input data without the need for blood sampling We have developed a model that describes the transfer of tracer from the intestinal arteries to the portal vein and successfully applied it to data from dynamic PET/CT studies using a range of tracers in pigs. Then the method was applied to estimate the hepatic blood perfusion using 3-min dynamic liver PET recordings with 18F-FDG in pigs. Subsequently we recently succeeded in the transfer of this method to human PET/CT studies using previously published 18F-FDGal data that allowed validation by comparison with independent measurements of the hepatic blood perfusion. One of the perspectives of these developments is that the 3-min blood perfusion measurement can become an integrated part of a routine clinical 18F-FDG or 18F-FDGal PET/CT examination without additional tracer administration and radiation burden to the patient.  Liver microcirculation. Analysis of dynamic PET studies is usually performed using "standard" compartmental models (Fig. 5, left). In these models the tracer and any degradation products are considered in separate compartments. The substances are exchanged between compartments as a function of time following injection of the tracer. The model parameters are rate constants describing this exchange. It is assumed that the concentration of the substance is always uniform throughout each compartment at a given time point and, as a consequence, that the blood concentration is the same throughout the sinusoid from the inlet to the outlet. From a practical point of view these models are often useful, but they clearly deviate from normal liver physiology. As illustrated on the right side of Fig. 5, the blood flows through the sinusoids from the inlet to the outlet. When a PET tracer passes through the sinusoids, spatial and temporal concentration gradients develop. We are currently developing microcirculation models that take these factors into account for determining liver tissue blood perfusion by dynamic 15O-carbon monoxide PET in pig experiments. This is not possible with the traditional compartmental model. Link to publications from our group . [Projects] [Top] 2. Hepatic metabolism and excretory function Regional liver metabolism. There is a clinical need for methods that can quantify regional hepatic function noninvasively in patients with liver disease. Galactose is metabolized primarily in the liver and we have developed a non-inversive 20-min dynamic 18F-FDGal PET/CT method for measuring regional metabolic function without blood sampling (Figs. 6 and 7: Sørensen et al. J Hepatol 2013). Our studies confirmed the hypothesis of increased intrahepatic metabolic heterogeneity in cirrhosis when compared with healthy subjects. This is likely to have clinical implications for the assessment of patients with liver disease as well as treatment planning and monitoring as for example in our on-going project on stereotactic radiotherapy of liver tumours.   Hepato-biliary bile acid excretion. Secretion of bile acids is an essential liver function. Impaired bile production results in accumulation of toxic levels of bile acids in the hepatocytes causing cholestatic liver cirrhosis. Today it is not possible to assess the precise pathogenic mechanism because suitable methods are lacking. We therefore have developed radio-synthesis of a novel bile acid tracer 11C-CSar and PET/CT studies in pigs, healthy human subjects and patients with cholestatic liver disease confirmed that 11C-CSar is rapidly taken up from blood by the hepatocytes and excreted in intrahepatic bile canaliculi (Fig. 8: Frisch et al. JNM 2012). We are currently working on on making the procedure totally non-invasive.  Link to publications from our group . [Projects] [Top] 3. Hepatic encephalopathy The aim of this research is to enhance our understanding of the biochemical disturbances in HE and the causal mechanisms, and thereby help improve the foundation for rational treatment of patients with hepatic encephalopathy (HE). Increased blood ammonia in patients with liver disease is assumed to play a key role in the pathogenesis of the toxic brain syndrome hepatic encephalopathy. We are studying possible impairment of brain metabolism by ammonia and inter-organ ammonia metabolism in a series of conceptually interrelated studies ranging from experiments in cultured mouse brain cells (neurons and astrocytes) to PET studies of rats with experimental cirrhosis and of patients with cirrhosis and HE. Here we combine in vivo studies in humans with impaired brain function because of liver impairment to in vitro studies of basic biochemical mechanisms. Paired brain PET/CT studies of cirrhotic patients during and after recovery from HE in conjunction with a group of cirrhotic patients with no history of HE confirm earlier findings of unimpaired blood-brain barrier for ammonia in patients with HE. Moreover, findings of reduced oxygen consumption and blood flow during HE that normalized when individual patients recovered from HE (Fig. 9: Dam et al. Hepatology 2012), while blood ammonia was reduced but not normalized, indicate that the brain metabolic disturbances are caused by the HE condition and not the cirrhotic conditions as such.  Conversion of ammonia to glutamine by glutamine synthetase (GS) may reduce cerebral ammonia but glutamine may also exert toxic effects in the brain. Inhibition of GS by methionine sulfoximine (MSO) reduced glutamine synthesis while that of an alternative pathway, viz. alanine synthesis was increased in co-cultures of neurons and astrocytes. In rats with experimental cirrhosis and sham-operated rats, mass spectroscopy examinations of tissue samples showed that MSO reduced incorporation of [15N]ammonia into glutamine in brain, liver, muscle and kidneys and it increased incorporation of [15N] into alanine in brain but not in any other tissue. Hence alanine synthesis can act as an alternative ammonia detoxifying process in the brain during hyperammonemia. Link to publications from our group . [Projects] [Top] 4. Primary and secondary cancer of the liver The Liver-PET group is part of AUH’s Multidisciplinary Liver Tumour Board and is responsible for its prospective consecutive database. Primary sclerosing cholangitis and cholangiocarcinoma. In a study comprising dynamic liver 18F-FDG PET in 24 patients on the waiting list for liver transplantation due to cirrhosis caused by primary sclerosing cholangitis, PET revealed signs of cancer in three patients that was subsequently confirmed by histology of the removed liver. Ultrasound and CT had not detected these malignancies. PET was thus significantly better than CT at detecting very small liver tumours in this group of patients. Hepatocellular carcinoma (HCC) is a primary liver cancer originating from hepatocytes. Several studies show that HCC can be impossible to visualize with CT, ultrasound or 18F-FDG PET. This is due to the great similarity with the surrounding tissue as regards both structure and metabolism. In a feasibility study of patients with known, previous or suspected HCC, the specificity of 18F-FDGal PET/CT was 100% and 18F-FDGal PET/CT detected extrahepatic disease in nine patients which was a novel finding in eight patients (Fig. 10: Sørensen et al. EJNMMI 2011). We are currently assessing the clinical impact of 18F-FDGal PET/CT.  Secondary cancer of the liver. 18F-FDG PET/CT is widely used to diagnose and monitor the treatment of patients with metastases in the liver. In one in five patients with metastases from colorectal cancer we find that 18F-FDG PET/CT improves treatment strategy. We use this scan in the planning and monitoring of treatment by surgical resection or other local treatment. Neuroendocrine tumours (NET) are usually localized in the intestines or pancreas and give rise to metastases in the liver. The Liver-PET group is part of a EU-accredited ENETS-Centre at AUH and we works on improving the diagnostic tools in terms of which imaging modalities should be used at various clinical conditions, using 18F-DOPA (serotonine metabolism), 68Ga-DOTA-peptides (somatostatin receptors on the cell membrane). Fig. 11 illustrates the use of 18F-DOPA in a patient with NET in the intestines with metastases to the liver and Fig. 12 illustrates 68Ga-DOTA PET/CT.   Link to publications from our group [Projects] [Top]
The ancient Greeks knew that the liver possessed an unusual ability to regenerate in response to damage. According to Greek mythology, when the Olympian god Zeus hid fire from mortals, the Titan deity Prometheus stole it from Zeus and retuned it to the mortals. This enraged Zeus, who then had Prometheus taken to the Caucasus Mountains and bound naked to a rock. Every morning an eagle came and pecked away at Prometheus' liver - here depicted by Rubens. Each night, though, Prometheus' liver regenerated. [Top] |
